Hereditary Breast and Ovarian Cancer Predisposition Syndrome (BRCA1/BRCA2)

Literature and regulatory information updated: 4 October 2026.

Hereditary Breast and Ovarian Cancer Syndrome (HBOC) associated with germline pathogenic variants in BRCA1 and BRCA2 — complete text for a lecture, book chapter or medical podcast

0. Initial Reference Table

1. Introduction

Hereditary breast and ovarian cancer predisposition syndrome associated with the BRCA1 and BRCA2 genes is also known in the international literature as Hereditary Breast and Ovarian Cancer Syndrome (HBOC). It is one of the most prevalent and clinically relevant inherited cancer predisposition conditions known to date, with an estimated frequency of pathogenic variants in the BRCA1 and BRCA2 genes of approximately 1 in every 300 to 500 women in the general population according to the U.S. Preventive Services Task Force (USPSTF) [13] and 1 in every 100 to 200 individuals according to more recent population-based sequencing studies [4,10], potentially reaching 1 in every 40 individuals in populations of Ashkenazi Jewish ancestry, where founder mutations have particularly high prevalence [4,9]. From a global epidemiological perspective, an estimated 5% to 10% of all breast cancer cases have an inherited basis, but pathogenic BRCA1/2 variants explain only approximately 2% to 3% of all breast cancers; in epithelial ovarian cancer, the fraction attributable to BRCA1/2 is 10% to 15% [1,4,5,12]. In Europe and North America, data are consistent with these global estimates, while Poland, Iceland, France, Hungary and French-speaking Canada have specific founder variants with frequencies higher than in the general population [11]. In the United States, data from the SEER registry (Surveillance, Epidemiology, and End Results) suggest that lifetime breast cancer risk in the general female population is 12% to 13%, whereas in carriers of a pathogenic BRCA1 variant this risk rises to 60% to 72%, and in carriers of a pathogenic BRCA2 variant to 55% to 69% [11,14]. The clinical impact is therefore extraordinarily relevant to the breast, gynaecological, pancreatic and prostatic systems, since female and male carriers of this syndrome face substantially elevated risks of developing malignant tumours in multiple organs throughout life, often with early onset and particular histopathological patterns that influence diagnosis and therapeutic and surgical options alike.

1.1 Historical overview and foundational articles

Familial aggregation of breast cancer was described in the nineteenth century by the French surgeon Paul Broca, who in 1866 documented multiple breast cancer cases across four generations of his wife's family, and revisited in the second half of the twentieth century by Henry T. Lynch, who described families with breast and ovarian cancer in a pattern consistent with autosomal dominant inheritance [4]. The founding molecular milestone occurred in 1990, when Mary-Claire King and colleagues (Hall et al.) demonstrated, through linkage analysis in families with early-onset breast cancer, the existence of a susceptibility locus on chromosome 17q21 [15]. In 1994, Miki and colleagues in Mark Skolnick's laboratory cloned the BRCA1 gene [16]; in the same year, Wooster and colleagues, studying families with male and female breast cancer, localised a second locus, BRCA2, to chromosome 13q12-13 [17], with the gene identified in 1995 [18]. Studies by the Breast Cancer Linkage Consortium (BCLC) produced the first comprehensive lifetime risk estimates and distinguished BRCA1- from BRCA2-associated risks; however, because they recruited families with a pronounced cancer history, they probably overestimated penetrance, prompting subsequent meta-analyses and prospective cohorts [2,14]. In 2005, the studies of Bryant and Farmer demonstrated that BRCA1- or BRCA2-deficient cells are selectively sensitive to PARP inhibition, establishing the therapeutic concept of synthetic lethality that led to olaparib approval a decade later [19,20].

2. Molecular Genetics and Pathophysiology

Hereditary breast and ovarian cancer predisposition syndrome is caused by pathogenic (PV) or likely pathogenic (LP) variants in the tumour suppressor genes BRCA1, located on chromosome 17q21.31, and BRCA2, located on chromosome 13q13.1, with an autosomal dominant inheritance pattern in both cases [2,11]. This means that the presence of a single heterozygous copy of the variant is sufficient to confer significantly increased cancer risk, and that each child of a carrier has a 50% probability of inheriting the disease-causing variant. The most frequent mutations include large-scale deletions and duplications, frameshift variants (such as the highly prevalent 185delAG and 5382insC in BRCA1 and 6174delT in BRCA2 in the Ashkenazi population) [4,5], missense, nonsense and splicing variants, which directly interfere with the synthesis, stability or function of the proteins encoded by these genes.

2.1 Gene structure and variant spectrum

BRCA1 is a large gene with 22 coding exons, of which exon 11 corresponds to approximately 60% of the coding sequence; pathogenic variants are distributed throughout the gene and 87% of identified variants are predicted to result in a truncated or absent protein [5]. BRCA2 is similarly large, with exons 10 and 11 corresponding to approximately 60% of the coding sequence, and most of its pathogenic variants are also truncating [5]. In HGVS (Human Genome Variation Society) nomenclature, the three Ashkenazi founder variants correspond to BRCA1 c.68_69delAG (BIC — Breast Cancer Information Core — designation 185delAG), BRCA1 c.5266dupC (BIC 5382insC) and BRCA2 c.5946delT (BIC 6174delT) [5]. In the current normalised form, which omits the deleted or duplicated nucleotides and specifies the MANE Select transcript with version, these variants are described as NM_007294.4(BRCA1):c.68_69del (p.Glu23fs), NM_007294.4(BRCA1):c.5266dup (p.Gln1756fs) and NM_000059.4(BRCA2):c.5946del (p.Ser1982fs), all classified as pathogenic by the ENIGMA expert panel in ClinVar [21]. BIC numbering counts nucleotides from the beginning of a historical reference complementary DNA sequence rather than from the A of the initiation codon as in c. numbering, and placed deletions and insertions in repetitive sequences according to conventions different from current ones, so the two numbering systems cannot be converted by simple subtraction; in this article, the BIC designation is provided only when the cited literature uses it, always accompanied by the normalised form. Many missense variants in BRCA1/2 are of uncertain significance and most will not be pathogenic; because breast cancer is a common disease, the probability of an observed rare variant being coincidental rather than causal is higher than in a rare disease, making multifactorial analysis of classification data necessary [5]. Pathogenic missense variants in BRCA1, BRCA2 and TP53 confer risks similar to those of truncating variants (PTV, protein-truncating variants), whereas rare missense variants in CHEK2, ATM and TP53 are associated only modestly with breast cancer [22].

2.2 Protein function and homologous recombination

Functionally, the BRCA1 and BRCA2 proteins are essential components of the DNA repair machinery operating through homologous recombination, a high-fidelity mechanism that recognises and corrects DNA double-strand breaks. BRCA1 acts as a multifunctional signalling protein coordinating the DNA damage response, activating cell cycle checkpoints and interacting with various proteins, including RAD51, PALB2 and repair complexes [4,11]. At the molecular level, BRCA1 forms a heterodimer with BARD1 with E3 ubiquitin ligase activity and, through direct interaction with PALB2, which in turn binds BRCA2, promotes recruitment of the BRCA2–RAD51 complex to break sites; BRCA2 displaces replication protein A (RPA) from single-stranded DNA, stabilises the RAD51 filament and protects stalled replication forks from nucleolytic degradation [23]. PALB2 (partner and localizer of BRCA2, also designated FANCN) thus functions as the structural bridge of the BRCA1–PALB2–BRCA2 complex, explaining the phenotypic overlap between the three genes both in heterozygosity (breast cancer predisposition) and in biallelic states (Fanconi anaemia) [23,24]. BRCA2, in turn, is the principal mediator of RAD51 recombinase loading onto single-stranded DNA sites resulting from processing of double-strand breaks, and is indispensable for formation of the RAD51 filaments that perform homology searching and strand exchange during homologous recombination [11]. When one of these proteins is absent or dysfunctional because of a germline pathogenic variant, cells become dependent on alternative, lower-fidelity repair mechanisms, such as non-homologous end joining (NHEJ), accumulating progressive genomic errors that culminate in chromosomal instability, aneuploidy and eventually malignant transformation [4]. Knudson's “second-hit” theory is particularly relevant in this context: tumours arising in carriers of germline BRCA1/2 variants generally show loss of the remaining wild-type allele (loss of heterozygosity, LOH), resulting in homologous recombination deficiency that underlies both pathogenesis and therapeutic sensitivity to agents such as PARP inhibitors [2,11]. This homologous recombination deficiency, often designated BRCAness, is also found in sporadic tumours with somatic inactivation of BRCA1/2 genes or BRCA1 promoter hypermethylation, and has growing therapeutic implications.

Homologous recombination repair (HRR, homologous recombination repair) is the most precise system for repairing double-strand breaks; its functional defects are designated homologous recombination deficiency (HRD, homologous recombination deficiency), whose known causes include loss-of-function variants in BRCA1, BRCA2, PALB2 and RAD51C/D, as well as hypermethylation of the BRCA1 and RAD51C promoters [2]. In ovarian high-grade serous carcinoma (HGSC), approximately 50% of cases exhibit HRD, which leaves genomic “scars” — loss of heterozygosity, telomeric allelic imbalance and large-scale state transitions — detectable by HRD assays; HRD results from germline or somatic BRCA1/2 variants (20%–25%), epigenetic silencing of BRCA1 (~10%) and loss of function of other pathway genes (for example RAD51B/C), with some mechanisms remaining unknown [22]. Somatic tumour sequencing identified a mutational signature suggestive of BRCAness (HRDetect algorithm) in a greater proportion of tumours than predicted by germline testing alone, with potential utility for selecting targeted treatments such as PARP inhibition [5]. CCNE1 amplification, present in 15%–20% of HGSC, occurs mainly in BRCA1/2 wild-type, homologous recombination-proficient tumours [22].

2.3 Intragenic penetrance heterogeneity

Specific variants may confer risks above or below the syndrome average. For example, the missense variant BRCA1 R1699Q (NM_007294.4:c.5096G>A, p.Arg1699Gln) has an estimated breast cancer risk of only 24% by 70 years, significantly below the average risk of BRCA1 PV carriers [4,11]; in ClinVar, the same variant is classified as pathogenic by the expert panel (2017 assessment), illustrating that ACMG/AMP classification answers the question “is the variant causal?” rather than “what is its penetrance?”, and reports and counselling should distinguish the two [21]. Similarly, certain missense and splicing variants in BRCA2 have been associated with reduced penetrance [11]. This intragenic penetrance heterogeneity justifies individualised interpretation of genetic results and risk management based on the best available estimate for the specific variant identified, combined with personal and family history [11]. In the international prospective cohort of Kuchenbaecker et al. (2017), breast cancer risk was higher when the variant lay outside the regions delimited by positions c.2282–c.4071 in BRCA1 (hazard ratio [HR] 1.46) and c.2831–c.6401 in BRCA2 (HR 1.93) than within them, and increased with the number of first- and second-degree relatives with breast cancer (HR of 1.99 in BRCA1 and 1.91 in BRCA2 for two or more affected relatives versus none) [14]. Among Ashkenazi founder variants, mean breast cancer risk by 70 years is similar for BRCA1 c.68_69delAG and c.5266dupC (64% and 67%), but lower for BRCA2 c.5946delT (43%), with corresponding ovarian cancer risks of 14%, 33% and 20% [5]. In families with multiple affected members, estimates at the upper end of risk intervals are most appropriate because of co-inheritance of possible modifier genes and shared environmental exposure [5]. Polygenic susceptibility also modulates risk: more than 100 common variants in non-coding DNA are associated with small increases in breast cancer risk (the actual number will be close to a thousand), and a polygenic score of 77 SNPs (single nucleotide polymorphisms) stratified lifetime risk from 5.2% to 16.6% (extreme quintiles) in women without a family history and from 8.6% to 24.4% in women with an affected first-degree relative [12].

3. Clinical Spectrum and System-Specific Manifestations

3.1 Breast cancer

Breast cancer is the most frequent and clinically relevant oncological manifestation of this syndrome. In terms of absolute lifetime risk, female BRCA1 PV carriers have an estimated 60% to 72% risk of developing primary breast cancer, whereas female BRCA2 PV carriers have a risk of 55% to 69% [11,14]. In addition, the risk of metachronous contralateral breast cancer (a new malignant tumour arising in the other breast some time — generally more than 6 months — after diagnosis of the first cancer) is substantially elevated: the 20-year cumulative rate is 30% to 40% for female BRCA1 PV carriers and 25% for female BRCA2 PV carriers, with this risk particularly relevant in premenopausal women diagnosed before 40 years [11].

More recent meta-analyses indicate breast cancer risks of 55%–72% for BRCA1 and 45%–69% for BRCA2 by 70–80 years [2]. The Oxford Desk Reference reports a mean risk by 70 years of 65% (44%–78%) for BRCA1 and 45% (CI 31%–56%) for BRCA2 [5]. Relative breast cancer risk in female BRCA1 carriers decreases with age, from more than 30-fold before 40 years to 14-fold after 60 years, so incidence reaches a plateau of approximately 3%–4% annually in the 40–49-year age group; in female BRCA2 carriers, relative risk is approximately 11-fold in all age groups above 40 years, and incidence follows the general population pattern, rising sharply until 50 years [5]. In the largest available prospective cohort (Kuchenbaecker et al., 2017; 6036 female BRCA1 carriers and 3820 BRCA2 carriers, 94% recruited through familial risk clinics and 6% in population-based studies), cumulative risk by 80 years was 72% (BRCA1) and 69% (BRCA2) for breast cancer and 44% and 17% for ovarian cancer; breast cancer incidence rose rapidly until 30–40 years in BRCA1 and 40–50 years in BRCA2, then remained constant at 20 to 30 per 1000 person-years until 80 years [14]. Because these estimates derive mainly from families with cancer aggregation, and estimates vary considerably with the context in which they were obtained, the upper end of the intervals should be used cautiously in carriers identified through population screening without a family history [4,14]. The age distribution of cumulative risk is summarised in the following table.

Cumulative cancer risk by age in female BRCA1/2 carriers (Table 4.1 of the Oxford Desk Reference) [5].

Cumulative contralateral breast cancer risk in a 30-year semiprospective series (Basu et al., 2015) was 10.4%, 25.7% and 44.4% at 5, 10 and 20 years for female BRCA1 carriers, and 6.8%, 19.5% and 48.1% for female BRCA2 carriers (8.6%, 22.3% and 45.7% overall) [5]. These values differ from the 30%–40% (BRCA1) and 25% (BRCA2) at 20 years cited by NCCN, reflecting differences in study design; in the prospective cohort of Kuchenbaecker et al. (2017), cumulative contralateral breast cancer risk 20 years after the first diagnosis was 40% (95% CI 35%–45%) in BRCA1 and 26% (95% CI 20%–33%) in BRCA2 (HR BRCA2 vs. BRCA1 0.62), and GeneReviews summarises risk as 20%–30% at 10 years and 40%–50% at 20 years [4,14]. Women who have already had breast cancer and are carriers have a risk of a new primary breast cancer of 2%–3% annually when the first cancer was early-onset, compared with approximately 0.6% annually in non-carriers [5].

Regarding histopathology, breast cancers associated with BRCA1 PVs are more frequently triple-negative (ER-negative, PR-negative, HER2-negative), meaning: ER-negative: oestrogen receptor-negative (does not depend on oestrogen for growth). PR-negative: progesterone receptor-negative (does not depend on progesterone for growth). HER2-negative: human epidermal growth factor receptor 2-negative (does not have an excess of this protein). Between 4.4% and 16% of triple-negative breast cancer cases harbour germline BRCA1 PVs [11]. By contrast, cancers associated with BRCA2 PVs are more frequently hormone receptor-positive (oestrogen and/or progesterone), although an association with the triple-negative subtype also exists [11]. In the CIMBA consortium series (Mavaddat et al., 2012; 4325 female BRCA1 carriers and 2568 BRCA2 carriers), 78% of tumours in female BRCA1 carriers were ER-negative and 68% triple-negative, whereas in female BRCA2 carriers 23% were ER-negative and 16% triple-negative (up to 25% between 50 and 60 years); the proportion of triple-negative tumours decreased with age at diagnosis in BRCA1 and increased in BRCA2, and lobular carcinomas were associated more with BRCA2 and medullary carcinomas with BRCA1 [25]. Approximately 80% of breast cancers in female BRCA1 carriers are triple-negative (basal subtype), whereas BRCA2 cancers are more heterogeneous and include hormone-dependent disease, more frequently luminal B [2,22]. Triple-negative breast cancer (TNBC) accounts for approximately 12%–15% of all breast cancers; in a series of more than 1800 patients with TNBC not selected by family history, 8.5% had BRCA1 variants, 2.7% BRCA2 variants and 1.2% PALB2 variants (Couch et al., 2015), and approximately 10% of women with ER/PR/HER2-negative breast cancer diagnosed before 50 years, without a known family history, carry BRCA1 or BRCA2 PVs [5,12]. Low-grade tumours or those with HER2 amplification make a BRCA1 variant less likely [12].

