Mutation-negative Women Research Articles

Assessment of ovarian reserve and reproductive outcomes in BRCA1 or BRCA2 mutation carriers

IntroductionThe clinical impact on fertility in carriers of BRCA1 and BRCA2 mutations remains unclear. The aim of this study was to assess ovarian reserve as measured by anti-mullerian hormone levels...

Breast cancer risk assessment in patients who test negative for a hereditary cancer syndrome

BackgroundThe majority of women who undergo genetic testing due to a significant family history of breast cancer will receive a negative result. The purpose of this study was to calculate the lifetime risk of breast cancer in women undergoing genetic counseling who received an uninformative genetic test result. MethodsA retrospective chart review of mutation-negative women presenting to a cancer risk assessment clinic was performed. Lifetime risks of breast cancer were calculated using the Claus, Gail, and Tyrer-Cuzick risk assessment models. ResultsApproximately half (51%) of the women were classified as high-risk by at least one risk assessment model. The Tyrer-Cuzick model identified the highest proportion (43.2%) of patients as high-risk. Four percent (n = 4) of the sample was considered high-risk by all three models. ConclusionsMore than half (51%) of women who underwent genetic counseling and received an uninformative negative genetic test result had a significantly elevated risk for the development of breast cancer. It is, therefore, imperative that women do not conclude that a negative genetic test result represents a lack of risk.

TP53 germline mutation testing in early-onset breast cancer: findings from a nationwide cohort.

Early-onset breast cancer may be due to Li-Fraumeni Syndrome (LFS). Current national and international guidelines recommend that TP53 genetic testing should be considered for women with breast cancer diagnosed before the age of 31years. However, large studies investigating TP53 mutation prevalence in this population are scarce. We collected nationwide laboratory records for all young breast cancer patients tested for TP53 mutations in the Netherlands. Between 2005 and 2016, 370 women diagnosed with breast cancer younger than 30years of age were tested for TP53 germline mutations, and eight (2.2%) were found to carry a (likely) pathogenic TP53 sequence variant. Among BRCA1/BRCA2 mutation negative women without a family history suggestive of LFS or a personal history of multiple LFS-related tumours, the TP53 mutation frequency was < 1% (2/233). Taking into consideration that TP53 mutation prevalence was comparable or even higher in some studies selecting patients with breast cancer onset at older ages or HER2-positive breast cancers, raises the question of whether a very early age of onset is an appropriate single TP53 genetic testing criterion.

Addition of triple negativity of breast cancer as an indicator for germline mutations in predisposing genes increases sensitivity of clinical selection criteria

BackgroundBreast cancer is the most common cancer in women. 12–15% of all tumors are triple-negative breast cancers (TNBC). So far, TNBC has been mainly associated with mutations in BRCA1. The presence of other predisposing genes seems likely since DNA damage repair is a complex process that involves several genes. Therefore we investigated if mutations in other genes are involved in cancer development and whether TNBC is an additional indicator of mutational status besides family history and age of onset.MethodsWe performed a germline panel-based screening of 10 high and low-moderate penetrance breast cancer susceptibility genes (BRCA1, BRCA2, ATM, CDH1, CHEK2, NBN, PALB2, RAD51C, RAD51D and TP53) in 229 consecutive individuals affected with TNBC unselected for age, family history or bilateral disease. Within this cohort we compared the number of mutation carriers fulfilling clinical selection criteria with the total number of carriers identified.ResultsAge at diagnosis ranged from 23 to 80 years with an average age of 50.2 years. In 57 women (24.9%) we detected a pathogenic mutation, with a higher frequency (29.7%) in the group manifesting cancer before 60 years. Deleterious BRCA1 mutations occurred in 14.8% of TNBC patients. These were predominantly recurrent frameshift mutations (24/34, 70.6%). Deleterious BRCA2 mutations occurred in 5.7% of patients, all but one (c.1813dupA) being unique.While no mutations were found in CDH1 and TP53, 10 mutations were detected in one of the six other predisposition genes. Remarkably, neither of the ATM, RAD51D, CHEK2 and PALB2 mutation carriers had a family history. Furthermore, patients with non-BRCA1/2 mutations were not significantly younger than mutation negative women (p = 0.3341). Most importantly, among the 57 mutation carriers, ten (17.5%) would be missed using current clinical testing criteria including five (8%) with BRCA1/2 mutations.ConclusionsIn summary, our data confirm and expand previous studies of a high frequency of germline mutations in genes associated with ineffective repair of DNA damage in women with TNBCs. Neither age of onset, contralateral disease nor family history were able to discern all mutation positive individuals. Therefore, TNBC should be considered as an additional criterion for panel based genetic testing.

