Predominance of BRCA2 Mutation and Estrogen Receptor Positivity in Unselected Breast Cancer with BRCA1 or BRCA2 Mutation.

BACKGROUND: Poly(ADP-ribose) polymerase 1 inhibitor (PARPi) agents can improve progression-free survival of patients with breast cancer who carry a germline BRCA1 or BRCA2 pathogenic or likely pathogenic variant (gBRCA) in both the metastatic and adjuvant setting. Therefore, we need to reassess the frequency of gBRCA1 and gBRCA2 in order to redefine the criteria for women and tumor phenotype that should be tested. OBJECTIVE: We studied the relative distribution of gBRCA1 and gBRCA2 in unselected populations of women with breast cancer and in unaffected individuals. We also analyzed the proportion of estrogen receptor (ER)-positive (ER+) tumors in unselected breast cancer patients with gBRCA. DESIGN: We performed a meta-analysis of studies of unselected breast cancer that analyzed the relative contribution of gBRCA1 versus gBRCA2 among unselected breast cancer cases in gBRCA carriers. We then performed a meta-analysis of gBRCA carriage in unaffected individuals from genome-wide population studies, the gnomAD databank, and case-control studies. RESULTS: The BRCA2 gene was involved in 54% of breast cancer cases in unselected patients with gBRCA (n = 108,699) and 60% of unaffected individuals (n = 238,973) as compared with 38% of the largest gBRCA family cohort (n = 29,700). The meta-analysis showed that 1.66% (95% CI 1.08-2.54) and 1.71% (95% CI 1.33-2.2) of unselected breast cancer patients carried gBRCA1 and gBRCA2, respectively. In a population of unaffected individuals, the frequency of heterozygosity for gBRCA1 and gBRCA2 was estimated at 1/434 and 1/288, respectively. Nearly 0.5% of unaffected individuals in the studied populations carried a gBRCA. Carriage of a gBRCA was 2.5% for patients with ER+ tumors (95% CI 1.5-4.1) and 5.7% (95% CI 5.1-6.2) for those with ER- tumors. Overall, 58% of breast tumors occurring in women carrying a gBRCA were ER+ (n = 86,870). CONCLUSIONS: This meta-analysis showed that gBRCA2 carriage is predominant in unselected breast cancer patients and unaffected individuals. ER+ tumors among women with gBRCA-related breast cancer are predominant and have been underestimated. Because PARPi agents improve progression-free survival with ER+ gBRCA breast cancer in most clinical trials, breast cancer should be considered, regardless of ER status, for BRCA1/2 screening for therapeutic purposes.

No Association of Early-Onset Breast or Ovarian Cancer with Early-Onset Cancer in Relatives in BRCA1 or BRCA2 Mutation Families.

According to clinical guidelines, the occurrence of very early-onset breast cancer (VEO-BC) (diagnosed ≤ age 30 years) or VEO ovarian cancer (VEO-OC) (diagnosed ≤ age 40 years) in families with BRCA1 or BRCA2 mutation (BRCAm) prompts advancing the age of risk-reducing strategies in relatives. This study aimed to assess the relation between the occurrence of VEO-BC or VEO-OC in families with BRCAm and age at BC or OC diagnosis in relatives. We conducted a retrospective multicenter study of 448 consecutive families with BRCAm from 2003 to 2018. Mean age and 5-year-span distribution of age at BC or OC in relatives were compared in families with or without VEO-BC or VEO-OC. Conditional probability calculation and Cochran-Mantel-Haenszel chi-square tests were used to investigate early-onset cancer occurrence in relatives of VEO-BC and VEO-OC cases. Overall, 15% (19/245) of families with BRCA1m and 9% (19/203) with BRCA2m featured at least one case of VEO-BC; 8% (37/245) and 2% (2/203) featured at least one case of VEO-OC, respectively. The cumulative prevalence of VEO-BC was 5.1% (95% CI 3.6-6.6) and 2.5% (95% CI 1.4-3.6) for families with BRCA1m and BRCA2m, respectively. The distribution of age and mean age at BC diagnosis in relatives did not differ by occurrence of VEO-BC for families with BRCA1m or BRCA2m. Conditional probability calculations did not show an increase of early-onset BC in VEO-BC families with BRCA1m or BRCA2m. Conversely, the probability of VEO-BC was not increased in families with early-onset BC. VEO-BC or VEO-OC occurrence may not be related to young age at BC or OC onset in relatives in families with BRCAm. This finding-together with a relatively high VEO-BC risk for women with BRCAm-advocates for MRI breast screening from age 25 regardless of family history.

