Cancer In BRCA1 Mutation Carriers Research Articles

Factors influencing ovulation and the risk of ovarian cancer in BRCA1 and BRCA2 mutation carriers.

The role of the lifetime number of ovulatory cycles has not been evaluated in the context of BRCA-associated ovarian cancer. Thus, we conducted a matched case-control study to evaluate the relationship between the cumulative number of ovulatory cycles (and contributing components) and risk of developing ovarian cancer in BRCA mutation carriers (1,329 cases and 5,267 controls). Information regarding reproductive and hormonal factors was collected from a routinely administered questionnaire. Conditional logistic regression was used to evaluate all associations. We observed a 45% reduction in the risk of developing ovarian cancer among women in the lowest vs. highest quartile of ovulatory cycles (OR = 0.55; 95% CI 0.41-0.75, p = 0.0001). Breastfeeding for more than 12 months was associated with a 38% (95% CI 0.48-0.79) and 50% (95% CI 0.29-0.84) reduction in risk among BRCA1 and BRCA2 mutation carriers, respectively. For oral contraceptive use, maximum benefit was seen with five or more years of use among BRCA1 mutation carriers (OR = 0.50; 95% CI 0.40-0.63) and three or more years for BRCA2 mutation carriers (OR = 0.42; 95% CI 0.22-0.83). Increasing parity was associated with a significant inverse trend among BRCA1 (OR = 0.87; 95% CI 0.79-0.96; p-trend = 0.005) but not BRCA2 mutation carriers (OR 0.98; 95% CI 0.81-1.19; p-trend = 0.85). A later age at menopause was associated with an increased risk in women with a BRCA1 mutation (OR trend = 1.18; 95% CI 1.03-1.35; p = 0.02). These findings support an important role of breastfeeding and oral contraceptive use for the primary prevention of ovarian cancer among women carrying BRCA mutations.

Breast cancer following ovarian cancer in BRCA mutation carriers.

BRCA mutation carriers are at increased risk of developing breast cancer. However, the incidence of breast cancer after a diagnosis of epithelial ovarian cancer (EOC), one of the tubal/peritoneal cancers collectively referred to as pelvic serous carcinomas, is not well known. Optimal breast cancer surveillance and detection for these patients have also not been well characterized. To determine the incidence of breast cancer after a diagnosis of EOC and to evaluate the need for breast cancer surveillance for these patients. A retrospective database review of 364 patients who underwent BRCA mutation testing for EOC (stages I-IV) between 1998 and 2012 at an academic medical center with gynecologic and breast cancer centers. Incidence of breast cancer and methods of surveillance. Of 364 patients, 135 (37.1%) were found to carry a germline BRCA1 or BRCA2 mutation. The mean age of patients at diagnosis of EOC was 49.5 years (range, 28-89 years). Of the 135 patients, 12 (8.9%) developed breast cancer. The median time from diagnosis of EOC to diagnosis of breast cancer was 50.5 months. Annual mammography was performed for 80 patients (59.3%), with annual magnetic resonance imaging of the breasts performed for 60 patients (44.4%). Thirteen patients (9.6%) underwent a bilateral prophylactic mastectomy at a median of 23 months following EOC diagnosis. Breast cancer was most commonly diagnosed by mammography for 7 of the 12 patients (58.3%), 3 (25.0%) of whom had a palpable mass and 2 (16.7%) of whom had incidental breast cancer detected during a prophylactic mastectomy. Seven patients with breast cancer (58.3%) underwent a bilateral mastectomy. All patients had early-stage breast cancer (stages 0-II). Four patients (33.3%) received adjuvant chemotherapy. At a median follow-up of 6.3 years, 4 of the 12 patients (33.3%) died of recurrent EOC after a diagnosis of breast cancer. The overall 10-year survival rate for the entire cohort of 135 patients was 17.0%. The risk of metachronous breast cancer is low in patients with known BRCA mutations and EOC. A majority of these cases of breast cancer at an early stage are detected by use of mammography. Despite the small number of patients in our study, these results suggest that optimal breast cancer surveillance for patients with BRCA-associated EOC needs to be reevaluated given the low incidence of breast cancer among these high-risk patients. Confirmation of our findings from larger studies seems to be indicated.

