Machine learning-based lifetime breast cancer risk reclassification compared with the BOADICEA model: impact on screening recommendations.

BACKGROUND: The clinical utility of machine-learning (ML) algorithms for breast cancer risk prediction and screening practices is unknown. We compared classification of lifetime breast cancer risk based on ML and the BOADICEA model. We explored the differences in risk classification and their clinical impact on screening practices. METHODS: We used three different ML algorithms and the BOADICEA model to estimate lifetime breast cancer risk in a sample of 112,587 individuals from 2481 families from the Oncogenetic Unit, Geneva University Hospitals. Performance of algorithms was evaluated using the area under the receiver operating characteristic (AU-ROC) curve. Risk reclassification was compared for 36,146 breast cancer-free women of ages 20-80. The impact on recommendations for mammography surveillance was based on the Swiss Surveillance Protocol. RESULTS: The predictive accuracy of ML-based algorithms (0.843 ≤ AU-ROC ≤ 0.889) was superior to BOADICEA (AU-ROC = 0.639) and reclassified 35.3% of women in different risk categories. The largest reclassification (20.8%) was observed in women characterised as 'near population' risk by BOADICEA. Reclassification had the largest impact on screening practices of women younger than 50. CONCLUSION: ML-based reclassification of lifetime breast cancer risk occurred in approximately one in three women. Reclassification is important for younger women because it impacts clinical decision- making for the initiation of screening.

Machine learning techniques for personalized breast cancer risk prediction: comparison with the BCRAT and BOADICEA models.

BACKGROUND: Comprehensive breast cancer risk prediction models enable identifying and targeting women at high-risk, while reducing interventions in those at low-risk. Breast cancer risk prediction models used in clinical practice have low discriminatory accuracy (0.53-0.64). Machine learning (ML) offers an alternative approach to standard prediction modeling that may address current limitations and improve accuracy of those tools. The purpose of this study was to compare the discriminatory accuracy of ML-based estimates against a pair of established methods-the Breast Cancer Risk Assessment Tool (BCRAT) and Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) models. METHODS: We quantified and compared the performance of eight different ML methods to the performance of BCRAT and BOADICEA using eight simulated datasets and two retrospective samples: a random population-based sample of U.S. breast cancer patients and their cancer-free female relatives (N = 1143), and a clinical sample of Swiss breast cancer patients and cancer-free women seeking genetic evaluation and/or testing (N = 2481). RESULTS: Predictive accuracy (AU-ROC curve) reached 88.28% using ML-Adaptive Boosting and 88.89% using ML-random forest versus 62.40% with BCRAT for the U.S. population-based sample. Predictive accuracy reached 90.17% using ML-adaptive boosting and 89.32% using ML-Markov chain Monte Carlo generalized linear mixed model versus 59.31% with BOADICEA for the Swiss clinic-based sample. CONCLUSIONS: There was a striking improvement in the accuracy of classification of women with and without breast cancer achieved with ML algorithms compared to the state-of-the-art model-based approaches. High-accuracy prediction techniques are important in personalized medicine because they facilitate stratification of prevention strategies and individualized clinical management.

BRCA1/BRCA2 germline mutations and chemotherapy-related hematological toxicity in breast cancer patients.