In male carriers (AMAB – assigned male at birth: AMAB means “Assigned Male at Birth”), lifetime breast cancer risk is 0.2% to 1.2% for BRCA1 PV carriers and 1.8% to 7.1% for BRCA2 PV carriers [11], which, although relatively low in absolute terms, represents a very significant excess risk compared with the male population risk of approximately 0.1%; GeneReviews summarises this risk as 1%–2% for BRCA1 and 6%–8% for BRCA2 [4]. Male breast cancer accounts for approximately 0.8% of all breast cancers; risk factors include testicular atrophy, benign breast disease, age, Jewish ancestry, family history and Klinefelter syndrome, and BRCA2 PVs explain 4%–14% of cases, with a lifetime risk of approximately 6%–8% in carriers, although most isolated cases are not due to BRCA2 [5,12].

3.2 Cancer of the ovary, fallopian tubes and peritoneum

Epithelial ovarian cancer (including fallopian tube cancer and primary peritoneal cancer) is the second major manifestation of this syndrome. Absolute lifetime ovarian cancer risk is 39% to 58% for female BRCA1 PV carriers and 13% to 29% for female BRCA2 PV carriers. More recent meta-analyses with population-based cohorts tend to present more conservative estimates (39%–44% for BRCA1 and 11%–17% for BRCA2 by 70–80 years), compared with historical studies based on high-risk families, which overestimated penetrance through ascertainment bias [2,26]. For clinical counselling, it is preferable to use intervals appropriate to each patient's context and the most recent available literature. The predominant histology is high-grade serous adenocarcinoma, usually non-mucinous, and these tumours have more favourable survival than sporadic ovarian cancers, partly because of their greater sensitivity to platinum-based chemotherapy and PARP inhibitors [4,11]. Ovarian cancer onset tends to be approximately 8 to 10 years later in female BRCA2 PV carriers than in female BRCA1 PV carriers, a fact with direct implications for the recommended age of risk-reducing salpingo-oophorectomy [2]. A residual risk of primary peritoneal cancer remains after risk-reducing bilateral oophorectomy, estimated at 1% to 4.3% [11], as does the possibility of identifying serous tubal intraepithelial carcinoma (STIC) lesions in the surgical specimen, thought to constitute precursor lesions of ovarian high-grade serous cancer [11].

Ovarian cancer risk in female BRCA1 carriers is low in absolute terms before 40 years, with subsequent incidences of 2% between 40 and 49 years, 15% between 50 and 59 years and 22% between 60 and 70 years; in female BRCA2 carriers it is very low before 50 years (2.6%), rising to 5% between 50 and 59 years and 10% between 60 and 70 years (Chen and Parmigiani, 2007) [27]. Approximately 10%–15% of all serous ovarian carcinomas are attributable to BRCA1/2; mucinous, borderline, benign and germ cell tumours do not belong to the BRCA spectrum, whereas mucinous and clear cell carcinomas are overrepresented in Lynch syndrome [5,27]. BRCA1/2 variants are also observed in approximately 10% of endometrioid carcinomas, clear cell carcinomas and carcinosarcomas, and anecdotally in low-grade serous carcinomas [22]. The theory of tubal origin of these carcinomas — based on the 1999 observation that serous ovarian carcinomas had the histological appearance of tubal epithelium and that serous tumours of the ovary, fallopian tube and peritoneum share biological and clinical behaviour — was validated by identification of STIC in the fimbrial end of the fallopian tubes of carriers undergoing RRSO [2].

3.3 Prostate cancer

Prostate cancer risk is increased in male BRCA1/2 PV carriers, with an absolute lifetime risk of 7% to 26% for BRCA1 PV carriers and 19% to 61% for BRCA2 PV carriers, compared with the population risk of 12% to 13%; GeneReviews estimates a risk of 21% by 75 years and 29% by 85 years for BRCA1 and 27% by 75 years and 60% by 85 years for BRCA2, compared with 6% by 69 years in the general population [4]. BRCA2 PVs are particularly associated with aggressive prostate disease (metastatic, Gleason ≥8), with greater nodal involvement and lower survival [11]. This has direct clinical implications, particularly for the indication for prostate screening with PSA from 40 years in these populations. BRCA2-associated prostate cancer arises at a younger age and is more frequently metastatic at diagnosis [2]. In BRCA2 carriers, cumulative prostate cancer risk is 0.1% by 50 years, 1.6% by 60, 7.5% by 70 and 19.8% by 80 years, and cumulative risk of any cancer is 4%, 13% and 32% by 50, 60 and 70 years [5]. Relative prostate cancer risk in BRCA2 carriers is 5- to 8.6-fold (higher at younger ages), but BRCA2 PVs are found in only approximately 2% of men diagnosed before 55 years and 1.2% of those diagnosed by 65 years; the BRCA1 effect is smaller (relative risk below 2 in some studies and 4.5 in others), and it is not established whether BRCA1-associated prostate cancer has a worse prognosis [28].

3.4 Pancreatic cancer and other tumours

Pancreatic cancer risk is also increased in this syndrome, with an absolute lifetime risk of up to 5% for female BRCA1 PV carriers and 5% to 10% for BRCA2 PV carriers, which, compared with a population risk of 1% to 2%, constitutes a clinically significant excess risk, particularly with a family history of pancreatic cancer; GeneReviews gives values of 1%–3% for BRCA1 and 3%–5% by 70 years for BRCA2, compared with 0.5% in the general population [4]. Germline PV prevalence in exocrine pancreatic neoplasms varies between 3.9% and 19.8% according to the population and number of genes studied; in one of the largest cohorts (Hu et al., 2018), PVs in six genes (CDKN2A, BRCA1/2, TP53, MLH1, ATM) were found in 5.5% of all patients, with higher risks associated with CDKN2A, BRCA2 and ATM [2]. BRCA-associated pancreatic cancers are predominantly ductal adenocarcinomas, although pancreatic neuroendocrine tumours have been described in BRCA2 carriers, with a favourable response to first-line platinum chemotherapy [2]. Other reported cancer risks include cutaneous melanoma (in BRCA2 PV carriers), gastric cancer, biliary cancer and oesophageal cancer. GeneReviews considers cutaneous and ocular melanoma risk elevated in BRCA2 carriers on the basis of family studies, including an analysis of 490 families with BRCA1 or BRCA2 PVs showing increased uveal melanoma risk in BRCA2 carriers [4]. Regarding gastric cancer, studies based on large family cohorts suggested an increased relative risk in BRCA1 and BRCA2 PV carriers (relative risks of 2.17 and 3.69, respectively); however, prospective studies with pathological confirmation have not demonstrated a consistent association to date, and current data are not sufficiently robust to recommend routine surveillance gastroscopy in all BRCA1/2 PV carriers [2]. The study concerned (Li et al., 2022) included more than 5000 BRCA families (95% CI: 1.25–3.77 for BRCA1 and 2.4–5.67 for BRCA2), but had limitations — retrospective family-based design, self-reported cancer history and missing age-at-diagnosis data [2]. What is considered reasonable, based on emerging evidence, is screening and treatment for Helicobacter pylori infection in BRCA1/2 PV carriers, given the potential modifying role of this infection in gastric cancer risk in these populations. BRCA2 carriers may also have an increased risk of gallbladder and biliary tract cancer [5]. There is also emerging evidence of increased serous uterine cancer risk in female BRCA1 PV carriers, although absolute risk is relatively low and its clinical significance remains under investigation [11].

Summary of lifetime risks by gene [2,4,5,11,14,27].

4. Clinical Recognition and Warning Signs

Clinically, this syndrome has no identifiable dysmorphic or external phenotypic features, so recognition depends fundamentally on a carefully obtained personal and family cancer history. The main warning signs that should raise clinical suspicion and prompt referral for genetic counselling and testing include breast cancer diagnosis before 50 years, triple-negative breast cancer at any age, bilateral breast cancer (synchronous or metachronous), breast cancer in males, epithelial ovarian cancer (including fallopian tube and peritoneal cancer) at any age, exocrine pancreatic cancer at any age (including acinar cell carcinoma), metastatic or high/very-high-risk prostate cancer at any age, and a first- or second-degree relative with any of the criteria listed above or with a known PV in a cancer predisposition syndrome. Ashkenazi Jewish ancestry is also a factor that, alone or combined with family history, may justify offering genetic testing for the specific founder mutations of this population. A history of serous endometrial cancer is also an emerging indication for BRCA1 PV testing [11].

It is also important to recognise criteria associated with a low probability of identifying variants in high-penetrance genes, particularly breast cancer diagnosis after 65 years without any relative with breast, ovarian, pancreatic or prostate cancer, or localised prostate cancer with Gleason below 7 without a relevant family history [11]. These scenarios have a probability below 2.5% of revealing a pathogenic variant in high-penetrance genes, which does not invalidate screening in the context of moderate-penetrance genes.

4.1 Family history features suggesting a susceptibility gene

History-taking should include a three-generation pedigree, with the full name and date of birth of affected relatives, cancer type, age at diagnosis, treating hospital and, when relevant, age at death, extending it as far as possible on the relevant branch; asking about treatment received helps assess the accuracy of the reported diagnosis [12]. Features suggesting a susceptibility gene include: a large number of individuals with breast, ovarian or prostate cancer on the same family branch; multiple affected generations; young mean age at diagnosis (more than 25% of breast cancers diagnosed before 30 years are due to a dominant gene, whereas 50% of all breast cancers in the general population are diagnosed after 65 years); a pattern of different cancer types in the family; and multiple primary tumours in the same individual with early onset (usually the first before 50 years) [12]. Families with breast cancer alone are less likely to be explained by BRCA1/2 than families with breast and ovarian cancer; probability increases with the number of affected relatives, younger age at diagnosis and high-grade, receptor-negative tumours [12].

Breast cancer diagnoses reported in close relatives are rarely incorrect, but ovarian cancer diagnoses are frequently incorrect (potentially corresponding to cervical cancer, endometrial cancer, a benign lesion, teratoma, intestinal adenocarcinoma or Krukenberg tumour — an ovarian metastasis usually of gastric origin) or of a type that does not count towards assessment (mucinous or borderline); confirmation of all ovarian cancer diagnoses and at least one breast cancer diagnosis is recommended when management decisions depend on risk assessment [12,27]. Physical examination rarely adds diagnostic information, except when a rare condition such as Cowden syndrome or Peutz-Jeghers syndrome is suspected [12]. Familial ovarian cancer is not necessarily characterised by very early age: in 202 families with at least two confirmed epithelial ovarian cancer cases, only 1.6% were diagnosed before 30 years, and no BRCA1/2 PVs were found in 101 women with ovarian cancer diagnosed before 30 years (Stratton et al., 1999) [27].

Probability of identifying a BRCA1/2 PV according to family history (Pharoah and Ponder, 2002) [27].

5. Diagnosis: Criteria, Tests and Algorithms

Diagnosis of this syndrome rests on combining detailed clinical and family assessment with molecular genetic tests. The process should always be accompanied by pre- and post-test genetic counselling, ideally conducted by a clinical geneticist, genetic counsellor or healthcare professional with training and experience in cancer genetics [11].

Regarding indications for genetic testing, NCCN Guidelines version 3.2026 identify a set of scenarios in which testing is clinically indicated: a relative with a known PV in a cancer predisposition gene; individuals meeting screening criteria for breast, ovarian, pancreatic or prostate cancer (as detailed on pages CRIT-2 to CRIT-6 of these guidelines); identification of a PV on a tumour sequencing panel with clinical implications if confirmed in the germline; and a need to guide systemic treatment decisions, such as PARP inhibitor use. Germline genetic testing may also be considered in women with breast cancer diagnosed by 65 years who do not meet other criteria, although in this scenario most identified PVs tend to involve moderate-penetrance genes. Pre-test probability can be estimated using validated models such as Tyrer-Cuzick, BRCAPro, CanRisk and BOADICEA, with a threshold of 5% probability of a BRCA1/2 PV generally considered an indication for testing [11].

Genetic Screening Criteria (CRIT-2 to CRIT-6) — Detailed Description

NCCN Guidelines version 3.2026 for Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate define detailed indications for germline genetic testing across pages CRIT-1 to CRIT-6. Their explicit presentation is essential for clinical practice, since they constitute the principal decision filter for referral and genetic testing. The complete criteria by cancer category are presented below, corresponding to the CRIT-2 to CRIT-6 content of the guideline.

Criteria for High-Penetrance Breast Cancer Genes — CRIT-2 (Main Criteria)

Genetic testing is formally indicated in individuals meeting at least one of the following criteria concerning a personal history of breast cancer:

• Breast cancer diagnosed by 50 years of age (irrespective of family history);

• Triple-negative breast cancer (ER-/PR-/HER2-) diagnosed by 60 years;

• Two or more independent primary breast cancers (ipsilateral or contralateral, synchronous or metachronous) in the same individual;

• Breast cancer in a male individual at any age;

• Breast cancer with epithelial ovarian cancer (including fallopian tube or peritoneal cancer) diagnosed in the same individual at any age;

• Lobular breast cancer with a personal or family history of diffuse gastric cancer (CDH1 syndrome — see NCCN Guidelines for Gastric Cancer);

• Breast cancer with a family history of one or more first-, second- or third-degree relatives with any of the above criteria, or with ovarian, pancreatic, or metastatic or high/very-high-risk prostate cancer;

• Breast cancer in an individual with known Ashkenazi Jewish ancestry, irrespective of age at diagnosis;

• Breast cancer with a greater than 5% probability of a BRCA1/2 pathogenic variant estimated by validated models (Tyrer-Cuzick, BRCAPro, CanRisk, BOADICEA);

• Breast cancer with a variant identified by tumour (somatic) sequencing with potential germline implications, justifying germline confirmation;

• Breast cancer requiring systemic treatment decisions dependent on a genetic result (for example, eligibility for PARP inhibitors in the adjuvant or metastatic setting).

Additional Criteria for Considering Testing — CRIT-3

In addition to the main criteria (CRIT-2), genetic testing may be considered in the following lower prior-probability scenarios, usually associated with an estimated pathogenic variant probability between 2.5% and 5%:

• Breast cancer diagnosed between 51 and 65 years, meeting none of the CRIT-2 criteria, but with an estimated pre-test probability according to formal models between 2.5% and 5% for BRCA1/2;

• Breast cancer diagnosed after 65 years, without a personal or family history of breast, ovarian, pancreatic or prostate cancer — in this scenario, the probability of a variant in high-penetrance genes is below 2.5% and genetic testing has a low diagnostic yield (not routinely indicated);

• Personal history of malignant phyllodes tumour of the breast (emerging association with variants in TP53 and other genes);

• An unaffected individual with a first- or second-degree relative meeting CRIT-2 criteria, when testing of the affected relative is not possible.

Criteria for Ovarian Cancer Susceptibility Genes — CRIT-4

Genetic testing is indicated in any individual with a personal history of epithelial ovarian, fallopian tube or primary peritoneal cancer, irrespective of histology, age at diagnosis and family history. This recommendation applies universally to all women with a confirmed diagnosis of non-mucinous epithelial ovarian cancer, including high-grade serous adenocarcinoma, endometrioid, clear cell and mucinous carcinoma in a suspicious clinical context. The indication for universal testing in this cancer group derives from the high detection rate of BRCA1/2 pathogenic variants (14% to 18% in sporadic ovarian cancers, potentially reaching higher values according to histology and geographical origin) and the direct therapeutic importance of the variants identified (eligibility for PARP inhibitors).

Additionally, testing is indicated in unaffected individuals with one or more first- or second-degree relatives with epithelial ovarian, fallopian tube or peritoneal cancer, irrespective of personal history. For rare histological types (germ cell tumours, sex cord tumours with annular tubules), other specific predisposition syndromes should be considered (for example, Peutz-Jeghers syndrome for sex cord tumours with annular tubules; DICER1 for Sertoli-Leydig cell tumours; SMARCA4 for small cell carcinoma of the ovary, hypercalcaemic type).

Criteria for Pancreatic Cancer Susceptibility Genes — CRIT-5

Genetic testing is indicated in the following scenarios concerning exocrine pancreatic cancer:

• Personal history of exocrine pancreatic cancer (ductal adenocarcinoma, acinar cell carcinoma or other exocrine subtypes) at any age — the germline pathogenic variant detection rate in this group is 4% to 10%, predominantly in BRCA2, ATM, PALB2 and Lynch syndrome genes;

• Family history of pancreatic cancer in at least one first-degree relative (father, mother, sibling, child) and one or more second-degree relatives (grandparent, uncle/aunt, cousin) on the same side of the family, even without a known germline variant — many specialist centres accept one affected first-degree and one affected second-degree relative as a criterion;

• Familial chronic pancreatitis, irrespective of cancer history (association with variants in PRSS1, SPINK1, CFTR — not directly related to BRCA1/2 but diagnostically relevant in expanded panels);

• An individual with a known germline pathogenic variant in BRCA2, ATM, PALB2 or Lynch syndrome genes, to guide pancreatic screening (according to guideline table PANC-A).

NCCN guideline version 1.2025 (preceding version 3.2026) introduced a relevant update to table PANC-A: the pancreatic screening recommendation was explicitly extended to carriers of pathogenic ATM or BRCA2 variants from 50 years (or 10 years before the youngest pancreatic cancer diagnosis in the family, whichever occurs first), even without a family history of pancreatic cancer. This update reflects growing evidence of significant pancreatic risk in female BRCA2 and ATM variant carriers irrespective of family history.