Setting the Threshold for Surgical Prevention in Women at Increased Risk of Ovarian Cancer.

The number of ovarian cancer cases is predicted to rise by 14% in Europe and 55% worldwide over the next 2 decades. The current absence of a screening program, rising drug/treatment costs, and only marginal improvements in survival seen over the past 30 years suggest the need for maximizing primary surgical prevention to reduce the burden of ovarian cancer. Primary surgical prevention through risk-reducing salpingo-oophorectomy (RRSO) is well established as the most effective method for preventing ovarian cancer. In the UK, it has traditionally been offered to high-risk women (>10% lifetime risk of ovarian cancer) who have completed their family. The cost-effectiveness of RRSO in BRCA1/BRCA2 carriers older than 35 years is well established. Recently, RRSO has been shown to be cost-effective in postmenopausal women at lifetime ovarian cancer risks of 5% or greater and in premenopausal women at lifetime risks greater than 4%. The acceptability, uptake, and satisfaction with RRSO at these intermediate-risk levels remain to be established. Prospective outcome data on risk-reducing salpingectomy and delayed-oophorectomy for preventing ovarian cancer is lacking, and hence, this is best offered for primary prevention within the context and safe environment of a clinical trial. An estimated 63% of ovarian cancers occur in women with greater than 4% lifetime risk and 53% in those with 5% or greater lifetime-risk. Risk-reducing salpingo-oophorectomy can be offered for primary surgical prevention to women at intermediate risk levels (4%-5% to 10%). This includes unaffected women who have completed their family and have RAD51C, RAD51D, or BRIP1 gene mutations; first-degree relatives of women with invasive epithelial ovarian cancer; BRCA mutation-negative women from high-risk breast-and-ovarian cancer or ovarian-cancer-only families. In those with BRCA1, RAD51C/RAD51D/MMR mutations and the occasional families with a history of ovarian cancer in their 40s, surgery needs to be considered at younger than 45. In other moderate-risk gene mutation carriers and those with polygenic risk, RRSO needs be considered at 50. There is need for establishment/expansion of well-defined pathways to increase clinical access to RRSO. It is time to lower the risk threshold for RRSO to enable introduction of a targeted primary prevention approach, which could significantly impact the future burden of ovarian cancer.

Abstract 4271: Population-wide vs. carrier-probability-based BRCA1/2 mutation testing in the Washington Ashkenazi Study

Abstract Background: Currently, women are referred for BRCA1/2 mutation testing if their family history of breast and ovarian cancer indicates they have sufficient probability of carrying mutations. In contrast, calls have intensified for population-wide testing for BRCA1/2 founder mutations among Ashkenazi Jews, due to relatively high mutation prevalence (2.5%) and decreasing genotyping costs. However, population-wide testing would strain genetic counseling resources and incur costs from testing mostly mutation-negative women. We compared the performance of population-wide vs. carrier-probability-based BRCA1/2 testing in the community-based Washington Ashkenazi Study (WAS). Methods: BRCA1/2 carrier-probabilities based on reported family histories were calculated using BRCAPRO for 4589 probands (102 BRCA1/2 mutation-carriers) in WAS. For each carrier-probability threshold, we compared the percent of mutations found (sensitivity) vs. the percent of women requiring mutation testing, overall and by proband age. At example carrier-probability thresholds, undetected and detected carriers’ attributes were compared using nonparametric tests. Results: A 1.2% carrier-probability threshold identified 80% of BRCA1/2 mutations in the 35% of women with highest carrier-probability. For women under age 40, 94% of BRCA1/2 mutations were identified in the 50% of women with highest carrier-probability. Compared to identified mutation-carriers, missed mutation-carriers had no personal cancer history, no affected first- and second-degree relatives (p&amp;lt;0.0001), more unaffected first-degree relatives (p=0.0002), and were older (p=0.012; median age=53). Conclusion: Carrier-probability-based BRCA1/2 mutation testing identified large majorities of mutation-carriers and would have avoided testing for many mutation-negative women. Missed mutation-carriers were older and cancer-free and would gain minimal benefit from risk-reducing interventions. A cost-effective carrier-probability threshold could acceptably tradeoff identifying BRCA1/2 mutation carriers before they get cancer while testing as few women as possible. Citation Format: Ana F. Best, Margaret A. Tucker, Hormuzd A. Katki. Population-wide vs. carrier-probability-based BRCA1/2 mutation testing in the Washington Ashkenazi Study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4271. doi:10.1158/1538-7445.AM2017-4271

