BRCA1 Mutation Carriers Research Articles

ASO Author Reflections: Prophylactic Nipple-Sparing Mastectomy as an Effective Risk-Reducing Strategy for BRCA Mutation Carriers.

ASO Author Reflections: Prophylactic Nipple-Sparing Mastectomy as an Effective Risk-Reducing Strategy for BRCA Mutation Carriers.

Identification of BRCA2 Cis Double Heterozygous Breast Cancer Cases Using Whole Exome Sequencing: Phenotypic Expression and Impact on Personalized Oncology.

BRCA1 and BRCA2 are the most commonly mutated breast cancer susceptibility genes that convey a high risk of breast and ovarian cancer. Most BRCA1 or BRCA2 mutation carriers have inherited a single heterozygous mutation. In recent years, very rare cases with biallelic or trans double heterozygous mutations on BRCA1 and or BRCA2 have been identified and seem to be associated with distinctive phenotypes. Given that this genotype-phenotype correlation in cancer predisposing hereditary conditions is of relevance for oncological prevention and genetic testing, it is important to investigate these rare BRCA genotypes for better clinical management of BRCA mutation carriers. Here we present the first report on Cis double heterozygosity (Cis DH) on BRCA2 gene identified using Whole exome sequencing (WES) in a Tunisian family with two BRCA2 mutations namely: c.632-1G>A and c.1310_1313DelAAGA that are both reported as pathogenic in ClinVar database. Subsequent analysis in 300 high-risk Tunisian breast cancer families detected this Cis double heterozygous genotype in 8 additional individuals belonging to 5 families from the same geographic origin suggesting a founder effect. Moreover, the observed Cis DH seems to be associated with an early age of onset (mean age = 35.33 years) and severe phenotype of the disease with high breast cancer grade and multiple cancer cases in the family. The identification of unusual BRCA genotypes in this Tunisian cohort highlights the importance of performing genetic studies in under-investigated populations. This will also potentially help avoiding erroneous classifications of genetic variants in African population and therefore avoiding clinical misdiagnosis of BRCA related cancers. Our findings will also have an impact on the genetic testing and the clinical management of North African breast cancer patients as well as patients from different other ethnic groups in regard to several emerging target therapies such as PARP inhibitors.

ASO Visual Abstract: How Protective are Nipple-Sparing Prophylactic Mastectomies in BRCA1 and BRCA2 Mutation Carriers?

ASO Visual Abstract: How Protective are Nipple-Sparing Prophylactic Mastectomies in BRCA1 and BRCA2 Mutation Carriers?

OTHR-03. Brain Metastasis Among Ovarian Cancer Patients

BackgroundBrain metastasis (BM) are uncommon among ovarian cancer (OC) patients. Their frequency, risk factors and clinical repercussions are not well described. We assessed OC patients who developed BM, the role of BRCA status and survival implications.MethodsStudy cohort included OC patients treated at our center, from 2002–2020. We retrospectively evaluated clinical parameters, risk for BM development and association with survival data.ResultsAmong 972 OC patients, 28 (2.9%) were diagnosed with BM. Comparing the BM to non-BM group, median age of 60 across both groups, stage III-IV at diagnosis was more common among BM group (96.4% vs. 84.8%, p=0.0065) while platinum sensitivity was similar (92.3% in BM vs. 80.8% in non-BM, p=0.2193). Out of 658 patients tested for BRCA, 33.6% (n=221) were BRCA mutation carriers (BRCA+). Of the patients with BM, 22 tested for BRCA, 13 were carriers. BRCA+ was significantly higher in the BM group compared to the non-BM group (59.1% vs. 32.9%, p=0.0123). Among BRCA+ the rate of BM was higher than among BRCA- (5.8% vs. 2.1%, p=0.0123, HR=3.029; 95%CI: 1.4–6.5). Median time from OC diagnosis to BM and from disease recurrence to BM, was longer for BRCA+ compared to BRCA- (44.3mo vs. 32.3mo and 11.8mo vs. 0.7mo, respectively). Median survival (mOS) was not significantly different among patients with BM compared to those without BM (59.4mo vs. 71.2mo, p=0.36). Following diagnosis of BM, mOS was 20.6mo among BRCA+ and 12.3mo among BRCA- (p=0.4266). No correlation was demonstrated with PARP inhibitors or bevacizumab treatment and subsequent development of BM.ConclusionBM are an infrequent event among OC patients. However, the risk is three-folds higher among BRCA+. Interestingly, BM do not significantly alter survival among OC patients. Our work suggests that the higher rate of BM in BRCA+ may be related to longer survival. Another hypothesis requiring further evaluation, is possible higher brain tropism among this population.