Criteria for Prostate Cancer Susceptibility Genes — CRIT-6

Genetic testing is formally indicated in the following scenarios concerning prostate cancer:

• Metastatic prostate cancer at any age (including castration-sensitive and castration-resistant disease) — germline BRCA2 variant detection rate of approximately 5% to 9%, higher than rates in localised disease;

• Very-high-risk prostate cancer (Gleason ≥ 8, T3b/T4, N1, or PSA > 20 ng/mL) or high-risk disease (Gleason 7 with pattern 4+3, T3a, or PSA 10-20 ng/mL) with onset before 60 years;

• Intraductal or cribriform prostate cancer in the biopsy specimen — this histological subtype has a specific association with BRCA2 variants and constitutes an independent indication for germline testing;

• Prostate cancer at any stage with a family history of: breast cancer diagnosed before 50 years, epithelial ovarian cancer, breast cancer in a male relative, pancreatic cancer, or metastatic or high-risk prostate cancer in a first-degree relative;

• Prostate cancer with two or more first-, second- or third-degree relatives with any potentially hereditary cancer in the BRCA1/2 spectrum (breast, ovary, pancreas, high-risk prostate);

• Prostate cancer of any grade with known Ashkenazi Jewish ancestry (higher probability of founder mutations);

• Prostate cancer with a variant identified on a tumour sequencing panel with potential germline relevance (for example, biallelic BRCA2 or ATM loss in the tumour).

For individuals unaffected by prostate cancer, germline testing is indicated when a first-degree relative diagnosed with prostate cancer meets any of the above criteria but has not been tested or cannot be tested. In all scenarios, the decision on prostate screening with PSA and/or multiparametric MRI (mpMRI) should include shared decision-making, with explicit discussion of benefits, limitations, false-positive results and the potential for overdiagnosis.

Genetic Tests and Interpretation of Results

Available genetic tests include next-generation sequencing (NGS) in a multigene panel, enabling simultaneous analysis of BRCA1, BRCA2 and a variable set of other cancer predisposition genes (such as PALB2, ATM, CHEK2, CDH1, PTEN, TP53, RAD51C, RAD51D, BRIP1, STK11, among others) [11]. This phenotypically directed multigene panel, tailored to each individual's personal and family history, is usually more efficient and cost-effective than sequential single-gene testing. Tests must be performed in certified laboratories (in the USA by CAP and CLIA; in Europe by equivalent regulatory bodies), and direct-to-consumer (DTC) or tumour-only sequencing results should not guide clinical decisions without laboratory germline confirmation [11]. MLPA (Multiplex Ligation-dependent Probe Amplification) analysis is essential for detecting large-scale rearrangements (deletions and duplications of one or more exons) undetectable by conventional sequencing.

Genetic test results may be: positive (an identified PV, with immediate clinical management implications), true negative (absence of a known familial variant, with implications for risk stratification), informative negative (absence of a PV in an individual without a positive relative, with less interpretative certainty), variant of uncertain significance (VUS, which should not guide clinical management), or a mosaic result [11]. When a VUS is identified, patients should be managed exclusively on the basis of personal and family history, and referral to variant reclassification programmes and periodic follow-up with the laboratory (every 3 to 5 years) to obtain updated information are recommended [11]. If the laboratory updates a VUS result to a PV, the clinician has an obligation to communicate this change to the patient [11].

 

Limitations of genetic tests and report content

A negative germline panel result has only the value conferred by the test's technical coverage. Capture-based next-generation sequencing reliably detects single-nucleotide variants and small insertions and deletions in coding regions and exon–intron junctions, but deletions and duplications of one or more exons require copy-number analysis (MLPA or a validated CNV detection algorithm using sequencing data) [11]. Mobile element insertions constitute an additional gap: the Portuguese founder variant BRCA2 c.156_157insAlu escapes conventional sequencing and standard MLPA and must be investigated by a targeted assay [29], and a case has been published of a woman aged 40 years with unilateral breast cancer whose initial panel (BRCA1, BRCA2 and PALB2) was negative and whose bioinformatic reanalysis targeting mobile elements identified an SVA retrotransposon insertion in BRCA2 (c.7894_7895insSVA), classified as likely pathogenic [30]. Deep intronic and regulatory variants usually lie outside the analysed region, and variants affecting splicing may require RNA studies for classification [31]. Low-level somatic mosaicism, possible with de novo variants, may not be detected at usual read depth, and a negative parental blood result does not exclude gonadal mosaicism [32]. Tumour sequencing identifies somatic variants relevant to treatment but cannot itself distinguish germline origin, and a variant detected in a tumour with potential germline implications should be confirmed in a constitutional sample [11]. For these reasons, a negative test does not exclude the syndrome in the presence of a convincing personal or family history: the genes, regions and variant types examined should be checked, an affected relative should preferably be tested, and surveillance determined by family history maintained [11,12].

The laboratory report should enable another laboratory to reproduce and reassess the result. It should state the gene and reference transcript with version (for BRCA1, NM_007294.4; for BRCA2, NM_000059.4, both MANE Select transcripts used by ClinVar), the variant in HGVS nomenclature at complementary DNA and protein levels, with genomic coordinates and reference genome version, zygosity (heterozygosity in the dominant syndrome; detection of two variants in the same gene requires determination of phase and consideration of Fanconi anaemia), classification according to ACMG/AMP (American College of Medical Genetics and Genomics/Association for Molecular Pathology) criteria with the gene-specific specifications of the ClinGen ENIGMA expert panel for BRCA1 and BRCA2, the criteria applied, methodology, coverage of analysed regions and test limitations [3,31]. ENIGMA consortium recommendations for reporting germline variants were updated in 2026, aligned with these specifications and translated into twenty languages, with the aim of reducing incorrect inferences arising from ambiguous terminology [33]. When the literature uses historical BIC numbering (for example 185delAG, 5382insC, 6174delT or 999del5), the report and clinical text should present the normalised form and mention the historical form only in parentheses; the founder variants referred to in this article are normalised in the following table.

Normalisation of variants cited in the article, consulted in ClinVar on 4 October 2026 [21].

A variant of uncertain significance (VUS) does not change class through an isolated clinical observation. A tumour's response to platinum or a PARP inhibitor does not demonstrate the pathogenicity of a germline VUS, because tumour homologous recombination deficiency may have other causes (somatic alteration, BRCA1 promoter methylation or defects in other pathway genes) [2,22]. Likewise, cosegregation observed in a few affected relatives is a research finding that has weight only when integrated into quantitative multifactorial models, such as those calibrated by the ENIGMA panel, and does not authorise reclassification or predictive testing of relatives [5,31]. Until the laboratory reclassifies the VUS, management is guided by personal and family history [11,34].

Diagnostic definition, probability models and testing thresholds

A diagnosis of BRCA1/2-associated hereditary breast and ovarian cancer syndrome is established in a proband by identifying a heterozygous germline pathogenic variant in BRCA1 or BRCA2 through molecular genetic testing [4]. Multigene testing has largely replaced single-gene or syndrome-directed testing, and has demonstrated that exclusive application of classical criteria would leave up to 50% of germline PV carriers unidentified; universal germline testing, irrespective of family history, is now recommended in ovarian cancer, pancreatic cancer and high-risk or metastatic prostate cancer, and several guidelines recommend BRCA1/2 testing in all breast cancer patients up to 65 years, acknowledging that between 50 and 65 years most identified PVs involve moderate-penetrance genes [2]. A gradual transition towards combined somatic tumour testing and germline testing in all patients with cancer is anticipated [2].

The joint guideline of ASCO (American Society of Clinical Oncology) and the Society of Surgical Oncology (Bedrosian et al., 2024) recommends offering BRCA1/2 testing to all patients with newly diagnosed breast cancer up to 65 years and, above that age, to patients selected by personal or family history, ancestry or eligibility for PARP inhibitors; it also recommends testing all patients with recurrent breast cancer who are candidates for PARP inhibitors, irrespective of family history, and women with a second primary cancer in the ipsilateral or contralateral breast, and establishes that variants of uncertain significance should not alter management [34]. In women without a cancer diagnosis, the USPSTF (2019) recommends that primary care physicians use a brief familial risk assessment tool to assess women with a personal or family history of breast, ovarian, fallopian tube or peritoneal cancer or ancestry associated with BRCA1/2 variants, referring those with a positive result for genetic counselling and, if indicated, testing (recommendation B), and advises against routine assessment, counselling and testing in women without these factors (recommendation D) [13]. In an unselected population, most carriers are not identified by clinical criteria: in a sequenced cohort of 50,726 adults, 82% of BRCA1/2 PV/LP carriers had no previous clinical test [10].

In the United Kingdom, NICE guideline CG164 bases the indication for BRCA1/2 testing in an affected relative on a PV probability above 10%, estimated by BOADICEA (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm, freely accessible software calculating breast and ovarian cancer risks and carrier probability for PVs in BRCA1, BRCA2 and other genes) or a Manchester score ≥16 [12]. Women with triple-negative breast cancer before 40 years or high-grade serous ovarian carcinoma without a family history have a greater than 10% probability of a BRCA1/2 PV and should be offered testing (Eccles et al., 2016) [12]. In individuals of Ashkenazi ancestry with one or more relatives with breast or ovarian cancer at any age, testing for the three founder variants may be offered; when a key affected relative has advanced disease, storage of their DNA should be considered [12].

Manchester scoring system (Evans et al., 2004) [12]. Scores are summed for each cancer in the same direct lineage; a combined score (BRCA1 + BRCA2, irrespective of previous testing) of 16 points corresponds to a 10% threshold and 20 points to a 20% threshold in Western populations without founder variants; in families without unaffected members, a lower threshold may be used, and tumours such as cholangiocarcinoma and ocular melanoma may contribute to the BRCA2 score, although numbers are insufficient to validate a precise score [12]. The pathology-adjusted version (Evans et al., 2009) adds to the index case's BRCA1 score: HER2-positive −4; lobular −2; DCIS only (ductal carcinoma in situ) −1; LCIS only (lobular carcinoma in situ) −4; invasive ductal carcinoma grade 1 −2, grade 2 0, grade 3 +2; ER-positive −1; ER-negative +1; grade 3 triple-negative +4 (final adjustment); mucinous, borderline and germ cell ovarian tumours (except granulosa cell tumours) are not scored [12].

Risk stratification for surveillance follows three NICE classes — near-population risk (lifetime risk < 17%; risk between 40 and 50 years < 3%), moderate risk (17%–30%; 3%–8%) and high risk (≥ 30%; > 8%), with high risk including female BRCA1, BRCA2 and TP53 PV carriers and rare conditions such as Peutz-Jeghers syndrome (STK11), Cowden syndrome (PTEN) and familial diffuse gastric cancer (CDH1) [12]. In the absence of BOADICEA, family history triage classifies as high risk a dominant pattern of early-onset breast and/or ovarian cancer with an affected first-degree relative, or a pattern consistent with Li-Fraumeni syndrome; as moderate–high risk (25%–30%) a dominant pattern with second-degree relatives on the paternal branch, a first-degree relative with breast and ovarian cancer with the first before 50 years, three relatives with breast and/or ovarian cancer at a mean age of 50–60 years, or two relatives (one first-degree) with breast cancer before 40 years; as moderate risk (17%–24%) two relatives with breast cancer at any age, a first-degree relative with breast cancer before 40 years, a male relative with breast cancer or a relative with breast and ovarian cancer; and as slightly increased risk (< 1 in 6) a first-degree relative or a few distant relatives without a dominant pattern and a mean age above 50 years (Eccles et al., 2000) [12]. Population risk corresponds to approximately 1 in 11 [12].

In ovarian cancer, classical high-risk criteria for BRCA1/2 testing included high-grade papillary serous ovarian cancer before 50 years, ovarian cancer at any age with a family history of breast cancer before 60 years, two or more ovarian cancer cases, or Ashkenazi ancestry with any family history of breast or ovarian cancer; practice has evolved towards testing all women with serous ovarian cancer irrespective of family history, and ESMO recommends germline and/or somatic BRCA1/2 and HRD testing at diagnosis in all patients with high-grade non-mucinous epithelial carcinoma, considering BRCA1/2 reversion mutation testing at recurrence when PARP inhibitors remain an option [22,27]. For ovarian cancer patients with possible access to immunotherapy, targeted treatments or clinical trials, mismatch repair (MMR) status should also be considered, particularly in endometrioid and clear cell carcinomas, NRAS, KRAS and BRAF mutations in low-grade serous carcinomas, and HER2 overexpression in clear cell carcinomas, mucinous carcinomas and carcinosarcomas; FOXL2 (somatic) and DICER1 (somatic and germline) should be tested in sex cord–stromal tumours for diagnostic purposes [22]. In the general population with a single relative affected by ovarian cancer, cumulative risk by 70 years is approximately 4% (relative risk 3), and the sister of a woman with “sporadic” ovarian cancer has a threefold higher lifetime risk; relative risk in a monozygotic twin is 6, twice that of a sister, indicating that most excess familial risk is genetic [27].

The testing criteria for high-penetrance susceptibility genes in NCCN version 1.2020, adapted in the Brazilian handbook Síndromes Genéticas: Reconhecer para Tratar, included: individuals with a blood relative carrying a known PV/LP; individuals meeting criteria but with previous limited testing (single gene and/or without deletion/duplication analysis) who wish to undergo multigene testing; breast cancer diagnosed before 45 years, or between 46 and 50 years with unknown or limited family history, a second breast cancer at any age, or ≥ 1 close relative with breast, ovarian, pancreatic or high-grade (Gleason ≥ 7) or intraductal prostate cancer; triple-negative breast cancer before 60 years; breast cancer at any age with Ashkenazi ancestry, ≥ 1 close relative with breast cancer before 50 years or ovarian, pancreatic or metastatic or intraductal prostate cancer, or ≥ 3 breast cancer diagnoses in the patient and/or close relatives; male breast cancer; epithelial ovarian cancer (including tube and peritoneum); exocrine pancreatic cancer; metastatic or intraductal prostate cancer at any age; high-grade prostate cancer (Gleason ≥ 7) with Ashkenazi ancestry, ≥ 1 close relative with breast cancer before 50 years or ovarian, pancreatic or metastatic/intraductal prostate cancer, or ≥ 2 close relatives with breast or prostate cancer; a mutation on somatic testing with implications if germline; and support for systemic treatment decisions, such as in HER2-negative metastatic breast cancer [1]. Limited family history was defined as fewer than two first- or second-degree female relatives, or fewer than two female relatives surviving beyond 45 years in either lineage; close relatives included first-, second- and third-degree relatives [1]. The same handbook estimates breast cancer risks by 80 years of 75% for BRCA1 (relative risk 11.4) and BRCA2 (11.7), 70% for TP53 (relative risk 105), 53% for CDH1 (6.6; lobular carcinoma) and 45% for PALB2 (5.3) [1].

Predictive testing may be offered to relatives once the familial variant is defined; given the impact of results, it should ideally take place in a clinical genetics service, is usually offered only to adults and is frequently deferred until the age at which surveillance or risk-reducing surgery becomes a consideration [5,12].

6. Differential Diagnosis

The differential diagnosis of this syndrome should consider other inherited predisposition conditions for breast and/or ovarian cancer.

Li-Fraumeni syndrome (LFS; germline TP53 PV) is an autosomal dominant syndrome conferring an 80% to 90% lifetime cancer risk, with up to 21% of cancers occurring before 15 years. The classical clinical spectrum includes soft tissue sarcomas, osteosarcomas, central nervous system tumours, leukaemias, adrenocortical tumours and breast cancer — the latter often beginning before 30 years, so LFS should be excluded in patients with breast cancer before 31 years [11]. More recently, early-onset gastric cancer was recognised as part of the LFS spectrum. Genetic testing for LFS is guided by the Chompret criteria (proposed in 2001 and modified in 2015), broadly including: diagnosis of an LFS-spectrum cancer (soft tissue sarcoma, osteosarcoma, CNS tumour, breast cancer, adrenocortical tumour, leukaemia, bronchioloalveolar lung cancer) before 46 years with at least one first- or second-degree relative with an LFS-spectrum cancer before 56 years or multiple primary tumours; multiple primary LFS-spectrum tumours in the same individual, of which two are sarcoma, brain tumour, breast cancer or adrenocortical tumour, with the first before 46 years; diagnosis of adrenocortical tumour or choroid plexus carcinoma at any age; and breast cancer before 31 years irrespective of family history [2,11].