Abstract 3812: Targeting BRCA1-deficient breast cancer by inhibition of the DEAD box RNA helicase DDX3X

Abstract Introduction: The DEAD box RNA helicase DDX3X (DDX3) has been demonstrated to have a pro-oncogenic role in breast cancer. Thus, abrogating DDX3 activity was explored as a viable anti-cancer strategy using a small molecule inhibitor of DDX3, referred to as RK-33. RK-33 was found to inhibit non-homologous end joining (NHEJ), a DNA double strand break (DSB) repair mechanism. Therefore, we set out to determine the utility of RK-33 in breast cancers of BRCA1 mutation carriers, as they exhibit deficiencies in homologous recombination, an additional DSB repair mechanism. We hypothesized that BRCA1-deficient breast cancers would be more dependent on NHEJ to maintain genomic stability and thus inhibiting DDX3 activity by RK-33 would be an efficacious treatment strategy. Methods: We evaluated DDX3 protein expression levels by immunohistochemistry in 102 BRCA1 and 29 BRCA2 germline mutation carriers and compared these to those of 345 sporadic breast cancer patients. In addition, DDX3 expression in two BRCA1-deficient (SUM149PT and HCC1937) and two BRCA1-proficient breast cancer cell lines (MCF-7 and MDA-MB-231) was quantified by immunoblotting. Furthermore, we compared the cell killing abilities of RK-33 in these BRCA1 pro- and deficient cell lines, as well as in MCF-7 cells before and after knockdown of BRCA1 by shRNA. Results: High cytoplasmic DDX3 expression is less frequent in BRCA1 (24.5%) and BRCA2 (20.7%) related breast cancer, when compared to sporadic breast cancer (34.2%; OR 0.63; 95% CI 0.38-1.03; P = 0.065). This difference is statistically significant when correcting for higher grade and basal-like subtype in the group of BRCA1 mutation carriers (OR 0.33; 95% CI 0.14-0.77; P = 0.01). The BRCA1 pro- and deficient cell lines expressed similar levels of DDX3 and had a comparable sensitivity to RK-33 with IC-50 values ranging between 2 and 7 uM. Knockdown of BRCA1 in MCF-7 did not result in an increased sensitivity to RK-33. Conclusion: DDX3 expression is lower in breast cancer in BRCA1 mutation carriers, when compared to sporadic breast cancers of similar grade and molecular subtype. BRCA1 pro- and deficient breast cancer cell lines are equally sensitive to inhibition of DDX3 by RK-33. This indicates that abrogating NHEJ activity by RK-33 results in cell death irrespective of additional deficiencies in the DNA repair pathway. Given that RK-33 showed good in vitro efficacy to kill all breast cancer cell lines, additional research is required to evaluate the use of RK-33 as a targeted chemotherapy agent for breast cancer. Citation Format: Marise R. Heerma van Voss, Farhad Vesuna, Guus M. Bol, Paul J. van Diest, Venu Raman. Targeting BRCA1-deficient breast cancer by inhibition of the DEAD box RNA helicase DDX3X. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3812. doi:10.1158/1538-7445.AM2014-3812

Distinct claudin expression characterizes BRCA1-related breast cancer.

Members of the claudin family are involved in cancer progression and are differentially expressed in subtypes of breast cancer. Breast cancers in BRCA1 germ line mutation carriers have distinct clinicopathological characteristics. Biomarkers that discriminate between BRCA1-related and sporadic breast cancer cases are needed to improve early identification of mutation carriers. In this study we evaluated protein expression of five major claudins in BRCA1-related breast cancers in comparison with sporadic controls. Forty breast cancers in BRCA1 mutation carriers and 40 age-matched sporadic breast cancers were immunohistochemically stained for claudins 1, 3, 4, 6 and 7. Total intratumoural expression levels were compared to those in the surrounding normal tissue. In addition, subcellular claudin expression was scored. Higher overexpression rates were observed for all five claudins in BRCA1-related breast cancers when compared to sporadic controls. In multivariate analysis, overexpression of claudin 3, 4, and 7 was mainly dependent on ER-status, whereas overexpression of claudin 6 and high membranous expression of claudin 1 were independent of other characteristics. BRCA1-related breast cancers are characterized by frequent overexpression of claudins. Especially claudin 1 and 6 expression may help to discriminate mutation carriers from sporadic breast cancer cases.