Bilateral Salpingo-oophorectomy and Breast Cancer Risk for BRCA1 and BRCA2 Mutation Carriers: Assessing the Evidence.

Without preventive interventions, women with germline pathogenic variants in BRCA1 or BRCA2 have high lifetime risks for breast cancer and tubo-ovarian cancer. The increased risk for breast cancer starts at a considerably younger age than that for tubo-ovarian cancer. Risk-reducing bilateral salpingo-oophorectomy (rrBSO) is effective in reducing tubo-ovarian cancer risk for BRCA1 and BRCA2 mutation carriers, but whether it reduces breast cancer risk is less clear. All studies of rrBSO and breast cancer risk are observational in nature and subject to various forms of bias and confounding, thus limiting conclusions that can be drawn about causation. Early studies supported a statistically significant protective association for rrBSO on breast cancer risk, which is reflected by several international guidelines that recommend consideration of premenopausal rrBSO for breast cancer risk reduction. However, these historical studies were hampered by the presence of several important biases, including immortal person-time bias, confounding by indication, informative censoring, and confounding by other risk factors, which may have led to overestimation of any protective benefit. Contemporary studies, specifically designed to reduce some of these biases, have yielded contradictory results. Taken together, there is no clear and consistent evidence for a role of premenopausal rrBSO in reducing breast cancer risk in BRCA1 or BRCA2 mutation carriers.

Bilateral Prophylactic Nipple-Sparing Mastectomy: Analysis of the Risk-Reducing Effect in BRCA1/2 Mutation Carriers.

Mutations in the BRCA1 or BRCA2 genes increase the lifetime risk of developing breast cancer to 68-72% by the age of 80. One of the modalities to manage the risk is a prophylactic mastectomy. Bilateral nipple-sparing mastectomy specifically offers the most favorable esthetic outcomes but the evidence for its oncological safety remains limited. Thus, we aimed to compare the occurrence of breast cancer between nipple-sparing mastectomy and surveillance groups of BRCA1 or BRCA 2 mutations carriers. BRCA1 or BRCA2-positive patients undergoing bilateral prophylactic nipple-sparing mastectomy at our department were identified. Only those unaffected by breast cancer were eligible. Each patient was pair-matched with a BRCA1 or BRCA2-positive patient of equal age from the surveillance group. Breast cancer incidence in both groups was recorded and the results were compared. None of 105 patients who underwent NSM between 2009 and 2019 at a single institution with a mean follow-up time of 50months developed breast cancer over this time period. One patient in this group died of an unrelated cause. Nine patients from 105 in the match-paired surveillance group were diagnosed with breast cancer during a mean follow-up time of 58.3months, however, none of them died. To the best of our knowledge, this is the largest single-center study of risk-reducing bilateral NSM in healthy BRCA1 or BRCA2 mutation carriers. Based on our results and those of other series, we conclude that NSM in its current form appears to be at least equally as safe as other types of mastectomy for preventing breast cancer in BRCA1 or BRCA2 mutation carriers. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Room for growth: Real-world maintenance and treatment PARP inhibitor use in BRCAm ovarian cancer patients

