Prevalence Of BRCA1 Mutations Research Articles

5 year Overall survival of triple negative breast cancer: A single institution experience.

e12580 Background: Triple negative breast cancer (TNBC) involves any breast cancer that does not express the genes for estrogen and progesterone receptors (ER /PR) and Her2/neu. TNBC accounts for approximately 10- 20% of invasive breast cancers and this sub-type carries a poorer prognosis. TNBC are also frequently associated with BRCA mutations. We performed a retrospective review of TNBC that were seen at our institution, Lehigh Valley Health Network from 2005 to 2009 for survival and prevalence of BRCA mutation. Methods: Breast Cancer cases that presented to Lehigh Valley Health Network (LVHN) from 2005 to 2009 and which were triple negative, hormone receptors negative/Her2 unknown and hormone receptor/Her2 unknown were retrieved from tumor registry. Records of the above cases were reviewed and only the breast cancer cases that were triple negative were included for the study. Data was collected for age, stage on presentation, treatment received, survival and presence of BRCA mutation if genetic testing was performed. Results: 388 Charts were reviewed and 224 cases were found to be TNBC with age range of 29 to 88 years. Of the TNBC cases, 41 were stage 0, 72 cases were stage 1, 64 cases were stage 2, 24 cases were stage 3 and 23 cases were stage 4 on presentation. Overall 5 year survival rate was 78.6%. The 5 year survival rates stage wise included 92.7% for stage 0, 95.8% for stage 1, 78.1% for stage 2, 54.2% for stage 3 and 26.1% for stage 4. 172 charts were reviewed for genetic testing. 144 cases did not get tested. Out of 32 cases that were tested, 17 had wild type, 9 had BRCA1 mutant and 6 had BRCA2 mutant. Conclusions: 224 triple negative breast cancer cases were seen at LVHN from 2005 to 2009. Majority of cases presented as early stages, stage 0 to II. Age ranges of patients were 29 to 88 years. Overall 5 year survival for TNBC was 78.6%. Prevalence of BRCA mutation is 7.21% of the triple negative breast cancer cases. This is lower than that reported in literature where the prevelance of BRCA mutation is approximately 20% of TNBC. Possible reasons for this variation include age at diagnosis and patients' refusal for testing. Of the patients that were tested the prevalence was 46.88% and may be attributed to additinal high risk features such as age and family history.

Identification of novel BRCA founder mutations in Middle Eastern breast cancer patients using capture and Sanger sequencing analysis.

Ethnic differences of breast cancer genomics have prompted us to investigate the spectra of BRCA1 and BRCA2 mutations in different populations. The prevalence and effect of BRCA 1 and BRCA 2 mutations in Middle Eastern population is not fully explored. To characterize the prevalence of BRCA mutations in Middle Eastern breast cancer patients, BRCA mutation screening was performed in 818 unselected breast cancer patients using Capture and/or Sanger sequencing. 19 short tandem repeat (STR) markers were used for founder mutation analysis. In our study, nine different types of deleterious mutation were identified in 28 (3.4%) cases, 25 (89.3%) cases in BRCA 1 and 3 (10.7%) cases in BRCA 2. Seven recurrent mutations identified accounted for 92.9% (26/28) of all the mutant cases. Haplotype analysis was performed to confirm c.1140 dupG and c.4136_4137delCT mutations as novel putative founder mutation, accounting for 46.4% (13/28) of all BRCA mutant cases and 1.6% (13/818) of all the breast cancer cases, respectively. Moreover, BRCA 1 mutation was significantly associated with BRCA 1 protein expression loss (p = 0.0005). Our finding revealed that a substantial number of BRCA mutations were identified in clinically high risk breast cancer from Middle East region. Identification of the mutation spectrum, prevalence and founder effect in Middle Eastern population facilitates genetic counseling, risk assessment and development of cost‐effective screening strategy.

Selecting Patients with Ovarian Cancer for Germline BRCA Mutation Testing: Findings from Guidelines and a Systematic Literature Review.

One of the most significant risk factors for the development of ovarian cancer (OC) is a genetic mutation in BRCA1 (breast cancer gene 1) or BRCA2. Here we describe the impact of previous and current guidance on BRCA testing practices and provide evidence about which characteristics best identify patients with OC and an underlying germline BRCA mutation. A search was conducted for guidelines recommending genetic testing to identify constitutional pathogenic mutations in the BRCA genes. In addition, a systematic literature search of studies published in 2003-2015 was performed to assess BRCA mutation frequency in population-based OC patients unselected for patient characteristics (personal history, family history, and Ashkenazi Jewish ethnicity) and to describe the association of patient characteristics with BRCA mutation. Exclusively, studies assessing epithelial OC or invasive epithelial OC with full-gene screening of both BRCA1 and BRCA2 mutations were evaluated. Of 15 guidelines recommending genetic testing for OC patients, only 5 do not require co-occurrence of specific patient or family characteristics. Twenty-two full publications were identified that assessed germline BRCA mutation frequency in women with OC, utilizing a range of different full mutation detection methods. Germline BRCA mutation prevalence in patients with OC was 5.8-24.8%. Using criteria recommended in guidelines that are yet to be updated, we estimated that 27.5% of all germline BRCA mutations present in patients with OC may be missed because patients do not meet appropriate criteria. With the availability of BRCA mutation-targeted therapies, identification of patients with OC with germline BRCA mutations has potential therapeutic consequences. For identified gene carriers, predictive testing to allow cancer prevention strategies, including bilateral salpingo-oophorectomy, provides wider benefit to identifying such gene carriers. Updating guidelines will increase the opportunity for targeted treatment among patients and risk reduction in relatives. AstraZeneca.