Cowden syndrome (PTEN) is associated with breast cancer risk of 40% to 60% and external phenotypic features such as trichilemmomas, macrocephaly and gastrointestinal hamartomatous polyps. Pathogenic PALB2 variants confer breast cancer risk of 32% to 53% and should be investigated in the same panel. In the segregation analysis of 362 members of 154 families (Antoniou et al., 2014), relative breast cancer risk in female PALB2 carriers was 8 to 9 before 40 years, 6 to 8 between 40 and 60 years and 5 after 60 years, with cumulative risk of 14% by 50 years and 35% by 70 years, varying by 70 years between 33% without a family history and 58% with two or more first-degree relatives affected by 50 years, values overlapping those of BRCA2 [35]. The ACMG clinical practice resource (American College of Medical Genetics and Genomics; Tischkowitz et al., 2021) recommends offering female PALB2 carriers breast surveillance equivalent to that of BRCA1/2, considering risk-reducing mastectomy based on personalised risk estimates and considering pancreatic surveillance, ideally within a clinical trial; it generally does not recommend ovarian surveillance, allows RRSO before 50 years only rarely and, given the mechanistic similarity, proposes that carriers be considered for the same treatment regimens and trials as female BRCA1/2 carriers [36]. ATM and CHEK2 variants are associated with moderate breast cancer risk (20% to 27% and 23% to 27%, respectively). For ovarian cancer, beyond BRCA1/2, genes such as RAD51C, RAD51D, BRIP1 and Lynch syndrome genes (MLH1, MSH2, MSH6, PMS2, EPCAM) are also relevant. For female PALB2 and ATM PV carriers, the indication for prophylactic RRSO is currently controversial: recent studies consistently demonstrate that ovarian cancer risk in these carriers depends on individual family history, not justifying a uniform recommendation for RRSO in all carriers, unlike BRCA1/2, BRIP1 and RAD51C/D, where RRSO benefit is well established [2,11]. Distinguishing these conditions determines the appropriateness of screening recommendations, risk-reduction strategies and family counselling..

Classification of susceptibility genes and non-BRCA HRD pathway genes

The Oxford Desk Reference classifies breast cancer predisposition genes into high risk (lifetime risk ≥ 40%: BRCA1, BRCA2, TP53, PTEN, CDH1, STK11, PALB2), moderate risk (20%–39%: CHEK2, ATM, NBN, RAD50, NF1, MLH1, PIK3CA, MRE11, XRCC2) and low-risk alleles (13%–19%; more than 100 common SNPs with multiplicative effects); three genes initially described as moderate-risk breast cancer genes — BRIP1, RAD51C and RAD51D — were discarded as such, but remain moderate-risk ovarian cancer genes [12]. High-penetrance genes (BRCA1/2, TP53, PTEN, CDH1, STK11, PALB2) explain only approximately 20% of familial relative risk, and the combined contribution of BRCA1 and BRCA2 to all breast cancers is approximately 2%–3% [5,12]. According to ESMO, hereditary breast cancer represents approximately 10% of cases: approximately 3% of patients have PVs in high-risk genes (odds ratio > 4) — BRCA1 (cumulative risk 72%, linked to TNBC), BRCA2 (69%, more frequently luminal B), PALB2 (33%–58%), CDH1 (39%–52%, lobular carcinoma), PTEN (25%–85%), STK11 (45%–50%) and TP53 (40%–79%) —, a further 3% have PVs in moderate-risk genes (ATM, CHEK2; odds ratio 2–4), and the remaining 4% have unidentified genetic factors; BARD1, RAD51C/D (specifically associated with TNBC) and MMR genes are considered low-risk breast cancer genes [22]. In Lynch syndrome and BRIP1/RAD51C/RAD51D genes, lifetime ovarian cancer risk is approximately 10% [27].

Non-BRCA HRD pathway genes and associated risks [2].

Classical Li-Fraumeni criteria, proposed in 1988, required a proband with sarcoma before 45 years, a first-degree relative with cancer before 45 years and another first- or second-degree relative with cancer before 45 years or sarcoma at any age [2]. In Peutz-Jeghers syndrome (STK11) and Cowden syndrome (PTEN), physical examination (mucocutaneous pigmentation, trichilemmomas, macrocephaly) is one of the rare situations in which examination contributes to diagnosis [12].

7. Treatments and Risk Management Strategies

7.1 Breast screening: population context and rationale for the intensive protocol

Breast cancer screening in Europe and the United States is based on regular mammography, but shows marked differences in starting age and the organisation of healthcare systems themselves. In **Europe**, the model rests predominantly on organised, population-based public health programmes, following guidelines recommending mammography every two years, traditionally for women between 50 and 69 years — an age range being extended to 45–74 years in several European countries. In the **United States**, the process tends to be more individualised and based on the health insurance system (opportunistic screening); the *U.S. Preventive Services Task Force* (USPSTF) recommends biennial screening (every two years) for average-risk women aged 40 to 74 years, although other leading American medical societies, such as the *American College of Radiology*, strongly advocate annual examinations from 40 years, resulting in a generally earlier and more intensive approach in the USA than the standardised European model. Women with mutations in BRCA1 or BRCA2 can and should undergo mammography, but the screening protocol is very different and more intensive than that adopted for the general population.

Concern that mammography might cause tumours in these patients is based on the biology of these genes:

• The radiation issue: The natural function of the BRCA1 and BRCA2 genes is to produce proteins repairing DNA damage in cells. In women with mutations in these genes, this cellular “repair” mechanism is compromised.

• The risk: Because mammography uses ionising radiation (X-rays) — which inherently causes small DNA breaks — there is concern that exposing these women to radiation may accumulate unrepaired damage in breast cells, precipitating cancer development.

Considerations:

Studies have demonstrated that breast radiation exposure before 30 years in BRCA mutation carriers does increase the risk of developing cancer. In addition, before 30 years, breast tissue is usually very dense, making mammography less effective at detecting abnormalities. However, from 30 years, global clinical consensus (such as National Comprehensive Cancer Network - NCCN guidelines) concludes that the benefit of detecting an aggressive tumour at its earliest stage far outweighs the small theoretical risk associated with mammography radiation. Because of the very high breast cancer risk, screening begins much earlier than in the general population and uses a different “principal tool”: breast magnetic resonance imaging (MRI), which does not use radiation.

Breast Cancer Screening in Female Carriers

Breast screening in female BRCA1/2 PV carriers is substantially more intensive than standard population screening because of high penetrance and early disease onset. Current recommendations include promoting breast awareness from 18 years, six-monthly clinical breast examination from 25 years and annual imaging screening with mammography and contrast-enhanced breast MRI between 30 and 75 years. Between 25 and 29 years, annual breast MRI is preferred to mammography alone, given MRI's greater sensitivity in this age group and the lower utility of mammography in young women with dense breast tissue. European guidelines (ESMO) recommend annual MRI from 25 to 39 years, transitioning to annual MRI + mammography only from 40 years — a minor difference from the transition at 30 years advocated by NCCN. Both approaches are clinically acceptable; the decision should be individualised and consider the clinical and institutional context. After 75 years, the decision should be individualised. In women treated for breast cancer who have not undergone bilateral mastectomy, imaging screening should continue according to age group. Evidence supports MRI's superiority over mammography for early detection in high-risk carriers, with sensitivity of 77% to 94% for MRI versus 33% to 59% for mammography [11].

The standard protocol usually follows this schedule:

From 18 years:

• Awareness and monthly self-examination (for the woman to know her body and notice changes).

From 25 years (or 10 years before the youngest cancer case in the family):

• Clinical breast examination by a specialist physician every 6 to 12 months.

• Annual contrast-enhanced breast magnetic resonance imaging (MRI). (Mammography is not recommended in this age group).

From 30 years until 75 years:

• Combined intensive imaging screening: annual breast MRI and annual mammography.

• Many physicians choose to alternate examinations (for example, MRI in January and mammography in July), ensuring that the patient undergoes an imaging examination every six months.

The role of ultrasonography: Ultrasonography does not replace MRI in screening these patients, but may be used as an adjunct or alternative if the patient has a contraindication to MRI (such as an incompatible pacemaker or severe contrast allergy).

Risk-Reducing Mastectomy

Bilateral risk-reducing mastectomy (RRM) is the most effective breast cancer risk-reduction option, with retrospective studies and meta-analyses demonstrating a risk reduction of approximately 90% to 95% in female BRCA1/2 PV carriers. The decision to undergo RRM is highly individual and should include counselling on the degree of protection, reconstruction options, surgical risks, psychosocial and quality-of-life aspects, family history and residual risk with age. Nipple-sparing mastectomy appears safe in this context, although more data are needed. Clinical breast screening should continue after RRM, but routine mammography and MRI screening is not indicated [11].

Chemoprevention

Selective oestrogen receptor modulators (tamoxifen, raloxifene) and aromatase inhibitors (exemestane, anastrozole) have demonstrated efficacy in reducing breast cancer risk in high-risk populations. In female BRCA1/2 PV carriers, tamoxifen demonstrated a reduction in contralateral breast cancer risk of approximately 45% to 60% [11]. Protection appears more pronounced for female BRCA2 PV carriers, partly because BRCA2-associated tumours are more frequently ER-positive. In female BRCA1 PV carriers, whose tumours are predominantly ER-negative, tamoxifen's efficacy as primary prevention is less clear. In the genomic analysis of cases from the NSABP-P1 prevention trial (King et al., 2001), tamoxifen reduced breast cancer incidence by 62% in healthy female BRCA2 carriers (relative risk 0.38), but not in female BRCA1 carriers starting it from 35 years, based on only 19 carrier cases; there are no prospective randomised chemoprevention trials specific to this population [4,37]. Tamoxifen is associated with increased endometrial cancer risk and thromboembolic events (including pulmonary embolism), so it should be avoided in women with a history of thromboembolic disease or coagulopathy, and users should immediately report any abnormal vaginal bleeding [4]. Evidence concerning the effect of oral contraceptives on breast cancer risk in female BRCA1/2 PV carriers is inconsistent, with studies suggesting increased risk with prolonged use (≥5 years), particularly in female BRCA1 PV carriers starting use before 20 years [11].

Management of Ovarian Cancer Risk

For management of ovarian cancer risk, bilateral risk-reducing salpingo-oophorectomy (RRSO) is the most effective intervention, reducing ovarian/peritoneal cancer risk by approximately 80% and overall mortality in female BRCA1/2 PV carriers [11,38,39]. RRSO is recommended between 35 and 40 years for female BRCA1 PV carriers and between 40 and 45 years for female BRCA2 PV carriers, because of later ovarian cancer onset in the latter. The decision should be individualised and discussed with a gynaecologist/gynaecological oncologist experienced in inherited predisposition, weighing the impact of premature menopause (cardiovascular, bone, neurocognitive, sexual and quality-of-life risks) and hormone replacement therapy (HRT) options. Post-RRSO HRT is generally not contraindicated in carriers without a personal history of breast cancer, and may include oestrogen alone (with concomitant hysterectomy), combined oestrogen/progestogen, a levonorgestrel intrauterine device with transdermal oestrogen, or combined oral contraceptives. Studies of HRT after RRSO have focused mostly on mean durations of use up to 3 to 5 years, and the safety of long-term use remains uncertain. After RRSO, a residual primary peritoneal cancer risk of 1% to 4.3% remains and should be communicated to patients [11].

As an alternative to RRSO, salpingectomy with delayed oophorectomy is an emerging option being investigated in several prospective clinical trials, allowing immediate risk reduction through removal of the fallopian tubes (considered the probable origin of high-grade serous cancers) with temporary preservation of the ovaries to avoid premature menopause. The main ongoing trials are: the TUBA study (Early Salpingectomy with Delayed Oophorectomy, NCT02321228), the PROTECTOR trial (United Kingdom, ISRCTN25173360), the WISP study (Women Choosing Surgical Prevention, NCT02760849) and the SOROCk study (NCT04251052). Long-term follow-up of these trials will determine whether SDO is comparable to RRSO in terms of ovarian risk reduction. If salpingectomy is performed, completion oophorectomy should follow gene-specific guidelines unless a clinical trial protocol provides otherwise. Preoperative assessment should include CA-125 and pelvic ultrasonography, and the SEE-FIM (Sectioning and Extensively Examining the Fimbriated End) pathological protocol should be applied to both salpingectomy and completion oophorectomy. In premenopausal women, early oophorectomy also reduces breast cancer risk, although the magnitude of this reduction remains uncertain and may be gene-specific [2,11,27].

Combined oral contraceptives (COCs) have demonstrated a 45% to 60% reduction in ovarian cancer risk in female BRCA1/2 PV carriers, with benefit increasing with duration of use. The levonorgestrel intrauterine device (LNG-IUD) has also been associated with reduced ovarian cancer risk in the general population [11]. These data are relevant to premenopausal women wishing to preserve fertility before RRSO.

Prostate Cancer Screening and Management

For male BRCA2 PV carriers, annual PSA screening from 40 years is formally recommended by NCCN guidelines. For BRCA1 PV carriers, annual PSA screening from 40 years is also considered. In addition, the option of baseline multiparametric MRI (mpMRI) by 50 years (or 10 years before the youngest prostate cancer diagnosis in the family) has recently been added, preferably within a clinical trial and in high-volume centres experienced in this modality. mpMRI demonstrated superior sensitivity (100%) and negative predictive value (100%) compared with PSA alone (57% sensitivity) for detecting clinically significant prostate cancer in BRCA1/2 PV carriers [11]. All screening discussions should include shared decision-making with the patient.

Male BRCA1 or BRCA2 PV carriers are also recommended education and training in breast self-examination when the variant is identified, monthly self-examination and annual clinical breast examination from 35 years [4].

Pancreatic Cancer Screening

Pancreatic cancer screening in BRCA1/2 PV carriers is recommended for those with a family history of pancreatic cancer in at least one first- or second-degree relative on the same side of the family as the PV. Screening should begin at 50 years (or 10 years before the youngest pancreatic cancer diagnosis in the family) and includes annual contrast-enhanced MRI/MRCP and/or endoscopic ultrasonography (EUS). Performance in high-volume centres, preferably within longitudinal studies, is strongly recommended [11].

Melanoma Screening

The association between BRCA2 PVs and increased melanoma risk was suggested by several early studies; however, a more recent, comprehensive study integrating somatic and germline sequencing did not validate this association. There are currently no specific melanoma screening guidelines for BRCA2 PV carriers, and systematic dermatological surveillance in this group is not recommended on evidence of sufficient strength. Nevertheless, minimising ultraviolet exposure is recommended as a general health measure [2,11]. GeneReviews advocates skin examination by a dermatologist at an interval individualised according to family history, in female and male carriers [4].

Additional evidence for breast surveillance and risk-reducing surgery

NICE guideline CG164 (United Kingdom) recommends annual MRI between 30 and 49 years in female BRCA1/2 PV carriers or women with a greater than 30% carrier probability, with or without a personal history of breast cancer, and annual mammography between 40 and 69 years in known carriers without a personal history; mammography is not offered before 30 years or, at any age, to female TP53 PV carriers, who are offered annual MRI between 20 and 49 years [12,40]. Between 50 and 69 years, MRI is considered only in female BRCA1/2 carriers with a dense breast pattern, and after 70 years mammography forms part of the population programme; women with an initial carrier probability ≥ 30% who reach 60 years without breast or ovarian cancer then have a probability below 30% and no longer have an MRI indication [40]. MRI has been demonstrated more cost-effective than mammography in high-risk women with a known BRCA or TP53 PV or a greater than 30% carrier probability, and ultrasonography is not routinely offered, being considered when MRI would be indicated but is unsuitable (for example, claustrophobia) or when mammography or MRI results are difficult to interpret [12]. Breast MRI is more sensitive and less specific than mammography and improves early detection in carriers younger than 50 years; breast ultrasonography does not detect microcalcifications and lacks an evidence base as a screening tool [5]. A population-based randomised trial in Shanghai (Thomas et al., 2002) showed that regular breast self-examination does not reduce breast cancer mortality and increases the number of biopsies and benign disease diagnoses, so “breast awareness” is promoted rather than systematic self-examination [12].

In the prospective multicentre study of Domchek et al. (2010), with 2482 female BRCA1/2 PV carriers, no breast cancer occurred in the 247 women undergoing risk-reducing mastectomy, compared with 98 cancers in the 1372 who did not [5,41]. Up to 30% of women undergoing prophylactic mastectomy have surgical complications, which should be weighed against psychological problems, the toxicity of treating a potential cancer and the probability of dying from diagnosed breast cancer [5]. In women with breast cancer who are carriers, bilateral mastectomy is not a necessary part of primary treatment, and completing recommended cancer treatment takes precedence over major reconstructive surgery; salpingo-oophorectomy may form part of treatment for ER-positive breast cancer, and surgery reducing the risk of new primaries should be considered at the appropriate time according to age at diagnosis, subtype, treatment and prognosis, in multidisciplinary discussion [5].

A retrospective analysis (Phillips et al., 2013) showed that tamoxifen after breast cancer surgery reduced contralateral breast cancer incidence by approximately 50% in female BRCA1 and BRCA2 PV carriers [5]. In a study of Ashkenazi Jewish female carriers (King et al., 2003), physical exercise and absence of obesity in adolescence were associated with significantly later breast cancer onset [5]. Regarding oral contraception, a case–control study (Narod et al., 1998) showed a 60% reduction in ovarian cancer frequency after 6 years of use, and female BRCA1 carriers who ever used oral contraception, or used it for more than 5 years, may have an increased risk of early-onset breast cancer (relative risks of 1.2 and 1.33, respectively; Narod et al., 2002); the small increase in breast cancer risk returns to baseline 5 years after discontinuation [5,27]. Ovarian cancer risk in female BRCA1 carriers decreases with parity, tubal ligation and oral contraceptive use (hazard ratio = 0.52), with a similar pattern in BRCA2 (Antoniou et al., 2009) [27].