Objectives: Significant clinical benefit has been demonstrated for poly-ADP ribose polymerase inhibitors (PARPi) in the maintenance and treatment settings for BRCA mutation (BRCAm) carriers with ovarian cancer (OC). We examined the institutional experience of real-world PARPi use in patients (pts) with BRCAm OC. Methods: This was a retrospective series at an urban academic institution with two satellite sites. Pts were identified by ICD-10 codes corresponding to germline BRCA1/2 mutations and cross-checked by our institutional record of patients with OC. Pts were included if they had a diagnosis of OC with BRCAm and either received post-surgical treatment at our institution or had well-documented records of OC treatment. PARPi eligibility was determined at the time of initial diagnosis and each recurrence if a PARPi was FDA approved at that given time for that line of therapy as maintenance or treatment for each pt or if they underwent a clinical trial for PARPi. Outcome of interest was the number of eligible pts who did and did not receive PARPi therapy. Results: There were 120 BRCAm OC pts diagnosed between 1/1997 and 4/2020 with a median age of diagnosis of 53 (IQR 46-60.25). Of those, 95 (79%) were advanced stage and 67 (56%) underwent primary debulking. Fifty-two (43%) pts received only initial chemotherapy without recurrence at the time of our study with median follow-up of 64 months (range 1-298 months). Overall, 55 (44%) received a PARPi during their OC treatment course: 15 (13%), maintenance; and 44 (37%), treatment (Table 1). Sixty-six pts never received PARPi; of these patients, 14 (21%) never received a PARPi even though they were FDA-eligible during their treatment course. Of those, 12/66 (18%) were eligible for a maintenance PARPi, and 6/66 (9%) were eligible for treatment PARPi. Of these 14 FDA-eligible pts, five were deemed to be too ill for PARPi treatment, one refused, and the rest did not have documented reasons. The highest adherence to FDA eligibility was in the frontline maintenance setting, where 10/16 (63%) eligible pts underwent appropriate therapy. Of 10 pts that received PARPi after prior PARPi therapy, 5 received treatment for recurrence after prior PARPi for maintenance indications. Download : Download high-res image (108KB) Download : Download full-size image Conclusions: A fifth of BRCAm pts eligible for PARPi in their OC treatment course did not receive a PARPi. Studies addressing PARPi as treatment for recurrence after prior PARPi use in the maintenance setting are needed to better understand utility in this setting in BRCAm carriers. Increased education to ensure all BRCAm carriers receive a PARPi in their treatment course is needed. This is particularly important in the frontline maintenance setting where significant long term benefit has been reported.

Obesity is associated with poor clinical outcomes in BRCA mutation carriers with epithelial ovarian cancer

<h3>Objectives:</h3> Mutations in <i>BRCA1</i> and <i>BRCA2</i> increase the risk of epithelial ovarian cancer (EOC). Emerging evidence suggests obesity may influence <i>BRCA</i> tumor biology; body mass index (BMI) appears to correlate with DNA damage in breast epithelium in <i>BRCA</i> women. We hypothesized that obesity negatively influences tumor biology in <i>BRCA</i> women with EOC, and sought to identify correlations with BMI and clinical outcomes in this population. <h3>Methods:</h3> We performed an IRB approved retrospective study. We identified patients with <i>BRCA</i>-associated EOC diagnosed between 1990-2015. All women underwent surgical resection with platinum-based chemotherapy. We abstracted clinical and pathologic data, and calculated BMI at the time of diagnosis. Obesity was examined per WHO criteria of normal weight, overweight, class I obesity, and class II obesity. We performed descriptive statistics with Kaplan-Meier, Cox Proportional Hazards Regression, and univariate analyses. <h3>Results:</h3> We identified 179 women meeting criteria. Most were <i>BRCA1</i> (125, or 70%); 53 (30%) were <i>BRCA2</i>; and 1 had both a <i>BRCA1</i> and <i>BRCA2</i> mutation. The majority had stage III/IV disease (137, 77%) and grade 3 serous histology (168, 94%); 150 patients underwent optimal cytoreduction (87%). BMI was distributed throughout the WHO strata: 101 women had normal weight; 46 were overweight; 20 had class I obesity; 12 had class II obesity. Age, medical comorbidities, and rates of optimal surgical cytoreduction were similar among these groups. In a subcohort of patients with stage III/IV disease, we identified a significant trend between increased BMI strata and poor disease-free survival (35, 32, 25, and 13.5 months, <i>p</i>=0.003). This was also observed for overall disease-specific survival (132, 144, 112, and 72.5 months, <i>p</i>=0.0306). Multivariable analyses of the entire cohort confirmed that age (<i>p</i>=0.035), stage (<i>p</i><0.001), and BMI (<i>p</i>=0.017) remained significant independent prognosticators after controlling for grade and optimal cytoreduction. <h3>Conclusions:</h3> We identified a significant and independent association between BMI and clinical outcome in <i>BRCA</i> positive women with EOC. Factors associated with obesity may negatively influence <i>BRCA</i> associated ovarian cancer biology, and suggest this may be a modifiable risk factor to target for therapy.