Abstract IA23: Steps to address the profound disparity in access to genetic cancer risk assessment in Mexico: Documenting hereditary breast and ovarian cancer and the beginning of a prevention program

Abstract IA23: Steps to address the profound disparity in access to genetic cancer risk assessment in Mexico: Documenting hereditary breast and ovarian cancer and the beginning of a prevention program

Abstract B17: Family history of breast and ovarian cancer prevalence and its association with triple-negative subtype in Hispanic women

Abstract Background: A family history of breast cancer in a first-degree relative is an established risk factor for breast cancer; however, little is known about the profile of breast and ovarian family history in Hispanic/Latina women. Importance of this relates to recent reports showing a high prevalence of BRCA mutations in Hispanic/Latina women and a pattern of multiple recurrent mutations. In addition, less is known about the association of family history and tumor subtype in this growing ethnic group in the U.S. Methods: Study participants included breast cancer patients of Mexican descent enrolled in the Ella Binational Breast Cancer Study. We first assessed the self-reported breast and ovarian family history profile in 1,150 women. Second, we compared differences in family history of breast and ovarian cancer prevalence between triple negative breast cancer (TNBC) and non-TNBC in 914 patients with available tumor subtype data. Logistic regression was conducted to compare odds of TNBC to non-TNBC according to family history of breast and ovarian cancer. Results: Prevalence of breast cancer family history in a first- and first- or second-degree relative was 13.1% and 24.1%, respectively. A history of breast or ovarian cancer in first-degree relatives was reported in 14.9% of the women. After adjustment for age and country of residence, women with a first-degree relative with breast cancer were more likely to be diagnosed with TNBC compared to non-TNBC (OR=1.98; 95% CI, 1.26-3.11). The odds of TNBC compared to non-TNBC was 1.93 (95% CI, 1.26–2.97) for women with first-degree relatives with breast or ovarian cancer. There was a suggestion of stronger associations between family history and TNBC among women diagnosed at age <50 compared to those >50 years for breast cancer history in first-degree (P-interaction=0.14) and first- or second-degree relatives (P-interaction=0.07). Conclusion: Findings suggest that familial cancers are associated with triple negative subtype, possibly related to the prevalence of BRCA mutations in Hispanic women, which are strongly associated with TNBC. Improvement in collection of family history through new tools and instruments targeting English- and Spanish-speaking Hispanic women should be a priority for future research. Identification of a strong family history can ultimately affect treatment plans, screening practices, and prevention options both for patients and their relatives. Citation Format: Maria Elena Martinez, Kristin Anderson, Patricia Thompson, Betsy C. Wertheim, Lorena Martin, Ian Komenaka, Melissa Bondy, Adrian Daneri-Navarro, Maria Mercedes Meza-Montenegro, Luis Enrique Gutierrez-Millan, Abenaa Brewster, Lisa Madlensky, Malaika Tobias, Loki Natarajan. Family history of breast and ovarian cancer prevalence and its association with triple-negative subtype in Hispanic women. [abstract]. In: Proceedings of the Seventh AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 9-12, 2014; San Antonio, TX. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2015;24(10 Suppl):Abstract nr B17.

Carcinogenic Factors of Breast Cancer in Female of Pakistan

Among all forms of cancers, Breast cancer is the most common type of cancer in females worldwide. It is in fact the second leading causes of death among female population. However, incidence rate of breast cancer is higher among Pakistani females compare to other countries of Asia. The major factors that play important role in the development of breast carcinoma are the genetics and environment, the reproductive experience, the effect of endogenous and exogenous hormones in females and the change in immune status. However, in the Pakistani women hormonal factors including age of menarche, use of oral contraceptives, central obesity, family history, polycystic ovaries, nulliparity, late age at first pregnancy, smoking, alcohol consumption and lack of breast feeding are some of the most common risk factors developing breast cancer. Furthermore, the high prevalence of BRCA mutations indicates the importance of genetic counseling. Focus should be given to find out the genetic factors causing breast cancer in Pakistani population to elucidate the genetic cause leading to breast cancer development in order to prevent and decrease its incidence.