Abstract B12: The effect of physical activity and body size on mammographic density in high-risk, BRCA mutation-negative women

Abstract Purpose: Mammographic density (MD) reflects the proportion of dense tissue in relation to non-dense tissue in the breast and is the strongest biological marker of breast cancer risk. MD is known to be higher among women with a family history compared to women in the general population. We have previously demonstrated that women with a strong family history of breast cancer but no BRCA mutation face an elevated lifetime risk of breast cancer estimated at 40% compared to 11% in the general population. Various lifestyle factors, such as physical activity and body mass index (BMI), have been shown to modify MD in the general population. It is of interest to determine if such an association exists among high-risk women. Objective: To evaluate the relationship between physical activity, BMI and MD in high-risk women. Methods: This study included 100 women enrolled in an on-going prospective study of high-risk women with a strong family history of breast cancer (two first-degree relatives with breast cancer under age 50 or three cases at any age) and no identified BRCA mutations in their families. Current physical activity levels and BMI were collected using self-reported questionnaires. Physical activity was defined as moderate to vigorous physical activity (MVPA). Two dichotomous variables were created to define high vs. low MVPA levels: 1) based on the Canadian Society for Exercise Physiology guideline of 2.5 hours of MVPA per week and 2) the 75th percentile of MVPA in the sample (3.5 hours per week). A BMI of 25 or more was defined as high using the World Health Organization criteria of overweight. Mammograms were assigned a percentage of density (0 - 100%) using a computer-assisted method (Cumulus 6). Multivariate linear regression modelling was used to evaluate the relationships between both MVPA and BMI with MD while adjusting for age, menopausal status, and parity. BMI models also adjusted for MVPA (continuous) and MVPA models adjusted for BMI (continuous). Results: Among all women, those with a high BMI had significantly lower mean percent density compared to women with a low BMI (13% vs. 23%; P = 0.01). This association was stronger for premenopausal (27% vs. 37%; P = 0.06) vs. postmenopausal (12% vs. 20%; P = 0.10) women. Women who engaged in MVPA for 2.5 hours per week or more had significantly greater mean percent density compared to women who were less physically active (29% vs. 22%; P = 0.04). This relationship did not vary by menopausal status (P ≥ 0.15). Based on the 75th percentile of MVPA, women with high MVPA levels had significantly greater mean percent density compared to women with low MVPA levels (31% vs. 22%; P = 0.02). This relationship was significant for postmenopausal (26% vs. 13%; P = 0.04) but not premenopausal (31% vs. 25%; P = 0.27) women. Conclusion: In this cohort of high-risk women, high BMI was associated with lower MD that was suggestively stronger for premenopausal women. Although preliminary, these findings suggest a possible mechanism by which a lifestyle factor may influence MD, and possibly breast cancer risk, in high-risk women. Further evaluation with a larger sample size is needed to elucidate the relationships between physical activity, as well as other modifiable factors, and MD in this cohort of women. This study adds to the growing evidence supporting the inclusion of MD into breast cancer risk prediction models, in order to improve individualized treatments and prevention strategies for women at an increased risk for disease. Citation Format: Olivia M. Moran, Dina Nikitina, Anoma Gunasekara, Martin J. Yaffe, Kelly A. Metcalfe, Steven A. Narod, Joanne Kotsopoulos. The effect of physical activity and body size on mammographic density in high-risk, BRCA mutation-negative women. [abstract]. In: Proceedings of the AACR Special Conference: Improving Cancer Risk Prediction for Prevention and Early Detection; Nov 16-19, 2016; Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(5 Suppl):Abstract nr B12.

Women's preferences for contralateral prophylactic mastectomy following unilateral breast cancer: What risk-reduction makes it worthwhile?

ObjectivesContralateral prophylactic mastectomy (CPM) reduces the risk of contralateral breast cancer (BC) following unilateral BC, but may not increase survival in BRCA1/2 mutation negative women. Despite this, and the risk for adverse physical and psychological impact, uptake is increasing in BRCA1/2 mutation negative women. We aimed to quantify the degree of reduction in lifetime contralateral BC risk women required to justify CPM, and to explore demographic, disease and psychosocial predictors of preferences using Protection Motivation Theory (PMT) as a theoretical framework. Reasoning behind preferences was also examined. Materials and methods388 women previously diagnosed with unilateral BC, of negative or unknown BRCA1/2 status, were recruited from an advocacy group research database. Two hypothetical risk trade-off scenarios were used to quantify the reduction in lifetime contralateral BC risk that women judged necessary to justify CPM, using a 5% and 20% baseline. Demographic, disease and PMT measures were assessed using a questionnaire. ResultsMost women required their risk to be more than halved from a 5% or 20% baseline to justify CPM. Polarised preferences were also common, with some women consistently accepting or refusing CPM independent of risk/benefit trade-offs. Preferences were associated with coping self-efficacy and having a prior CPM. Explanations for judging CPM worthwhile included reducing or eliminating contralateral BC risk, attaining breast symmetry and reducing worry. ConclusionRisk-reduction preferences were highly variable. Decisive factors in women's preferences for CPM related to clinical, psychological and cosmetic outcomes, but not to demographic or disease characteristics.