PURPOSE: BRCA1 and BRCA2 proteins are central to DNA repair process through homologous recombination. We hypothesize that BRCA1/BRCA2 mutation carriers may exhibit increased hematological toxicity when receiving genotoxic chemotherapy. METHODS: We included women with primary breast cancers screened for BRCA1/BRCA2 germline mutations and treated with (neo)adjuvant chemotherapy in Geneva (Swiss cohort). The primary endpoint was the incidence of febrile neutropenia following the first chemotherapy cycle (C1). Secondary endpoints were the incidence of grade 3-4 neutropenia, grade 4 neutropenia and hospitalization during C1, G-CSF use and chemotherapy dose reduction during the entire chemotherapy regimen. Long-term toxicities (hematological, cardiac and neuropathy) were assessed in the Swiss cohort and a second cohort of patients from Lyon (French cohort). RESULTS: Overall, 221 patients were assessed for acute hematological toxicity, including 23 BRCA1 and 22 BRCA2 carriers. Following the C1, febrile neutropenia had an incidence of 35% (p = 0.002), 14% (p = 0.562) and 10% among BRCA1, BRCA2 and non-carriers, respectively. Grade 4 neutropenia was found in 57% of BRCA1 (p < 0.001), 14% of BRCA2 (p = 0.861) and 18% of non-carriers. G-CSF support was necessary in 86% of BRCA1 (p = 0.005), 64% of BRCA2 (p = 0.285) and 51% of non-carriers. For long-term toxicity analysis, 898 patients were included (167 BRCA1-, 91 BRCA2- and 640 non-carriers). There was no difference between the 3 groups. CONCLUSIONS: BRCA1 germline mutations is associated with greater acute hematological toxicity in breast cancer patients. These observations could have implication for primary prophylaxis with G-CSF.

A new bioinformatics tool to help assess the significance of BRCA1 variants.

BACKGROUND: Germline pathogenic variants in the breast cancer type 1 susceptibility gene BRCA1 are associated with a 60% lifetime risk for breast and ovarian cancer. This overall risk estimate is for all BRCA1 variants; obviously, not all variants confer the same risk of developing a disease. In cancer patients, loss of BRCA1 function in tumor tissue has been associated with an increased sensitivity to platinum agents and to poly-(ADP-ribose) polymerase (PARP) inhibitors. For clinical management of both at-risk individuals and cancer patients, it would be important that each identified genetic variant be associated with clinical significance. Unfortunately for the vast majority of variants, the clinical impact is unknown. The availability of results from studies assessing the impact of variants on protein function may provide insight of crucial importance. RESULTS AND CONCLUSION: We have collected, curated, and structured the molecular and cellular phenotypic impact of 3654 distinct BRCA1 variants. The data was modeled in triple format, using the variant as a subject, the studied function as the object, and a predicate describing the relation between the two. Each annotation is supported by a fully traceable evidence. The data was captured using standard ontologies to ensure consistency, and enhance searchability and interoperability. We have assessed the extent to which functional defects at the molecular and cellular levels correlate with the clinical interpretation of variants by ClinVar submitters. Approximately 30% of the ClinVar BRCA1 missense variants have some molecular or cellular assay available in the literature. Pathogenic variants (as assigned by ClinVar) have at least some significant functional defect in 94% of testable cases. For benign variants, 77% of ClinVar benign variants, for which neXtProt Cancer variant portal has data, shows either no or mild experimental functional defects. While this does not provide evidence for clinical interpretation of variants, it may provide some guidance for variants of unknown significance, in the absence of more reliable data. The neXtProt Cancer variant portal ( https://www.nextprot.org/portals/breast-cancer ) contains over 6300 observations at the molecular and/or cellular level for BRCA1 variants.

Clinical factors associated with prolonged response and survival under olaparib as maintenance therapy in BRCA mutated ovarian cancers.

OBJECTIVE: To investigate clinical factors associated with prolonged progression-free survival (PFS) and overall survival (OS) in relapsing epithelial ovarian cancer (EOC) patients with BRCA mutations and receiving olaparib as maintenance therapy in daily practice. METHODS: Multicenter (8 hospitals) European retrospective study of relapsing EOC patients having germline or somatic mutations of BRCA1/BRCA2 genes and treated with olaparib as maintenance therapy after platinum-based chemotherapy. RESULTS: One hundred and fifteen patients were included. Median age was 54 years. There were 90 BRCA1 carriers, 24 BRCA2 carriers and one patient had germline mutation of BRCA1 and BRCA2. Six patients had somatic mutations (all BRCA1) and 109 had germline mutations. Ninety percent had serous carcinomas and were platinum-sensitive. Following ultimate platinum-based chemotherapy, 69% of the patients had normalization of CA-125 levels and 87% had RECIST objective responses, either partial (53%) or complete (34%). After a median follow-up of 21 months, median PFS was 12.7 months and median OS was 35.4 months. In multivariate analysis, factors associated with prolonged PFS under olaparib were: platinum-free interval (PFI) ≥ 12 months, RECIST complete response (CR) or partial response (PR) and normalization of CA-125 upon ultimate platinum-based chemotherapy. Factors associated with prolonged OS were PFI ≥ 12 months, CR and normalization of CA-125. CONCLUSIONS: Platinum-free interval ≥ 12 months, complete response and normalized CA-125 levels after ultimate platinum-based chemotherapy are associated with prolonged PFS and OS in relapsing BRCA1/BRCA2 mutated ovarian cancer patients who received olaparib as maintenance therapy.

