An exploratory study to determine if BRCA1 and BRCA2 mutation carriers have higher risk of cardiac toxicity.

1585 Background: Anthracycline related cardiac toxicity (CT) is a concern in treating women with breast cancer. The prevalence of heart failure (HF) affects 2% of the population, less so in women. Patients receiving anthracycline based therapy (ABT) have a dose-dependent risk of reduction in ejection fraction. Recent work by Dr. Verma suggests that BRCA-deficient mice manifest increased levels of cardiac failure. We sought to explore the risk for CT and evaluate the association between ABT and HF in female BRCA mutation carriers. Methods: An online survey was developed to collect information about breast cancer treatment (including HF) in BRCA mutation carriers through the national BRCA patient advocacy organization FORCE via their 2011 conference and their website as well as the Moffitt-based Inherited Cancer Registry (ICARE). The prevalence of CT and HF was calculated in both BRCA 1 and 2 breast cancer patients and compared to general population risks. Data from those that received ABT was compared to published HF rates from ABT. Results: Our sample included 227 BRCA1 carriers and 164 BRCA2 carriers in whom 6.4% reported cardiac toxicity (i.e., either HF and/or CT). This included similar proportions in BRCA1 vs BRCA2 carriers (i.e., 6.6% and 6.1%, respectively). These proportions are significantly higher than the published rate of 2% (all p-values < 0.001). Specifically regarding ABT, 112 mutation carriers had doxorubicin (Adriamycin) for treatment of whom 8% reported HF, similar to the 11 who had Epirubicin (11 patients), of whom 9% reported HF. Conclusions: Our data suggests that BRCA mutation carriers may have an increased risk of CT compared to the general population. In particular, women with BRCA mutations treated with ABT also appear to have a higher risk of developing CT and/or HF. This exploratory study provides the basis upon which larger retrospective and prospective studies are currently being planned. The high percentage of CT observed in this study requires confirmation as they could inform recommendation for cardiac screening and review of the current standard for ABT use in this population.

Download Full-text

Increased risk of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers after breast-conserving therapy compared to mastectomy

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.1512 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 1512-1512

Author(s):

R. K. Schmutzler ◽

M. K. Graeser ◽

K. Rhiem ◽

B. Schlehe ◽

W. Hofmann ◽

...

Keyword(s):

Breast Cancer ◽

Contralateral Breast Cancer ◽

Brca Mutation ◽

Brca2 Mutation ◽

Breast Conserving Therapy ◽

Contralateral Breast ◽

Cox Regression Analysis ◽

Mutation Carriers ◽

Increased Risk ◽

Brca Mutation Carriers

1512 Background: BRCA mutation carriers affected by breast cancer face an elevated risk of contralateral breast cancer (clBrCa). We here aimed at estimating the influence of breast conserving therapy (BCT) versus mastectomy (MXT) on the rik of clBrCa. Methods: We conducted a retrospective cohort study in 3810 index patients (pts) collected within the CHBOC. Deleterious BRCA1 or BRCA2 mutations were detected in 921 pts and medical records were obtained from 532 pts (344 BRCA1, 184 BRCA2 mutation carriers, 4 both) of whom 261 (49%) underwent BCT and 271 (51%) MXT. Pts were followed from the initial diagnosis of breast cancer until clBrCa or censored at time of prophylactic contralateral mastectomy, oophorectomy, death, or date of last visit. Median age at first diagnosis was 39.9 years (range 17.5 to 79.0) and median follow up 48.84 months (3413 person years). The hazard ratio (HR) was estimated using multivariate Cox regression analysis adjusting for conduct of radiotherapy, age at first breast cancer, and affected BRCA gene. Results: In the univariate analysis the risk of clBrCa was 12.2% (95% CI 7.6 to 16.8) at 5 years and 24.9% (95% CI 18.0 to 31.9) at 10 years for pts treated with MXT and 25.9% (95% CI 18.8 to 33.1) at 5 years and 45.7% (95% CI 35.0 to 56.5) at 10 years for pts treated with BCT. In the multivariate analysis, the HR was 1.8 for BCT versus MXT (95% CI 1.2 to 2.7). Neither age at diagnosis of the first primary nor BRCA mutation status were significantly predictive. A subgroup analysis comparing BCT plus radiotherapy with MXT minus radiotherapy revealed a HR of 1.6 (95% CI 1.02 to 2.56) for the BCT group. Conclusions: We report for the first time a 1.8-fold increased risk of clBrCa in BRCA mutation carriers undergoing BCT versus MXT. Scattered radiation is the most probable causation. Although results from further studies such as the WECARE study should be awaited, our results provide evidence that recommendations for primary brCa treatment of BRCA mutation carriers must to be reconsidered. No significant financial relationships to disclose.

