Breast Cancer In Mutation Carriers Research Articles

Are Mutation Carrier Patients Different from Non-Carrier Patients? Genetic, Pathology, and US Features of Patients with Breast Cancer.

Simple SummaryUp to 30% of breast cancer patients are carriers of pathogenic mutations in breast cancer susceptibility genes. Except for BRCA1/2 genes that account only for 22–30% of hereditary breast cancer, less is known about the remaining genes that are prone to breast cancer. Our aim was to retrospectively evaluate the relationship between the pathogenic mutations (BRCA and non-BRCA), US features, and histopathologic findings of breast cancer patients with and without mutations. We concluded that carrier patients (BRCA, TP53, PALB, CHEK, ATM, RAD) seem to exhibit benign imaging findings on US compared to mutation-negative patients. Furthermore, carrier patients had the majority of tumors with higher histologic grade and a higher proliferation index. BRCA1, TP53, and RAD carriers accounted for up to one third of the ER-negative tumors from the mutation group. Axillary US performed worse in depicting axillary metastatic lymph nodes in carrier patients, compared to negative patients.The purpose of this study is to evaluate the relationship between the pathogenic/likely pathogenic mutations, US features, and histopathologic findings of breast cancer in mutation carriers compared to non-carrier patients. Methods: In this retrospective study, we identified 264 patients with breast cancer and multigene panel testing admitted to our clinic from January 2018 to December 2020. Patient data US findings, US assessment of the axilla, multigene panel tests, histopathology, and immunochemistry reports were reviewed according to the BI-RADS lexicon. Results: The study population was comprised of 40% pathogenic mutation carriers (BRCA1, BRCA2, CHEK2, ATM, PALB, TP 53, NBN, MSH, BRIP 1 genes) and 60% mutation-negative patients. The mean patient age was 43.5 years in the carrier group and 44 years in the negative group. Carrier patients developed breast cancer with benign morphology (acoustic enhancement, soft elastography appearance) compared to non-carriers (p < 0.05). A tendency towards specific US features was observed for each mutation. BRCA1 carriers were associated with BC with microlobulated margins, hyperechoic rim, and soft elastography appearance (p < 0.05). Estrogen receptor (ER)-negative tumors were associated with BRCA1, TP53, and RAD mutations, while BRCA2 and CHEK2 were associated with ER-positive tumors. Conclusions: Patients with pathogenic mutations may exhibit BC with benign US features compared to negative, non-carrier patients. BRCA1, TP53, and RAD carriers account for up to one third of the ER tumors from the carrier group. Axillary US performed worse in depicting involved lymph nodes in carrier patients, compared to negative patients.

OUTCOME OF SIMULTANEOUS PREIMPLANTATION GENETIC TESTING (PGT) FOR ANEUPLOIDY AND HEREDITARY BREAST CANCER (PGT-A/M) FOR FERTILITY PRESERVATION OR PREVENTION OF VERTICAL TRANSMISSION

Hereditary Breast Cancer (BC) accounts for 5-10% of BCs. Carriers of mutations in BRCA1/2, CHECK2, ATM, Lynch sy and other oncogenes have higher lifetime risk for BC (65-80%), ovarian (30-45%) and other cancers, with chance of 50% transmission to their offspring. Oocyte and/or embryo cryopreservation is an option for fertility preservation (FP), and when coupled with PGT-A/M for BC mutations, allowing prevention of vertical transmission. Our objective was to evaluate the utilization and outcomes of simultaneous PGT-A/M for BC mutation carriers.

Beneficial Molecular Adaptations in BRCA-Mutation Carriers by Combined HIT/HIRT Intervention: Results from a Pilot Study

Based on growing evidence that breast cancer (BRCA) also plays a pivotal role in the regulation of skeletal muscle metabolism and the response to anti-oxidative stress, we examined the influence of regular exercise in human BRCA mutation carriers on their BRCA1 gene/protein expression and inflammatory/oxidative response. Sixteen BRCA-mutation carriers were assigned to an intervention (IG) or control group (CG). IG received a combination of high-intensity interval endurance (HIT) and strength training (HIRT) for six weeks, whereas CG received a low-intensity activity program. Before (T0) and at the end of the intervention (T1), muscle biopsy, physiological performance, blood withdrawal and anthropometry were obtained. Parameters included: Muscle BRCA1 gene/protein expression, inflammatory/oxidative stress, anti-oxidative capacity, peak oxygen capacity (VO2peak) and 1-repetition maximum (1-RM) at six different training machines. VO2peak and 1-RM of IG were increased at T1 compared to T0, whereas CG performance, physiological and molecular parameters remained unchanged. IG showed increased BRCA1 protein concentration as well as anti-oxidative capacity, whereas gene expression was unaltered. IG inflammatory and oxidative damage did not differ between time points. Combined HIT/HIRT increases aerobic and strength performance of BRCA-mutation carriers with up regulated BRCA1 protein expression and improved anti-oxidative status without showing an increased inflammatory response.