A high frequency of BRCA mutations in young black women with breast cancer residing in Florida.

Black women are disproportionately affected with triple-negative breast cancer and have relatively poor survival. To the authors' knowledge, it is not known to what extent differences in the clinical presentation of breast cancer between non-Hispanic white women and black women can be accounted for by the presence of mutations in the BRCA1 and BRCA2 genes. The authors sought to evaluate the frequency of BRCA pathogenic variants in a population-based sample of young black women with breast cancer. Black women diagnosed with invasive breast cancer at age ≤50 years from 2009 to 2012 were recruited to the study through the Florida Cancer Registry. Participants underwent genetic counseling, completed a study questionnaire, and consented to release of their medical records. Saliva specimens were collected for BRCA sequencing and large rearrangement testing through multiplex ligation-dependent probe amplification. A DNA sample was evaluated for 396 women, 49 of whom (12.4%) had a mutation in BRCA1 or BRCA2. Eight recurrent mutations accounted for 49% of all pathogenic variants. To the authors' knowledge, the prevalence of BRCA mutations among the Florida-based sample of young black women with breast cancer in the current study exceeds that previously reported for non-Hispanic white women. It is appropriate to recommend BRCA testing in all young black women with invasive breast cancer.

Abstract B113: Prevalence of germline BRCA and mismatch repair (MMR) gene mutations in pancreatic cancer

Abstract Background: Germline mutations of BRCA1, BRCA2, MLH1, MSH2, and MSH6 are known to increase risk of pancreatic cancer. However, the prevalence of pathogenic germline mutations of these genes among pancreatic cancer patients is unknown. Accurately characterizing the frequencies of mutations of these genes will inform patient selection for future gene discovery studies and, clinically, foster screening strategies and tailored treatments. Objective: To determine the prevalence of pathogenic germline mutations of BRCA1, BRCA2, MLH1, MSH2, and MSH6 in a cohort of pancreatic cancer patients, and to determine the association between mutation carrier status and personal and family history of cancer. Methods: The Ontario Pancreas Cancer Study (OPCS) enrolls all consenting participants with a diagnosis of pancreatic cancer into a province-wide electronic pathology database. A cross-sectional sample of 300 patients from 715 OPCS probands enrolled between April 2003 and August 2012 were randomly selected from three strata based on a family history of pancreatic, breast, and ovarian cancer. Targeted next-generation sequencing was successfully performed on germline DNA from 291 of the 300 selected probands. Mutations were classified as benign, of unknown significance, or pathogenic by literature and database review. Pathogenic mutations were confirmed with Sanger sequencing. Prevalence estimates representing the whole OPCS were estimated using the Horvitz-Thompson estimator. Univariate analysis determined association between carrier status and clinical covariates, and regression analysis for overall survival. Results: A total of 7 pathogenic germline mutations were identified: 1 BRCA1, 2 BRCA2, 1 MLH1, 2 MSH2, and 1 MSH6. The estimated prevalence of pathogenic mutations in BRCA1 and BRCA2 among probands in this OPCS series was 1.1% (95% confidence interval: 0.1-2.0%); in the mismatch repair genes MLH1, MSH2, and MSH6 it was 1.5% (0.3-2.6%). Both a personal history of colorectal cancer and a first-degree relative with colorectal cancer, breast cancer, or melanoma were significantly associated (p<0.001 and p<0.01, respectively) with MMR mutations. There were no significant differences in tumor location within the pancreas (head/uncinate versus body/tail), clinical nodal status, rates of resection, age at diagnosis, BMI, history of smoking, history of pancreatitis, family history of pancreatic cancer, family history of colorectal cancer, or differences in survival between the MMR or sporadic cohorts. Conclusion: This study is the first to quantify population-based prevalences of germline mutations of BRCA1, BRCA2, MLH1, MSH2, and MSH6 in pancreatic cancer. Surprisingly, the prevalence of pathogenic germline mutations of the MMR genes in pancreatic cancer is higher than expected, and is comparable to that of BRCA1 and BRCA2. The prevalence of the MMR germline mutations is also comparable to the prevalence of MMR germline mutations in colorectal cancer cohorts. Relatives who carry MMR gene mutations can benefit from tailored cancer prevention strategies; thus mutational analysis of MLH1, MSH2, and MSH6 should be included in molecular genetic testing and counseling strategies for pancreatic cancer patients, especially those with a family history of malignancy. Translational studies will follow to determine if stratifying pancreatic cancer risk by familial susceptibility genes, as in colorectal cancer, fosters tailored and cost-effective primary and secondary prevention strategies for carriers. Moreover, unique chemotherapy sensitivity and resistance patterns would be expected for MMR-associated pancreatic cancer, as is emerging for BRCA-associated pancreatic cancer. Citation Format: Iris Selander, Robert Grant, Ashton Connor, Shamini Selvarajah, Ayelet Borgida, Laurent Briollais, Jordan Lerner-Ellis, Spring Holter, Steven Gallinger. Prevalence of germline BRCA and mismatch repair (MMR) gene mutations in pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B113.