Download Full-text

Aromatase Inhibitors and Contralateral Breast Cancer in BRCA Mutation Carriers: A long-term Follow-up

10.21203/rs.3.rs-1158051/v1 ◽

2021 ◽

Author(s):

Maryam Nemati Shafaee ◽

Kristina Goutsouliak ◽

Heather Lin ◽

Therese B Bevers ◽

Angelica Gutierrez-Barrera ◽

...

Keyword(s):

Breast Cancer ◽

Aromatase Inhibitors ◽

Prophylactic Mastectomy ◽

Brca Mutation ◽

Brca1 Mutation ◽

Brca2 Mutation ◽

Mutation Status ◽

Mutation Carriers ◽

Brca Mutation Carriers

Abstract Background: Deleterious BRCA mutations confer a significant lifetime risk of breast cancer (BC) as well as contralateral BC (CBC) in patients who do not undergo prophylactic mastectomy. Prior reports have suggested that tamoxifen reduces the risk of CBC in BRCA mutation carriers. Whether aromatase inhibitors (AI) have the same effect is unknown. Methods: This is a retrospective review of patients diagnosed with non-metastatic ER+ BC between 2004-2014 with known BRCA mutation status. Patients were followed from primary diagnosis until CBC diagnosis or death. Median follow up was 11.5 years. Risk of CBC was evaluated as time to event. Results: 935 subjects were included in this analysis, with 53 BRCA1 mutation carriers, and 94 BRCA2 mutation carriers. Median age at diagnosis was 42.7 years. Seventy-two percent (676) received tamoxifen and 43% (405) received AI. A total of 66 CBCs occurred, of which 10% (15/147) occurred in BRCA mutation carriers vs %6.5 (51/788) in BRCA wild type. Multivariate analyses indicated that BRCA status and AI use were significantly associated with CBC risk. AI use resulted in a significant reduction in risk of CBC (HR 0.44, p=0.004) regardless of the BRCA mutation status. Tamoxifen use was not associated with reduced risk of CBC. Conclusions: This is the first report showing that AIs reduce the risk of CBC in BRCA mutation carriers. The potential role of AIs as chemoprevention should be validated in larger independent cohorts.

Download Full-text

Update on chemoprevention in BRCA1 and BRCA2 mutation carriers

Breast Cancer Online ◽

10.1017/s1470903105002890 ◽

2005 ◽

Vol 8 (9) ◽

Author(s):

M. Stumacher ◽

S. M. Domchek

Keyword(s):

Breast Cancer ◽

Prophylactic Mastectomy ◽

Brca Mutation ◽

Brca2 Mutation ◽

Breast Cancers ◽

Brca1 And Brca2 ◽

Prophylactic Oophorectomy ◽

Estrogen Exposure ◽

Mutation Carriers ◽

Increased Risk

Chemoprevention with tamoxifen and oophorectomy are thought to be effective in decreasing the incidence of breast cancer in women at increased risk for the disease. There is mounting data supporting the idea that hormonal interventions that reduce estrogen exposure to breast epithelium, such as prophylactic oophorectomy and tamoxifen, are effective in breast cancer prevention in both BRCA1 and BRCA2 mutations carriers. Several recent studies directly address the protective effect of tamoxifen and oophorectomy in BRCA mutation carriers and suggest that these endocrine manipulations decrease the risk of primary and secondary breast cancers. Ongoing studies aim to better define the effect of tamoxifen in these very high-risk women and determining whether factors, such as earlier age of use or prior prophylactic oophorectomy, impact tamoxifen's effect. Based on existing data, we recommend that women with deleterious mutations in BRCA1 or BRCA2 be informed of the beneficial effect of oophorectomy on breast cancer risk and that women who choose breast cancer screening instead of prophylactic mastectomy be offered tamoxifen as a prevention option.