Overall survival and clinical characteristics of pancreatic cancer in BRCA mutation carriers.

Background:The BRCA1/2 proteins are involved in regulation of cellular proliferation by DNA damage repair via homologous recombination. Therefore, BRCA1/2 mutation carriers with pancreatic cancer may have distinct biologic outcomes.Methods:Patients with BRCA1/2-associated pancreatic ductal adenocarcinoma (PDAC) diagnosed between January 1994 and December 2012 were identified from databases at three participating institutions. Clinical data were collected. Disease-free survival and overall survival (OS) were analysed.Results:Overall, 71 patients with PDAC and BRCA1 (n=21), BRCA2 (n=49) or both (n=1) mutations were identified. Mean age at diagnosis was 60.3 years (range 33–83), 81.7% (n=58) had any family history of malignancy; 30% (n=21) underwent primary resection. Out of 71 participants, 12 received experimental therapy; one patient had missing data, these 13 cases were excluded from OS analysis. Median OS for 58 patients was 14 months (95% CI 10–23 months). Median OS for patients with stage 1/2 disease has not been reached with 52% still alive at 60 months. Median OS for stage 3/4 was 12 months (95% CI 6–15). Superior OS was observed for patients with stage 3/4 treated with platinum vs those treated with non-platinum chemotherapies (22 vs 9 months; P=0.039).Conclusion:Superior OS was observed for advanced-disease BRCA-associated PDAC with platinum exposure.

Breast cancer following ovarian cancer in BRCA mutation carriers: What is the cost of surveillance?

Objectives: Women with BRCA mutations have an elevated risk of developing breast cancer and epithelial ovarian cancer (EOC) (ovary, fallopian tube, and peritoneal carcinomas). We compared the costs of breast cancer surveillance between BRCA mutation carriers and women without mutations (WT) following a diagnosis of EOC.

Modifiers of cancer risk in BRCA1 and BRCA2 mutation carriers: systematic review and meta-analysis.

There is substantial variability in cancer risk in women who have inherited a BRCA1 or BRCA2 (BRCA1/2) mutation. Numerous factors have been hypothesized to modify these risks, but studies are of variable quality, and it remains unclear which of these may be of value in clinical risk assessment. PubMed and Web of Science databases were searched for articles published through September 2013. Fixed effects meta-analysis was done using the hazard ratios and/or odds ratios to estimate the pooled effect estimates (ES) and 95% confidence intervals (CIs) to identify factors that are associated with cancer risk modification in BRCA1/2 mutation carriers. We identified 44 nonoverlapping studies that met predefined quality criteria. Sufficient evidence is available to make clinically relevant inferences about a number of cancer risk modifiers. The only variable examined that produced a probable association was late age at first live birth, a meta-analysis showed a decrease in the risk of breast cancer in BRCA1 mutation carriers with women aged 30 years or older vs. women younger than 30 years (ES = 0.65; 95% CI =0.42 to 0.99). The same was shown for women aged 25 to 29 years versus those aged less than 25 years (ES = 0.69; 95% CI = 0.48 to 0.99). Breastfeeding and tubal ligation were associated with reduced ovarian cancer risk in BRCA1 mutation carriers; oral contraceptives were associated with reduced risk among BRCA1/2 mutation carriers. Smoking was associated with increased breast cancer risk in BRCA2 mutation carriers only. Data assessing many potential risk modifiers are inadequate, and many have not been externally validated. Although additional studies are required to confirm some associations, sufficient information is available for some risk factors to be used in risk counseling or lifestyle modification to minimize cancer risk in BRCA1/2 mutation carriers

Surgical management of breast cancer in BRCA-mutation carriers: a systematic review and meta-analysis