Abstract P1-11-04: Implementation of cancer risk assessment and genetic testing in underserved patients

Abstract PURPOSE: There is great disparity in genetic testing for breast cancer. Hispanic/Latina women with breast cancer are more likely to have adverse clinical features and have a high prevalence of BRCA mutations. We propose that Academic-Community clinic partnerships offer great potential to provide access to genetic cancer risk assessment (GCRA) for underserved communities, including Hispanic/Latina women. The study also evaluated the willingness of these patients to participate in biospecimen collection. METHODS: This study assessed the implementation of a limited GRCA and testing service at a safety net institution from July 1, 2011 to December 31, 2013. In the 10 years prior, only two breast cancer patients had undergone genetic testing and both were insured. The inability to perform GCRA was recognized as a critical area of need. Therefore, a breast surgical oncologist received training with City of Hope National Medical Center. The goal is to provide clinicians the appropriate skills to provide GCRA services in areas where these are not available. Three generation pedigrees and sociodemographic information were collected including health literacy, education, self-reported income, employment status, and insurance status. We conducted a comparison of the patient characteristics along the continuum of GCRA, genetic testing, and mutation carriers, and for the latter group, we describe the BRCA mutation profile. RESULTS: 125 patients were offered GCRA and all accepted, of which 70% of this patient population was Hispanic and 66% did not have health insurance. Of the 125 patients, 84 (67%) were recommended to undergo genetic testing and 81 (96%) agreed. Of the 81 patients who underwent genetic testing, 68 were also asked to participate in the City of Hope Cancer Screening and Prevention registry and all but one (94%) agreed. Significant differences between patients who had genetic testing and those who did not were shown for race/ethnicity, insurance, and family history. A higher percentage of Hispanic patients and patients with no insurance underwent testing. Additional trends in differences between patients who were tested vs. those who were not were observed for education and health literacy but these were not statistically significant. Few differences were observed between women who had genetic testing and mutation carriers; however, the number of carriers was too small to merit statistical testing. Twelve of 81 (15%) patients were found to have deleterious mutations, seven BRCA 1 and five BRCA 2. Of the 12 mutation carriers, one patient had ovarian cancer and therefore had already undergone bilateral salpingo-oophorectomy and two others underwent RRSO. Six are either considering RRSO or getting financial assistance for the operation. The last three are still undergoing breast cancer treatment. CONCLUSION: Results of our experience at a safety net hospital with a largely minority and uninsured population show that limited GCRA and testing can be successfully implemented. The great majority of patients agree to undergo counseling, testing, and participate in biospecimen research registries. Current recommendations for genetic counseling are far from being met across the country and this model could be considered for similar safety net populations. Citation Format: Ian K Komenaka, Lisa M Winton, Jesse N Nodora, Lisa Madlensky, Meredith A Heberer, Richard Schwab, Marcia E Bouton, Jeffrey N Weitzel, Maria Elena Martinez. Implementation of cancer risk assessment and genetic testing in underserved patients [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 P1-11-04.

The prevalence and spectrum of BRCA1 and BRCA2 mutations in Korean population: recent update of the Korean Hereditary Breast Cancer (KOHBRA) study.

The Korean Hereditary Breast Cancer (KOHBRA) study was established to evaluate the prevalence and spectrum of BRCA1/2 mutations in Korean breast cancer patients at risk for hereditary breast and ovarian cancer. A total of 2953 subjects (2403 index patients and 550 family members of affected carriers) from 36 centers participated in this study between May 2007 and December 2013. All participants received genetic counseling and BRCA genetic testing. In total, 378 mutation carriers among 2403 index patients were identified. The prevalence of BRCA mutations in specific subgroups was as follows: 22.3% (274/1228) for breast cancer patients with a family history of breast/ovarian cancers, 8.8% (39/441) for patients with early-onset (<35years) breast cancer without a family history, 16.3% (34/209) for patients with bilateral breast cancer, 4.8% (1/21) for male patients with breast cancer, and 37.5% (3/8) for patients with both breast and ovarian cancer. From an analysis of the mutation spectrum, 63 BRCA1 and 90 BRCA2 different mutations, including 44 novel mutations, were identified. The c.7480 (p.Arg2494Ter) mutation in BRCA2 (10.1%) was the most commonly identified in this cohort. The KOHBRA study is the largest cohort to identify BRCA mutation carriers in Asia. The results suggest that the prevalence of BRCA mutations in familial breast cancer patients is similar to that among Western cohorts. However, some single risk factors without family histories (early-onset breast cancer, male breast cancer, or multiple organ cancers) may limit the utility of BRCA gene testing in the Korean population.