BRCA1/2 gene mutations are associated with diminished primordial follicle density and increased oocyte DNA damage in the human ovary

BRCA1 and BRCA2 (BRCA1/2) genes are members of the ATM-mediated DNA repair pathway and are essential for DNA double strand break (DSB) repair. Multiple studies associated BRCA1/2 mutations with earlier natural menopause, lower serum AMH and low response to ovarian stimulation compared to BRCA1/2 mutation negative women, suggesting a role for BRCA1/2 genes in maintaining ovarian reserve. Additional evidence showed the age-related impairment in DSB repair might be a cause of normal oocyte aging and follicular depletion.

Abstract P1-17-04: Association of BRCA1 mutations with impaired ovarian reserve: A plausible connection between infertility and breast/ovarian cancer risks

Abstract Purpose: Mutations in either the BRCA1 or BRCA2 gene are associated with breast and ovarian cancer susceptibility. Lifetime risk estimates for ovarian cancer in the general population indicate that 1.4 percent (14 out of 1,000) of women will be diagnosed with ovarian cancer compared with 15 to 40 percent of women (150-400 out of 1,000) who have a BRCA1 or BRCA2 mutation. For decades, scientists have been attempting to establish a link between the risk of developing cancer and infertility. One prospective study suggested an association with BRCA1 mutations and occult primary ovarian insufficiency. This study showed a novel association between low response to ovarian stimulation and BRCA1 mutations, suggesting a link between double-strand DNA break repair dysfunction, infertility, and breast/ovarian cancer risks. If substantiated, this may place BRCA mutation positive women at higher risk for chemotherapy induced ovarian failure. We also know that reproductive factors including low parity and infertility may place women at increased risk for breast cancer. Taking into account that 1% of females suffer from primary ovarian insufficiency and that the underlying mechanism remains unknown most of the time, discovery of susceptibility gene may have implications for understanding the link between infertility and breast/ovarian cancer. We hypothesize that mutations in the BRCA1 gene will adversely affect ovarian reserve, as measured by AMH levels. Participants and Methods: Subset analysis of serum samples taken from Northwestern Ovarian Cancer Early Detection Program (NOCEDPP) of reproductive aged women who had testing for the BRCA mutation. Using an IRB approved protocol, the NOCEDPP database was searched for women 18-45 years old who had previous BRCA testing. These women must have also provided consent for their stored serum to be used for research purposes. We excluded those with a BRCA2 mutation, a previous history of cancer and/or cancer treatment, and those with a previous unilateral or bilateral oophorectomy or other ovarian surgery. Statistical analysis was done using parametric and nonparametric testing. Results: A total of 125 met the criteria for our study. 66 women were BRCA1 mutation-positive and 59 were BRCA mutation- negative. The median age for BRCA1 mutation-positive women was 33.5 years while BRCA mutation-negative patients was 37 years (p&amp;lt;0.05). Body mass index, gravidity, parity, and duration of birth control were similar between the groups. Overall median AMH values were 2.6ng/mL in both groups. However, when broken into age groups, BRCA1 mutation-positive women aged 35-39 had a significantly lower AMH level when compared to BRCA mutation-negative women (median 3.6ng/mL vs 1.3ng/mL, p&amp;lt;0.05). Conclusion: AMH values were significantly lower in BRCA1 mutation-positive women aged 35-39. Women with the BRCA1 mutation should be counseled regarding this potential decrease in ovarian reserve. Citation Format: Sara B Giordano, Navdha Mittal, Kristin Smith, Mary Ellen Pavone. Association of BRCA1 mutations with impaired ovarian reserve: A plausible connection between infertility and breast/ovarian cancer risks [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 P1-17-04.