The BRCA1 c. 5096G>A p.Arg1699Gln (R1699Q) intermediate risk variant: breast and ovarian cancer risk estimation and recommendations for clinical management from the ENIGMA consortium.

BACKGROUND: We previously showed that the BRCA1 variant c.5096G>A p.Arg1699Gln (R1699Q) was associated with an intermediate risk of breast cancer (BC) and ovarian cancer (OC). This study aimed to assess these cancer risks for R1699Q carriers in a larger cohort, including follow-up of previously studied families, to further define cancer risks and to propose adjusted clinical management of female BRCA1*R1699Q carriers. METHODS: Data were collected from 129 BRCA1*R1699Q families ascertained internationally by ENIGMA (Evidence-based Network for the Interpretation of Germline Mutant Alleles) consortium members. A modified segregation analysis was used to calculate BC and OC risks. Relative risks were calculated under both monogenic model and major gene plus polygenic model assumptions. RESULTS: In this cohort the cumulative risk of BC and OC by age 70 years was 20% and 6%, respectively. The relative risk for developing cancer was higher when using a model that included the effects of both the R1699Q variant and a residual polygenic component compared with monogenic model (for BC 3.67 vs 2.83, and for OC 6.41 vs 5.83). CONCLUSION: Our results confirm that BRCA1*R1699Q confers an intermediate risk for BC and OC. Breast surveillance for female carriers based on mammogram annually from age 40 is advised. Bilateral salpingo-oophorectomy should be considered based on family history.

FANCM c.5791C>T nonsense mutation (rs144567652) induces exon skipping, affects DNA repair activity and is a familial breast cancer risk factor.

Numerous genetic factors that influence breast cancer risk are known. However, approximately two-thirds of the overall familial risk remain unexplained. To determine whether some of the missing heritability is due to rare variants conferring high to moderate risk, we tested for an association between the c.5791C>T nonsense mutation (p.Arg1931*; rs144567652) in exon 22 of FANCM gene and breast cancer. An analysis of genotyping data from 8635 familial breast cancer cases and 6625 controls from different countries yielded an association between the c.5791C>T mutation and breast cancer risk [odds ratio (OR) = 3.93 (95% confidence interval (CI) = 1.28-12.11; P = 0.017)]. Moreover, we performed two meta-analyses of studies from countries with carriers in both cases and controls and of all available data. These analyses showed breast cancer associations with OR = 3.67 (95% CI = 1.04-12.87; P = 0.043) and OR = 3.33 (95% CI = 1.09-13.62; P = 0.032), respectively. Based on information theory-based prediction, we established that the mutation caused an out-of-frame deletion of exon 22, due to the creation of a binding site for the pre-mRNA processing protein hnRNP A1. Furthermore, genetic complementation analyses showed that the mutation influenced the DNA repair activity of the FANCM protein. In summary, we provide evidence for the first time showing that the common p.Arg1931* loss-of-function variant in FANCM is a risk factor for familial breast cancer.

[When to refer patients for oncogenetic counseling?]. / Quand faut-il demander une consultation d'oncogénétique?