Prevalence of BRCA1 mutations and responses to neoadjuvant chemotherapy among BRCA1 carriers and non-carriers with triple-negative breast cancer

The frequency of BRCA1 germline mutations among Chinese women with triple-negative breast cancer is unclear, and the association between BRCA1 mutations and the response to neoadjuvant chemotherapy in women with triple-negative breast cancer has not been determined. Nine hundred and fifty-six triple-negative breast cancer patients were treated at our institute between 2003 and 2012; we tested the BRCA1/2 mutations for 956 patients and 953 patients in this cohort, respectively. Among the 956 patients, 652 patients received neoadjuvant chemotherapy. In this cohort, 7.1% (68/956) and 2.3% (22/953) of patients carried a BRCA1 or BRCA2 mutation, respectively. The BRCA1/2 mutation rates were 10.5% and 3.0% among the patients who were diagnosed at or before the age of 50 in this cohort, respectively. The pCR (pathologic complete response) rate was 31.6% in the 652 patients who received neoadjuvant chemotherapy. BRCA1 carriers had a significantly higher pCR rate than non-carriers (BRCA1 carriers versus non-carriers, 53.8% versus 29.7%, P < 0.001). Among women treated with anthracycline with or without taxane regimens, the pCR rate was 57.1% for BRCA1 carriers, 29.0% for non-carriers (P < 0.001); among women treated with taxane regimens, the pCR rate was 40.0% for BRCA1 carriers, 32.9% for non-carriers (P = 0.73). At a median follow-up of 43 months, the recurrence-free survival was similar between BRCA1 carriers and non-carriers among the 947 patients of this study (adjusted hazard ratio = 0.92; 95% confidence interval: 0.45-1.90; P = 0.82). Chinese women with triple-negative breast cancer who are diagnosed at or before age of 50 are candidates for BRCA1 genetic testing. Among triple-negative breast cancer patients, BRCA1 carriers are more likely to respond to neoadjuvant anthracycline-based regimens than are non-carriers.

Prevalence of BRCA1 and BRCA2 germline mutations in patients with triple-negative breast cancer

Triple-negative breast cancers(TNBC) lack expression of oestrogen, progesterone and HER2 receptors. The gene expression profiles of TNBCs are similar to those of breast tumours in women with BRCA1 mutations. Reports to date indicate that up to 20% of TNBC patients harbour germline BRCA mutations; however, the prevalence of BRCA mutations in TNBC patients varies widely between countries and from study to study. We studied 774 women with triple-negative breast cancer, diagnosed on average at age 58.0years. Samples of genomic DNA were provided by the Australian Breast Cancer Tissue Bank (ABCTB) (439 patients) and by the Department of Genetics and Pathology of the Pomeranian Medical University (335 patients). The entire coding regions and the exon-intron boundaries of BRCA1 and BRCA2 were amplified and sequenced by next-generation sequencing. We identified a BRCA1 or BRCA2 mutation in 74 of 774 (9.6%) triple-negative patients. The mutation prevalence was 9.3% in Australia and was 9.9% in Poland. In both countries, the mean age of diagnoses of BRCA1 mutation carriers was significantly lower than that of non-carriers, while the age of onset of BRCA2 mutation carriers was similar to that of non-carriers. In the Australian cohort, 59% of the mutation-positive patients did not have a family history of breast or ovarian cancer, and would not have qualified for genetic testing. The triple-negative phenotype should be added as a criterion to genetic screening guidelines.

Mutational analysis of BRCA1/2 gene and pathologic characteristics from Kazakh population with sporadic breast cancer in northwestern China

Mutations in the BRCA1/2 genes are associated with an increased risk of breast cancer, but no large-scale research have examined the BRCA1/2 mutations in Chinese Kazakh women. We evaluated the frequency and distributions of BRCA1 and BRCA2 gene mutations in Kazakh sporadic breast cancer patients and healthy women in China. The association between the clinical-pathologic features of Kazakh breast cancer patients and BRCA1/2 mutations were also investigated. Two unclassified variants (T539M and T1915M) and 16 polymorphisms were detected in this study, 4 of which (G356A, His743, Asn991Asp, Val1269) were detected more frequently in breast cancer patients than in healthy controls. We observed a higher prevalence of BRCA1/2 common sequence alterations and a large number of Kazakh women carrying multiple co-existing BRCA1/2 mutations. The prevalence of BRCA1 mutations was similar to that of BRCA2 mutations. Although no significant differences were observed, BRCA1/2 carriers were generally younger at diagnosis of wild-type breast cancer patients. BRCA1-associated Kazakh sporadic breast cancers present with high tumor grade, early stage, negative lymph node status, absence of estrogen receptor expression and progesterone-positive status. Estrogen receptor expression was the only predominant histological type in BRCA2 carriers. In this study, we determined the BRCA1 and BRCA2 gene mutation status and determined the association with clinical-pathologic characteristics in a Chinese Kazakh population. Larger population-based screening studies screening the entire coding region of BRCA1/2 are required to evaluate the breast cancer risk induced by the sequence alterations detected in this study.