Download Full-text

Risk-reducing salpingo-oophorectomy and breast cancer incidence among BRCA-mutation carriers.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.10548 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 10548-10548

Author(s):

Tamar Perri ◽

Shani Naor-Ravel ◽

Perry Eliassi-Revivo ◽

Dror Lifshitz ◽

Eitan Friedman ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Incidence ◽

Brca Mutation ◽

Brca2 Mutation ◽

Breast Cancer Incidence ◽

Mutation Carriers ◽

Age At Surgery ◽

Significant Difference ◽

Brca Mutation Carriers ◽

Risk Reducing

10548 Background: Uncertainty exists with regard to the role of bilateral salpingo-oophorectomy in altering the risk of breast cancer in BRCA-mutation carriers. Methods: Included were 1645 healthy Jewish Israeli BRCA1/2 -mutation carriers from a single center without prophylactic mastectomy. Carriers with and without risk-reducing bilateral salpingo-oophorectomy (RRBSO) were matched according to BRCA-mutation type (BRCA1 vs. BRCA2) and year of birth (±1 year). Hormonal and reproductive variables were compared and incidence of breast cancer recorded. Association between RRBSO and breast cancer was studied. Results: Seventy-seven and 50 matched-pairs had BRCA1 and BRCA2 mutation respectively. Fifty-two carriers had breast cancer, 21 in RRBSO-group and 31 in no- RRBSO group, with no statistically significant difference. When analysing each mutation group separately, stratified by age at surgery, no association between RRBSO and breast cancer incidence was found among BRCA1-mutation carriers. However, in BRCA2 mutation carriers, RRBSO was associated with a statistically significant decreased overall incidence of breast cancer, HR = 0.2 (confidence interval 0.44-0.913, p = 0.038). Breast cancer incidence was lower after 5, 10,15 and 20 years in BRCA2-mutation carriers with RRBSO compared to no-RRBSO. Age at menarche, age at surgery, parity and oral contraceptive use were not significant risk factors for breast cancer. Hormone replacement therapy was used by 62 mutation carriers, 52 in the RRBSO group and 10 in the no-RRBSO group, and its use did not alter breast cancer risk (p = 0.463). Conclusions: According to our findings, RRBSO is associated with a reduced risk of breast cancer only in BRCA2 mutation carriers, regardless of HRT use.

Download Full-text

Is mammography adequate for screening BRCA mutation carriers with low breast density?

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.10014 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 10014-10014 ◽

Cited By ~ 1

Author(s):

R. Bigenwald ◽

E. Warner ◽

A. Gunasekara ◽

K. Hill ◽

P. Causer ◽

...

Keyword(s):

Breast Cancer ◽

Breast Density ◽

Brca Mutation ◽

Brca1 Mutation ◽

Brca2 Mutation ◽

Brca1 And Brca2 ◽

Younger Women ◽

Mutation Carriers ◽

Brca Mutation Carriers

10014 Background: Several large observational studies have demonstrated that magnetic resonance imaging (MRI) is much more sensitive than M (sensitivity 71–96% vs. 28–43%) for screening women > age 25 at high risk for hereditary breast cancer. However, MRI is much more costly and less specific than M. The extent to which the low sensitivity of M in these studies is due to the greater average breast density of younger women is unknown. Accordingly, we sought to determine the sensitivity of M and MRI according to breast density for the detection of breast cancer in a screening study of BRCA mutation carriers. Methods: Breast density was measured on the screening mammogram of the contralateral breast for all women who developed in-situ or invasive breast cancer on study. Density was measured in 2 ways: qualitatively according to the four categories characterized by the BIRADS system: 1) mostly fatty, 2) scattered fibroglandular tissue, 3) heterogeneously dense, 4) extremely dense; and semi-quantitatively using computer-aided techniques with subsequent classification as: A) ≤10%, B) 11–25%, C) 26%-50%, or D) >50% density. Results: Between 11/97 and 06/05 a total of 39 cases (12 in-situ and 27 invasive) were found in 36 mutation carriers (19 BRCA1 and 17 BRCA2). Mean age of the women with cancer was 48 (range 34 to 64). Average semi-quantitative breast density for BRCA1 mutation carriers was 28% and for BRCA2 was 27%. Sensitivity of M vs. MRI for in-situ cases was 25% vs. 83%, and for invasive cases was 30% vs. 93%. Sensitivities for BRCA1 and BRCA2 mutation carriers were similar. For BIRADS 1 to 4 respectively M detected 1/3 (33%), 5/11 (45%), 4/22 (18%), and 1/3 (33%) of cases; and for density groups A to D respectively detected 2/6 (33%), 7/15 (47%), 1/11 (9%) and, 1/7 (14%). Conclusion: Although there was a trend towards decreasing mammographic sensitivity with increasing density, even among BRCA mutation carriers with low breast density mammography is an inadequate screening tool. No significant financial relationships to disclose.