This meta-analysis investigates the oncological safety of breast-conserving therapy BCT in BRCA-mutation carriers and the risk for contralateral breast cancer (CBC) compared with non-carriers, potential risk factors for ipsilateral breast recurrence (IBR) or CBC and grades these factors based on the level of evidence. A PubMed search was conducted through April 2013 to identify studies that described the risk for IBR and CBC after BCT in BRCA-mutation carriers versus non-carriers as well as studies that investigated risk factors for IBR and CBC in BRCA-mutation carriers. Results were summarized using meta-analysis when sufficient studies were available. Ten studies investigated the oncological safety of BCT in BRCA-mutation carriers versus non-carriers. There was no significant difference in IBR between carriers and controls (RR 1.45, 95 % CI 0.98-2.14). However, a significant higher risk for IBR in BRCA-mutation carriers was observed in studies with a median follow-up ≥7 years (RR 1.51, 95 % CI 1.15-1.98). CBCs were significantly greater in carriers versus controls (RR 3.56, 95 % CI 2.50-5.08). Use of adjuvant chemotherapy and oophorectomy were associated with a significantly lower risk for IBR in BRCA-mutation carriers. Three factors were associated with a lower risk for CBC in BRCA-mutation carriers: oophorectomy, use of tamoxifen, and age at first breast cancer. Based on current evidence, the use of BCT in BRCA-mutation carriers can be considered a reasonable option since it does not seem to increase the risk for IBR. However, several aspects should be taken into account before the final decision-making.

Abstract P5-15-06: Surgical management of breast cancer in BRCA-mutation carriers: A clinical approach based on a systematic review

Abstract Background The optimal local management of early-stage breast cancer in BRCA-mutation carriers remains a matter of debate. These patients are facing the difficult question to choose among breast-conserving therapy (BCT), unilateral mastectomy or prophylactic bilateral mastectomy. The purpose of this meta-analysis is to investigate the oncological safety of BCT in BRCA-mutation carriers and the risk for contralateral breast cancer (CBC) compared with non-carriers, to identify potential risk or protective factors for ipsilateral breast recurrence (IBR) or CBC and to grade these factors based on the level of evidence. Methods A PubMed search was conducted through March 2013 to identify studies that described the risk for IBR and CBC after BCT in BCRA-mutation carriers versus non-carriers as long as studies that investigated risk/protective factors for IBR and CBC in BRCA-mutation carriers. We collated the risk/protective factors into four levels of evidence (high, moderate, low, inconclusive), depending on consistency of findings and quality and quantity of studies contributing to findings. For each risk factor, we abstracted odds ratios (ORs), hazard ratios (HRs), or risk ratios (RRs) and associated 95% Confidence Intervals (CIs), based only on adjusted estimates obtained from multivariate analyses. Results were summarized by using meta-analysis when sufficient studies were available. Results Ten studies (7 cohort and 3 case-control; 2826 patients) investigated the oncological safety of BCT in BRCA-mutation carriers versus non-carriers. There was no significant difference in IBR between carriers and controls (RR: 1.45, 95% CI: 0.98-2.14, p-value = 0.07). However, CBCs were significantly greater in carriers versus controls (RR: 3.56, 95% CI: 2.50 – 5.08, p-value < 0.001) (11 studies; 3970 patients). Patients with BRCA-1 mutation had a higher risk of CBC than patients with BRCA-2 mutation (RR: 1.42, 95% CI: 1.01-1.99, p-value = 0.04). Use of adjuvant chemotherapy (HR: 0.51, 95% CI 0.31-0.84) and oophorectomy (HR: 0.42, 95% CI 0.22-0.81) were associated with a significantly lower risk for IBR in BRCA-mutation carriers, with a moderate level of evidence, while use of tamoxifen did not significantly alter the risk. Three factors were associated with a lower risk of CBC in BRCA-mutation carriers: oophorectomy (moderate level of evidence), use of tamoxifen (moderate level of evidence), and age at first breast cancer (decreased incidence of CBC with increasing age; high level of evidence). Conclusion Based on current evidence, the use of BCT in BRCA-mutation carriers can be considered a reasonable option since it does not seem to increase the risk of IBR. However, several aspects should be taken into account before the final decision-making, including the 3.5-fold increased risk for CBC and the presence of several factors that can alter the risk of IBR and CBC. The identification of these risk factors may be useful in the discussion on the different surgical treatment options with these patients. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-15-06.