A clinically structured and partnered approach to genetic testing in Trinidadian women with breast cancer and their families.

Breast cancer (BC) is the leading cause of cancer death in Caribbean women. Across the Caribbean islands, the prevalence of hereditary breast cancer among unselected breast cancer patients ranges from 5 to 25%. Moreover, the prevalence of BC among younger women and the high mortality in the Caribbean region are notable. This BC burden presents an opportunity for cancer prevention and control that begins with genetic testing among high-risk women. Measured response to positive genetic test results includes the number of preventive procedures and cascade testing in family members. We previously reported data on an active approach to promote cascade testing in the Bahamas and report on preventive procedures showing moderate uptake. Here, we describe a clinically structured and community-partnered approach to the dissemination and follow-up of genetic test results including family counseling for the promotion of risk mitigation strategies and cascade testing in our Trinidadian cohort of patients tested positive for BC predisposition genes. As a part of our initial study of BC genetic testing in Trinidad and Tobago, all participants received pre-test counseling including three-generation pedigree and genetic testing for BRCA1/2, PALB2, and RAD51C. The study was approved by the University of Miami IRB and the Ethics Committee of the Ministry of Health, Trinidad and Tobago. We prospectively evaluated a clinically structured approach to genetic counseling and follow-up of BC mutation carriers in Trinidad and Tobago in 2015. The intervention consisted of (1) engaging twenty-nine BC patients with a deleterious gene mutation (probands), and (2) invitation of their at-risk relatives to attend to a family counseling session. The session included information on the meaning of their results, risk of inheritance, risk of cancer, risk-reduction options, offering of cascade testing to family members, and follow-up of proband decision-making over two years. Twenty-four of twenty-nine mutation carriers (82.8%) consented to enroll in the study. At initial pedigree review, we identified 125 at-risk relatives (ARR). Seventy-seven ARR (62%) attended the family counseling sessions; of these, 76 ARR (99%) consented to be tested for their family gene mutation. Genetic sequencing revealed that of the 76 tested, 35 (46%) ARR were carriers of their family mutation. The ARR received their results and were urged to take preventative measures at post-test counseling. At 2-year follow-up, 6 of 21 probands with intact breasts elected to pursue preventive mastectomy (28.5%) and 4 of 20 women with intact ovaries underwent RRSO (20%). In Trinidad and Tobago, a clinically structured and partnered approach to our testing program led to a significant rate of proband response by completing the intervention counseling session, executing risk-reducing procedures as well as informing and motivating at-risk relatives, thereby demonstrating the utility and efficacy of this BC control program.

Association between the Lynch syndrome gene MSH2 and breast cancer susceptibility in a Canadian familial cancer registry

BackgroundPrevious studies assessing breast cancer risk in families with Lynch syndrome (LS) have yielded conflicting results. Furthermore, conclusions are limited by small sample size and few breast cancer outcomes. This...

Risks of Breast, Ovarian, and Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers

The clinical management of BRCA1 and BRCA2 mutation carriers requires accurate, prospective cancer risk estimates. To estimate age-specific risks of breast, ovarian, and contralateral breast cancer for mutation carriers and to evaluate risk modification by family cancer history and mutation location. Prospective cohort study of 6036 BRCA1 and 3820 BRCA2 female carriers (5046 unaffected and 4810 with breast or ovarian cancer or both at baseline) recruited in 1997-2011 through the International BRCA1/2 Carrier Cohort Study, the Breast Cancer Family Registry and the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer, with ascertainment through family clinics (94%) and population-based studies (6%). The majority were from large national studies in the United Kingdom (EMBRACE), the Netherlands (HEBON), and France (GENEPSO). Follow-up ended December 2013; median follow-up was 5 years. BRCA1/2 mutations, family cancer history, and mutation location. Annual incidences, standardized incidence ratios, and cumulative risks of breast, ovarian, and contralateral breast cancer. Among 3886 women (median age, 38 years; interquartile range [IQR], 30-46 years) eligible for the breast cancer analysis, 5066 women (median age, 38 years; IQR, 31-47 years) eligible for the ovarian cancer analysis, and 2213 women (median age, 47 years; IQR, 40-55 years) eligible for the contralateral breast cancer analysis, 426 were diagnosed with breast cancer, 109 with ovarian cancer, and 245 with contralateral breast cancer during follow-up. The cumulative breast cancer risk to age 80 years was 72% (95% CI, 65%-79%) for BRCA1 and 69% (95% CI, 61%-77%) for BRCA2 carriers. Breast cancer incidences increased rapidly in early adulthood until ages 30 to 40 years for BRCA1 and until ages 40 to 50 years for BRCA2 carriers, then remained at a similar, constant incidence (20-30 per 1000 person-years) until age 80 years. The cumulative ovarian cancer risk to age 80 years was 44% (95% CI, 36%-53%) for BRCA1 and 17% (95% CI, 11%-25%) for BRCA2 carriers. For contralateral breast cancer, the cumulative risk 20 years after breast cancer diagnosis was 40% (95% CI, 35%-45%) for BRCA1 and 26% (95% CI, 20%-33%) for BRCA2 carriers (hazard ratio [HR] for comparing BRCA2 vs BRCA1, 0.62; 95% CI, 0.47-0.82; P=.001 for difference). Breast cancer risk increased with increasing number of first- and second-degree relatives diagnosed as having breast cancer for both BRCA1 (HR for ≥2 vs 0 affected relatives, 1.99; 95% CI, 1.41-2.82; P<.001 for trend) and BRCA2 carriers (HR, 1.91; 95% CI, 1.08-3.37; P=.02 for trend). Breast cancer risk was higher if mutations were located outside vs within the regions bounded by positions c.2282-c.4071 in BRCA1 (HR, 1.46; 95% CI, 1.11-1.93; P=.007) and c.2831-c.6401 in BRCA2 (HR, 1.93; 95% CI, 1.36-2.74; P<.001). These findings provide estimates of cancer risk based on BRCA1 and BRCA2 mutation carrier status using prospective data collection and demonstrate the potential importance of family history and mutation location in risk assessment.

A novel hysteroscopic approach for ovarian cancer screening/early diagnosis.

The lethality of epithelial ovarian cancer (EOC) may be due to common misconceptions regarding etiology and the absence of effective screening and early diagnostic tools. Reviews of histopathological surveys performed on the resected fallopian tubes of breast cancer (BRCA) mutation carriers, who underwent risk-reducing salpingo-oophorectomy, unexpectedly revealed the presence of occult carcinomas of the fallopian tubes. This finding prompted studies that demonstrated the most accredited theory of type II EOC development, which suggests that a large proportion of these tumors are derived from the fallopian tube. At present, no diagnostic tools or screening programs have been demonstrated to be effective or cost-effective in improving the outcome of EOC; it is therefore imperative that the scientific community unite its efforts in the identification of a valid screening and/or early diagnostic method for the treatment of this lethal gynecological malignancy. To this end, the present paper proposes a novel tool for the screening/early diagnosis of EOC: The 'Tuba-check'. This novel approach is based on the possibility of acquiring specimens for tubal lumen cytology via hysteroscopy in a minimally-invasive outpatient setting. The present study protocol aimed to validate the technical feasibility and oncological accuracy of the proposed approach, commencing with a cohort of patients with an expected increased oncological risk, including BRCA mutation carriers or those with a gene expression profile of 'BRCA-ness'. If the data collected by the present study protocol validates this approach, the 'Tuba-check' may, in the near future, be extended for the treatment of all women, therefore reducing the number of victims of epithelial ovarian carcinoma.