BRCA1 Gene's EXON 11 and Breast Carcinoma: A Mutational Hot Spot for Familial Patients and Prone to Metastases in Northern India

Background: The prevalence of mutation in BRCA1 genes alarmingly augmented threat of Breast carcinoma among women. The occurrence of BRCA1 gene mutation in India is heterogeneous and varies according to geographical origin. Previous investigations have relied on subjective methods of recording prevalence and familial association. The influence of specific mutation biomarkers which may explain the link between, age, metastases, clinicopathological markers and risk of breast cancer has not been investigated prospectively in Uttar Pradesh (Northern India). Methods: This study was carried out on patients (N=381) diagnosed with breast cancer and further categorized into three groups according to family history. In the present work, blood/tissue samples were collected and mutations were detected using a PCR-SSCP (Single-strand conformation polymorphism) technique followed by sequencing. Results: In the study, 12 sequence variants out of which, eleven novels were identified in exon 11 of BRCA1 gene. BRCA1 mutations were detected in 4.7% (18/381) patients. Mutations in BRCA1 genes were significantly associated with family history and these mutations were found to be strongly associated with metastatic presentation (P=0.042, OR=6.567, 95% CI=1.073-40.174), younger age (P=0.032, OR=11.244, 95% CI=1.227-103.062), and negatively correlated with ER/PR/HER2. Thus, this can serve as important milestone in diagnosis of familial breast cancer. Conclusion: The higher prevalence of BRCA1 mutation among North Indian Breast cancer patients was associated with family history, metastases and younger age. The only alternate apart from early diagnosis is opting for a routine breast screening, which will prove to be a viable option for prevention in carcinoma of breast & better survival.

Abstract PL03-01: Origins of ovarian cancer, the biology of premalignancy, and cancer health disparities

Abstract Epithelial ovarian cancer (EOC) is the 5th leading cause of cancer-related deaths in women in the United States1. High-grade serous carcinoma (HGSC) is the most aggressive EOC and women usually present at high-grade and high stage, leading to only a 30% 5 year survival rate after adjuvant platinum-based chemotherapy2. Women who have an inherited mutation in the BRCA1 or BRCA2 genes have a substantial increased lifetime risk (11%-60%) in developing high-grade serous cancer – the predominant histotype associated with hereditary breast-ovarian cancer3. The distal end of the fallopian tube is now the accepted site of origin of high-grade serous ovarian cancer4. It is known that factors related to parity, ovulation and hormone regulation have a dramatic effect on the risk of developing ovarian cancer in both BRCA mutation carriers and non-carriers. Recently, we have shown that the transcriptional profile of histologically normal fallopian tube epithelia of BRCA mutation carriers is different from wild type FTE and possibly hints at BRCA haploinsufficiency5,6. We propose that changes of the transcriptome in BRCA mutation carriers reflect an altered response to the microenvironment ovulatory stresses, which may include altered reproductive hormone levels and the ovulatory inflammatory response. The prevalence of the BRCA mutation in the Bahamas where 23% of unselected breast cancer patients carry a mutation in the BRCA1 is the highest hereditary proportion in the world7,8. We are determining the importance of genetic founder effects in the two BRCA genes in the Caribbean basin - a region with a large African population (the Caymans, Barbados, Dominica and Jamaica). Epithelial ovarian cancer rates are low in the Caribbean and risk factors such as parity, age at menarche and menopause may be strong indicators of decreased risk in the population. The results of this extensive study will help direct health policies towards genetic testing in the Caribbean with implications for the immigrant US population, and should lead to regional policies regarding preventative strategies.

Abstract 3833: Molecular subtypes of breast cancer in Algeria: a population-based study of 3014 women