Breast cancer risk in BRCA1 mutation carriers: insight from mouse models

Since its identification 20 years ago, the biological basis for the high breast cancer risk in women who have germline BRCA1 mutations has been an area of intense study for three reasons. First, BRCA1 was the first gene shown to associate with breast cancer risk, and therefore serves as model for understanding genetic susceptibility. Second, the type of breast cancer that occurs in these women has specific features that have engendered new hypotheses about the cancer biology. Third, it is hoped that understanding the origins of this disease may provide the means to prevent disease. Resolving this question has proven extremely challenging because the biology controlled by BRCA1 is complex. Our working model is that the high frequency of basal-like breast cancer in BRCA1 mutation carriers is the result of a self-perpetuating triad of cellular phenotypes consisting of: (i) intrinsic defects in DNA repair and centrosome regulation that lead to genomic instability and increases spontaneous transformation; (ii) aberrant lineage commitment; and (iii) increased proliferation due to in large part to increased IGF-1 activity. We propose that the last is key and is a potential entree for preventing breast cancer in BRCA1 mutation carriers.

Ovarian Cancer in BRCA Mutation Carriers: Improved Outcome After Intraperitoneal (IP) Cisplatin

Ovarian cancer arising in women with BRCA mutations is known to have a more favorable outcome and to be more responsive to platinum-based regimens than in those without a hereditary background. We analyze our previously published intraperitoneal (IP) studies in relation to BRCA mutation status and update their outcomes. Among 62 patients with ovarian cancer enrolled in IP platinum doublet studies in clinical trials (with etoposide (n = 18), with floxuridine (n = 30), and with topotecan (n = 14)), a deleterious BRCA mutation was eventually identified in 10 patients. The outcomes in these BRCA mutation carriers are described and compared with survival of others in respective trials. Ten patients that were confirmed to have BRCA mutations-all with high-grade and stages IIC to IV disease-survived a median of 10 years (range: 4-18+) after receiving IP cisplatin-based regimens. Two continue with no evidence of disease since their IP treatment, while four others remain alive with recurrences after 8, 9, 10, and 11 years, respectively. This experience suggests that IP cisplatin leads to favorable long term outcomes in advanced ovarian cancer in women with defective homologous recombination (i.e., with deleterious BRCA mutations). Whether such cisplatin dose-intensification from IP relative to (intravenous) IV drug administration leads to superior results in these mutation carriers requires further study.

When you hear hoof beats, don’t forget the zebra: The role of nonserous ovarian cancer in BRCA mutation carriers

When you hear hoof beats, don’t forget the zebra: The role of nonserous ovarian cancer in BRCA mutation carriers

The claudin expression signature of BRCA1-deficient breast cancer.

e22174 Background: Unraveling the biology of BRCA1 related breast cancers may help to improve early detection methods in mutation carriers and patient tailored therapy. Claudins constitute a family of integral membrane proteins, forming the backbone of tight junctions. Altered claudin expression has been linked to oncogenesis in several ways. Decreased cellular polarity increases nutrient and growth factor supply to the rapid expanding tumor cells and decreased intercellular attachments might increase metastatic potential. The discovery of a claudin-low intrinsic subtype of breast cancer has further increased the interest in claudin expression. This study searched for distinct claudin expression profiles that characterize BRCA1 related breast cancers. Methods: 40 BRCA1 related breast cancers and 40 age-matched sporadic breast cancers were immunohistochemically stained for claudin 3, claudin 4, claudin 6 and claudin 7. Cytoplasmic and membranous expression were scored. In addition, a score was given for the overall expression (cytoplasmic and membranous combined) in comparison to the surrounding normal breast tissue. Results: Distinct claudin expression profiles were observed in BRCA1 deficient breast cancers. The hereditary cases had significantly more overexpression of claudin 3, when compared to the tumor surrounding tissue (45.7% vs 17.9%, p=0.03). Membranous claudin 6 expression was seen in 28% in BRCA1 related, compared to only 2.9% in sporadic cases (p=0.007; OR 13.2 95% CI 1.50-116). Claudin 6 was also more often overexpressed, when compared to the normal surrounding tissue in BRCA1 cases (62.5% vs. 19.4%). For claudin 7 an interesting pattern was observed. Membranous expression was observed more often in sporadic (80.0%) than hereditary (42.0%) carcinomas (p=0.001; OR 0.19 95% CI 0.07-0.50), whereas cytoplasmic expression was more abundant in BRCA1 related tumors (85.0% vs. 66.7%; p=0.06; OR 2.83 95% CI 0.95-8.46). Conclusions: Distinct claudin expression profiles characterize breast cancer in BRCA1 mutation carriers. Therefore, claudins may serve as biomarkers for diagnosis of BRCA1 related breast cancer. The mechanism of cytoplasmic relocalization of claudin 7 in BRCA1 deficient tumors deserves to be further studied.