Abstract P4-12-16: Teasing out the PALB2 phenotype

Abstract Background: Biallelic mutations in PALB2 (Partner and Localizer of BRCA2) are known to cause Fanconi Anemia Type N. Multiple reports have demonstrated an increased risk for cancer in individuals heterozygous for PALB2 mutations. For example, a recent study by Antoniou et al reported a 33-58% lifetime risk for breast cancer in PALB2 mutation carriers, with 30% of carriers reporting triple negative breast cancer (TNBC). Other studies have suggested associations between PALB2 heterozygosity and pancreatic cancer, ovarian cancer, male breast cancer, and prostate cancer as well. We aimed to better define PALB2 phenotypes by assessing clinical history of TNBC, pancreatic, ovarian, and prostate cancers amongst PALB2 mutation carriers identified via multigene panel testing. Methods: We reviewed clinical histories of 11,007 individuals who underwent PALB2 sequence and deletion/duplication analysis as part of a multigene hereditary cancer panel. Descriptive statistics were utilized for clinical histories of PALB2 carriers, and chi square analysis was used to compare clinical histories of PALB2 mutation carriers to mutation-negative controls. Individuals with mutations in other cancer susceptibility genes were excluded from analysis. Results: A total of 98 PALB2 mutation carriers identified among 9610 individuals were included in our analysis. The majority of mutation carriers were Caucasian (80%) and female (92.8%). All identified mutations were truncating (nonsense, frameshift, or gross deletions). No pathogenic missense mutations were identified in this cohort. 77.6% (n=76) of mutation carriers had breast cancer, diagnosed at a mean age of 48. Hormone receptor status was available for 48 mutation carriers and 2469 controls. 37.5% (18/48) of breast cancers in mutation carriers were reported as triple negative, compared to 17.1% (423/2469) of breast cancers in controls (OR: 2.9 ; p= 0.0002). 7.8% (n= 8) of PALB2 mutation carriers had ovarian cancer. There was no significant difference in the incidence of ovarian cancer between PALB2 mutation carriers and controls (OR: 0.65 ; p= 0.25). Additionally, mutation carriers were significantly less likely to have a family history of ovarian cancer than controls (OR: 0.5; p= 0.02). 5.9% (n=6) of mutation carriers had pancreatic cancer, diagnosed at a mean age of 57.8, compared to 61 for controls. PALB2 mutation carriers were 1.3 times more likely to have personal and/or family history of pancreatic cancer, although this was not statistically significant (p= 0.22). Similarly, PALB2 mutation carriers were 1.5 times more likely to have a family history of prostate cancer, although this was not statistically significant (p= 0.09). Conclusions: Our data supports existing literature associating PALB2 mutations with TNBC. We did not observe significant associations between PALB2 carrier status and a clinical history of pancreatic, prostate, or ovarian cancers. However, this data should be interpreted with caution, as it is possible that unidentified genetic factors contributed to the clinical history of cancer in our mutation-negative controls. Investigation of PALB2-associated cancer risks in an unselected prospective cohort would help to further elucidate the PALB2 phenotype. Citation Format: Emily K Dalton, Rachel McFarland, Holly Laduca, Shuwei Li, Chia-Ling Gau. Teasing out the PALB2 phenotype [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-12-16.

Oral contraceptives as a risk factor for developing breast cancer in breast cancer (BRCA) gene carrier female in-the 30–60 years age group: a meta analysis

The literature linking breast cancer with oral contraceptives and BRCA mutation as possible risk factors is equivocal. Hence, to account for these conflicting results in the existing literature and to observe the net effect, this meta-analysis aims to investigate whether oral contraceptives are a risk factor for developing breast cancer in breast cancer (BRCA) gene carrier female in the 30 -60 years age group. Method: Systematic review of the literature, both published and unpublished, and meta-analysis of relevant data. Results: Meta-analysis of data from five relevant studies, with a total of 6682 BRCA carrie rs (3,269 BRCA1 carriers and 791 BRCA2 carriers), revealed that use of oral contraceptives is associated with increased risk of breast cancer among BRCA mutation carriers (OR=2.267; 95 % CI= 1.311, 3.919). When the same risk was stratified by mutation type , both BRCA1 and BRCA2 were at increased risk. However, BRCA2 carriers (OR= 3.060; 95% CI=0.951, 9.848) were found to be at elevated risk compared to BRCA1 carriers (OR= 2.347; 95% CI=0.939, 5.865). Conclusions: This meta- analytical finding suggests that o ral contraceptives are a risk factor for developing breast cancer in breast cancer (BRCA) gene carrier females.