In the general population, relative breast cancer risk decreases by 7% for each birth and 4.3% for every 12 months of breastfeeding, increases by 7% for every 10 g/day of alcohol and, with combined oestrogen–progestogen hormone therapy, increases by approximately 5% per year of use (10 years of use result in 19 additional cancers per 1000 combined therapy users, compared with 5 per 1000 with oestrogen alone), with the additional risk disappearing approximately 5 years after discontinuation [12]. Women with increased genetic risk should be encouraged to control their weight, exercise and reduce alcohol consumption [12].

Additional evidence for risk-reducing gynaecological surgery

In a prospective study of 170 female BRCA1/2 PV carriers with a mean follow-up of 2 years (Kauff et al., 2002), bilateral risk-reducing salpingo-oophorectomy was associated with an ovarian cancer hazard ratio of 0.15 compared with surveillance alone [27]. The meta-analysis of Rebbeck et al. (2009) estimated an approximately 80% reduction in ovarian/fallopian tube cancer risk, and the cohort of Finch et al. (2014) demonstrated reduced all-cause mortality after oophorectomy in female BRCA1/2 carriers [38,39]. In the prospective multicentre cohort of Domchek et al. (2010), with 2482 female carriers followed at 22 centres, salpingo-oophorectomy was associated with lower all-cause mortality (3% vs. 10%; HR 0.40), breast cancer mortality (HR 0.44) and ovarian cancer mortality (0.4% vs. 3%; HR 0.21), corresponding to reductions of approximately 60% and 79%, respectively, in overall mortality and ovarian cancer mortality [41]. Salpingo-oophorectomy, rather than oophorectomy alone, should be performed because of growing evidence that tumours originate in the fallopian tubes [27]. Earlier studies reported an approximately 50% reduction in breast cancer risk after RRSO (for example Domchek et al., 2010), but were subject to biases; a study minimising those biases (Heemskerk-Gerritsen et al., 2015) found no protective effect on breast cancer risk, so the magnitude of that reduction is nonexistent or much smaller than previously thought [5,27]. Ovarian cancer risk before 40 years is low, even in women at high genetic risk; premenopausal oophorectomy causes abrupt menopause, with hot flushes, sleep disturbance, vaginal dryness and increased osteoporosis and cardiovascular disease risk [27]. The NICE guideline (2013) considers that the benefits of oestrogen replacement probably outweigh the small increase in breast cancer risk, favouring oestrogen alone with intrauterine progestogen release in women with a uterus [5]. CA-125 measurement and ovarian ultrasonography are not recommended as screening outside clinical trials because they do not reduce mortality [5,27]. Kwon et al. (2013) compared bilateral salpingo-oophorectomy at 40 years, bilateral salpingectomy at 40 years and salpingectomy at 40 years followed by oophorectomy at 50 years in female carriers without cancer: salpingo-oophorectomy had the lowest cost and greatest life expectancy, but when quality of life was included, salpingectomy with delayed oophorectomy achieved the highest quality-adjusted life expectancy [2]. In families at high ovarian cancer risk where an affected relative with serous histology tested negative for BRCA1/2, women should nevertheless be managed as having high breast cancer risk [27].

Additional evidence for prostate and pancreatic screening

In the international IMPACT study, with a PSA threshold of 3 ng/mL for transrectal prostate biopsy, the positive predictive value of biopsy in BRCA2 carriers was 48%, twice that observed in population screening above 55 years, and 66% of detected tumours were intermediate- or high-risk [28]. PSA has limitations: up to two-thirds of men with elevated PSA do not have prostate cancer and up to 20% of men with prostate cancer have normal PSA [28]. Regarding the pancreas, a recent study demonstrated potential for detecting tumours at an earlier stage, with possible survival improvement, and the September 2024 NCCN update began recommending consideration of pancreatic screening in high-risk individuals with specific germline PVs [2].

Targeted Systemic Pharmacological Treatment

PARP Inhibitors — Pharmacological Basis and General Indications

One of the most relevant therapeutic implications of this syndrome is the sensitivity of BRCA-associated tumours to PARP (Poly-ADP Ribose Polymerase) inhibitors, a class of agents exploiting synthetic lethality: in tumour cells already deficient in homologous recombination through BRCA1/2 loss of function, additional PARP inhibition prevents repair of single-strand DNA lesions through alternative pathways, leading to accumulation of lethal damage and selective cell death [11,19,20]. This synthetic lethality strategy is the pharmacological basis of a growing set of approved therapeutic indications.

Olaparib (Lynparza®) is approved for treatment of HER2-negative metastatic breast cancer in female germline BRCA1/2 PV carriers (based on the OlympiAD trial) [11,42], and as adjuvant therapy in high-risk HER2-negative breast cancer in female germline BRCA1/2 PV carriers (based on OlympiA, defining high risk as triple-negative or ER-positive cancer with ≥4 positive nodes after neoadjuvant chemotherapy or residual invasive disease with CPS+EG ≥3) [11,43]. Olaparib is also approved as maintenance in recurrent platinum-sensitive serous ovarian cancer, in first-line ovarian cancer in patients responding to platinum-based chemotherapy, in castration-resistant prostate cancer with PVs in homologous recombination repair genes (including BRCA1/2), and as maintenance in metastatic pancreatic cancer with a germline BRCA1/2 PV after first-line chemotherapy with a platinum response [11,44,45]. Talazoparib (Talzenna®) is approved for HER2-negative metastatic breast cancer in female germline BRCA1/2 PV carriers. Niraparib (Zejula®) and rucaparib (Rubraca®) have approved indications mainly in recurrent ovarian cancer [11]. Current FDA prescribing information distinguishes three levels of requirement: a germline BRCA variant (olaparib in breast cancer, adjuvant and metastatic, and maintenance of metastatic pancreatic cancer after at least 16 weeks of first-line platinum; talazoparib monotherapy in locally advanced or metastatic breast cancer; niraparib in maintenance of ovarian recurrence); a germline and/or somatic BRCA variant (olaparib in first-line and recurrent ovarian maintenance and combined with abiraterone and prednisone/prednisolone in prostate cancer; rucaparib in maintenance of ovarian recurrence and mCRPC after androgen receptor-directed therapy); and broader homologous recombination deficiency (olaparib with bevacizumab and niraparib in first-line ovarian maintenance, in HRD-positive tumours defined by a BRCA variant and/or genomic instability; olaparib monotherapy and talazoparib with enzalutamide in mCRPC with an HRR gene variant). All are adult indications, with selection by an approved companion diagnostic [46]. Veliparib is in advanced clinical investigation.

For the adjuvant setting in high-risk HER2-negative breast cancer in female carriers of a germline BRCA1/2 pathogenic variant, NCCN stipulates strict timing and sequencing criteria based on consolidated OlympiA trial data. Oral olaparib treatment should be instituted for a total duration of 12 months (1 year), preferably beginning after completion of all definitive local treatments (surgery and radiotherapy) and neoadjuvant or adjuvant chemotherapy regimens. In hormone receptor-positive (ER-positive) tumours, olaparib should be administered concurrently with standard endocrine therapy, which should not be delayed.

PARP Inhibitors in Ovarian Cancer — Complete Indications and Evidence

The indication profile of PARP inhibitors in ovarian cancer encompasses multiple clinical scenarios, as detailed in the following table:

Assessment of Homologous Recombination Deficiency (HRD) — Clinical Relevance

A particularly relevant clinical aspect is the role of HRD (Homologous Recombination Deficiency) tests in guiding ovarian cancer treatment. Although PARP inhibitors are indicated in female BRCA1/2 carriers on the basis of the germline variant, NCCN also recommends tumour HRD testing (using commercial tests such as Myriad MyChoice CDx or Foundation Medicine CDx) in ovarian cancer patients without an identified germline BRCA1/2 variant, since 20% to 30% of ovarian cancers have somatic HRD (through BRCA1 promoter methylation, a somatic BRCA1/2 variant or alterations in other HR pathway genes such as RAD51C, RAD51D, BRIP1, PALB2). HRD status determines eligibility for olaparib + bevacizumab and niraparib as first-line maintenance, and should ideally be assessed before or during first-line chemotherapy to guide maintenance decisions.

PARP Inhibitors in Breast Cancer — Complete Indications

ESCAT Classification and Other Relevant Molecular Targets in Breast Cancer

The European Society for Medical Oncology (ESMO) introduced the ESMO Scale for Clinical Actionability of molecular Targets (ESCAT) in 2018, a classification system for genomic alterations according to clinical utility. In breast cancer, the targets most relevant to female BRCA1/2 PV carriers are classified as follows [22]: germline BRCA1/2 PVs and ERBB2 amplification are ESCAT IA targets (ready for routine use, with randomised trial evidence and survival improvement); PIK3CA mutations, AKT1/PTEN alterations and ESR1 mutations are ESCAT IA targets for advanced hormone receptor-positive tumours after progression on endocrine therapy with CDK4/6 inhibitors; germline PALB2 PVs and somatic BRCA1/2 mutations are ESCAT IIB targets (an option following progression when a targeted drug is available).

Regarding targeted therapeutic agents beyond PARP inhibitors, the following are relevant to female BRCA2 carriers with advanced hormone receptor-positive tumours:

(1) alpelisib (PI3K inhibitor), approved combined with fulvestrant for advanced HR-positive/HER2-negative breast cancer with a PIK3CA mutation, after progression on endocrine therapy with a CDK4/6 inhibitor (SOLAR-1 trial);

(2) capivasertib (AKT inhibitor), approved combined with fulvestrant for tumours with PIK3CA, AKT1 or PTEN alterations (CAPItello-291 trial, approved by FDA and EMA); and

(3) elacestrant (selective oestrogen receptor degrader, SERD), approved by FDA and EMA for advanced luminal breast cancer with an ESR1 mutation after progression on endocrine therapy with a CDK4/6 inhibitor (EMERALD trial).

ESR1 mutations are common in advanced luminal breast cancer (30%–40%) after aromatase inhibitor treatment, and screening for them is currently recommended in patients eligible for elacestrant. In addition, the phase II TBCRC 048 study demonstrated clinical efficacy of olaparib in female germline PALB2 PV carriers and patients with somatic BRCA1/2 mutations (present in approximately 3% of patients), supporting ESCAT IIB classification for these subgroups [11,22].

PARP Inhibitors in Pancreatic Cancer — Maintenance Indication

Olaparib (Lynparza®) is FDA-approved (since December 2019) and incorporated into NCCN guidelines as maintenance therapy in germline BRCA1/2 variant carriers with metastatic pancreatic cancer who have not progressed after at least 16 weeks of first-line platinum-based chemotherapy (usually modified FOLFIRINOX or gemcitabine + cisplatin). POLO trial (phase 3): PFS of 7.4 vs. 3.8 months (HR=0.53, p=0.004) compared with placebo; at 2 years, 22.1% vs. 9.6% of patients remained progression-free; interim OS analysis showed no difference (18.9 vs. 18.1 months; HR=0.91) [45]. At the final survival analysis (Kindler et al., 2022), median overall survival was 19.0 vs. 19.2 months (HR=0.83; p=0.35), with estimated 3-year survival of 33.9% vs. 17.8% and prolonged time to subsequent treatment [45,49]. Oral olaparib at 300 mg twice daily is administered until progression or unacceptable toxicity. Baseline CT after induction chemotherapy is mandatory to confirm absence of progression before maintenance begins. This indication is particularly relevant given the very poor overall prognosis of metastatic pancreatic ductal adenocarcinoma and scarcity of effective second-line options.

Antiangiogenic Monoclonal Antibodies: Bevacizumab (Avastin®)

Beyond PARP inhibitors, a therapeutic category of growing relevance and increasingly incorporated into NCCN guidelines encompasses monoclonal antibodies, antibody–drug conjugates (ADC — Antibody-Drug Conjugates) and immunomodulatory agents (immune checkpoint inhibitors), whose indications are essential to clinical practice for BRCA1/2 pathogenic variant carriers.

Bevacizumab is a humanised anti-VEGF (Vascular Endothelial Growth Factor) monoclonal antibody inhibiting tumour angiogenesis, approved in multiple cancer indications relevant to BRCA1/2 variant carriers.

In first-line ovarian cancer, bevacizumab is approved and recommended by NCCN combined with carboplatin and paclitaxel in first-line chemotherapy (stages III/IV), followed by bevacizumab maintenance for up to 15 to 22 months. The bevacizumab/olaparib combination as first-line maintenance (after response to platinum-based chemotherapy) is recommended by NCCN as Category 1 in female germline or somatic BRCA1/2 pathogenic variant carriers, based on PAOLA-1 data (olaparib + bevacizumab vs. bevacizumab alone as maintenance: improved rPFS of 22.1 vs. 16.6 months in the overall ITT population; and 37.2 vs. 17.7 months in the HRD/BRCA-mutated subgroup). The 5-year overall survival benefit in the HRD subgroup was 65.5% (bevacizumab + olaparib) vs. 48.4% (bevacizumab). This combination is particularly relevant to female BRCA1/2 carriers who received first-line bevacizumab.

In recurrent platinum-sensitive ovarian cancer, bevacizumab combined with carboplatin/gemcitabine or carboplatin/paclitaxel is recommended by NCCN as second-line or later treatment, based on the OCEANS and GOG-213 trials. Niraparib + bevacizumab is also incorporated into the guidelines as a maintenance option for patients unable to tolerate olaparib (Category 2A, included in the 2025-2026 guideline update).

In recurrent platinum-resistant ovarian cancer, bevacizumab alone or combined with salvage agents (weekly paclitaxel, oral cyclophosphamide, topotecan) is recommended by NCCN as a treatment option for patients with platinum-resistant disease. Mirvetuximab soravtansine + bevacizumab (see following section) was recently included in NCCN guidelines for platinum-resistant FRα-positive tumours.

Immune Checkpoint Inhibitors (Anti-PD-1): Pembrolizumab (Keytruda®)

Pembrolizumab is an anti-PD-1 (Programmed Death-1) monoclonal antibody restoring T-cell cytotoxic activity against tumour cells by blocking the immunoinhibitory PD-1/PD-L1 pathway. Its relevance to female BRCA1/2 carriers derives mainly from the high frequency of triple-negative breast cancer (TNBC) associated with BRCA1 variants, a subgroup that has been the principal target of breast cancer immunotherapy studies.

In triple-negative breast cancer (TNBC) in the neoadjuvant/adjuvant setting, pembrolizumab combined with neoadjuvant chemotherapy (weekly paclitaxel + carboplatin for 12 weeks, followed by 4 cycles of doxorubicin or epirubicin + cyclophosphamide for 12 weeks; pembrolizumab 200 mg IV every 3 weeks during the neoadjuvant phase) followed by adjuvant pembrolizumab (9 cycles every 3 weeks, totalling approximately 1 year of treatment) is recommended by NCCN as Category 1 in early TNBC (stage II/III), based on KEYNOTE-522 data. In this pivotal study, pembrolizumab added to neoadjuvant chemotherapy increased the pathological complete response (pCR) rate from 51.2% to 64.8% (p<0.001), and improved 3-year event-free survival (EFS) from 76.8% to 84.5% (HR=0.63; p<0.001). This benefit was observed irrespective of PD-L1 status and presence of a germline BRCA1/2 variant, and is therefore applicable to female BRCA1 carriers with early TNBC in general [50].

In first-line metastatic triple-negative breast cancer (mTNBC), NCCN recommends pembrolizumab combined with chemotherapy (nab-paclitaxel, paclitaxel or gemcitabine + carboplatin) as first-line treatment in mTNBC with PD-L1 expression (CPS ≥ 10), based on KEYNOTE-355 data (PFS and OS improvement in the PD-L1+ subgroup with CPS ≥ 10; KEYNOTE-522 concerns the early rather than metastatic setting). In female germline BRCA1/2 variant carriers, first-line treatment decisions should weigh the relative benefit of pembrolizumab vs. PARP inhibitors (olaparib or talazoparib), with PARP inhibitors preferred when a germline variant is confirmed. However, PD-L1 assessment (by CPS) should be performed in all mTNBC patients to identify those who may benefit from immunotherapy, irrespective of BRCA status.

In PD-L1+ metastatic TNBC with sacituzumab govitecan + pembrolizumab (ASCENT-04), this combination was added to NCCN guidelines (version 1.2026) as preferred first-line Category 1 treatment for PD-L1-positive mTNBC (CPS ≥ 10), based on ASCENT-04/KEYNOTE-D19. This combination demonstrated significant superiority over standard chemotherapy + pembrolizumab in progression-free survival and response rate (443 patients; median PFS 11.2 vs. 7.8 months; HR=0.65; p=0.0009). FDA approved this combination on 24 June 2026 for first-line PD-L1+ mTNBC (CPS ≥ 10), with sacituzumab govitecan 10 mg/kg IV on days 1 and 8 of 21-day cycles [51]. Specifically in PD-L1+ germline BRCA1/2 variant carriers, the combination represents the first treatment in the first-line setting combining an ADC and immunotherapy — although guidelines recommend parallel assessment of olaparib/talazoparib eligibility.

PD-L1 Assessment and Selection of Immunotherapy Candidates

Assessment of predictive biomarkers of immunotherapy response, particularly PD-L1 expression by immunohistochemistry and the role of tumour mutational burden (TMB — Tumor Mutational Burden), is essential for selecting female BRCA1/2 carriers as pembrolizumab candidates in breast cancer.