Effect of the MDM2 promoter polymorphisms SNP309T>G and SNP285G>C on the risk of ovarian cancer in BRCA1 mutation carriers

BackgroundWhile BRCA mutation carriers possess a 20-40% lifetime risk of developing ovarian cancer, knowledge about genetic modifying factors influencing the phenotypic expression remains obscure. We explored the distribution of the MDM2 polymorphisms SNP309T>G and the recently discovered SNP285G>C in Norwegian patients with BRCA related ovarian cancer.Methods221 BRCA related ovarian cancer cases (BRCA1; n = 161 and BRCA2; n = 60) were tested for the MDM2 polymorphisms. Results were compared to healthy controls (n = 2,465).ResultsThe SNP309G allele was associated with elevated OR for ovarian cancer in BRCA1 mutation carriers (SNP309TG: OR 1.53; CI 1.07-2.19; p = 0.020; SNP309GG: OR 1.92; CI 1.19-3.10; p = 0.009; SNP309TG+GG combined: OR 1.61; CI 1.15-2.27; p = 0.005). In contrast, the SNP285C allele reduced risk of BRCA1 related ovarian cancer in carriers of the SNP309G allele (OR 0.50; CI 0.24-1.04; p = 0.057). Censoring individuals carrying the SNP285C/309G haplotype from the analysis elevated the OR related to the SNP309G allele (OR 1.73; CI 1.23-2.45; p = 0.002). The mean age at disease onset was 3.1 years earlier in carriers of SNP309TG+GG as compared to carriers of SNP309TT (p = 0.068). No such associations were found in BRCA2 related ovarian cancer.ConclusionsOur results indicate the SNP309G allele to increase and the SNP285C allele to reduce the risk of BRCA1 related ovarian cancer. If confirmed in independent studies, this finding may have implications to counseling and decision-making regarding risk reducing measures in BRCA1 mutation carriers.

Pathologic Features and Immunophenotype of Estrogen Receptor–positive Breast Cancers in BRCA1 Mutation Carriers

Although most breast cancers in BRCA1 mutation carriers are estrogen receptor negative (ER-) with a basal-like phenotype, up to one third are ER positive (ER+). Little is known about the characteristics of this subgroup. To address this, we compared histologic and immunophenotypic features of 60 BRCA1-related ER+ breast cancers with those of 85 BRCA1-related ER- cancers and 174 matched ER+ sporadic cancers. ER+ BRCA1-related cancers were significantly less likely than ER- BRCA1-related cancers to be of pure invasive ductal type (P<0.001) and to be of histologic grade 3 (P<0.001), and less frequently to have a high mitotic rate (P<0.001), pushing (or unknown) margins (P<0.001), a moderate/marked lymphocytic infiltrate (P=0.003), or geographic necrosis/fibrotic focus (P<0.001). In addition, ER+ BRCA1-related cancers less often expressed CK5/6 (P<0.0001), CK14 (P<0.0001), and epidermal growth factor receptor (P<0.0001) and more often expressed progesterone receptor (P<0.0001). In contrast, when compared with ER+ sporadic cancers, ER+ BRCA1-related cancers were significantly more often of invasive ductal type (P=0.005) and of histologic grade 3 (P=0.006), more frequently had a high mitotic rate (P=0.0003), and were more often CK14+ (P=0.03). On unsupervised cluster analysis, some ER+ BRCA1 cancers clustered more closely with sporadic ER+ cancers, whereas others clustered more closely with ER- BRCA1-related cancers. Nuclear expression levels of poly(ADP) ribose polymerase 1 in ER+ BRCA1-related cancers were similar to those in ER- BRCA1-related cancers but significantly higher than in ER+ sporadic cancers. We conclude that ER+ BRCA1-related breast cancers show several morphologic and immunophenotypic differences from ER+ sporadic breast cancers as well as some similarities to ER- BRCA1-related cancers.