Abstract Background:Breast cancer is currently the leading cause of cancer morbidity and mortality among Algerian women. Molecular classification of breast cancer is an important factor for prognosis and clinical outcome.To our best knowledge,few studies have been reported on molecular subtypes of female breast cancer in Algeria.The objective of the present study was to evaluate age at diagnosis,distribution,prevalence, and association with menopausal status, histological type and histological grade of molecular subtypes of breast cancer in Algerian women.In addition, we screened for the prevalence of BRCA1 mutations in TNBC patients with and without family history of breast cancer. Methods: We analyzed breast cancers from cancer registries of academic medical oncology service of public hospital of Rouiba, anticancer center of Blida, and anticancer center of Batna.Breast cancers were diagnosed between 2008 and July 2013. ER (oestrogen receptor), PR (progesterone receptor) and HER2 (human epidermal growth factor receptor-2) status were obtained from medical records for 3014 patients.Breast cancer subtypes definitions were as follow:Luminal A (ER+ and/or PR+,HER2-), Luminal B (ER+ and/or PR+,HER2+),TNBC(ER-,PR-,HER2-), HER2+ (ER-,PR-,HER2+). 20 TNBC patients with family history of breast cancer and 33 sporadic TNBC women were screened by using PCR-direct sequencing for 3 common BRCA1 mutations c.83_84delTG, c181T&amp;gt;G and c.798_799delTT detected in previous studies in Algerian population. Results: The median age at diagnosis of 3014 patients with breast cancer was 48.5 years. The prevalence of the Luminal A, TNBC, Luminal B and HER2+ were 50.59%,20.80%, 19.67% and 8.92%,respectively.Luminal A, Luminal B, TNBC and HER2+ subtypes were more prevalent among premenopausal women (29.24%, 13.26%, 12.19% and 4.80%) compared with postmenopausal women (21.74%, 7.31%, 7.89% and 3.87%). Invasive Ductal Carcinoma was the most prevalent histological type in all breast cancer subtypes at any age. Tumors with histological grade 2 were more prevalent in younger patients for the four breast cancer subtypes. High prevalence of histological grade 3 was showed in older patients. The BRCA1 mutation c.83_84delTG was detected in one young TNBC patient with a family history of cancer. Conclusion: For the first time, we report the distribution of molecular subtypes of breast cancer and some clinical characteristics in a large cohort of Algerian women. In our current study, the median age of diagnosis for all breast cancer subtypes was younger than the average age in Europe and America.Interestingly, TNBC subtype was the second most prevalent in our patients,and the prevalence of luminal subtype was lesser than reported in white women with breast cancer in Europe and America. The high prevalence of TNBC reported here could be linked to Sub-Saharan African genetic elements of Algerian population.Screening for BRCA1 mutations in large series of TNBC patients is ongoing. Citation Format: Farid Cherbal, Hadjer Gaceb, Chiraz Mehemmai, Rabah Bakour, Kada Boualga, Wassila Benbrahim, Hassen Mahfouf. Molecular subtypes of breast cancer in Algeria: a population-based study of 3014 women. [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 3833. doi:10.1158/1538-7445.AM2014-3833

Significant clinical impact of recurrent BRCA1 and BRCA2 mutations in Mexico.

Frequent recurrent mutations in the breast and ovarian cancer susceptibility (BRCA) genes BRCA1 and BRCA2 among Hispanics, including a large rearrangement Mexican founder mutation (BRCA1 exon 9-12 deletion [ex9-12del]), suggest that an ancestry-informed BRCA-testing strategy could reduce disparities and promote cancer prevention by enabling economic screening for hereditary breast and ovarian cancer in Mexico. In a multistage approach, 188 patients with cancer who were unselected for family cancer history (92 with ovarian cancer and 96 with breast cancer) were screened for BRCA mutations using a Hispanic mutation panel (HISPANEL) of 115 recurrent mutations in a multiplex assay (114 were screened on a mass spectroscopy platform, and a polymerase chain reaction assay was used to screen for the BRCA1 ex9-12del mutation). This was followed by sequencing of all BRCA exons and adjacent intronic regions and a BRCA1 multiplex ligation-dependent probe amplification assay (MLPA) for HISPANEL-negative patients. BRCA mutation prevalence was calculated and correlated with histology and tumor receptor status, and HISPANEL sensitivity was estimated. BRCA mutations were detected in 26 of 92 patients (28%) with ovarian cancer, in 14 of 96 patients (15%) with breast cancer overall, and in 9 of 33 patients (27%) who had tumors that were negative for estrogen receptor, progesterone receptor, and human epithelial growth factor 2 (triple-negative breast cancer). Most patients with breast cancer were diagnosed with locally advanced disease. The Mexican founder mutation (BRCA1 ex9-12del) accounted for 35% of BRCA-associated ovarian cancers and 29% of BRCA-associated breast cancers. At 2% of the sequencing and MLPA cost, HISPANEL detected 68% of all BRCA mutations. In this study, a remarkably high prevalence of BRCA mutations was observed among patients with ovarian cancer and breast cancer who were not selected for family history, and the BRCA1 ex9-12del mutation explained 33% of the total. The remarkable frequency of BRCA1 ex9-12del in Mexico City supports a nearby origin of this Mexican founder mutation and may constitute a regional public health problem. The HISPANEL mutation panel presents a translational opportunity for cost-effective genetic testing to enable breast and ovarian cancer prevention.

Prevalence of BRCA2 mutations and other clinical characteristics in women with triple-negative breast cancer.