PD-L1 expression should be assessed by the Combined Positive Score (CPS), which counts the proportion of PD-L1-positive cells (tumour cells + lymphocytes + macrophages) relative to the total viable tumour cells. A CPS ≥ 10 defines PD-L1 positivity for eligibility for pembrolizumab combined with sacituzumab govitecan (ASCENT-04 regimen) in first-line mTNBC; CPS ≥ 1 was one threshold analysed in KEYNOTE-355 for pembrolizumab + conventional chemotherapy, but statistically significant benefit and regulatory approval (FDA and EMA) concern CPS ≥ 10. NCCN recommends CPS-based PD-L1 testing in every mTNBC patient at metastatic diagnosis (or recurrence).

In ovarian cancer, PD-L1 expression and immune checkpoint inhibitor use have not demonstrated consistent clinical benefit in randomised phase 3 trials (atezolizumab + bevacizumab + chemotherapy in IMagyn050; pembrolizumab + chemotherapy in KEYNOTE-100), which is why anti-PD-1/PD-L1 immunotherapy is not recommended by NCCN ovarian cancer guidelines for female BRCA1/2 carriers, except within a clinical trial or for tumours with microsatellite instability (MSI-H) identified by tumour sequencing.

Antibody–Drug Conjugates (ADC): Sacituzumab Govitecan (Trodelvy®)

Sacituzumab govitecan (SG) is an antibody–drug conjugate combining an anti-TROP-2 (trophoblast cell-surface antigen 2) antibody with the topoisomerase I inhibitor SN-38 (active metabolite of irinotecan), linked by a hydrolysable linker. TROP-2 is overexpressed in 85% to 90% of triple-negative breast cancers, making it a highly relevant therapeutic target for female BRCA1 carriers with TNBC.

In PD-L1-negative metastatic TNBC (Category 1, Preferred — NCCN 1.2026 Update), sacituzumab govitecan monotherapy was added to NCCN version 1.2026 as Category 1 and a preferred first-line regimen for mTNBC patients with CPS < 10 (PD-L1-negative) without a germline BRCA1/2 variant. This update is supported by ASCENT-03 data (phase 3, published in NEJM in 2025), demonstrating superiority of SG monotherapy over physician's choice in PD-L1-negative patients, with significant improvement in progression-free survival (PFS: 9.7 vs. 6.9 months; HR=0.62; p<0.0001). FDA approved first-line sacituzumab govitecan monotherapy on 24 June 2026 for mTNBC patients who are not candidates for PD-1/PD-L1 inhibitors [51]. For female germline BRCA1/2 variant carriers, PARP inhibitors (olaparib, talazoparib) remain the preferred first-line option; however, SG is a relevant salvage option after progression.

In second-line and later metastatic TNBC, sacituzumab govitecan is FDA-approved and incorporated into NCCN guidelines as a second-line or later option in pretreated mTNBC, based on ASCENT data (phase 3, 2021): PFS of 5.6 vs. 1.7 months (HR=0.41) and OS of 12.1 vs. 6.7 months (HR=0.48) compared with physician's-choice chemotherapy [52]. In female BRCA1/2 carriers with mTNBC progressing after PARP inhibitors, SG is currently one of the second-line options most recommended by NCCN.

Antibody–Drug Conjugates: Mirvetuximab Soravtansine (Elahere®)

Mirvetuximab soravtansine is an anti-FRα (folate receptor alpha) ADC conjugating an anti-FOLR1 antibody with the antimicrotubule agent DM4. FRα is overexpressed in 30% to 40% of high-grade serous ovarian cancers, constituting a predictive response biomarker and mandatory selection criterion (tested by immunohistochemistry with the VENTANA FOLR1 diagnostic test — medium–high expression is required for eligibility).

In recurrent platinum-resistant, FRα-positive ovarian cancer (Category 1), mirvetuximab soravtansine monotherapy received FDA approval in November 2022 (accelerated), confirmed on 22 March 2024 (regular), with European Commission authorisation in November 2024 (favourable CHMP opinion in September 2024), and is incorporated into NCCN guidelines as Category 1 for patients with epithelial ovarian, fallopian tube or peritoneal cancer recurring after 1 to 3 previous treatment lines, with an FRα-positive tumour (medium to high expression) and a platinum-free interval below 6 months (platinum-resistant). MIRASOL demonstrated superiority in PFS (5.6 vs. 4.0 months, HR=0.65, p<0.001), OS (16.5 vs. 12.7 months, HR=0.67, p=0.005) and objective response rate (42% vs. 16%) over physician's-choice chemotherapy [53,54].

In recurrent platinum-sensitive, FRα-positive ovarian cancer, mirvetuximab soravtansine + bevacizumab was added to NCCN guidelines (version 3.2024 and retained in version 3.2026) as a Category 2A option for patients with FRα-positive ovarian cancer with platinum-sensitive recurrence (platinum-free interval ≥ 6 months), as an alternative or complement to platinum regimens. For female BRCA1/2 pathogenic variant carriers with platinum-sensitive recurrence, the preferred treatment sequence typically involves retreatment with platinum-based chemotherapy and PARP inhibitor maintenance, reserving mirvetuximab for subsequent lines or as an alternative with contraindication/intolerance to platinum and/or PARP inhibitors.

FRα immunohistochemistry testing is not yet incorporated into routine pathological assessment at most European centres, often requiring retrospective testing of archived tumour tissue. NCCN recommends that all patients with high-grade serous ovarian cancer be tested for FRα at diagnosis or first recurrence, anticipating a possible need for mirvetuximab in later lines.

Antibody–Drug Conjugates: Trastuzumab Deruxtecan (T-DXd / Enhertu®) in Ovarian Cancer

Trastuzumab deruxtecan (T-DXd) is an anti-HER2 ADC with a high payload (deruxtecan, DXd — an exatecan derivative and topoisomerase I inhibitor; it should not be confused with the SN-38 in sacituzumab govitecan) that demonstrated activity in multiple HER2-expressing solid tumours, including ovarian cancer. The 2025 NCCN updates (version 3.2025) included T-DXd as an option in recurrent HER2-expressing ovarian cancer guidelines (IHC 2+ or 3+), representing a new treatment pathway for patients with ovarian cancer after multiple lines. In female BRCA1/2 carriers with recurrent ovarian cancer, HER2 expression should be prospectively assessed in tumour tissue, since approximately 30% of high-grade serous ovarian cancers show some level of HER2 expression, potentially determining eligibility for T-DXd in advanced lines.

First-Line Platinum-Based Chemotherapy Preferences

Regarding platinum-based chemotherapy (cisplatin, carboplatin), BRCA-associated tumours demonstrate greater sensitivity to these agents for pathophysiological reasons analogous to those explaining PARP inhibitor efficacy, particularly inability to repair efficiently the intrastrand adducts and double-strand breaks induced by platinum [11]. This influences the choice of chemotherapy regimen in different clinical scenarios (metastatic prostate cancer, pancreatic cancer, ovarian cancer and breast cancer).

In metastatic pancreatic cancer, platinum-containing regimens, specifically modified FOLFIRINOX or gemcitabine combined with cisplatin, are preferred over the standard gemcitabine with nab-paclitaxel regimen because of markedly higher response rates resulting from DNA repair deficiency. Similarly, in BRCA-associated metastatic triple-negative breast cancer (mTNBC), carboplatin monotherapy demonstrated therapeutic superiority and a more favourable tolerability profile in first-line treatment compared with taxanes (such as docetaxel).

Therapeutic Developments in Metastatic Prostate Cancer (mCRPC)

In metastatic castration-resistant prostate cancer (mCRPC), the NCCN-guided approach has evolved substantially beyond olaparib or rucaparib monotherapy. There are currently strong recommendations for first-line synthetic lethality combination regimens in mCRPC with BRCA1/2 mutations, combining PARP inhibitors with androgen receptor signalling pathway inhibitors (ARPI). Notable combinations are talazoparib with enzalutamide, olaparib with abiraterone and niraparib with abiraterone, which demonstrated a robust gain in radiographic progression-free survival compared with standard hormone therapy alone in these homologous recombination-deficient populations.

The approved PARP + ARPI combination regimens incorporated into NCCN guidelines version 3.2026 for mCRPC with HRR gene variants are as follows:

ESMO perspective: treatment sequence, resistance and biomarkers in ovarian cancer

First-line maintenance with olaparib, niraparib or rucaparib reduced progression risk by 60%–70% in advanced ovarian cancers with a BRCA mutation, and by 40%–50% in HRD tumours treated with rucaparib or niraparib [22]. In PAOLA-1, fewer than 30% of patients progressed on the PARP inhibitor–bevacizumab combination, compared with more than 50% on a PARP inhibitor alone, suggesting that bevacizumab may delay PARP inhibitor resistance; patients progressing on a PARP inhibitor respond less well to subsequent platinum chemotherapy and have a worse prognosis [22]. Because benefit in platinum-sensitive recurrence is smaller, ESMO favours PARP inhibitors in first-line maintenance, with HRD and BRCA1/2 testing performed at diagnosis and before neoadjuvant chemotherapy in patients unsuitable for primary cytoreductive surgery [22]. CCNE1 amplification and BRCA1/2 reversion mutations confer resistance to PARP inhibitors and platinum; early trials suggest efficacy of CDK2 and WEE1 inhibitors (adavosertib, ESCAT IIB) in CCNE1-amplified tumours [22]. Immune checkpoint inhibitors should be considered in recurrent ovarian cancer with MMR deficiency (dMMR), and the phase II DESTINY-PanTumor02 trial (2024) demonstrated T-DXd efficacy in HER2-overexpressing tumours, including ovarian cancer (ESCAT IC for HER2 2+/3+ at recurrence after standard treatment) [22]. In the gynaecological ESCAT classification, somatic or germline BRCA1/2 variants and HRD are level IA targets for PARP inhibitors ± bevacizumab in first-line maintenance of stage III/IV disease and platinum-sensitive recurrence without previous PARP inhibitor exposure, in all non-mucinous epithelial ovarian carcinomas; somatic alterations in PALB2, ATM, ATR, CHEK1/2, RAD51B/C/D and CDK12 are level IIIB [22].

ESMO perspective: breast cancer and prostate cancer

In breast cancer, germline BRCA1/2 PVs predict response to platinum chemotherapy and PARP inhibitors (olaparib, talazoparib), approved for early and advanced stages based on phase III trials demonstrating improved PFS (OlympiAD and EMBRACA, advanced disease) or overall survival (OlympiA, early disease) [22]. SOLAR-1 (alpelisib) and CAPItello-291 (capivasertib, with tissue NGS as the companion diagnostic because PTEN deletions are difficult to detect in blood) showed improved PFS without overall survival benefit, and the ESCAT level (I or II) of AKT1/PTEN alterations is debated [22]. In prostate cancer, germline and somatic BRCA1 and BRCA2 alterations predict PARP inhibitor response; PROfound was the first biomarker-guided phase III trial in mCRPC and demonstrated rPFS and overall survival benefit with olaparib in cohort A (BRCA1, BRCA2 and ATM) compared with a second androgen receptor pathway inhibitor, and TRITON3 demonstrated rPFS benefit with rucaparib compared with docetaxel or a second ARPI in BRCA1/2 alterations, but not ATM mutations [60]. PROpel, TALAPRO-2 and MAGNITUDE demonstrated a hierarchical benefit aligned with biology: BRCA1/2 alterations > HRR alterations > unselected patients > HRR-proficient tumours; a pooled FDA analysis (2024) confirmed that the greatest benefit occurs with BRCA1/2 and PALB2 alterations, with apparent absence of benefit in CHEK2 or ATM mutations, and that patients with CDK12 defects do not benefit from PARP inhibitor monotherapy but benefit from combination with an ARPI [60].

Reference dosing of the main drugs

Dosing according to NCCN guidelines, with FDA/EMA product information as comparison; the dose should be confirmed in the current Summary of Product Characteristics [51,64].

Investigational treatments

Selective PARP1 inhibitors such as saruparib (AZD5305), designed to maintain synthetic lethality with less haematological toxicity than first-generation PARP1/2 inhibitors, are being evaluated in phase III trials in prostate cancer (EvoPAR-Prostate01, NCT06120491, saruparib + ARPI in mHSPC with and without HRR alterations; EvoPAR-Prostate02, NCT06952803, adjuvant saruparib in high-risk localised disease with a BRCA1/2 variant; EvoPAR-Prostate05, NCT07711002, not yet recruiting) and breast cancer (EvoPAR-Breast01, NCT06380751, saruparib + camizestrant as first-line treatment in advanced HR+/HER2− cancer with a BRCA1, BRCA2 or PALB2 variant); at the date of this review (4 October 2026), according to ClinicalTrials.gov, EvoPAR-Prostate01 is active, not recruiting, with estimated primary completion in September 2027, EvoPAR-Prostate02 and EvoPAR-Breast01 are recruiting and EvoPAR-Prostate05 has not yet begun recruitment; there are no phase III results or announced authorisation application [65]. WEE1, ATR and CDK2 inhibitors are being studied in tumours resistant through CCNE1 amplification or reversion mutations [22].

Comparative regulatory status: United States and European Union

The indications described in the preceding subsections combine evidence of different kinds, requiring four levels to be distinguished: a peer-reviewed trial publication (for example, AMPLITUDE in Nature Medicine or the OlympiA update in Annals of Oncology); a sponsor press release with preliminary (topline) results not yet scrutinised by independent reviewers; an opinion from the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA), which is a recommendation rather than authorisation; and an authorisation decision by the European Commission in the European Union or the Food and Drug Administration (FDA) in the United States. Even authorisation does not guarantee marketing, reimbursement or effective access in each country, decided in Portugal by INFARMED and in Brazil by ANVISA (registration) and, for the Unified Health System (SUS), the National Commission for the Incorporation of Technologies (CONITEC). The following table summarises the status of drugs whose indication depends on BRCA or HRR status, according to FDA prescribing information, the EMA medicines dataset, current European SmPCs and post-authorisation procedure records, consulted on 4 October 2026 [46,58,61].

FDA approval dates according to Drugs@FDA and indications from current labels; European dates from the EMA medicines database and post-authorisation procedure documents; European indications from current SmPCs. Where the indication recorded in the EMA database differed from the SmPC (case of Trodelvy®), the SmPC prevailed [46,51,58,61].

The developments over the past twelve months affecting this syndrome are as follows. AMPLITUDE (peer-reviewed publication) randomised 696 patients with metastatic castration-sensitive prostate cancer and HRR gene alterations (56% with BRCA1/2) to niraparib with abiraterone and prednisone or placebo with abiraterone and prednisone; radiographic progression-free survival improved in the BRCA subgroup (HR 0.52; 95% CI 0.37–0.72) and overall population (HR 0.63; 95% CI 0.49–0.80), with overall survival still immature (HR 0.79; 95% CI 0.59–1.04) and grade 3–4 adverse events in 75% vs. 59% (anaemia in 29%, with transfusion in 25%) [66]; this trial supported the Akeega® indication extensions described above, with different genetic scope between the two agencies. TALAPRO-3 (talazoparib with enzalutamide in metastatic castration-sensitive prostate cancer with HRR alterations) was announced as positive in a sponsor press release in March 2026 and detailed results, communicated in May 2026 with no peer-reviewed publication yet located, indicate a radiographic progression or death HR of 0.48 (95% CI 0.36–0.65), with estimated 3-year progression-free survival of 77% vs. 56%; FDA accepted the supplemental application with priority review and a target date (PDUFA) in the last quarter of 2026 [67]. The third interim OlympiA analysis, published in 2026 with median follow-up of 6.1 years, maintained the adjuvant olaparib benefit in invasive disease-free survival (HR 0.65; 95% CI 0.53–0.78) and overall survival (HR 0.72; 95% CI 0.56–0.93; 87.5% vs. 83.2% at 6 years), without increased myelodysplastic syndrome or acute myeloid leukaemia (0.4% vs. 0.7%) [68]. In metastatic triple-negative breast cancer, beyond the sacituzumab govitecan decisions in the table, the European Commission approved datopotamab deruxtecan (Datroway®) as first-line monotherapy in July 2026 for patients unsuitable for immunotherapy, based on TROPION-Breast02 (information from the sponsor press release concerning the European decision); this indication is independent of BRCA status [69]. No PARP inhibitor indication withdrawals were identified during this period.

In Brazil, CONITEC recommended and the Ministry of Health decided to incorporate olaparib into SUS for first-line maintenance of high-grade serous or endometrioid ovarian carcinoma, FIGO stages III–IV, with a BRCA1/2 variant and response to platinum chemotherapy, conditional on variant identification testing and a Ministry of Health protocol (Ordinance SECTICS/MS no. 45, of 4 October 2024); for the same indication, niraparib was not incorporated (final decision in 2025, report no. 494), because of overall survival uncertainty and cost-effectiveness above the threshold [70,71]. These examples show that regulatory authorisation and public system access are separate decisions.