Clinical correlates of ‘BRCAness’ in triple-negative breast cancer of patients receiving adjuvant chemotherapy

We have previously reported an array comparative genomic hybridization profile that identifies triple-negative breast cancers (TNBC), with BRCA1 dysfunction and a high sensitivity to intensified dose bifunctional alkylating agents. To determine the effect of conventional-dose chemotherapy in patients with this so-called BRCA1-like profile, clinical characteristics and survival were studied in a large group of TNBC patients. DNA was isolated and BRCA1-like status was assessed in 101 patients with early-stage TNBC receiving adjuvant cyclophosphamide-based chemotherapy. Clinical characteristics and survival were compared between BRCA1-like and non-BRCA1-like groups. Results Sixty-six tumors (65%) had a BRCA1-like profile. Patients with BRCA1-like tumors tended to be younger and had more often node-negative disease (P = 0.06 and P = 0.03, respectively). Five-year recurrence-free survival was 80% for the BRCA1-like group and 75% for the non-BRCA1-like group (P = 0.35). T stage was the only variable significantly associated with survival. BRCA1-like tumors share clinical features, like young age at diagnosis and similar nodal status, with breast cancers in BRCA1 mutation carriers. Their prognosis is similar to that of non-BRCA1-like tumors when conventional-dose chemotherapy is administered. TNBCs that are classified as BRCA1-like may contain a defect in homologous recombination and could, in theory, benefit from the addition of poly ADP ribose polymerase inhibitors.

Differences in Natural History between Breast Cancers in BRCA1 and BRCA2 Mutation Carriers and Effects of MRI Screening-MRISC, MARIBS, and Canadian Studies Combined

It is recommended that BRCA1/2 mutation carriers undergo breast cancer screening using MRI because of their very high cancer risk and the high sensitivity of MRI in detecting invasive cancers. Clinical observations suggest important differences in the natural history between breast cancers due to mutations in BRCA1 and BRCA2, potentially requiring different screening guidelines. Three studies of mutation carriers using annual MRI and mammography were analyzed. Separate natural history models for BRCA1 and BRCA2 were calibrated to the results of these studies and used to predict the impact of various screening protocols on detection characteristics and mortality. BRCA1/2 mutation carriers (N = 1,275) participated in the studies and 124 cancers (99 invasive) were diagnosed. Cancers detected in BRCA2 mutation carriers were smaller [80% ductal carcinoma in situ (DCIS) or ≤10 mm vs. 49% for BRCA1, P < 0.001]. Below the age of 40, one (invasive) cancer of the 25 screen-detected cancers in BRCA1 mutation carriers was detected by mammography alone, compared with seven (three invasive) of 11 screen-detected cancers in BRCA2 (P < 0.0001). In the model, the preclinical period during which cancer is screen-detectable was 1 to 4 years for BRCA1 and 2 to 7 years for BRCA2. The model predicted breast cancer mortality reductions of 42% to 47% for mammography, 48% to 61% for MRI, and 50% to 62% for combined screening. Our studies suggest substantial mortality benefits in using MRI to screen BRCA1/2 mutation carriers aged 25 to 60 years but show important clinical differences in natural history. BRCA1 and BRCA2 mutation carriers may benefit from different screening protocols, for example, below the age of 40.