Timing of genetic testing in BRCA mutation carriers: an unfortunate lost opportunity for those meeting NCCN testing criteria

Objectives: NCCN recommends testing for BRCA based on personal and family history of cancer and known mutations. BRCA testing can have preventative implications with increased screening and risk-reducing surgery if a mutation is diagnosed. The objective of this study was to determine the number of patients meeting BRCA testing criteria prior to a personal diagnosis of a BRCA related-cancer (BRC) and reasons for genetic testing in those without a BRC among a cohort of BRCA carriers. Methods: This was a retrospective cohort study at three satellite sites within one institution from 2014 to 2018. Patients were identified by ICD-10 codes associated with hereditary disposition of malignancy (Z15.01, Z15.02, Z15.09, Z15.89, C50.919, Q99.8, C54.1). Patients with BRCA1 and BRCA2 pathogenic mutations with and without a personal history of cancer were included in this study; BRCA1/2 not specified, variants of uncertain significance, and unknown dates of testing and cancer diagnosis were excluded. NCCN testing criteria were applied to those who underwent testing with and without a diagnosis of a BRCA-related cancer (BRC). Outcomes of interest were the number of patients meeting NCCN criteria for BRCA testing and reasons for testing in those without a BRC. Chi-square and Mann-Whitney U tests were performed with significance at p Download : Download high-res image (129KB) Download : Download full-size image Results: Six hundred thirty-eight patients met inclusion criteria; 331 (51.9%) had a BRCA1 mutation and 312 (48.9%) a BRCA2 mutation. The median age of genetic testing was 40 (range 19-90). Of 281 patients with a personal history of a BRC, 193 (68.7%) underwent genetic testing after a diagnosis of cancer. The majority (205/281, 73.0%) of these patients with a cancer diagnosis met NCCN criteria for testing by either family history of mutation or family history of cancer. Patients with a family history of known mutation were more likely to be tested prior to their cancer diagnosis (44/88, 50.0% vs 49/193, 25.4%, p Conclusions: Almost 70% of patients with BRCA mutations and BRC undergo genetic testing after a personal cancer diagnosis; approximately 75% of these patients met criteria for testing based on family history of cancer or family history of mutation. Those with a family history of a mutation were twice as likely to be tested before their cancer diagnosis. Identification of these mutations prior to development of cancer is critical to improve screening and preventative measures. Increased education of genetic testing criteria and methods to improve identification and cascade testing with outreach efforts are desperately needed.

Utility of anti-Mullerian hormone in clinical decision making in BRCA mutation carriers

Objectives: BRCA1/2 mutations increase cancer risk and may also confer risk for reduced fertility potential, posing a dilemma for BRCA mutation carriers desiring future fertility. On December 19, 2016, the FDA approved the use of Anti-Mullerian Hormone (AMH) assay for use in the assessment of ovarian reserve. AMH serum concentration accurately reflects the size of the pool of antral follicles, representing the quantity of the remaining primordial follicles and is not dependent on timing in the menstrual cycle. The purpose of this study is to determine the frequency of AMH testing to monitor ovarian reserve and utility in clinical decision making among patients with BRCA1/2 mutations. Methods: BRCA1/2 mutation carriers were retrospectively identified from electronic medical records using ICD-10 codes, and BRCA1/2 mutation carriers between the ages of 18 and 50 seen between January 1, 2017 and August 1, 2020 were included in the study. CPT codes were used to identify patients with prior AMH testing; for patients who received testing, AMH levels and clinical data were abstracted from medical records. AMH levels were categorized as low or normal based on reported age-dependent reference ranges1. Referral to REI and cryopreservation were outcomes of interest and were compared between patients with low vs. normal AMH levels using Fisher's exact test. Results: Of 1,186 BRCA1/2 mutation carriers of reproductive age seen at NYU Langone Health, 73 (6.2%) received AMH laboratory testing. Of the 73 patients who had AMH testing, 39 (53.4%) had BRCA1 mutation and 36 (49.3%) had BRCA2 mutations; two patients (2.7%) carried mutations on both genes. AMH tests were ordered by the following providers: 64 (87.7%), gynecologic oncologists; 7 (9.6%), general gynecologist; and 2 (2.7%), reproductive endocrinologists (REI). Of the 73 women, 53 (72.6%) were interested in future fertility and 11 (15.1%) were unsure. The median age at the time of AMH testing was 30 years (Interquartile range [IQR] 27-34 years), and the median AMH level was 3.6 ng/mL (IQR 1.9-6.0 ng/mL). Twenty-nine patients (39.7%) had low AMH levels and of patients with low AMH levels, 14 (48.3%) received REI referrals and 9 (31.0%) patients were seen by REI. Significantly more patients with low AMH underwent cryopreservation compared to patients with normal AMH (17.2% vs 2.3%, p=0.03). One patient decided to undergo risk reducing surgery following a very low AMH value of Conclusions: Only 6% of BRCA1/2 mutation carriers of reproductive age at our institution received AMH testing. Incorporation of AMH monitoring into the screening and preventative care of BRCA1/2 mutation carriers desiring future fertility may help guide patient decision making regarding oocyte cryopreservation and timing of risk reducing surgery; further prospective evaluation in needed to better assess the role of AMH in these patients.