Evidence extrapolation and off-label use

Extrapolating evidence and prescribing off-label are different things. Off-label use is defined by the label text in each jurisdiction, age and specified population; extrapolation is application of a trial result to a population not included in the trial or included in insufficient numbers. All PARP inhibitors are authorised only in adults, and the European olaparib SmPC states that safety and efficacy below 18 years are not established, so any paediatric use (for example, in a child with biallelic variants and a solid tumour) is off-label [58]. Metastatic and adjuvant breast cancer labels refer to “adult patients” without sex restriction, so treatment of a man with breast cancer and gBRCA is within the indication, although evidence derives from trials with very few men. In pregnancy, the olaparib SmPC requires pregnancy testing before initiation, two forms of contraception during treatment and for up to 6 months after the last dose, and contraindicates breastfeeding during treatment and for up to 1 month after the last dose [58]. Olaparib use in female germline PALB2 variant carriers or breast tumours with somatic BRCA1/2 variants, supported by the phase II TBCRC 048 study (ESCAT IIB), is off-label in both labels, which require a germline BRCA variant [22,46,58]. Conversely, olaparib with abiraterone in a patient without a BRCA variant is off-label in the USA and within the indication in the EU (if chemotherapy is not clinically indicated), and the same reasoning applies to niraparib/abiraterone in a BRCA1 carrier with castration-sensitive disease [46,58,61].

Pivotal PARP inhibitor trials and limitations of comparisons between trials

Pivotal trials supporting BRCA/HRR-dependent indications. PFS, progression-free survival; rPFS, radiographic PFS; OS, overall survival; ITT, intention-to-treat population.

These trials do not allow PARP inhibitors to be ranked against one another. None directly compared two PARP inhibitors, and populations differ in the number of previous lines, germline or somatic variant requirements, control (chemotherapy, placebo or another hormonal agent) and outcome assessment method (independent central review or investigator). PFS medians describe time until half the patients progress in each arm, rather than the expected gain for an individual patient; the hazard ratio expresses a relative reduction that should be read alongside the residual absolute rate (in OlympiA, the overall survival difference at 6 years was 4.4 percentage points, with estimated mortality of 12.5% at 6 years in the olaparib arm compared with 16.8% in the placebo arm) [68]. Primary outcomes are PFS or disease-free survival rather than overall survival, and several trials positive for the primary outcome were negative for overall survival: OlympiAD, EMBRACA and POLO did not demonstrate a statistically significant overall survival benefit, partly because of crossover and subsequent treatments [45,49,72,73]. In prostate trials with hierarchical analysis, benefit is greatest in BRCA1/2 alterations and disappears in populations without HRR alterations (futility in the HRR-negative MAGNITUDE cohort), so results for the overall population should not be transferred to non-BRCA subgroups [60,77]. FDA–EMA divergences in PARP inhibitor–ARPI combinations arise precisely from these designs: PROpel did not stratify by biomarker and had underpowered subgroups, TALAPRO-2 combined an unselected cohort with an enriched cohort, and only MAGNITUDE, which prospectively isolated the subgroup with greatest benefit, led to concordant conclusions from the two agencies [78].

Adverse Effects and Their Management by Treatment

This section details the toxicity profile and management strategies of the main therapeutic agents used in BRCA1/2 syndrome, organised by treatment.

Olaparib (Lynparza®). The most frequent adverse effects of olaparib include nausea (in approximately 70% of patients, the most common toxicity), vomiting, intense fatigue, anaemia, neutropenia and thrombocytopenia. Dyspnoea and abdominal pain are also reported. The risk of myelodysplastic syndrome (MDS) or acute myeloid leukaemia (AML) is below 1%, but constitutes a serious late toxicity requiring periodic full blood count surveillance throughout treatment and after completion. Management includes antiemetics (ondansetron, metoclopramide) when necessary, baseline and monthly blood count monitoring during the first 12 months of treatment, and dose adjustment (reduction to 250 mg twice daily and, if necessary, 200 mg twice daily, according to the current SmPC/labelling) for grade ≥3 haematological toxicity; temporary drug interruption may be necessary until haematological recovery.

Talazoparib (Talzenna®). Talazoparib has the greatest PARP-trapping potential among inhibitors of this class, translating into substantially greater haematological toxicity than olaparib: grade 3-4 haematological adverse events in approximately 55% of patients in EMBRACA (mainly grade 3-4 anaemia, in approximately 39%; anaemia of any grade in approximately 53%), grade 3-4 neutropenia in approximately 21% and grade 3-4 thrombocytopenia in approximately 15% [48]. Fatigue is also very frequent. Management requires baseline and monthly full blood counts (according to the SmPC/labelling), with closer clinical surveillance in initial cycles, interruption and stepwise dose reduction for grade ≥3 haematological toxicities, transfusion support (red cell and/or platelet concentrates) when clinically indicated, and consideration of growth factors (G-CSF) in recurrent severe neutropenia. Given the toxicity profile, talazoparib should be prescribed cautiously in patients with reduced haematological reserve.

Niraparib (Zejula®). The most relevant niraparib toxicities are grade 3-4 thrombocytopenia (in approximately 34% of patients at the starting dose of 300 mg/day, decreasing with individualised doses of 200 mg/day), anaemia, neutropenia, hypertension, nausea, fatigue and insomnia. MDS/AML risk is similar to that of other PARP inhibitors. Management includes weekly haematological monitoring during the first treatment month, followed by monthly monitoring for the following 11 months and periodically thereafter, and individualisation of the starting dose according to body weight and baseline platelet count (patients weighing < 77 kg or with platelet count < 150,000/μL start at 200 mg/day rather than 300 mg/day; this individualisation applies, in FDA labelling, to first-line maintenance and, in the EU SmPC, to all indications). Hypertension should be monitored and treated with appropriate antihypertensives; temporary niraparib interruption is necessary in hypertensive crisis or grade ≥3 haematological toxicity not resolved by dose adjustment.

Rucaparib (Rubraca®). The most common rucaparib adverse effects are nausea and vomiting (frequently moderate), fatigue, anaemia (grade 3-4 in approximately 25%), elevated hepatic transaminases (AST/ALT, generally transient), thrombocytopenia and dysgeusia. Hepatotoxicity, although usually reversible and asymptomatic, requires periodic liver function monitoring (each cycle during the first year). Management includes antiemetics (ondansetron or palonosetron), monthly haematological and hepatic monitoring, and dose adjustment for grade ≥3 toxicity.

Bevacizumab (Avastin®). The most frequent and clinically relevant bevacizumab adverse effects are hypertension (grade 3-4 in 5% to 10% of patients), proteinuria (potentially reaching nephrotic syndrome in severe cases), bleeding (including frequent epistaxis, but also severe bleeding such as haemoptysis or gastrointestinal haemorrhage), gastrointestinal perforation (in fewer than 1% but potentially fatal), arterial and venous thromboembolism, and impaired surgical wound healing (contraindicated perioperatively). Management includes blood pressure monitoring each cycle with introduction or adjustment of antihypertensives as necessary, dipstick proteinuria screening before each cycle (with 24-hour proteinuria measurement if > 2+), temporary interruption if proteinuria ≥ 2 g in 24 hours (until below 2 g/24 h), permanent discontinuation for nephrotic syndrome, gastrointestinal perforation, fistula, posterior reversible encephalopathy syndrome (PRES) or uncontrolled hypertensive crisis, and a minimum interval of 28 days between the last bevacizumab dose and any elective surgery.

Pembrolizumab (Keytruda®). Pembrolizumab toxicities are predominantly immune-mediated and may affect any organ or system. The most frequent include immune-mediated pneumonitis (grade 1-2 in 3% to 5% of patients, potentially fatal if not treated promptly), immune-mediated hepatitis (in approximately 1%), colitis (1% to 2%), endocrinopathies — hypothyroidism in 8% to 10%, hyperthyroidism, adrenal insufficiency and hypophysitis —, nephritis, skin reactions (maculopapular rash, vitiligo) and arthralgia. Fatigue is very common. Management requires regular clinical and laboratory surveillance (thyroid, hepatic and renal function tests before each cycle), temporary interruption (generally for grade 2–3 toxicities) or permanent discontinuation (grade 4, recurrent grade 3 or, for pneumonitis, grade ≥3) of pembrolizumab, according to the affected organ and severity, as specified in labelling, early aggressive systemic corticosteroid therapy for severe immune-mediated toxicities (prednisolone 1 to 2 mg/kg/day or equivalent orally or intravenously, with slow tapering over at least 4 to 6 weeks), additional immunosuppressants such as infliximab or mycophenolate mofetil for corticosteroid-refractory toxicities, and permanent hormone replacement in endocrinopathies (levothyroxine, hydrocortisone/fludrocortisone as applicable).

Sacituzumab Govitecan (Trodelvy®). The most relevant sacituzumab govitecan adverse effects are severe neutropenia (grade 3-4 in approximately 47% of patients), febrile neutropenia (in approximately 6%), severe diarrhoea (grade 3-4 in 10% to 15%), anaemia, nausea, vomiting and alopecia. Gastrointestinal and haematological toxicity risk is particularly high in patients homozygous for the UGT1A128 polymorphism, who have reduced SN-38 metabolism (active metabolite). Management includes antiemetic premedication (two or three drugs) and premedication for infusion reactions, close surveillance of patients with known reduced UGT1A1 activity (labelling does not require prior genotyping or provide for starting dose reduction in UGT1A128 homozygotes, recommending interruption or discontinuation according to observed toxicity), immediate loperamide initiation after excluding an infectious cause (4 mg initially, followed by 2 mg for each diarrhoeal episode, maximum 16 mg/day, stopping 12 hours after resolution), full blood count monitoring before each administration, primary G-CSF prophylaxis from the first cycle in patients at increased febrile neutropenia risk, and dose reduction to 7.5 mg/kg and then 5 mg/kg for grade 3–4 toxicities (febrile or prolonged neutropenia, uncontrolled diarrhoea), with discontinuation if 5 mg/kg is not tolerated [51].

Mirvetuximab Soravtansine (Elahere®). The principal dose-limiting toxicity of mirvetuximab soravtansine is ocular toxicity, including blurred vision, dry eye, keratitis and corneal epithelial defects, affecting 40% to 60% of patients at any grade and constituting the most frequent cause of dose adjustment and treatment interruption. Peripheral neuropathy, fatigue, nausea, diarrhoea and elevated transaminases are also described. Ocular toxicity management is multidisciplinary and includes, according to labelling: artificial tears (lubricant eye drops) and corticosteroid eye drops (one drop in each eye 6 times daily from the day before each infusion until day 4, and 4 times daily on days 5 to 8 of each cycle, prescribed only after slit-lamp examination), ophthalmological examination with visual acuity and slit lamp before initiation, on alternate cycles during the first 8 cycles and whenever ocular symptoms arise, interruption until improvement (maintaining or reducing the dose) for confluent superficial keratitis, an epithelial defect or loss of ≥3 lines of visual acuity, reduction by one dose level after a corneal stromal ulcer or opacity, and permanent discontinuation for corneal perforation.

Trastuzumab Deruxtecan (T-DXd / Enhertu®). The most serious and clinically relevant T-DXd toxicity is interstitial lung disease (ILD)/pneumonitis, occurring at any grade in 10% to 15% of patients and at grade ≥3 in approximately 3%, potentially fatal (grade 5 described in 0.3% to 1% of patients in some studies). Nausea and vomiting (very frequent), alopecia, fatigue, neutropenia, anaemia and diarrhoea are also common effects. ILD management requires rigorous symptom surveillance (dyspnoea, dry cough, unexplained fever) and consideration of periodic chest CT or CT for any new respiratory symptom; T-DXd should be interrupted for any suspected ILD; in asymptomatic ILD (grade 1), it is resumed after resolution (at the same dose if resolved within ≤ 28 days, with reduction by one level if > 28 days), and in symptomatic ILD (grade ≥2) discontinuation is permanent, with early systemic corticosteroid initiation (prednisolone ≥ 1 mg/kg/day or equivalent, with slow tapering over at least 4 weeks).

Platinum-Based Chemotherapy (Cisplatin and Carboplatin). Cisplatin causes renal toxicity (nephrotoxicity, requiring intensive IV hyperhydration and creatinine monitoring before each cycle), sensory peripheral neurotoxicity (cumulative and often irreversible at high doses), ototoxicity (tinnitus and high-frequency hearing loss, cumulative) and grade 3-4 nausea/vomiting (among the most emetogenic chemotherapy agents). Carboplatin has a different toxicity profile, with predominant myelosuppression (thrombocytopenia and neutropenia), moderate nausea and a relevant risk of hypersensitivity/anaphylactic reaction — particularly after six or more previous exposures. Cisplatin management includes pre- and post-chemotherapy hyperhydration with normal saline (volume according to institutional protocol), amifostine for nephroprotection in selected cases, periodic audiometric monitoring and antiemetic prophylaxis for highly emetogenic chemotherapy (5-HT3 antagonist, such as ondansetron or palonosetron, + aprepitant + dexamethasone); for carboplatin, management includes full blood count monitoring at nadir intervals (days 14-21), prophylactic G-CSF in high-risk patients, and a desensitisation protocol for hypersensitivity reactions in patients for whom carboplatin retreatment is clinically essential.

Tamoxifen and Selective Oestrogen Receptor Modulators (SERMs). Tamoxifen produces vasomotor symptoms (hot flushes and night sweats) in more than 50% of patients, vaginal dryness and dyspareunia, menstrual irregularity and amenorrhoea in premenopausal women, and increased venous thromboembolism risk (approximately 2 to 3 times that of the general population). Endometrial cancer risk is slightly increased (absolute risk approximately 0.1%/year). Cataracts and other visual changes are described with prolonged use. Management includes symptomatic treatment of hot flushes (venlafaxine, gabapentin or oxybutynin, off-label, as an alternative to oestrogens), annual gynaecological surveillance with transvaginal ultrasonography for abnormal uterine bleeding (not routinely indicated without symptoms), contraindication of tamoxifen in patients with a previous history of venous or arterial thromboembolism, and preference for aromatase inhibitors (anastrozole, letrozole, exemestane) in postmenopausal women because of their different toxicity profile (no thromboembolic or endometrial risk, but an effect on bone mineral density and arthralgia).

PARP + ARPI Combinations (Olaparib+Abiraterone, Talazoparib+Enzalutamide, Niraparib+Abiraterone). Combinations of PARP inhibitors with androgen receptor signalling inhibitors have overlapping toxicity profiles, dominated by PARP inhibitor haematological toxicity (anaemia, thrombocytopenia, neutropenia, amplified with talazoparib) and the specific toxicities of each ARPI: abiraterone is associated with fluid retention, hypertension and hypokalaemia through mineralocorticoid excess (making coadministration of prednisone 5 mg twice daily mandatory to prevent this effect), hepatotoxicity and fatigue; enzalutamide is associated with intense fatigue, restless legs syndrome, a rare but documented seizure risk (contraindicated in patients with previous epilepsy or brain lesions carrying an epilepsy risk), and posterior reversible encephalopathy syndrome (PRES) in rare cases. Combination management requires frequent haematological monitoring (full blood count before each cycle), liver function and electrolyte monitoring before each cycle (with particular attention to potassium with abiraterone), blood pressure and cardiac monitoring, neurological assessment in any patient with seizures or altered mental status (with immediate enzalutamide interruption), and stepwise PARP inhibitor dose adjustment for grade ≥3 haematological toxicity.

Lutetium-177 PSMA (Pluvicto®). The most frequent lutetium-177 PSMA-617 adverse effects include fatigue (very frequent, in more than 50% of patients), xerostomia (dryness of the mouth and salivary glands, resulting from PSMA expression in the parotid and submandibular glands, present in more than 40% of patients), nausea, haematological toxicity (grade 3-4 anaemia in approximately 14%, thrombocytopenia and neutropenia in approximately 10%), and nephrotoxicity (with renal function changes in patients with previous renal disease or obstructive metastases). Given the ionising radiation mechanism of action, patients should follow specific radiation protection precautions after administration (according to labelling: limit close contact with others for 2 days and children and pregnant women for 7 days, sleep in a separate room for 3 days, 7 days if children are present and 15 days if a pregnant woman is present, abstain from sex for 7 days; careful handwashing and exclusive bathroom use when possible are also recommended). Management includes adequate hydration and salivary protection measures (sugar-free lozenges; pilocarpine is off-label) to reduce salivary gland dose, full blood count and renal function monitoring before each cycle and 4 weeks after each administration, and interruption or postponement for grade ≥3 haematological toxicity or significant renal function deterioration.

8. Reproductive Options and Family Counselling

Diagnosis of a BRCA1/2 PV has profound implications for reproductive health and family planning. Female carriers of reproductive age should be informed about prenatal diagnosis options (through chorionic villus sampling or amniocentesis) and preimplantation genetic diagnosis (PGD), which allows selection of non-carrier embryos after in vitro fertilisation, avoiding the need for termination of pregnancy [11]. PGD resulting in successful births is documented in female BRCA1/2 PV carriers. The decision to use these technologies involves medical, ethical, religious and cultural considerations that should be explored in specialist genetic counselling. Female BRCA1 PV carriers may also experience an earlier decline in ovarian reserve, potentially affecting options for egg or embryo cryopreservation [11].