Plasma micronutrients, trace elements, and breast cancer in BRCA1 mutation carriers: an exploratory study

Few studies have evaluated the role of micronutrients or trace elements in breast cancer development among BRCA1 mutation carriers. To investigate a possible role of dietary and environmental exposures on cancer risk, we undertook an exploratory study, using a matched case-control design (n = 48 cases and 96 controls), to evaluate the relationships between plasma levels of 14 micronutrients and breast cancer risk among BRCA1 mutation carriers in Poland. We estimated the univariate odds ratios (OR) and 95 % confidence intervals (CI) for breast cancer associated with plasma levels for each of 14 micronutrients. Of the 14 analytes quantified, significant differences between cases and controls were seen for two (iron and retinol; p = 0.009 and p = 0.03, respectively). Women in the highest tertile of plasma iron had a 57 % lower risk, compared with those in the lowest quartile (OR = 0.43; 95 % CI 0.18-1.04; p for trend = 0.06). Increasing antimony levels were associated with an increased risk of breast cancer (p for trend = 0.05). Women in the highest tertile had a 2.43-fold increase in breast cancer risk compared with women in the lowest tertile (OR = 2.43; 95 % CI 1.00-5.91). This study provides some preliminary evidence regarding a role of diet, specifically iron and antimony, in the etiology of BRCA1-associated breast cancer. Prospective studies are necessary to confirm these findings.

P4-18-03: Basal-Like Phenotype of BRCA Associated Ductal Carcinoma In-Situ.

Abstract Background: Molecular profiling has identified different subtypes of invasive carcinoma. The basal-like tumors represent a subgroup that is known for aggressive behavior. The NCCN guidelines recommend genetic testing for patients with triple negative breast cancer as over 80% of breast cancers in BRCA1 mutation carriers are triple negative tumors, and 70% of those fulfill criteria for basal-like tumors. Ductal carcinoma in-situ (DCIS) is thought to represent a non-obligate precursor to invasive breast cancer. Little is known about basal-like precursor lesions and their association with germline BRCA mutations. The aims of this study were to characterize the immunohistochemical phenotype of BRCA associated DCIS and evaluate the clinical importance of such lesions. Material and Methods: We identified 32 cases of DCIS from 28 women with a known BRCA1/2 mutation, from our genetics database. Tumor samples were reviewed to identify areas of DCIS for staining. Five micron sections were stained on the Dako Autostainer with antibodies to estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER-2), epidermal growth factor receptor (EGFR), and CK 5/6. Results: 44% of the DCIS tumors were from BRCA1 mutation carriers and 56% from BRCA2 mutation carriers. 53% of the samples were triple negative (staining negative for ER, PR, HER-2) and 69% of the triple negative tumors were basal-like tumors (staining positive for either EGFR or CK5/6). The basal-like DCIS specimens were all high grade, and they all came from BRCA1 positive patients. 71% of BRCA1 positive DCIS had basal-like features. Conclusions: DCIS in BRCA1 mutation carriers shows basal-like features that are in line with historical control for invasive carcinomas in the same group, suggesting that DCIS is a precursor lesion for BRCA1 positive cancer. Although further investigation is needed, our data suggest that patients with basal-like DCIS should be offered genetic testing. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-18-03.

Common variants of the BRCA1 wild-type allele modify the risk of breast cancer in BRCA1 mutation carriers.

Mutations in the BRCA1 gene substantially increase a woman's lifetime risk of breast cancer. However, there is great variation in this increase in risk with several genetic and non-genetic modifiers identified. The BRCA1 protein plays a central role in DNA repair, a mechanism that is particularly instrumental in safeguarding cells against tumorigenesis. We hypothesized that polymorphisms that alter the expression and/or function of BRCA1 carried on the wild-type (non-mutated) copy of the BRCA1 gene would modify the risk of breast cancer in carriers of BRCA1 mutations. A total of 9874 BRCA1 mutation carriers were available in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) for haplotype analyses of BRCA1. Women carrying the rare allele of single nucleotide polymorphism rs16942 on the wild-type copy of BRCA1 were at decreased risk of breast cancer (hazard ratio 0.86, 95% confidence interval 0.77-0.95, P = 0.003). Promoter in vitro assays of the major BRCA1 haplotypes showed that common polymorphisms in the regulatory region alter its activity and that this effect may be attributed to the differential binding affinity of nuclear proteins. In conclusion, variants on the wild-type copy of BRCA1 modify risk of breast cancer among carriers of BRCA1 mutations, possibly by altering the efficiency of BRCA1 transcription.