Breast-Cancer Risk in Families With Mutations in PALB2

Germline mutations in the BRCA1 and BRCA2 genes confer a marked increase in risk of breast cancer. Loss-of-function mutations have been identified in the PALB2 gene that also increase the risk of breast cancer. PALB2 interacts with BRCA1 and BRCA2 genes. In previous studies, the risk of breast cancer was estimated to be 2 to 4 times higher among carriers of PALB2 loss-of-function mutations as the risk among nonmutation carriers. Prior to the present study, the exact lifetime risk of breast cancer conferred by such mutations was unknown. The aim of this study was to obtain a robust estimate of the breast cancer risk associated with inherited loss-of-function mutations in PALB2. Data were collected for mutation carriers and their relatives from multiple centers worldwide. The risk of breast cancer was determined for 362 members from 154 families with PALB2 loss-of-function mutations A total of 311 women in these families had PALB2 mutations; 229 of these had breast cancer. The age-specific risk of breast cancer for mutation carriers was estimated using a modified segregation-analysis approach that allowed for the effects of inheritance patterns of disease and PALB2 genotype. Mutation carriers were divided into cohorts of women older than 60 years, between 40 and 60 years of age, and younger than 40 years. Compared with the general population, the risk of breast cancer for women who carried the PALB2 mutation was 8 to 9 times higher among those younger than 40 years, 6 to 8 times higher among those 40 to 60 years of age, and 5 times higher among those older than 60 years. The cumulative risk of breast cancer for female PALB2 mutation carriers was estimated to be 14% (95% confidence interval [CI], 9%–20%) by 50 years of age and 35% (95% CI, 26%–46%) by 70 years of age. Breast cancer risk among mutation carriers increased significantly as the birth cohort became more recent (P < 0.001); risk also was affected by other family factors (P = 0.04). By 70 years of age, the absolute risk of breast cancer for a woman who carried the PALB2 mutation ranged from 33% (95% CI, 25%–44%) if she had no family history of breast cancer to 58% (95% CI, 50%–66%) if she had a strong family history (≥2 first-degree relatives with breast cancer at 50 years of age). These data suggest that the level of breast cancer risk for a PALB2 mutation carrier, with or without a family history of breast cancer, is high. This level of risk may justify adding screening for PALB2 mutations to genetic testing panels used for BRCA1 and BRCA2.

Evaluation of chromosome 6p22 as a breast cancer risk modifier locus in a follow-up study of BRCA2 mutation carriers

Several common germline variants identified through genome-wide association studies of breast cancer risk in the general population have recently been shown to be associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. When combined, these variants can identify marked differences in the absolute risk of developing breast cancer for mutation carriers, suggesting that additional modifier loci may further enhance individual risk assessment for BRCA1 and BRCA2 mutation carriers. Recently, a common variant on 6p22 (rs9393597) was found to be associated with increased breast cancer risk for BRCA2 mutation carriers [hazard ratio (HR)=1.55, 95% confidence interval (CI) 1.25-1.92, p=6.0×10(-5)]. This observation was based on data from GWAS studies in which, despite statistical correction for multiple comparisons, the possibility of false discovery remains a concern. Here, we report on an analysis of this variant in an additional 6,165 BRCA1 and 3,900 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). In this replication analysis, rs9393597 was not associated with breast cancer risk for BRCA2 mutation carriers (HR=1.09, 95% CI 0.96-1.24, p=0.18). No association with ovarian cancer risk for BRCA1 or BRCA2 mutation carriers or with breast cancer risk for BRCA1 mutation carriers was observed. This follow-up study suggests that, contrary to our initial report, this variant is not associated with breast cancer risk among individuals with germline BRCA2 mutations.

Earlier age of onset of BRCA mutation‐related cancers in subsequent generations

Women who are diagnosed with a deleterious mutation in either breast cancer (BRCA) gene have a high risk of developing breast and ovarian cancers at young ages. In this study, the authors assessed age at diagnosis in 2 generations of families with known mutations to investigate for earlier onset in subsequent generations. Of the 132 BRCA-positive women with breast cancer who participated in a high-risk protocol at The University of Texas MD Anderson Cancer Center (Gen 2), 106 women could be paired with a family member in the previous generation (Gen 1) who was diagnosed with a BRCA-related cancer (either breast cancer or ovarian cancer). Age at diagnosis, location of the mutation, and year of birth were recorded. A previously published parametric anticipation model was applied in these genetically predisposed families. The median age of cancer diagnosis was 42 years (range, 28-55 years) in Gen 2 and 48 years (range, 30-72 years) in Gen 1 (P < .001). [corrected]. In the parametric model, the estimated change in the expected age at onset for the entire cohort was 7.9 years (P < .0001). Statistically significant earlier ages at diagnosis also were observed within subgroups of BRCA1 and BRCA2 mutations, maternal inheritance, paternal inheritance, breast cancer only, and breast cancer-identified and ovarian cancer-identified families. Breast and ovarian cancers in BRCA mutation carriers appeared to be diagnosed at an earlier age in later generations. The authors concluded that patients who are younger at the onset of BRCA-related cancers should continue to be tracked to offer appropriate screening modalities at appropriate ages.