Endometrial cancer in germline BRCA mutation carriers: a systematic review and meta-analysis

<h3>Results:</h3> The search produced a total of 924 results. After duplicate removal and primary review, 41 articles were selected for full review, and 11 studies that reported the outcome of interest were included in the final meta-analysis. In total, 13871 carriers of <i>BRCA1</i> and <i>BRCA2</i> mutations were identified. The pooled prevalence rates of EC and UPSC in <i>BRCA1/2</i> mutations carriers were 82/13827 (0.59%) and 19/11582 (0.16%), respectively. EC prevalence was 46/7429 (0.62%) in <i>BRCA1</i>, and 17/3546 (0.47%) in <i>BRCA2</i> mutation carriers, with RR of 1.18 (95% CI 0.7-2.0). For UPSC, the prevalence was 15/7429 (0.2%) and 3/3546 (0.08%) among <i>BRCA1</i> and <i>BRCA2</i> mutation carriers, respectively, (RR=1.39, 95% CI 0.5-3.7). <h3>Conclusions:</h3> This meta-analysis suggests a slightly increased risk of EC in <i>BRCA</i> mutation carriers, mainly for <i>BRCA1</i>. The absolute risk is low and needs to be balanced with the potential mild increase in surgical morbidity associated with the addition of a hysterectomy.

A new hybrid record linkage process to make epidemiological databases interoperable: application to the GEMO and GENEPSO studies involving BRCA1 and BRCA2 mutation carriers

BackgroundLinking independent sources of data describing the same individuals enable innovative epidemiological and health studies but require a robust record linkage approach. We describe a hybrid record linkage process to link databases from two independent ongoing French national studies, GEMO (Genetic Modifiers of BRCA1 and BRCA2), which focuses on the identification of genetic factors modifying cancer risk of BRCA1 and BRCA2 mutation carriers, and GENEPSO (prospective cohort of BRCAx mutation carriers), which focuses on environmental and lifestyle risk factors.MethodsTo identify as many as possible of the individuals participating in the two studies but not registered by a shared identifier, we combined probabilistic record linkage (PRL) and supervised machine learning (ML). This approach (named “PRL + ML”) combined together the candidate matches identified by both approaches. We built the ML model using the gold standard on a first version of the two databases as a training dataset. This gold standard was obtained from PRL-derived matches verified by an exhaustive manual review. ResultsThe Random Forest (RF) algorithm showed a highest recall (0.985) among six widely used ML algorithms: RF, Bagged trees, AdaBoost, Support Vector Machine, Neural Network.Therefore, RF was selected to build the ML model since our goal was to identify the maximum number of true matches. Our combined linkage PRL + ML showed a higher recall (range 0.988–0.992) than either PRL (range 0.916–0.991) or ML (0.981) alone. It identified 1995 individuals participating in both GEMO (6375 participants) and GENEPSO (4925 participants).ConclusionsOur hybrid linkage process represents an efficient tool for linking GEMO and GENEPSO. It may be generalizable to other epidemiological studies involving other databases and registries.

Endocrine Treatment and Targeted Therapy for Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer: ASCO Guideline Update.

To update recommendations of the ASCO systemic therapy for hormone receptor (HR)-positive metastatic breast cancer (MBC) guideline. An Expert Panel conducted a systematic review to identify new, potentially practice-changing data. Fifty-one articles met eligibility criteria and form the evidentiary basis for the recommendations. Alpelisib in combination with endocrine therapy (ET) should be offered to postmenopausal patients, and to male patients, with HR-positive, human epidermal growth factor receptor 2 (HER2)-negative, PIK3CA-mutated, ABC, or MBC following prior endocrine therapy with or without a cyclin-dependent kinase (CDK) 4/6 inhibitor. Clinicians should use next-generation sequencing in tumor tissue or cell-free DNA in plasma to detect PIK3CA mutations. If no mutation is found in cell-free DNA, testing in tumor tissue, if available, should be used as this will detect a small number of additional patients with PIK3CA mutations. There are insufficient data at present to recommend routine testing for ESR1 mutations to guide therapy for HR-positive, HER2-negative MBC. For BRCA1 or BRCA2 mutation carriers with metastatic HER2-negative breast cancer, olaparib or talazoparib should be offered in the 1st-line through 3rd-line setting. A nonsteroidal aromatase inhibitor (AI) and a CDK4/6 inhibitor should be offered to postmenopausal women with treatment-naïve HR-positive MBC. Fulvestrant and a CDK4/6 inhibitor should be offered to patients with progressive disease during treatment with AIs (or who develop a recurrence within 1 year of adjuvant AI therapy) with or without one line of prior chemotherapy for metastatic disease, or as first-line therapy. Treatment should be limited to those without prior exposure to CDK4/6 inhibitors in the metastatic setting.Additional information can be found at www.asco.org/breast-cancer-guidelines.