Outcome and response to neoadjuvant chemotherapy in patients with advanced stage Müllerian cancer in BRCA1/2 mutation-positive compared to mutation-negative women

Outcome and response to neoadjuvant chemotherapy in patients with advanced stage Müllerian cancer in BRCA1/2 mutation-positive compared to mutation-negative women

Prospective study of breast cancer risk for mutation negative women from BRCA1 or BRCA2 mutation positive families

Published studies have reached contradictory conclusions regarding breast cancer risk for women from families segregating a BRCA1 or BRCA2 mutation who do not carry the family-specific mutation. Accurate estimation of breast cancer risk is crucial for appropriate counselling regarding risk management. The aim of this study is to prospectively assess whether breast cancer risk for mutation negative women from families segregating BRCA1 or BRCA2 mutations is greater than for women in the general population. Eligible women were 722 first-, second- and third-degree relatives of a BRCA1 or BRCA2 mutation carrier from 224 mutation positive (128 BRCA1, 96 BRCA2) families, had no personal cancer history at baseline, and had been tested and found not to carry the family-specific mutation. Self-reported family history of cancer, preventive interventions and verified cancer diagnoses were collected at baseline, and every 3 years thereafter. Median follow-up was 6.1 years (range 0.1-12.4 years). Time at risk of breast cancer was censored at cancer diagnosis or risk-reducing surgery. Standardised incidence ratios (SIR) were estimated by comparing observed to population incidences of invasive breast cancer using Australian Cancer Incidence and Mortality Books. Six cases of invasive breast cancer were observed. The estimated SIRs were 1.14 (95% CI: 0.51-2.53) overall (n = 722), 1.29 (95% CI: 0.58-2.88) when restricted to first- and second-degree relatives of an affected mutation carrier (n = 442) and 0.48 (95% CI: 0.12-1.93) when restricted to those with no family history of breast cancer in the non-mutation carrying parental lineage (n = 424). There was no evidence that mutation negative women from families segregating BRCA1 or BRCA2 mutations are at increased risk of breast cancer. Despite this being the largest prospective cohort to assess this issue, moderately increased breast cancer risk (2-fold) cannot be ruled out.

Prospective study of breast cancer risk in mutation-negative women from BRCA1 or BRCA2 mutation-positive families in the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab).

1516 Background: Published studies have reached contradictory conclusions regarding the breast cancer (BC) risk for mutation negative women from families segregating a BRCA1 or BRCA2 mutation. Accurate estimation of BC risk is crucial for appropriate counselling regarding risk management. Aim: To assess prospectively whether BC risk for non-carrier women from families segregating BRCA1 or BRCA2 mutations is greater than that for the general population. Methods: Eligible women were first-, second- or third-degree relatives of a BRCA1 or BRCA2 mutation carrier, had no personal cancer history at entry into the kConFab cohort, and were not carriers of the family mutation. Self-reported family history of cancer, preventive interventions and verified cancer diagnoses were collected at entry, and every 3 years thereafter. Time at risk of BC was censored at cancer diagnosis or risk-reducing surgery. Standardised incidence ratios (SIR) were estimated by comparing observed to population incidences of invasive breast cancer using the Australian Cancer Incidence and Mortality Books. Results: 728 women from 244 mutation positive (128 BRCA1, 96 BRCA2) families were eligible. Median follow-up was 6.1 years (range 0.1-12.4 years). Six cases of invasive BC were observed. The estimated SIRs were: 1.14 (95% CI=0.51-2.53) for all eligible women (n=728); 1.29 (95% CI=0.58-2.88) for eligible 1st and 2nd degree relatives of an affected mutation carrier (n=442) and 0.48 (95% CI=0.12-1.93) for eligible women with no family history of BC in the non-mutation carrying parental lineage (n=424). Conclusions: We observed no evidence that women from families with BRCA1 or BRCA2 mutations who test negative are at increased risk of BC. Nevertheless, despite this being the largest prospective cohort yet studied for this issue, moderately increased breast cancer risk (2-fold) could not be ruled out. Meta-analysis of this and similar recent prospective studies may provide further clarification.

Germ-line BRCA mutations in high-grade ovarian cancer: A case for routine BRCA mutation screening after a diagnosis of invasive ovarian cancer.

