BRCA Mutation Testing Research Articles

Abstract P4-12-13: Experience of pre-operative genetic testing on surgical decision making in newly diagnosed breast cancer patients

Abstract Introduction: BRCA 1 and 2 testing has been widely incorporated into clinical care for women at risk for hereditary breast cancer. Knowledge of BRCA mutation status prior to surgery may influence decision regarding type of surgery. This study analyzes the experience with pre-operative BRCA mutation testing in patients with suspected hereditary predisposition to breast cancer. Methodology: Records of 150 patients referred to Cancer Genetics between November 01, 2013 and April 30, 2014 for pre-operative genetic testing were analyzed. This cohort consisted of patients with newly diagnosed breast cancer who met current genetic testing criteria. Patients were excluded if their surgical records were not available or they had not yet completed surgery. A total of 80 patients who completed genetic evaluation and definitive surgery were evaluated. Data on demographic characteristics, tumor pathology, BRCA mutation status and surgical management was collected on all evaluable patients. Results: Records of 80 patients who underwent pre-operative genetic testing for hereditary breast cancer risk were evaluated. The median age at diagnosis was 51.5 years. Median time from biopsy to initiation of genetics referral was 10 days. From that point, the median time to cancer genetics appointment was 3 days. Median time from initial genetics visit to definitive surgery was 24 days. 7 (9%) patients underwent surgery within 10 days of the genetics appointment, and prior to receiving the results of the genetic tests. Of the 80 patients, 5 (6%) tested positive for a BRCA mutation, 3(4%) had a BRCA variant of unknown significance(VUS), and the rest tested negative. 4 of the 5 BRCA mutation carriers underwent bilateral mastectomy, as did 2 of the 3 patients with a BRCA VUS. Of the 72 BRCA -ve patients, 22 (30%) underwent bilateral mastectomies, 42 (58%) underwent partial mastectomy, 7 (10%) patients underwent unilateral mastectomy, and 1 underwent bilateral partial mastectomy. There was no significant difference on univariate analysis in the age, histopathology (grade, receptor status, lymph node status and margins) in the patients who underwent bilateral mastectomy and those who underwent breast conservation. Mean tumor size was 24.5 mm in the bilateral mastectomy group, compared to 15.8 mm in the unilateral mastectomy group(p=NS). The bilateral mastectomy group had a greater number of close relatives with breast cancer reflecting a more significant family history. Conclusions: This study demonstrates the feasibility and successful implementation of preoperative genetic testing in newly diagnosed breast cancer patients. The majority of mutation carriers underwent bilateral mastectomies as did a significant proportion of BRCA -ve patients. Larger tumor size and a more significant family history of breast cancer appeared to be associated with the decision to pursue bilateral mastectomy. Further studies are needed to better characterize the impact of preoperative genetic testing in newly diagnosed breast cancer patients. Citation Format: Siddhartha Yadav, Otavio Pereira-Rodrigues, Lindsay Dohany, Heidi Dreyfuss, Jennifer Fulbright, Ashley Reeves, Dana Zakalik. Experience of pre-operative genetic testing on surgical decision making in newly diagnosed breast cancer 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 P4-12-13.

Breast Cancer Risk Gene Discovery: Opportunities and Challenges

DNA-based testing has become routine in modern health care. Today, genetic testing for BRCA1 or BRCA2 germline mutations is routinely offered to women with personal and/or family history of breast cancer (BC) and/or ovarian cancer (OC). The identification of a pathogenic mutation in an index case allows relatives to be offered predictive testing and to provide clinical advice-related risk management to women with a high risk of BC and OC. A pathogenic BRCA1 or BRCA2 mutation is identified in less than 20 % of index cases tested, while variants of unknown biological and clinical significance (VUS) are detected in at least another 10 %. Additional BC predisposition genes (PALB2, RAD51C, RAD51D, XRCC2, RINT1, etc.) have been recently identified, and as a consequence of the introduction of new sequencing technologies into clinical testing laboratories, some of these genes are already being screened as part of gene panel testing. However, the use of these new BC-predisposing genes remains limited in clinical practice because their associated cancer risks are not precisely estimated at the present time due to the small number of families that are known to carry variants in these genes. Many more BC and OC genes with an expected wide range of associated risks remain unidentified. In this review, we will focus on recent advances in the field of BC genetics and will discuss future challenges for clinical utility of new tests.