The preventive effect of breastfeeding against ovarian cancer in BRCA1 and BRCA2 mutation carriers: A systematic review and meta-analysis

ObjectiveA recent study showed that even a few months of breastfeeding is associated with a significant decrease in the risk of ovarian cancer in the general population. This study aimed to perform a systematic review and meta-analysis to determine the significance of the length of the breastfeeding period on ovarian cancer risk in BRCA1/2 mutation carriers. MethodsPubMed, EMBASE, and Cochrane databases were searched up to June 1, 2021. We included case-control and cohort studies that contained information on breastfeeding and the risk of ovarian cancer in BRCA1/2 mutation carriers. Odds ratios (OR) were meta-analytically pooled using a fixed-effects model.dd ResultsFive studies, including one cohort study and four case-control studies, were included in this meta-analysis. Of the 14,601 BRCA1/2 mutation carriers, the overall pooled OR of ever having performed breastfeeding in patients who had ovarian cancer was 0.767 (95% confidence interval [CI], 0.688–0.856) and 0.817 (95% CI, 0.650–1.028) for patients with BRCA1 and BRCA2 mutation, respectively. Breastfeeding for >1 year acted as a protective factor in both BRCA1 [OR: 0.787 (95% CI, 0.682–0.907)] and BRCA2 [OR: 0.567 (95% CI, 0.400–0.802)] mutation carriers. No significant heterogeneity was present (I2 = 0%), and the funnel plot was also properly distributed, showing no publication bias. ConclusionsBreastfeeding is a preventive, modifiable factor for ovarian cancer in BRCA1/2 mutation carriers. Ever having performed breastfeeding was significantly preventive for ovarian cancer in the BRCA1 mutation carriers, however a period of 1 year or more of breastfeeding is required for a reduced ovarian cancer risk in BRCA2 mutation carriers.

How Protective are Nipple-Sparing Prophylactic Mastectomies in BRCA1 and BRCA2 Mutation Carriers?

Nipple-sparing mastectomy (NSM) is now routinely offered to BRCA mutation carriers for risk reduction. We assessed the rates of ipsilateral cancer events after prophylactic and therapeutic NSM in BRCA1 and BRCA2 mutation carriers. BRCA1 and BRCA2 mutation carriers undergoing NSM from October 2007 to June 2019 were identified in a single-institution prospective database, with variants of unknown significance being excluded. Patient, tumor, and outcomes data were collected. Follow-up analysis was by cumulative breast-years (total years of follow-up of each breast) and woman-years (total years of follow-up of each woman). Overall, 307 BRCA1 and BRCA2 mutation carriers (160 BRCA1, mean age 41.4years [range 21-65]; and 147 BRCA2, mean age 43.8years [range 23-65]) underwent 607 NSMs, with a median follow-up of 42 months (range 1-143). 388 bilateral prophylactic NSMs had 744 cumulative woman-years of follow-up, with no new cancers seen (< 0.0013 new cancers per woman-years); 251 BRCA1 prophylactic NSMs had 1034 cumulative breast-years of follow-up, with no new ipsilateral cancers seen (< 0.0010 per breast-year); 66 BRCA1 therapeutic NSMs had 328 cumulative breast-years of follow-up, with one ipsilateral cancer recurrence not directly involving the nipple or areola (0.0030 per breast-year); 237 BRCA2 prophylactic NSMs had 926 cumulative breast-years of follow-up, with no new ipsilateral cancers seen (< 0.0011 per breast-year); and 53 BRCA2 therapeutic NSMs had 239 cumulative breast-years of follow-up, with two ipsilateral recurrent cancers, neither of which directly involved the nipple or areola (0.0084 per breast-year). The risk of new ipsilateral breast cancers is extremely low after NSM in BRCA1 and BRCA2 mutation carriers. NSM is an effective risk-reducing strategy for BRCA gene mutations.