5026 Background: It has been accepted that 5-10% of all invasive epithelial ovarian cancer cases can be attributed to hereditary pathogenic mutations in cancer predisposition genes. Consequently genetic testing is mostly offered to those patients who also have a strong family history of relevant cancers or specific ancestry. We investigated the frequency and clinical characteristics, including the treatment response to platinum therapeutics, of germline BRCA1/2 pathogenic mutation carriers in a large population-based prospective cohort of Australian women with ovarian cancer. Methods: Participants were ascertained from the Australian Ovarian Cancer Study which recruited women presenting for surgery for ovarian cancer between 2002-2006. Women were eligible for BRCA1/2 genotyping if diagnosed with invasive epithelial ovarian, peritoneal or fallopian tube tumors. Mucinous histology was excluded from analysis. Full BRCA1 and BRCA2 analysis was done by gene sequencing and multiplex ligation-dependent probe amplification. Germline status was related to tumor features, clinical response and potential familiality in first degree relatives, including incidences of early onset breast cancer. Results: 134 pathogenic germline mutations were identified within the cohort, for an overall mutation frequency of 13.3% in the Australian ovarian cancer population. 113 (84.3%) mutations were associated with serous histology. 57% of mutation carriers had no evidence of familiality. Mutation carriers were more responsive to primary platinum treatment than non-carriers (87.4% had >6 months progression free survival, versus 68.4%), and were more likely to respond to platinum upon relapse (86% of mutation positive women responded to secondary platinum after relapsing <6 months after primary platinum treatment versus 60% of mutation negative women). Conclusions: Pathogenic BRCA1/2 mutations are common in invasive ovarian cancer and are associated with improved overall survival and response to systemic chemotherapy. BRCA testing should be implemented for all ovarian cancer patients as mutation status has important prognostic and therapeutic clinical utility.

Discriminatory accuracy and potential clinical utility of genomic profiling for breast cancer risk in BRCA-negative women

Several single nucleotide polymorphisms (SNPs) are associated with an increased risk of breast cancer. The clinical utility of genotyping individuals at these loci is not known. Subjects were 519 unaffected women without BRCA mutations. Gail, Claus, and IBIS models were used to estimate absolute breast cancer risks. Subjects were then genotyped at 15 independent risk loci. Published per-allele and genotype-specific odds ratios were used to calculate the composite cumulative genomic risk (CGR) for each subject. Affected age- and ethnicity-matched BRCA mutation-negative women were also genotyped as a comparison group for the calculation of discriminatory accuracy. The CGR was used to adjust absolute breast cancer risks calculated by Gail, Claus and IBIS models to determine the proportion of subjects whose recommendations for chemoprevention or MRI screening might be altered (reclassified) by such adjustment. Mean lifetime breast cancer risks calculated using the Gail, Claus, and IBIS models were 19.4, 13.0, and 17.7%, respectively. CGR did not correlate with breast cancer risk as calculated using any model. CGR was significantly higher in affected women (mean 3.35 vs. 3.12, P = 0.009). The discriminatory accuracy of the CGR alone was 0.55 (SE 0.019; P = 0.006). CGR adjustment of model-derived absolute risk estimates would have altered clinical recommendations for chemoprevention in 11-19% of subjects and for MRI screening in 8-32%. CGR has limited discriminatory accuracy. However, the use of a genomic risk term to adjust model-derived estimates has the potential to alter individual recommendations. These observations warrant investigation to evaluate the calibration of adjusted risk estimates.

Effect of BRCA1 gene and estrogen-receptor α on regulation of serum estradiol levels in women with breast cancer.

1536 Background: A BRCA1 gene mutation is well-known risk factor for breast cancer. Recently, BRCA1 gene was found to negatively regulate aromatase expression in a human granulosa cell line and also modulate estrogen-receptor α (ERα). We evaluated the estradiol (E2) levels in breast cancer patients in association with BRCA1 gene mutation and ERα status. Methods: We performed a secondary analysis of the Controlled Ovarian Stimulation Treatment with Letrozole Supplementation Study (COST-LESS, JCO 2009). Sixty-four women with breast cancer who underwent BRCA testing with known ERα status, and who were undergoing oocyte/embryo cryopreservation for fertility preservation were included. Results: The mean menstrual cycle day-2 E2 level was significantly higher in BRCA1 mutation/ERα-positive women compared to ERα and/or BRCA1 mutation negative women. Compared to BRCA1 mutation-negative women, the relative rise in E2 from baseline to the peak levels in response to ovarian stimulation was lower in BRCA1 mutation/ERα-positive women (Table). Conclusions: We speculate that under the upregulated aromatase expression in BRCA1 mutation-positive women, ERα may act as a scavenger to E2, which in turn increases E2 levels through a negative feedback. The lower relative rise of E2 in BRCA1 mutation/ERα-positive women in response to ovarian stimulation with letrozole might reflect the fact that aromatase activity is increased in this group and hence an aromatase inhibitor has a stronger effect in suppressing aromatization of androgens to estrogens. From the latter, one can speculate that aromatase inhibitors may have a stronger benefit in breast cancer treatment in BRCA1 mutation/ERα-positive women. We propose that BRCA1 gene and ERα may coregulate E2 levels in breast cancer. BRCA1 mutation (-) BRCA1 mutation (+) p value ERα (-)a(n=4) ERα (+)b(n=50) ERα (-)c(n=6) ERα (+)d(n=4) Age (years) 32.0 ± 5.7 35.5 ± 4.6 32.2 ± 4.6 32.5 ± 3.5 NS Day2 E2 (pg/mL) 31.5 ± 8.7 34.8 ± 11.9 33.4 ± 11.8 61.4 ± 21.5 d vs. a, b, c:≤0.001 Relative rise of E2 (%) (95% C.I.) 894.0(285.2∼1,502.9) 1,490.5(1,024.5∼1956.5) 1,062.8(494.8∼1630.8) 746.2(-1092.0∼2584.4) d vs. b, (a + b):0.028 No significant financial relationships to disclose.