Clinical practice guidelines for BRCA1 and BRCA2 genetic testing.

BRCA1 and BRCA2 gene pathogenic variants account for most hereditary breast cancer and are increasingly used to determine eligibility for PARP inhibitor (PARPi) therapy of BRCA-related cancer. Because issues of BRCA testing in clinical practice now overlap with both preventive and therapeutic management, updated and comprehensive practice guidelines for BRCA genotyping are needed. The integrative recommendations for BRCA testing presented here aim to (1) identify individuals who may benefit from genetic counselling and risk-reducing strategies; (2) update germline and tumour-testing indications for PARPi-approved therapies; (3) provide testing recommendations for personalised management of early and metastatic breast cancer; and (4) address the issues of rapid process and tumour analysis. An international group of experts, including geneticists, medical and surgical oncologists, pathologists, ethicists and patient representatives, was commissioned by the French Society of Predictive and Personalised Medicine (SFMPP). The group followed a methodology based on specific formal guidelines development, including (1) evaluating the likelihood of BRCAm from a combined systematic review of the literature, risk assessment models and expert quotations, and (2) therapeutic values of BRCAm status for PARPi therapy in BRCA-related cancer and for management of early and advanced breast cancer. These international guidelines may help clinicians comprehensively update and standardise BRCA testing practices.

Psychosocial and clinical factors of probands impacting intrafamilial disclosure and uptake of genetic testing among families with BRCA1/2 or MMR gene mutations.

OBJECTIVE: Intrafamilial disclosure of hereditary cancer predisposition in BRCA1/2 and mismatch repair gene (MMR) syndromes allows appropriate prevention strategies in at-risk relatives. We previously showed in a nationwide study that the uptake of genetic targeted testing (GTT) in these families was only 30%. We aimed to identify the clinical and psychosocial factors affecting the probands' intrafamilial disclosure and relatives' uptake of GTT in BRCA1/2 or MMR syndromes. METHODS: We assessed clinical variables, family history, and psychosocial variables of probands (depressive symptoms, anxiety, alexithymia, optimism, coping, family relationship, perception of cancer risks, and of hereditary transmission), together with disclosure and uptake of GTT within 103 French BRCA1/2 or MMR families. RESULTS: Among relatives eligible for GTT, 68% were informed of the predisposition, and 37% underwent GTT, according to probands' reports. Intrafamilial disclosure was inversely associated with the degree of kinship (P < .01). In multivariable analysis, disclosure increased with time since probands' genetic diagnosis (P < .01) and probands' feeling of family cohesion (0.01). GTT uptake increased with probands' depressive symptoms (0.02) and decreased with probands' perception of cancer risks (0.03). BRCA1/2 and MMR groups did not differ concerning family information and GTT uptake. CONCLUSIONS: This study identified factors affecting disclosure to relatives and GTT uptake in BRCA1/2 and MMR syndromes and gives new insights to improve probands' follow-up and intrafamilial sharing of genetic information.

Role of the general practitioner in the care of BRCA1 and BRCA2 mutation carriers: General practitioner and patient perspectives.