OncotypeDX© Recurrence Score in BRCA mutation carriers: a systematic review and meta-analysis

IntroductionThere are limited data comparing the OncotypeDX© Recurrence Score (RS) among BRCA mutation carriers and patients with sporadic breast cancer. AimTo compare RS results among BRCA mutation carriers and patients with sporadic breast cancer in oestrogen receptor positive (ER+), human epidermal growth factor receptor-2 negative (HER2−) breast cancer. MethodsA systematic review was performed in accordance with PRISMA and MOOSE guidelines. Retrospective cohort studies comparing RS in BRCA mutation carriers and cases of sporadic cancer were included. Dichotomous variables were pooled as odds ratios (ORs) and associated 95% confidence intervals (CIs) using the Mantel–Haenszel method. ResultsFive studies involving 4286 patients were included with a mean age of 60 years (range 22–85). Overall, 7.8% were BRCA mutation carriers (333/4286). The mean RS was 18.0 (range 0–71), and the mean RS in BRCA carriers was 25 (range 10–71) versus 18.4 in cases of sporadic disease (range 0–62). Patients with sporadic cancers were more likely to have RS < 18 (OR 0.27, 95% CI 0.14–0.51, P = 0.010). BRCA mutation carriers were more likely to have RS 18–30 (OR 1.74, 95% CI 1.28–2.37, P < 0.001) and RS > 30 (OR 3.71, 95% CI 2.55–5.40, P < 0.001). ConclusionThere is an increased likelihood of high-risk RS among patients with known germline BRCA mutations when compared to patients developing sporadic ER+/HER2-early breast cancer. This study offers insight into genomic testing results within BRCA mutation carriers which may be useful in counselling patients with BRCA mutations in future practice.

The Distinct Performances of Ultrasound, Mammograms, and MRI in Detecting Breast Cancer in Patients With Germline Pathogenic Variants in Cancer Predisposition Genes.

A proportion of up to 10% of breast cancer resulted from hereditary germline pathogenic variants (GPVs) in cancer predisposition genes (CPGs), which been demonstrated distinct clinical features and imaging manifestations. However, the performance of imaging modalities for breast cancer surveillance in CPG mutation-carriers is still unclear, especially in Asian women. A population of 3002 breast cancer patients who received germline genetic testing of CPGs was enrolled from three hospitals in China. In total, 343 (11.6%) patients were found to harbor GPVs in CPGs, including 137 (4.6%) in BRCA1 and 135 (4.6%) in BRCA2. We compared the performances of ultrasound, mammograms, MRI, and the combining strategies in CPG mutation carriers and non-carriers. As a result, the ultrasound showed a higher detection rate compared with mammograms regardless of the mutation status. However, its detection rate was lower in CPG mutation carriers than in non-carriers (93.2% vs 98.0%, P=2.1×10-4), especially in the BRCA1 mutation carriers (90.9% vs 98.0%, P=2.0×10-4). MRI presented the highest sensitivity (98.5%) and the lowest underestimation rate (14.5%) in CPG mutation carriers among ultrasound, mammograms, and their combination. Supplemental ultrasound or mammograms would add no significant value to MRI for detecting breast cancer (P>0.05). In multivariate logistic regression analysis, the family or personal cancer history could not replace the mutation status as the impact factor for the false-negative result and underestimation. In summary, clinicians and radiologists should be aware of the atypical imaging presentation of breast cancer in patients with GPVs in CPGs.

A competing risks model with binary time varying covariates for estimation of breast cancer risks in BRCA1 families.

Mammographic screening and prophylactic surgery such as risk-reducing salpingo oophorectomy can potentially reduce breast cancer risks among mutation carriers of BRCA families. The evaluation of these interventions is usually complicated by the fact that their effects on breast cancer may change over time and by the presence of competing risks. We introduce a correlated competing risks model to model breast and ovarian cancer risks within BRCA1 families that accounts for time-varying covariates. Different parametric forms for the effects of time-varying covariates are proposed for more flexibility and a correlated gamma frailty model is specified to account for the correlated competing events.We also introduce a new ascertainment correction approach that accounts for the selection of families through probands affected with either breast or ovarian cancer, or unaffected. Our simulation studies demonstrate the good performances of our proposed approach in terms of bias and precision of the estimators of model parameters and cause-specific penetrances over different levels of familial correlations. We applied our new approach to 498 BRCA1 mutation carrier families recruited through the Breast Cancer Family Registry. Our results demonstrate the importance of the functional form of the time-varying covariate effect when assessing the role of risk-reducing salpingo oophorectomy on breast cancer. In particular, under the best fitting time-varying covariate model, the overall effect of risk-reducing salpingo oophorectomy on breast cancer risk was statistically significant in women with BRCA1 mutation.