No evidence of excess breast cancer risk among mutation-negative women from BRCA mutation-positive families

This analysis addresses risk of breast cancer among women in BRCA-positive families who test negative for the family mutation. We compared the number of prospectively diagnosed breast cancers in 395 mutation-negative women from 28 BRCA1/2-positive families to an age-, race-, and calendar time-specific expected number of breast cancers derived from the SEER 9 Cancer Registry. Study participants contributed a total of 7008.1 person-years of follow-up. The mean age at study entry was 31.3 years; mean follow-up was 17.7 years. Ten women developed breast cancer yielding an observed-to-expected ratio of 0.82 (95% CI 0.39-1.51). Adjustment for possible reduction in breast cancer risk due to oophorectomy by two different methods resulted in O/E ratios in the range of 0.80-0.99. Stratification by degree of relatedness to the nearest mutation carrier did not substantially alter these results, however, women with at least one-first degree relative with breast cancer appeared to have a slightly increased, though not statistically significant, risk of breast cancer (O/E ratio = 1.33, 95% CI 0.41-2.91). Our data suggest that breast cancer risk among mutation-negative women from BRCA1/2 mutation-positive families is similar to that observed in the general population, with a possible slight increase in risk among mutation-negative women with a family history of breast cancer in a first degree relative. Although this is the largest prospective cohort yet assembled to address this important question, the number of breast cancer events is still relatively small.

Head circumference in the clinical detection of PTEN hamartoma tumor syndrome in a clinic population at high-risk of breast cancer

PTEN Hamartoma Tumor Syndrome (PHTS) is often recognized by the presence of macrocephaly and associated mucocutaneous features, and is notable for a profound predisposition to breast and thyroid cancers. Head circumference (HC) is rarely measured when evaluating women at high risk for breast cancer, but may offer insight into characterizing cancer risk. Patients enrolled in the University of Michigan Cancer Genetics registry for breast cancer evaluation were analyzed for personal and family history of cancer and features of PHTS. This group of women was compared to all women who had undergone PTEN testing and whether or not they met clinical criteria for PHTS. Among the 164 women referred for breast cancer risk evaluation, a statistically significant difference in mean HC was found between women who did (57.3 cm) and did not (55.4 cm) meet clinical criteria for PHTS with both values below the established threshold for macrocephaly (58 cm). The sensitivity and specificity of macrocephaly for the presence of a PTEN mutation were 100 and 53%, respectively, among the 28 women tested. The positive predictive value was 14%. PTEN mutation positive and PTEN mutation negative women were not well differentiated by PHTS clinical criteria (P = 0.2348). The high sensitivity of HC suggests that this simple measure can improve the detection of unrecognized patients with PHTS. Measuring HC is a useful clinical feature, but is insufficient as a singular screening tool for PHTS. Even in a high risk population, the PPV of this test is low. Diagnosis of this important genetic syndrome still relies heavily on detailed history and full physical exam.

Breast Cancer Risk Single Nucleotide Polymorphism (SNP) Genotypes Do Not Correlate with Risk Estimates from Existing Prediction Models.