Approximately 5 to 10% of all malignant tumors can be attributed to highly penetrant cancer predisposition genes. More than 100 of these genes have been identified. Taking into account the complexity and the various implications of predictive oncology, and in accordance with the current regulation, every constitutional molecular analysis must be performed within the framework of a genetic counseling. Besides the implementation of the next generation sequencing technology in clinical laboratory, family history remains a key information to identify hereditary cancer syndromes and to propose genetic counseling. New challenge areas for clinicians involved in predictive oncology are also associated with this technical revolution.

Determinants of genetic counseling uptake and its impact on breast cancer outcome: a population-based study.

Genetic counseling and BRCA1/BRCA2 genes testing are routinely offered in a clinical setting. However, no data are available on the proportion of breast cancer patients with a positive family history undergoing genetic counseling. By linking databases of the Oncogenetics and Cancer Prevention Unit at the Geneva University Hospitals and the population-based Geneva Cancer Registry, we evaluated the uptake of genetic counseling among 1709 breast cancer patients with familial risk of breast cancer and the determinants of such a consultation process. We also studied the impact of genetic counseling on contralateral breast cancer occurrence and survival. Overall, 191 (11.2 %) breast cancer patients had genetic counseling; this proportion was 25.1 % within the high familial risk group. Recent period of diagnosis, early-onset breast cancer, female offspring, high familial risk, tumor size, and chemotherapy treatment were statistically significantly associated with genetic counseling uptake in multivariate analysis. More than 2 % of patients had developed contralateral metachronous breast cancer. An increased risk of contralateral breast cancer of borderline significance was found for patients who had genetic counseling versus those who had not (Cox model adjusted hazard ratio 2.2, 95 % confidence intervals 1.0-5.2, P = 0.063). Stratification by BRCA1/BRCA2 mutation status showed that the occurrence of contralateral breast cancer was 8-fold higher among mutation carriers compared with non-carriers. Age-adjusted overall survival and breast cancer-specific survival were not significantly different between patients who underwent genetic counseling and those who did not. In conclusion, we observed a significant increase in the use of genetic counseling over time and found that breast cancer patients with high familial risk had more often genetic counseling than those with moderate familial risk. A more thorough evaluation of sociodemographic and clinical predictors to attend the cancer genetic unit may help improving the use of genetic counseling services for at-risk individuals at a population level.

Prevalence of CDKN2A, CDK4, POT1, BAP1, MITF, ATM, and TERT Pathogenic Variants in a Single-Center Retrospective Series of Patients With Melanoma and Personal or Family History Suggestive of Genetic Predisposition.

INTRODUCTION: Approximately 20%-45% of familial melanoma (FM) cases are associated with genetic predisposition. OBJECTIVES: This single-center retrospective study aimed to assess the frequency of pathogenic variants (PV) in the main melanoma-predisposing genes in patients with cutaneous melanoma and investigate the clinical predictors of genetic predisposition. METHODS: Patients included were those diagnosed with cutaneous melanoma at the Dermatology Unit of the University Hospital of Verona, Italy, from 2000 to 2022, presenting at least one of the followings: multiple melanomas (≥ 3); personal/family history of pancreatic cancer (PC) (up to 2nd-degree relatives); ≥ 2 1st-degree relatives with melanoma; ≥ 1 1st-degree relatives with early-onset (<45 years) melanoma and tested for CDKN2A, CDK4, POT1, BAP1, MITF, ATM, and TERT. RESULTS: During the study period, 35 out of 1320 patients (2.7%) underwent genetic testing. Four patients (11.4%) harbored a PV in a melanoma-predisposing gene, three in CDKN2A (8.6%), and one in MITF (2.9%). Variants currently classified as being of unknown clinical significance (VUS) were detected in CDKN2A (N = 1), MITF (N = 1), and ATM (N = 2). Family history of PC and ≥5 melanomas, personal history of ≥50 nevi, and ≥4 melanomas were significantly associated with PV in tested genes (P < 0.05). CONCLUSIONS: The prevalence of PV in predisposing genes in FM was lower than previously reported in Italian registries. Possible reasons include deleterious variants in untested intermediate/low-penetrance genes or yet-to-be-discovered high-penetrance genes and environmental risk factors. A family history of PC, a high number of nevi and melanomas predict a monogenic predisposition to melanoma.