Abstract P3-08-03: Defects in BRCA1 Contribute to Global Differential Allele-Specific Expression

Abstract Differential allele-specific expression (DASE) has been shown to contribute to phenotypic variability in humans and more recently to the pathogenesis of cancer. DASE is associated with X-chromosome inactivation and genomic imprinting and is relatively common among non-imprinted autosomal genes. The DASE phenotype can also be transmitted by Mendelian inheritance. We have previously reported that nonsense-mediated mRNA decay (NMD) of mutant BRCA1 as well as other epigenetic mechanisms can lead to DASE of BRCA1 and enhanced susceptibility to breast cancer. BRCA1 has been implicated in many cellular processes including DNA repair, cell-cycle-checkpoint control, protein ubiquitination, and chromatin remodeling. Importantly, cells carrying a deleterious BRCA1 mutation exhibit increased genome instability, therefore, we hypothesize that defects in BRCA1 lead not only to DASE of itself, but increase genome-wide DASE and thus contribute to increased breast cancer susceptibility. To test this hypothesis, we employed a genome-wide ASE assay (Illumina Human Omni1-Quad BeadChip) using primary mammary epithelial cells [3 BRCA1 wild-type vs. 3 BRCA1 mutant carrying (2800delAA, 4154delA and R1751X)]. As shown in Table 1, cells carrying a BRCA1 mutation had significantly more DASE events as compared to wild-type cell (P&amp;lt;10-7). In addition, we identified 351 genes demonstrating DASE that were unique to the BRCA1 mutant cells. The cellular functions of these genes are wideranging, including DNA repair, cell cycle control, lipid metabolism and protein degradation. In summary, this study provides the first evidence that mutant BRCA1 can lead to global DASE, which in turn may contribute to the development of breast cancer in mutation carriers. This work was supported in part by the Eileen Stein-Jacoby Fund and a grant from the Congressionally Directed Medical Research Programs, Department of Defense, W81XWH-08-1-0361 (XC). Table 1. BRCA1 mutations increase the global DASE in PMECs t; A DASE event is defined as that the Log-ratio of allele-specific expression level of one gene is more than 1 or less than -1, i.e. the expression level from one allele is at least 50% less than the level of another allele Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-08-03.

Population-Based Study of the Risk of Second Primary Contralateral Breast Cancer Associated With Carrying a Mutation inBRCA1orBRCA2

Women with breast cancer diagnosed early in life comprise a substantial portion of those tested for BRCA1/BRCA2 mutations; however, little information is available on the subsequent risks of contralateral breast cancer in mutation carriers. This study assessed the risk of subsequent contralateral breast cancer associated with carrying a BRCA1 or BRCA2 mutation. In this nested case-control study, patients with contralateral breast cancer diagnosed 1 year or more after a first primary breast cancer (n = 705) and controls with unilateral breast cancer (n = 1,398) were ascertained from an underlying population-based cohort of 52,536 women diagnosed with a first invasive breast cancer before age 55 years. Interviews and medical record reviews were used to collect risk factor and treatment histories. All women were tested for BRCA1/BRCA2 mutations. Relative (rate ratios) and absolute (5- and 10-year cumulative) risks of developing contralateral breast cancer following a first invasive breast cancer were computed. Compared with noncarriers, BRCA1 and BRCA2 mutation carriers had 4.5-fold (95% CI, 2.8- to 7.1-fold) and 3.4-fold (95% CI, 2.0- to 5.8-fold) increased risks of contralateral breast cancer, respectively. The relative risk of contralateral breast cancer for BRCA1 mutation carriers increased as age of first diagnosis decreased. Age-specific cumulative risks are provided for clinical guidance. The risks of subsequent contralateral breast cancer are substantial for women who carry a BRCA1/BRCA2 mutation. These findings have important clinical relevance regarding the assessment of BRCA1/BRCA2 status in patients with breast cancer and the counseling and clinical management of patients found to carry a mutation.

Evaluation of established breast cancer risk factors as modifiers of BRCA1 or BRCA2: a multi-center case-only analysis

The incomplete penetrance of mutations in BRCA1 and BRCA2 suggests that some combination of environmental and genetic factors modifies the risk of breast cancer in mutation carriers. This study sought to identify possible interactions between established breast cancer risk factors and BRCA1 or BRCA2 mutations using a case-only study design. Breast cancer cases that had been tested for BRCA1 and BRCA2 mutations were identified from 11 collaborating centers. Comparisons of reproductive and lifestyle risk factors were made between women with breast cancer who were positive for BRCA1 mutations (n = 283), BRCA2 mutations (n = 204), or negative for both BRCA1 and BRCA2 mutations (n = 894). Interaction risk ratios (IRRs) were calculated using multinominal logistic regression models. Compared with non-carriers, statistically significant IRRs were observed for later age at menarche among BRCA2 mutation carriers, for a greater number of pregnancies among both BRCA1 and BRCA2 mutation carriers, and for alcohol use among BRCA1 mutation carriers. Our data suggest that the risk for breast cancer among BRCA1 or BRCA2 carriers may be modified by reproductive characteristics and alcohol use. However, our results should be interpreted cautiously given the overall inconsistency in the epidemiologic literature on modifiers of BRCA1 and BRCA2.