Abstract 878: Contraceptive use and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers: A prospective cohort study

Abstract Background: Oral contraceptive use is associated with a significantly reduced risk of ovarian cancer among BRCA1 and BRCA2 mutation carriers. To date, there have been no prospective analyses of this relationship, and the impact of other types of contraception (e.g. intrauterine device (IUD), implant, patch, injection) on BRCA-associated ovarian cancer risk is unknown. The goal of this study is to prospectively evaluate the relationship between types of contraception and ovarian cancer incidence in women with a BRCA1 or BRCA2 mutation. Methods: The longitudinal study included 3,298 eligible BRCA1/2 mutation carriers. Self-reported information regarding contraceptive use, including medication name, start year, end year, duration of use and method of administration were collected by biennial questionnaire. Women were classified according to history of contraceptive use (ever/never), duration of use, contraceptive method, calendar year of initiation and time since last use. Time-dependent Cox proportional hazards regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) of ovarian cancer associated with each contraceptive method. Results: There were 84 incident ovarian cancer cases diagnosed over a mean follow-up period of 5.1 years. There was no significant association between ever use of an IUD (HR: 0.78; 95% CI: 0.28-2.14) and risk of ovarian cancer compared to IUD never users. Ongoing analyses will focus on the relationships between other contraceptive methods, formulations and duration of use on ovarian cancer risk, further stratified by histology and site of origin. Conclusions: Preliminary findings from this prospective analysis suggest that IUD use may not be protective among BRCA1/2 mutation carriers. Ongoing results will elucidate the impact of contraceptive formulation and method on ovarian cancer risk to inform clinical recommendations surrounding the use of contraceptive agents for chemoprevention in high risk women. Citation Format: Yue Yin Xia, Jan Lubinski, Barry Rosen, Pal Moller, Andrea Eisen, Peter Ainsworth, Leigha Senter, Louise Bordeleau, Susan L. Neuhausen, Christian F. Singer, Jennifer Brooks, Ping Sun, Steven A. Narod, Joanne Kotsopoulos. Contraceptive use and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers: A prospective cohort study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 878.

Abstract 799: Reduced diversity of HLA class II alleles may contribute to the early manifestation of breast cancer in BRCA1 mutation carriers

Abstract Female carriers of germline BRCA1 mutation almost inevitably develop breast cancer (BC). However, the age of BRCA1-associated cancer onset varies widely. We hypothesize that age-related penetrance of BRCA1 mutations may depend on the inherited variability in the host immune system. We utilized high-throughput HLA-typing to describe 10 classical HLA class I/II loci for 90 young (&amp;lt;38 y.o.) and 73 elderly (&amp;gt;57 y.o.) BRCA1-mutated BC patients. 39% of young females were homozygous for two or more HLA-II loci; this was significantly higher than in the “elderly” cohort [OR = 3.23; p = 0.002]. In contrast, women who harboured identical alleles at HLA-B locus (class I) had increased chances to stay tumour-free to their older ages [OR = 3.02; p = 0.077]. Allele HLA-DBR1*11:03/04 was overtly overrepresented in elderly BRCA1-driven BC [11% vs. 3%, p = 0.006]. The frequencies of HLA-DRB1*01:01 and HLA-DQB1*05 were significantly higher in group of “young” patients [p = 0.020 and p = 0.011, correspondently]. The tumour immunogenicity was analyzed in early-onset and late-onset BC patients through the evaluation of the intratumoral density of cytotoxic T-lymphocytes (TILs) with anti-CD8 IHC staining. 5/10 carcinomas arisen in young BRCA1-carriers were classified as a “hot” phenotype with a high density of TILs across the tumour. Inversely, the BC developed in “elderly” women was characterized by the reduced levels of TILs. Conclusions: 1) the limited repertoire of HLA peptides caused by the homozygosity for HLA II loci may increase susceptibility to BC in BRCA1-carriers and manifest by early disease onset; 2) tumours from “elderly” BRCA1-associated patients have reduced levels of lymphocytic infiltration compared to “young” patients. The research is supported by RSF grant #19-15-00207 Citation Format: Ekaterina ShKuligina, Alexandr A. Romanko, Tatjana Jankevic, Aleksandr S. Martianov, Tatyana N. Sokolova, Alexandr O. Ivantsov, Evgeny N. Imyanitov. Reduced diversity of HLA class II alleles may contribute to the early manifestation of breast cancer in BRCA1 mutation carriers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 799.