Deep Neural Network Integrated into Network-Based Stratification (D3NS): A Method to Uncover Cancer Subtypes from Somatic Mutations.

(1) Background: The identification of tumor subtypes is fundamental in precision medicine for accurate diagnoses and personalized therapies. Cancer development is often driven by the accumulation of somatic mutations that can cause alterations in tissue functions and morphologies. In this work, a method based on a deep neural network integrated into a network-based stratification framework (D3NS) is proposed to stratify tumors according to somatic mutations. (2) Methods: This approach leverages the power of deep neural networks to detect hidden information in the data by combining the knowledge contained in a network of gene interactions, as typical of network-based stratification methods. D3NS was applied using real-world data from The Cancer Genome Atlas for bladder, ovarian, and kidney cancers. (3) Results: This technique allows for the identification of tumor subtypes characterized by different survival rates and significant associations with several clinical outcomes (tumor stage, grade or response to therapy). (4) Conclusion: D3NS can provide a base model in cancer research and could be considered as a useful tool for tumor stratification, offering potential support in clinical settings.

Chemotherapy-related agranulocytosis as a predictive factor for germline BRCA1 pathogenic variants in breast cancer patients: a retrospective cohort study.

BACKGROUND: Carriers of germline pathogenic variants of the BRCA1 gene (gBRCA1) tend to have a higher incidence of haematological toxicity upon exposure to chemotherapy. We hypothesised that the occurrence of agranulocytosis during the first cycle of (neo-)adjuvant chemotherapy (C1) in breast cancer (BC) patients could predict gBRCA1 pathogenic variants. PATIENTS AND METHODS: The study population included non-metastatic BC patients selected for genetic counselling at Hôpitaux Universitaires de Genève (Jan. 1998 to Dec. 2017) with available mid-cycle blood counts performed during C1. The BOADICEA and Manchester scoring system risk-prediction models were applied. The primary outcome was the predicted likelihood of harbouring gBRCA1 pathogenic variants among patients presenting agranulocytosis during C1. RESULTS: Three hundred seven BC patients were included: 32 (10.4%) gBRCA1, 27 (8.8%) gBRCA2, and 248 (81.1%) non-heterozygotes. Mean age at diagnosis was 40 years. Compared with non-heterozygotes, gBRCA1 heterozygotes more frequently had grade 3 BC (78.1%; p = 0.014), triple-negative subtype (68.8%; p <0.001), bilateral BC (25%; p = 0.004), and agranulocytosis following the first cycle of (neo-)adjuvant chemotherapy (45.8%; p = 0.002). Agranulocytosis and febrile neutropenia that developed following the first cycle of chemotherapy were independently predictive for gBRCA1 pathogenic variants (odds ratio: 6.1; p = 0.002). The sensitivity, specificity, positive predictive value, and negative predictive value for agranulocytosis predicting gBRCA1 were 45.8% (25.6-67.2%), 82.8% (77.5-87.3%), 22.9% (6.1-37.3%), and 93.4% (88.9-96.4%), respectively. Agranulocytosis substantially improved the positive predictive value of the risk-prediction models used for gBRCA1 evaluation. CONCLUSION: Agranulocytosis following the first cycle of (neo-)adjuvant chemotherapy is an independent predictive factor for gBRCA1 detection in non-metastatic BC patients.

Hematologic toxicities of chemotherapy in breast and ovarian cancer patients carrying BRCA1/BRCA2 germline pathogenic variants. A single center experience and review of the literature.