Abstract Background:Breast cancer risk assessment professionals employ models to estimate individual probabilities of developing breast cancer. The Gail, Claus and BRCAPro models integrate personal, reproductive and family history variables to generate absolute risk estimates. A number of common DNA variants (single nucleotide polymorphisms, SNPs) are associated with modest elevations (relative risk &amp;lt; 2) of breast cancer risk. We investigated the correlation between genotype at 18 published risk SNPs and model-derived breast cancer risk estimates.Methods:Subjects were 475 unaffected, BRCA mutation-negative women who were evaluated for a family history of breast or ovarian cancer. At the time of testing, subjects provided information that was used to estimate absolute breast cancer risk by Gail, Claus, and BRCAPro models. Subjects were genotyped by Sequenom iPLEX MassArray (Sequenom, Inc., San Diego, CA) at loci reported to be associated with elevations in breast cancer risk (1p11.2, 2q35, 5p12, 6q22.33, 8q24, CASP8, COX11, FGFR2, LSP1, MAP3K1, RAD51L1, SLC4A7, TNRC9). Kruskal-Wallis and Spearman correlation tests were used to compare risk estimates for individuals by genotype and number of risk alleles.Results:The median age at sample donation was 46 years (range 24-83). Most subjects (94.9%) were white, and 65.5% were of Ashkenazi Jewish (AJ) ancestry. Median breast cancer risk scores risk estimates were significantly lower from BRCAPro (5 yr: 1.1%, lifetime (LT): 11.6%) than those derived from Gail (5 yr: 1.8%, LT: 18.5%) or Claus (5 yr: 1.5%, LT: 11.8%) models. No significant differences (p&amp;gt;0.05) in distribution of estimated breast cancer risk scores were found between women carrying 0, 1, or 2 risk alleles at any locus except 6q22.33, where AJ women homozygous for the risk allele rs2180341 were noted to have higher LT Claus (p=0.001) and BRCAPro (p=0.01) estimates. When comparing subjects with no risk alleles to those with 1-2 risk alleles for each SNP, no significant differences in distribution of estimated risk were noted at any loci, including 6q22.33. There was no significant correlation between the total number of risk alleles carried by a subject and her estimated lifetime Gail (ρ=-0.052, P=0.27), Claus (ρ=0.051, P=0.32), or BRCAPro (ρ=0.024, P=0.60) risk.Conclusions:In this analysis, risk allele genotype did not correlate with absolute breast cancer risk estimated by standard models. This suggests that the contribution to risk of genotype at these SNPs is insufficient to impact the modeled estimate. Further studies are necessary to evaluate whether incorporation of genotypic information can improve the calibration or discriminatory accuracy of existing models. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 901.

Breast cancer risk in mutation-negative members of known BRCA1/2 mutation-positive families.

Abstract Abstract #1093 Background: Women with deleterious mutations in BRCA1 and BRCA2 have a 40-85% lifetime risk of breast cancer. Female members of BRCA1/2 mutation-positive families who do not carry the family mutation have been counseled as having a breast cancer risk similar to that of the general population. However, recent data suggest that such women may have a 2-to 5-fold increased breast cancer risk, despite being mutation-negative.&amp;#x2028; Methods: We compared the number of prospectively-diagnosed breast cancers in mutation-negative women in an NCI cohort of families with known deleterious BRCA1/2 mutations to an age-, race-, calendar time-specific expected number derived from the SEER 9 Cancer Registries. The family population included all bloodline individuals within three degrees of relatedness to a known mutation carrier. Data were obtained via mailed questionnaire or in-person follow-up. Individuals were eligible for analysis if (1) we had updated cancer status from the individual or a first-, second- or third-degree relative within the past year; and (2) they were tested- or inferred-negative for the family mutation. Individual follow-up began at date of family ascertainment or at age 25 for women who were &amp;lt;25 at family ascertainment. Study follow-up was completed at the date of the most recent family or personal contact, date of death, date of breast cancer diagnosis or date of bilateral mastectomy.&amp;#x2028; Results: We included 395 mutation-negative members from 28 BRCA1/2 positive families in this analysis. Cancer status was obtained from: subjects (33%), first-degree relatives (34%), second-degree relatives (16%), and third-degree relatives (13%). 3% of the participants did not have close family contact within the past year; their follow-up was truncated at last personal contact date. The mean age at study entry was 31.3 years. The mean length of follow-up was 17.7 years. 50 women underwent bilateral oophorectomy prior to or during study follow-up (13%). Study participants contributed a total of 6982.6 person-years of follow-up. Nine women developed breast cancer (all were invasive), yielding an observed-to-expected ratio (O/E ratio) for invasive plus in situ breast cancer of 0.75 (95% CI 0.34-1.41), O/E ratio for invasive disease only = 0.86 (95% CI 0.39–1.63). Adjusting the expected breast cancer number for the known decrease in breast cancer risk among women undergoing oophorectomy did not substantially alter these results.&amp;#x2028; Conclusion: Our data suggest that breast cancer risk among mutation-negative women from BRCA1/2 mutation-positive families is similar to that observed in the general population. Although this is the largest prospective cohort yet assembled to address this important question, the number of breast cancer events is still small. Thus, we cannot exclude a small increase in breast cancer risk. Additional data are required to accurately determine risk in this population, in order to formulate evidence-based screening recommendations for this group of women. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1093.