BACKGROUND: General practitioners (GPs) have an increasing role in referring patients with putative mutation in BRCA1/2 genes for genetics consultation and for long-term follow-up of mutation carriers. METHODS: We compared the expectations of the GPs' role according to BRCA1/2 mutation carriers and to GPs themselves. RESULTS: Overall, 38% (58/152) of eligible GPs and 70% (176/252) of eligible patients were surveyed. Although 81% of GPs collected the family history, only 24% considered that they know criteria indicating genetics consultation and 39% sufficient knowledge of BRCA1/2 guidelines to answer patients' questions. Twelve% of GPs were aware of the French national guidelines. Among unsatisfied patients, 40% felt that their GP was able to answer (moderately, sufficiently, or completely) specific questions about BRCA1/2 care as compared with 81% in satisfied patients. Only 33% of GPs reported being informed directly by the geneticist about the patients' results. GPs' main expectations for their role in BRCA1/2 carrier care were psychological support and informing relatives about screening (72% and 71%, respectively), which contrasts with the perceptions of patients, who mainly requested medical advice for BRCA1/2-related care (51%). CONCLUSION: There is an important need for GP training and enhancing interactions between GPs and geneticists to improve the GP's role in BRCA1/2 screening and management.

Guidelines for reporting secondary findings of genome sequencing in cancer genes: the SFMPP recommendations.

In oncology, the expanding use of multi-gene panels to explore familial cancer predisposition and tumor genome analysis has led to increased secondary findings discoveries (SFs) and has given rise to important medical, ethical, and legal issues. The American College of Medical Genetics and Genomics published a policy statement for managing SFs for a list of genes, including 25 cancer-related genes. Currently, there are few recommendations in Europe. From June 2016 to May 2017, the French Society of Predictive and Personalized Medicine (SFMPP) established a working group of 47 experts to elaborate guidelines for managing information given on the SFs for genes related to cancers. A subgroup of ethicists, lawyers, patients' representatives, and psychologists provided ethical reflection, information guidelines, and materials (written consent form and video). A subgroup with medical expertise, including oncologists and clinical and molecular geneticists, provided independent evaluation and classification of 60 genes. The main criteria were the "actionability" of the genes (available screening or prevention strategies), the risk evaluation (severity, penetrance, and age of disease onset), and the level of evidence from published data. Genes were divided into three classes: for class 1 genes (n = 36), delivering the information on SFs was recommended; for class 2 genes (n = 5), delivering the information remained questionable because of insufficient data from the literature and/or level of evidence; and for class 3 genes (n = 19), delivering the information on SFs was not recommended. These guidelines for managing SFs for cancer-predisposing genes provide new insights for clinicians and laboratories to standardize clinical practices.

Early onset breast cancer: differences in risk factors, tumor phenotype, and genotype between North African and South European women.

PURPOSE: This report compares the risk factors, the tumor phenotypes, and the BRCA1/BRCA2 genotype of early onset breast cancer (EOBC) patients between Southern Europe and North Africa. METHODS: Four hundred and fifty six women with invasive EOBC (≤40 years) were prospectively included from four centers in France (n = 270) and four centers in North Africa (Algeria, Egypt, Morocco, Tunisia; n = 186). Life style, tumor phenotype, familial history, BRCA1/BRCA2 genotype were compared between the two populations. RESULTS: We found an older age at menarche, a higher number of childbearing, a more frequent breastfeeding, a higher body mass index, a lower use of oral contraceptives in North African women compared to French women. TNM stage at diagnosis was higher in North African women than in French women. North African women had a lower incidence of triple negative and proliferative (Ki 67 index > 20%) tumors. There was a lower rate of BRCA1 mutation in North Africa (7 vs. 15%, P = 0.02). Three putative BRCA1/2 founder mutations were identified in North Africa. CONCLUSIONS: In EOBC, we found significant differences in risk factors, phenotype and a higher incidence of BRCA1 mutations in Southern Europe as compared to North Africa. The worst prognosis previously reported for EOBC in North Africa is more likely due to a higher stage at diagnosis than to a more aggressive phenotype, since triple negative tumors are more common in Southern Europe and advanced tumors in North Africa.