BRCA1 and BRCA2 play a central role in DNA repair and their germline pathogenic variants (gBRCA) confer a high risk for developing breast and ovarian cancer. Standard chemotherapy regimens for these cancers include DNA-damaging agents. We hypothesized that gBRCA carriers might be at higher risk of developing chemotherapy-related hematologic toxicity and therapy-related myeloid neoplasms (t-MN). We conducted a retrospective study of women newly diagnosed with invasive breast or ovarian cancer who were screened for gBRCA1/gBRCA2 at Geneva University Hospitals. All patients were treated with (neo-)adjuvant chemotherapy. We evaluated acute hematologic toxicities by analyzing the occurrence of febrile neutropenia and severe neutropenia (grade 4) at day 7-14 of the first cycle of chemotherapy and G-CSF use during the entire chemotherapy regimen. Characteristics of t-MN were collected. We reviewed medical records from 447 patients: 58 gBRCA1 and 40 gBRCA2 carriers and 349 non-carriers. gBRCA1 carriers were at higher risk of developing severe neutropenia (32% vs. 14.5%, p = 0.007; OR = 3.3, 95% CI [1.6-7], p = 0.001) and of requiring G-CSF for secondary prophylaxis (58.3% vs. 38.2%, p = 0.011; OR = 2.5, 95% CI [1.4-4.8], p = 0.004). gBRCA2 carriers did not show increased acute hematologic toxicities. t-MN were observed in 2 patients (1 gBRCA1 and one non-carrier). Our results suggested an increased acute hematologic toxicity upon exposure to chemotherapy for breast and ovarian cancer among gBRCA1 but not gBRCA2 carriers. A deeper characterization of t-MN is warranted with the recent development of PARP inhibitors in frontline therapy in gBRCA breast and ovarian cancer.

Cohort profile: population-based cohorts of patients with colorectal cancer and of their relatives in Geneva, Switzerland.

PURPOSE: Colorectal cancer (CRC) is the third leading cause of cancer death worldwide. Variability between patients in prognosis and treatment response is partially explained by traditional clinicopathological factors. We established a large population-based cohort of patients with CRC and their first-degree and second-degree relatives registered in the Canton of Geneva, to evaluate the role of family history and tumour biomarkers on patient outcomes. PARTICIPANTS: The cohort includes all patients with CRC diagnosed between 1985 and 2013. Detailed information on patient and tumour characteristics, treatment and outcomes were extracted from the Geneva Cancer Registry database, completed by medical records review and linkage with administrative and oncogenetics databases. Next-generation tissue microarrays were constructed from tissue samples of the primary tumour. A prospective follow-up of the cohort is realised annually to collect data on outcomes. First-degree and second-degree relatives of patients are identified through linkage with the Cantonal Population Office database and information about cancer among relatives is retrieved from the Geneva Cancer Registry database. The cohort of relatives is updated annually. FINDINGS TO DATE: The cohort includes 5499 patients (4244 patients with colon cancer and 1255 patients with rectal cancer). The great majority of patients were diagnosed because of occurrence of symptoms and almost half of the cases were diagnosed with an advanced disease. At the end of 2019, 337 local recurrences, 1143 distant recurrences and 4035 deaths were reported. At the same date, the cohort of first-degree relatives included 344 fathers, 538 mothers, 3485 children and 375 siblings. Among them, we identified 28 fathers, 31 mothers, 18 siblings and 53 children who had a diagnosis of CRC. FUTURE PLANS: The cohort will be used for long-term studies of CRC epidemiology with focus on clinicopathological factors and molecular markers. These data will be correlated with the most up-to-date follow-up data.

Triple X syndrome: characteristics of 42 Italian girls and parental emotional response to prenatal diagnosis.