Download Full-text

Detecting prostate cancer in BRCA1 and BRCA2 mutation carriers: A role for EN2?

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.4653 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 4653-4653

Author(s):

Emma Killick ◽

Richard Morgan ◽

Francesca Launchbury ◽

Nicola E. Annels ◽

Elizabeth Bancroft ◽

...

Keyword(s):

Prostate Cancer ◽

Risk Group ◽

Brca Mutation ◽

Brca2 Mutation ◽

Digital Rectal Examination ◽

Brca1 And Brca2 ◽

Mutation Carriers ◽

Increased Risk ◽

Brca Mutation Carriers ◽

The Impact

4653 Background: EN2 is part of the HOX gene family and plays a role in foetal development. More recently a potential oncogenic role for the protein has been postulated and its utility as a cancer biomarker has been explored in prostate cancer (PrCa) and breast cancer. Carriers of mutations in the BRCA1 and BRCA2 genes have an increased risk of PrCa (1.8-fold and 5-fold respectively) and their tumours tend to be more aggressive and advanced than sporadic cases. Currently there is no national screening program for BRCA mutation carriers in the UK, and the IMPACT study was set up to evaluate PSA screening in this particular group. Here we analyse the efficacy of the urinary EN2 protein as a marker of early cancer detection within this higher risk group. Methods: First pass urine (without preceding digital rectal examination) was collected as part of the IMPACT screening study which enrolled individuals aged between 40 and 69 who were unaffected by PrCa at time of enrolment into the study (n= 418). All participants were from families harbouring a BRCA1 or BRCA2 mutation and were either BRCA mutation carriers themselves or controls with a negative predictive BRCA genetic test. They underwent annual PSA test with a PSA of > 3.0 ng/ml triggering a diagnostic biopsy. EN2 protein was measured in the urine using an ELISA; (positive = > 42.5ng/ml). Results: Our initial results demonstrated urinary EN2 had a sensitivity of 66.67% and a specificity of 89.29% when discriminating which men had been diagnosed with PrCa; the ROC AUC was 0.816. The difference in EN2 level between those diagnosed with cancer and those who were not was significant (p = <0.001). There was trend towards higher EN2 levels in those with more aggressive tumours (median EN2 84.5ng/mL in Gleason ≤3+4 vs 111ng/mL in Gleason ≥4+3), however this was not statistically significant. In one PrCa case EN2 rise preceded PSA rise by 2 years. Further samples are in the process of being analysed, results from these will be included. Conclusions: Urinary EN2 protein measurement warrants further investigation as a PrCa biomarker in this higher risk group with genetic predisposition to PrCa.

Download Full-text

A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

Nature Communications ◽

10.1038/s41467-020-20496-3 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Juliette Coignard ◽

◽

Michael Lush ◽

Jonathan Beesley ◽

Tracy A. O’Mara ◽

...

Keyword(s):

Breast Cancer ◽

General Population ◽

Genome Wide Association Study ◽

Brca2 Mutation ◽

Risk Scores ◽

Genetic Modifiers ◽

Mutation Carriers ◽

Genotype Frequencies ◽

Genome Wide ◽

Brca1 Brca2

AbstractBreast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10−8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers.

Download Full-text