BRCA in breast cancer: ESMO Clinical Recommendations

Familial susceptibility to breast cancer accounts for ∼25% of all breast cancer cases. In familial breast cancer, mutations in the BRCA1, BRCA2, CHEK2, TP53 and PTEN genes account for ∼5–10% of breast and ovarian cancer cases overall. The prevalence of BRCA1 or BRCA2 mutations varies considerably between ethnic groups and geographical areas. Population-specific mutations have been described in Iceland, the Netherlands, Sweden, Norway, Germany, France, Spain, countries of central and eastern Europe and among Ashkenazi Jews. The prevalence of BRCA mutation carriers in the general population is estimated at between 1/800 and 1/1000. BRCA1 and BRCA2 mutation frequencies in breast and ovarian cancer patients unselected for family history or age at onset are generally low (<1–7% for BRCA1 and 1–3% for BRCA2). Higher prevalence is associated with a family history of breast or ovarian cancer, young age at onset, male breast cancer or multiple tumors (bilateral breast cancer or breast and ovarian cancer in the same patient). Women with an inherited BRCA1 mutation have a lifetime risk of 65–80% of developing breast cancer and 37–62% of developing ovarian cancer, while BRCA2 mutation carriers have a lifetime risk of 45–85% for breast cancer and 11–23% for ovarian cancer. There is an increased risk of prostate cancer among BRCA carriers (5–25%) and breast cancer among males with BRCA2 mutations (6%). Other cancers at increased risk are pancreatic (up to 2%), stomach, and head and neck. Genetic testing criteria may differ between countries based on mutation prevalence. Widely accepted criteria for referral include: three or more breast and/or ovarian cancer cases, at least one aged <50 years; two breast cancer cases aged <40 years; male breast cancer and early onset female breast cancer; and breast and ovarian cancer in the same patient [IV, C]. In some countries, the criterion for testing is that there should be at least a 10–20% probability of finding a mutation. In all cases, genetic testing should be performed after genetic counseling and informed consent. Most clinically deleterious mutations are protein-truncating mutations and a small number are missense mutations. Genetic testing should include complete sequencing of coding regions, either directly or after a screening method. Since 2–12% of high-risk families may harbor a large genomic alteration, specific techniques to detect duplications or deletions of one or more exons may be indicated [III, B]. Surveillance of breast cancer in BRCA carriers includes monthly self-examinations, clinical breast examinations once or twice a year and yearly mammograms and magnetic resonance imaging (MRI) of breasts starting at age 25–30 [IIa, B]. There are yet no data available to determine whether alternating mammogram and MRI every 6 months or having both once yearly is more effective at young ages, considering the high rate of interval cancers. Adjuvant tamoxifen reduces the risk of contralateral breast cancer in affected BRCA mutation carriers [III, B], while the benefit of tamoxifen for primary prevention of breast cancer has not been demonstrated [III,B]. It is the most effective strategy available for risk reduction of breast cancer in mutation carriers [III, B], although no benefit in survival has been demonstrated and many women do not find this strategy acceptable for cosmetic reasons. Contralateral prophylactic mastectomy is an option to consider in those BRCA mutation carriers with early breast cancer and unilateral mastectomy [IV, C]. It is associated with a risk reduction of breast cancer in premenopausal BRCA mutation carriers, risk reduction of ovarian cancer and there is evidence of reduction in overall mortality. Bilateral salpingo-oophorectomy is recommended after age 35 and when childbearing decisions are complete [IIa, B]. Short-term hormonal replacement therapy after bilateral salpingo-oophorectomy seems not to decrease the overall benefit of this strategy for breast cancer risk reduction [III, B]. Decisions about surgical treatment of breast cancer in BRCA mutation carriers should be based on the same parameters as sporadic cancer, while considering the higher risk of contralateral breast cancer [III, B]. Standard prognostic features should be used to decide adjuvant treatment in BRCA mutation carriers with breast cancer. Ongoing clinical trials in the metastatic setting are testing the sensitivity to platinum-based chemotherapy of BRCA tumors and the specific DNA-repair deficiency with the use of PARP inhibitors. Levels of evidence [I–V] and grades of recommendation [A–D] as used by the American Society of Clinical Oncology are given in square brackets. Statements without grading were considered justified standard clinical practice by the experts and the ESMO Faculty.