160 Background: Triple-negative breast cancers (TNBC) represent 10%–20% of invasive breast cancers. Current guidelines recommend genetic testing for women who are diagnosed with TNBC. Studies have shown that BRCA1 mutations are associated with TNBC, but there is little information on the relationship of BRCA2 mutations and TNBC. The purpose of this study was to look at the clinical characteristics of TNBC compared to non-TNBC in a cohort of women with newly diagnosed breast cancer. Methods: The Breast Cancer Database at our institution was queried for patients with invasive breast cancer. We included the following variables: age, race, BRCA1,2, tumor characteristics, and personal history of breast cancer (PHBC). Statistical analyses included Pearson’s Chi-Square and Fisher’s Exact Tests. Results: Out of a total of 1,332 women, 125 (9%) had TNBC. The median age for both TNBC and non-TNBC was 59 years. Majority of women had early stage breast cancer (92%) with ductal carcinoma (80%). There was a significantly higher proportion of Blacks and Asians with TNBC (p &lt; 0.0001). Women with TNBC had higher Ki-67 (p &lt; 0.0001). Within the TNBC group, there were 12 (29%) patients who tested positive for BRCA1,2 mutation and 23 (8%) who tested positive for BRCA 1,2 mutations in the non-TNBC group. Interestingly, BRCA1 was not associated with TNBC (p = 0.40) and BRCA2 was significantly associated with TNBC (p &lt; 0.0001). We also found a higher proportion of TNBC in women who had a PHBC (p = 0.01). Conclusions: In our study, women with TNBC were similar in age to women who did not have TNBC. We found that the women with TNBC in our cohort had elevated rates of BRCA2 mutations. We also found that women with a personal history of breast cancer were at risk for developing TNBC. This may be related to the use of hormonal therapy that reduces the risk of ER/PR-positive tumors. Women of all ages are at risk for developing TNBC and older age at TNBC should not deter from genetic testing.

The prevalence of BRCA1/2 mutations of triple-negative breast cancer patients in Xinjiang multiple ethnic region of China.

BackgroundThe screening of BRCA1 and BRCA2 mutations is now an established component of risk evaluation and management of familial breast cancer, early-onset breast cancer and bilateral breast cancer patients. There is still some controversy about whether this screening should be done in triple-negative breast cancers. Therefore, we evaluated the BRCA mutation prevalence in patients with triple-negative breast cancer in a multi-ethnic region of China.MethodsA total 96 women who were diagnosed with triple-negative breast cancer in the Xinjiang region of China were enrolled in this study. BRCA1 and BRCA2 screening was performed by polymerase chain reaction-denaturing high-performance liquid chromatography (PCR-DHPLC) sequencing analysis. All mutations were confirmed with direct sequencing.ResultsThe prevalence of a BRCA1/2 germline mutation was about 25% (24/96) in the Xinjiang region of China. Among 35 selected cases with a family history and/or bilateral breast cancers, the BRCA1/2 mutation prevalence was 25.7% (9/35). Of the remaining 61 patients with unselected triple-negative breast cancer, the BRCA1/2 mutation prevalence was 24.6% (15/61), and all 15 individuals with these mutations were premenopausal patients.ConclusionsThese results suggest that premenopausal women with triple-negative breast cancer may be candidates for genetic testing for BRCA1/2 in the Xinjiang region of China, even in the absence of a family history or bilateral breast cancer.

BRCA1 gene exon 11 mutations in Uighur and Han women with early-onset sporadic breast cancer in the northwest region of China.

The prevalence of BRCA1 gene mutations in breast cancer differs between diverse ethnic groups. Relatively little information is known about patterns of BRCA1 mutations in early-onset breast cancer in women of Uighur or Han descent, the major ethnic populations of the Xinjiang region in China. The aim of this study was to identify BRCA1 mutations in Uighur and Han patients with early-onset (age <35 years), and sporadic breast cancer for genetic predisposition to breast cancer. For detection of BRCA1 mutations, we used a polymerase chain reaction single-stranded conformation polymorphism approach, followed by direct DNA sequencing in 22 Uighur and 13 Han women with early-onset sporadic breast cancer, and 32 women with benign breast diseases. The prevalence of BRCA1 mutations in this population was 22.9% (8/35) among early-onset sporadic breast cancer cases. Of these, 31.8% (7/22) of Uighur patients and 7.69% (1/13) of Han patients were found to have BRCA1 mutations. In 7 Uighur patients with BRCA1 mutations, there were 11 unique sequence alterations in the BRCA1 gene, including 4 clearly disease-associated mutations on exon 11 and 3 variants of uncertain clinical significance on exon 11, meanwhile 4 neutral variants on intron 20 or 2. None of the 11 BRCA1 mutations identified have been previously reported in the Breast Cancer Information Core database. These findings reflect the prevalence of BRCA1 mutations in Uighur women with early-onset and sporadic breast cancer, which will allow for provision of appropriate genetic counseling and treatment for Uighur patients in the Xinjiang region.