We report clinical and behavioural evaluation data in 42 Italian girls with triple X syndrome whose diagnosis was made prenatally between 1998 and 2006 in three Italian centres. At initial evaluation, reproductive and medical histories were collected. Clinical assessment of the child was performed by a clinical geneticist and included a detailed personal history, physical evaluation and auxological measurements. To analyse how parents coped with specific events in the prenatal and postnatal periods, we conducted an interview that included 35 specific questions designed to elicit retrospective judgements on prenatal communication, present and future worries, needs and expectations. In a subset of probands, we also administered the formal Italian Temperament Questionnaire assessment test that investigates adaptation, general environment and socialisation. This test also assesses the emotional component of temperament. Clinical results in the affected children are similar to those previously reported with evidence of increased growth in the pre-puberal age and an average incidence of congenital malformation and health needs. Median age for the time first words were pronounced was 12 months, showing a slight delay in language skills, which tended to improve by the time they reached school age. Parental responses to the interview demonstrated residual anxiety but with a satisfactory adaptation to and a positive recall of the prenatal counselling session. Parental adaptation of the 47,XXX girls require indeed a proper educational support. This support seems to be available in Italy. An integrated approach to prenatal counselling is the best way to manage the anxiety and falsely imagined consequences that parents feel after being told that their foetus bears such a genetic abnormality.

Concordance of tumour characteristics and survival clustering among pairs of first-degree relatives with breast cancer.

BACKGROUND: Family history is a known risk factor for breast cancer, but its prognostic value and the prognostic value of tumour characteristics in relation to family history has not been clearly established. In addition, studies of intra-familial tumour characteristics and prognosis in population-based settings are very rare. Two previous studies have suggested that breast cancer prognosis clusters within families. However, both studies lack information on HER2 expression status, which is a strong prognostic factor and could contribute to the observed results. METHODS: We conducted a population-based study on 145 mother-daughter and sister-sister affected pairs using data extracted from the Geneva Cancer Registry. Histopathological characteristics were determined in archived tumour blocks by immunochemistry techniques. Breast cancer survival among family members was studied according to patient and tumour characteristics. RESULTS: No significant intra-familial agreement of pathological characteristic features was observed. We found that relatives of breast cancer patients experienced a much higher risk of breast cancer death compared to the general population. However, we did not find significant concordance in good and poor breast cancer-specific survival between pairs. The small number of family pairs and deaths from breast cancer may partly explain our results. CONCLUSIONS: Large-scale studies with accurate data on strong prognosticators are still needed to confirm the possibility of familial inheritance of breast cancer prognosis.  .

Publisher Correction: Clinical outcome of breast cancer in carriers of BRCA1 and BRCA2 mutations according to molecular subtypes.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Clinical outcome of breast cancer in carriers of BRCA1 and BRCA2 mutations according to molecular subtypes.

BRCA1/BRCA2 genes play a central role in DNA repair and their mutations increase sensitivity to DNA-damaging agents. There are conflicting data regarding the prognostic value of BRCA germline mutations in breast cancer (BC) patients. We collected clinical, pathological and genetic data of a cohort 925 BC patients preselected for genetic screening and treated with neoadjuvant or adjuvant chemotherapy, of whom 266 were BRCA carriers. Overall, 171 women carried a BRCA1 mutation, 95 carried a BRCA2 mutation, and 659 were non-carriers. In the entire cohort, there was a prolonged disease-free survival (DFS) for BRCA carriers (hazard ratio (HR) = 0.63; 95% confidence interval (CI), 0.44-0.90 for BRCA1; HR = 0.72; 95%CI, 0.47-1.1 for BRCA2; p = 0.020) and a trend toward prolonged disease-specific survival (DSS; HR = 0.65; 95%CI, 0.40-1.1 for BRCA1; HR = 0.78; 95%CI, 0.44-1.38 for BRCA2; p = 0.19) though not statistically significant. In the TNBC group, BRCA carriers had prolonged DFS (adjusted HR = 0.50; 95%CI, 0.28-0.89 for BRCA1; adjusted HR = 0.37; 95%CI, 0.11-1.25, for BRCA2; p = 0.034) and DSS (adjusted HR = 0.42; 95%CI, 0.21-0.82 for BRCA1; adjusted HR = 0.45; 95%CI, 0.11-1.9 for BRCA2; p = 0.023). In the non-TNBC group, the BRCA1 or BRCA2 mutations did not have any impact on survival. These results suggest that BRCA1/BRCA2 germline mutations are associated with prolonged survival only if women were diagnosed with TNBC.