S10 Chemoprevention of breast cancer for mutation carriers and other high risk women

S10 Chemoprevention of breast cancer for mutation carriers and other high risk women

Spontaneous and therapeutic abortions and the risk of breast cancer among BRCAmutation carriers

IntroductionBRCA1 and BRCA2 mutation carriers are at increased risk for developing both breast and ovarian cancer. It has been suggested that carriers of BRCA1/2 mutations may also be at increased risk of having recurrent (three or more) miscarriages. Several reproductive factors have been shown to influence the risk of breast cancer in mutation carriers, but the effects of spontaneous and therapeutic abortions on the risk of hereditary breast cancer risk have not been well studied to date.MethodsIn a matched case-control study, the frequencies of spontaneous abortions were compared among 1,878 BRCA1 mutation carriers, 950 BRCA2 mutation carriers and 657 related non-carrier controls. The rates of spontaneous and therapeutic abortions were compared for carriers with and without breast cancer.ResultsThere was no difference in the rate of spontaneous abortions between carriers of BRCA1 or BRCA2 mutations and non-carriers. The number of spontaneous abortions was not associated with breast cancer risk among BRCA1 or BRCA2 mutation carriers. However, BRCA2 carriers who had two or more therapeutic abortions faced a 64% decrease in the risk of breast cancer (odds ratio = 0.36; 95% confidence interval 0.16–0.83; p = 0.02).ConclusionCarrying a BRCA1 or BRCA2 mutation is not a risk factor for spontaneous abortions and spontaneous abortions do not appear to influence the risk of breast cancer in carriers of BRCA1 or BRCA2 mutations. However, having two or more therapeutic abortions may be associated with a lowered risk of breast cancer among BRCA2 carriers.

Update on hereditary breast cancer

Women with BRCA1 or BRCA2 mutations are at substantial risk for breast and ovarian cancer. This review describes recent developments in the approach to hereditary breast cancer. Risk-reducing surgeries remain the most effective means of preventing breast cancer in mutation carriers. For women with breast tissue at risk, magnetic resonance imaging is rapidly becoming incorporated into screening programs. For affected women, management does not currently differ from that of women with sporadic breast cancer, although women may choose to undergo bilateral mastectomy. Preclinical data suggest that BRCA mutation-associated breast cancers may benefit from specific targeted therapeutic approaches.

Risk of breast cancer recurrence and contralateral breast cancer in relation to BRCA1 and BRCA2 mutation status following breast-conserving surgery and radiotherapy

BRCA1 and BRCA2 germline mutations are associated with a strong risk of breast cancer, which may preclude breast-conserving treatment in carriers. This study examined whether mutation status influenced the rate of breast cancer recurrence following breast-conserving treatment. BRCA1 and BRCA2 genes were screened for germline mutations in 131 patients with a family history of breast and/or ovarian cancer, who had been treated with breast-conserving surgery and radiotherapy. The 131 patients with familial history were matched to 261 patients without, according to age at diagnosis and year of treatment. The follow-up of controls was at least equal to the time-interval between diagnosis and genetic testing in familial cases. Matched cohorts were compared according to rates of breast cancer recurrence as first event and contralateral breast cancer using log-rank tests. BRCA1/2 mutations were found in 20.6% patients with a family history. Nineteen patients had a BRCA1 mutation and 8 had a BRCA2 mutation. Breast cancers in mutation carriers were more often grade III ( p < 10-4) and oestrogen receptor negative ( p = 0.005) than tumours in both non-carriers and controls. Median follow-up for all 392 patients was 8.75 years. No significant differences in breast cancer recurrence as first event were seen between BRCA1/2 tumours and controls ( p = 0.47), carriers and non-carriers with a family history ( p = 0.96), or non-carriers and controls ( p = 0.10). On multivariate analysis, age was the most important factor significantly predicting for breast cancer recurrence. The rate of contralateral breast cancer was significantly increased in all patients with a family history: BRCA1/2 carriers versus controls ( p = 0.0003), non-carriers versus controls ( p = 0.0034) and carriers versus non-carriers ( p = 0.02). At a 9-year median follow-up, the rate of ipsilateral breast cancer recurrence was not higher in BRCA1 and BRCA2 mutation carriers than in non-carriers with a family history or sporadic cases. These results support the hypothesis that breast tumours in BRCA carriers are more sensitive to radiation. Therefore, breast-conserving treatment can be offered to these patients. However, longer follow-up is needed to ensure that the rate of new primary cancer in the treated breast does not increase in the long-term.