The European Reference Network for Genetic Tumour Risk Syndromes (ERN GENTURIS), which includes hereditary breast and ovarian cancer syndrome, published a guideline in 2026 on reproductive counselling in cancer predisposition syndromes, based on a review of 851 publications and consensus among experts and patient representatives, with 16 recommendations; the central recommendation is proactively to offer reproductive counselling to all individuals with a predisposition syndrome and relevant relatives, with psychological support and multidisciplinary collaboration [79].

In addition to counselling focused on ovarian reserve and preimplantation diagnosis (PGD) techniques, patients of reproductive age must know about the severe teratogenic potential of PARP inhibitors. Because their mechanism of action directly interferes with cellular replication and genomic integrity, these molecules cause severe embryofoetal toxicity and structural malformations in animal models.

Regarding family counselling, identification of a PV in a family has direct implications for all at-risk relatives (children, siblings, parents, uncles/aunts, cousins), which justifies promoting communication and targeted cascade genetic testing. In populations of Ashkenazi ancestry, testing should include the three specific founder mutations (185delAG and 5382insC in BRCA1, and 6174delT in BRCA2), in addition to complete sequencing of both genes when indicated [11]. In other populations with documented founder mutations (Polish, Icelandic, French Canadian, Hispanic, Hungarian, Bahamian), family and clinical history should guide panel choice and test type [11].

The implications of biallelic BRCA1 and BRCA2 variants should also be considered: although rare, they may cause severe autosomal recessive conditions: biallelic BRCA2 variation is associated with Fanconi anaemia complementation group D1 (FA-D1), characterised by developmental abnormalities, early bone marrow failure and predisposition to leukaemias and solid tumours in early childhood [11]. Biallelic BRCA1 variants have rarely caused an analogous form of Fanconi anaemia (FANCS). In the series of 27 patients with biallelic BRCA2 variants analysed by Alter et al. (2007), cumulative probability of any malignancy reached 97% by 5.2 years; the splicing variants IVS7+1G>A and IVS7+2T>G (historical numbering, = NM_000059.4(BRCA2):c.631+1G>A p.? and c.631+2T>G p.?) were associated with acute myeloid leukaemia and the variants 886delGT and 6174delT (the latter an Ashkenazi founder) with brain tumours, and several observed variants were not associated with cancer in presumed heterozygous carriers, adding uncertainty to counselling [80]. Biallelic PALB2 variants cause subtype FA-N, likewise associated with high cancer risk in early childhood [24]. In these situations, reproductive counselling for the couple should include discussion of the risk that offspring inherit biallelic variants if the partner also carries a PV in the same gene [11].

Predictive testing, cascade testing and biallelic variants

Once the familial variant is defined, predictive testing may be offered to extended family members, ideally through a clinical genetics service; it is usually offered only to adults and may be deferred until the age at which surveillance or risk-reducing surgery becomes a consideration, ensuring that counselling, surveillance and predictive testing are offered to all at-risk relatives from an appropriate age in early adulthood (Lobb and Meiser, 2004) [5,12]. Testing for founder variants alone may be appropriate in unaffected individuals of Ashkenazi ancestry in certain circumstances [12]. Orphanet distinguishes the cancer predisposition syndrome due to biallelic BRCA2 variants (ORPHA:319462), corresponding to Fanconi anaemia group D1, whose spectrum includes acute myeloid leukaemia, medulloblastoma and Wilms tumour in childhood; in counselling couples where both partners carry PVs in the same gene, the risk of offspring with biallelic variants is 25% per pregnancy [4,7].

9. Special Considerations: Population Diversity and Epidemiology

9.1 Global and regional epidemiology

Estimated carrier frequency in the general population is approximately 1 in 381 for BRCA1 and 1 in 277 for BRCA2, with higher frequencies in populations with founder effects, such as Ashkenazi Jewish, Icelandic and Finnish populations [2]. In an exome sequencing study of 50,726 unselected adults in a US healthcare system (Manickam et al., 2018), 0.5% carried BRCA1/2 PV/LPs (35.6% in BRCA1 and 64.4% in BRCA2), and GeneReviews estimates combined prevalence at 1:100 to 1:200 [4,10]. In developed countries, cumulative breast cancer incidence by 70 years is 6.3 per 100 women, with lifetime risk of approximately 10%–12%; the Western diet, associated with early menarche and postmenopausal obesity, combined with low parity, late first childbirth and short or absent breastfeeding, largely explains the higher incidence in developed countries [12]. Lifetime ovarian cancer risk in the general population is approximately 1 in 70 (1.4%) [27]. In prostate cancer, men of Black African and Caribbean ancestry have higher risk than Europeans, who in turn have higher risk than Asians [28].

9.2 Founder effect

The Portuguese BRCA2 c.156_157insAlu variant is particularly relevant to practice in Portugal and emigrant communities of Portuguese origin: as an approximately 300-base-pair mobile element insertion, it escapes conventional next-generation sequencing and standard MLPA, so laboratories should include a specific assay in assessment of Portuguese families [29]. The same variant and the two Portuguese BRCA1 founder variants have been identified in Brazilian patients, consistent with the contribution of Portuguese migration to the Brazilian variant spectrum and justifying inclusion of the Alu insertion-targeted assay in investigation of Brazilian families of Portuguese ancestry [82]. In Portugal, a multicentre quality improvement study in three Local Health Units in the Lisbon region (Lisboa Ocidental, Amadora-Sintra and Loures-Odivelas) showed underuse of BRCA testing in cancer practice and an increase from 14.2 to 29.7 tests per month (+109%) after implementing a standardised protocol; this is a healthcare practice indicator rather than a prevalence estimate [85]. In Brazil, in the multicentre Neo-Real/GBECAM-0123 cohort of early triple-negative breast cancer treated with neoadjuvant pembrolizumab, 105 of 600 tested patients (17.5%) had a pathogenic BRCA1/2 variant (78% in BRCA1), and pathological complete response was 74.0% in carriers and 61.7% in the remainder; this proportion likewise describes a selected hospital series rather than the Brazilian population [86].

9.3 Regional data gaps

Carrier prevalence and penetrance data derive mainly from European and North American populations and populations with founder effects. For sub-Saharan Africa, the Middle East, much of Asia and Latin America, the consulted reference texts provide no population-based prevalence estimates for BRCA1/2 PVs; in these regions, including Brazil, available data derive from selected patient series or compilations of laboratory reports describing the variant spectrum and proportion of carriers among tested patients, but should not be extrapolated to carrier frequency in the general population [84,86]. Underrepresentation of these populations in variant databases increases the proportion of VUSs reported in individuals of non-European ancestry, reinforcing the importance of periodic reclassification (see section 5).

9.4 Transgender, Non-Binary and Gender-Diverse Individuals

Screening and risk-reduction recommendations for BRCA1/2 PV carriers who are transgender, non-binary or gender-diverse should be individualised according to organs present, history of gender-affirming surgery and exposure to gender-affirming hormone therapy. In individuals of female biological sex at birth (AFAB – assigned female at birth) with BRCA1/2 PVs who have undergone top surgery (breast reduction preserving tissue), breast screening should be considered and may include mammography and/or MRI, potentially beginning earlier than in the general population. RRSO is recommended irrespective of gender identity, using the same criteria as for cisgender women. In individuals of male biological sex at birth (AMAB – assigned male at birth) with BRCA1/2 PVs who have received gender-affirming oestrogen therapy, breast cancer risk may be increased relative to cisgender men, although it remains substantially below that of cisgender women. PSA prostate screening should continue, although gender-affirming hormone therapy alters PSA values, reducing its efficacy as a marker [11].

10. Illustrative Clinical Case

10.1 Illustrative clinical case — an unaffected carrier identified by cascade testing

The following is a composite case constructed for teaching purposes from situations commonly encountered in clinical practice and does not correspond to a real patient. To consolidate the concepts discussed, consider this typical clinical case: a woman aged 38 years, without a personal cancer history, is referred to medical genetics by the oncologist who identified left-sided triple-negative breast cancer (ER-negative, PR-negative, HER2-negative) in her sister aged 35 years. Family history also revealed a maternal aunt with ovarian cancer at 52 years. Pre-test probability of a BRCA1/2 PV was estimated by BRCAPro at 35%. After appropriate pre-test genetic counselling, an NGS multigene panel analysed BRCA1, BRCA2 and 25 other cancer predisposition genes. The result revealed a heterozygous pathogenic BRCA1 variant: NM_007294.4:c.5266dup (p.Gln1756Profs*74), described in the literature as c.5266dupC and, in historical BIC numbering, as 5382insC, with ACMG/AMP Class 5 classification (Pathogenic). Cascade testing was performed in the affected sister, confirming the same variant, and all first-degree relatives were referred for counselling. The patient, still without a personal cancer history, began intensified screening with annual breast MRI and mammography, was referred to gynaecological oncology for RRSO planning after discussion of ideal timing (intending to undergo it before 40 years), and received counselling on risk-reducing mastectomy options, choosing intensive surveillance while assessing the decision's psychosocial impact. She was also referred to an oncologist to discuss chemoprevention and enrolled in a prospective registry of BRCA1/2 PV carriers. This case illustrates the importance of cascade testing, multidisciplinary genetic counselling and proactive, personalised risk management in female carriers identified before cancer diagnosis.

10.2 Published real case — public disclosure by a BRCA1 PV carrier and the “Angelina Jolie effect”

In May 2013, actress Angelina Jolie publicly described, in a New York Times opinion article, her decision to undergo bilateral risk-reducing mastectomy after identification of a pathogenic BRCA1 variant [87]. Her mother had died at 56 years from ovarian cancer; the estimated risks communicated to her were 87% for breast cancer and 50% for ovarian cancer, and after mastectomy with reconstruction her estimated breast cancer risk fell below 5% [87]. In 2015 she reported undergoing bilateral risk-reducing salpingo-oophorectomy [88]. This disclosure was associated with more than a doubling of referrals to family history and genetics clinics in the United Kingdom over the following months, with increased appropriate referrals and BRCA1/2 test requests — the “Angelina Jolie effect” [89]. For teaching purposes, the case illustrates shared decision-making on risk-reducing surgery, timing of RRSO after completion of reproductive plans and the impact of public communication on genetic counselling access; the 87% estimate corresponds to the upper end of penetrance intervals, consistent with the recommendation to use higher values in families with several affected members (section 2.3).

10.3 Published case — a de novo BRCA1 variant in a woman without a family history (Dencker et al., 2026)

Dencker and colleagues described a woman aged 37 years with grade 3 invasive carcinoma of the right breast, oestrogen and progesterone receptor-positive (100%) and HER2 3+, clinical stage T1c N0 M0, without a relevant family history of breast or ovarian cancer (pedigree in Supplementary Figure S1 of the original article, available open-access at https://doi.org/10.1186/s13053-026-00333-2) [32]. She received neoadjuvant paclitaxel and dual HER2 blockade, followed by epirubicin and cyclophosphamide, breast-conserving surgery with sentinel lymph node biopsy, adjuvant trastuzumab emtansine for residual disease, radiotherapy and endocrine therapy with ovarian suppression [32]. Germline sequencing panel testing, performed two years after diagnosis at another centre and confirmed by the authors, identified the heterozygous variant NM_007294.4:c.1335_1336del, p.(Arg446Serfs*9), classified as pathogenic according to the ClinGen ENIGMA specifications of ACMG/AMP criteria (PVS1, PM5_STR_PTC and PM2_SUP), without evidence of mosaicism in the blood sample [32]. Both parents tested negative and microsatellite analysis confirmed parentage, so the variant was considered de novo; the authors emphasise that low-level gonadal mosaicism in a parent cannot be excluded by blood testing, and identified only 12 de novo BRCA1 variants published since 1999 [32]. The patient did not meet German hereditary breast and ovarian cancer testing criteria (age above 36 years, non-triple-negative tumour and no family history) [32]. For teaching purposes, the case demonstrates three points from this article: an ER-positive, HER2-positive tumour makes a BRCA1 variant less likely but does not exclude it (section 3.1); absence of family history is expected with de novo variants, which family-based criteria fail to identify (section 5); and sibling risk depends on possible parental mosaicism, while the risk to the patient's own offspring is 50% (section 8). Calculation of a polygenic score, described by the authors as integrated practice at their centre, is not part of routine recommendations in the guidelines cited in this article.

11. Prognosis and Long-Term Follow-Up

Prognosis in BRCA1/2 PV carriers depends on multiple factors, including the affected gene, specific variant, family history, presence or absence of diagnosed cancer, adherence to screening and risk-reduction measures, and access to specialist care. In female carriers without diagnosed cancer who adhere to structured intensified screening programmes, survival approaches that of the general population. In female carriers with diagnosed breast or ovarian cancer, overall survival appears favourable compared with non-carriers with histologically equivalent tumours, partly because of greater sensitivity to platinum-based chemotherapy and PARP inhibitors, and partly because of frequently earlier diagnosis through regular screening [11]. Long-term screening adherence tends to decline over time, making periodic genetic follow-up consultations essential to maintain adherence, reassess risk-reduction options at different life stages, update recommendations according to new scientific evidence, and discuss additional or emerging genetic tests [11].

Clinical follow-up should include, beyond the cancer screening already detailed, regular psychosocial monitoring (with support from a psychologist specialising in cancer genetics), assessment of bone health (particularly after early RRSO, with increased osteoporosis risk), cardiovascular health, sexual health and quality of life. Participation in clinical trials and prospective registries is strongly encouraged because it advances knowledge and offers access to technologies and advanced investigational interventions.

In an analysis of 3879 ovarian cancer cases (2666 non-carriers, 909 female BRCA1 carriers and 304 BRCA2 carriers), adjusted hazard ratios for overall mortality at 5 years were 0.73 for BRCA1 and 0.49 for BRCA2 compared with non-carriers (Bolton et al., 2012), making BRCA2 status in particular a prognostic and predictive marker in epithelial ovarian cancer [27]. In a phase II olaparib study (Gelmon et al., 2011), objective responses were observed in 7 of 17 patients (41%) with BRCA1/2 mutations compared with 11 of 46 (24%) without mutations [27]. Women who have already had breast cancer and are carriers should have the opportunity to review estimated new primary risks (breast and ovary), but this review is not necessary during primary cancer treatment [5]. When family history changes, the genetics team should be contacted to update risk assessment [12]. Support organisations such as Breast Cancer Now and the Hereditary Breast Cancer Helpline in the United Kingdom provide information and support to families [5,12]. In Europe, reference centres for this syndrome form part of ERN GENTURIS (https://www.genturis.eu), which includes patient representatives and publishes European guidelines; in the United States, the patient association FORCE (Facing Our Risk of Cancer Empowered, https://www.facingourrisk.org) is specifically dedicated to people with hereditary cancer and BRCA1/2 variant carriers, and in Brazil Instituto Oncoguia (https://www.oncoguia.org.br) provides general cancer information for patients and relatives [79,90].

12. Summary and Final Considerations

In summary, hereditary breast and ovarian cancer predisposition syndrome associated with germline BRCA1 and BRCA2 PVs is one of the most relevant inherited cancer predisposition conditions in contemporary medicine, with far-reaching clinical, therapeutic and family implications. Diagnosis requires qualified genetic counselling, a detailed family cancer history and molecular NGS testing in a multigene panel performed in certified laboratories. Clinical management is multidisciplinary, dynamic and individualised, combining intensified screening, pharmacological and surgical risk-reduction strategies, targeted systemic therapy with PARP inhibitors, monoclonal antibodies, antibody–drug conjugates, immune checkpoint inhibitors and platinum agents, and continuous psychosocial follow-up. Detailed, current knowledge of this syndrome is indispensable to clinical geneticists, oncologists, gynaecologists, surgeons, urologists and all healthcare professionals caring for these families. For additional information and updated guidelines, we recommend consulting OMIM (#604370 and #612555), Orphanet (ORPHA:145), GeneReviews (NBK1247) and NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate, version 3.2026.

The gene-by-gene distinction can be summarised as follows: in BRCA1, breast cancer risk is concentrated before 50 years, with predominance of triple-negative tumours of basal phenotype, and ovarian cancer risk begins increasing from 40 years, justifying RRSO between 35 and 40 years; in BRCA2, breast risk follows the general population's age pattern with a relative risk of approximately 11, tumours are more frequently hormone-dependent, ovarian risk is low before 50 years (RRSO between 40 and 45 years), and risks of aggressive prostate cancer, male breast cancer and pancreatic cancer exceed those of BRCA1 [2,5,11].

In laboratory interpretation, a negative panel excludes only the variant classes it covered: mobile element insertions such as the Portuguese founder BRCA2 c.156_157insAlu variant, deep intronic variants and mosaicism require targeted methods, and the report should specify the MANE Select transcript with version, normalised HGVS nomenclature (with the historical BIC designation only in parentheses), zygosity and ACMG/AMP classification according to ClinGen ENIGMA specifications [29,31]. In treatment, regulatory status on 4 October 2026 shows divergent United States and European Union labels, particularly in prostate cancer (qualifying genes and biomarker requirements), and recent extensions to metastatic castration-sensitive prostate cancer (niraparib/abiraterone approved; talazoparib with enzalutamide under FDA assessment), so the indication should be confirmed in the jurisdiction's label and authorisation should not be confused with access or reimbursement [58,61,67].

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