Large genomic rearrangements in the familial breast and ovarian cancer gene BRCA1 are associated with an increased frequency of high risk features

Large genomic rearrangements (LGRs) account for at least 10% of the mutations in BRCA1 and 5% of BRCA2 mutations in outbred hereditary breast and ovarian cancer (HBOC) families. Data from some series suggest LGRs represent particularly penetrant mutations. 1,034 index cases from HBOC families underwent comprehensive BRCA1 and BRCA2 mutation testing, including screening for LGRs. The personal and family history of 254 identified mutation carriers were compared based on mutation type. Thirty-six LGRs were detected; 32/122 (26%) BRCA1 and 4/132 (3%) BRCA2 mutations. High risk features (bilateral breast cancer, diagnosis <40 years, ovarian cancer, male breast cancer) were more commonly associated with an LGR than a non-LGR mutation (p = 0.008), In families with a BRCA1 LGR the mean age of breast cancer diagnosis was younger than in families with a non-LGR BRCA1 mutation (42.5 vs. 46.1 years, p = 0.007). Across the entire group of mutation positive families the number of relatives affected by breast or ovarian cancer was increased [LGR 3.7 vs. non- LGR 2.8 per family, p value (adjusted for genotype) = 0.047]. Excluding index cases, the odds ratio for breast cancer in BRCA1 families with an LGR was 1.42 (95% CI 1.24-1.63) and for ovarian cancer 1.66 (95% CI 1.10-2.49). The increased cancer risk was reflected in significantly higher risk assessments by mutation prediction tools. LGRs are associated with higher cancer risks. If validated, LGRs could be included in cancer risk prediction tools to improve personalised cancer risk prediction estimates and may guide cost-minimising mutation screening strategies in some healthcare settings.

Hereditary predisposition to ovarian cancer, looking beyond BRCA1/BRCA2

ObjectiveGenetic predisposition to ovarian cancer is well documented. With the advent of next generation sequencing, hereditary panel testing provides an efficient method for evaluating multiple genes simultaneously. Therefore, we sought to investigate the contribution of 19 genes identified in the literature as increasing the risk of hereditary breast and ovarian cancer (HBOC) in a BRCA1 and BRCA2 negative population of patients with a personal history of breast and/or ovarian cancer by means of a hereditary cancer panel. MethodsSubjects were referred for multi-gene panel testing between February 2012 and March 2014. Clinical data was ascertained from requisition forms. The incidence of pathogenic mutations (including likely pathogenic), and variant of unknown significance were then calculated for each gene and/or patient cohort. ResultsIn this cohort of 911 subjects, panel testing identified 67 mutations. With 7.4% of subjects harboring a mutation on this multi-gene panel, the diagnostic yield was increased, compared to testing for BRCA1 and BRCA2 mutations alone. In the ovarian cancer probands, the most frequently mutated genes were BRIP1 (n=8; 1.72%) and MSH6 (n=6; 1.29%). In the breast cancer probands, mutations were most commonly observed in CHEK2 (n=9; 2.54%), ATM (n=3; 0.85%), and TP53 (n=3; 0.85%). ConclusionsAlthough further studies are needed to clarify the exact management of patients with a mutation in each gene, this study highlights information that can be captured with panel testing and provides support for incorporation of panel testing into clinical practice.

Exome sequencing in a breast cancer family without BRCA mutation.

PurposeWe performed exome sequencing in a breast cancer family without BRCA mutations.Materials and MethodsA family that three sisters have a history of breast cancer was selected for analysis. There were no family members with breast cancer in the previous generation. Genetic testing for BRCA mutation was negative, even by the multiplex ligation-dependent probe amplification method. Two sisters with breast cancer were selected as affected members, while the mother of the sisters was a non-affected member. Whole exome sequencing was performed on the HiSeq 2000 platform with paired-end reads of 101 bp in the three members.ResultsWe identified 19,436, 19,468, and 19,345 single-nucleotide polymorphisms (SNPs) in the coding regions. Among them, 8,759, 8,789, and 8,772 were non-synonymous SNPs, respectively. After filtering out 12,843 synonymous variations and 12,105 known variations with indels found in the dbSNP135 or 1000 Genomes Project database, we selected 73 variations in the samples from the affected sisters that did not occur in the sample from the unaffected mother. Using the Sorting Intolerant From Tolerant (SIFT), PolyPhen-2, and MutationTaster algorithms to predict amino acid substitutions, the XCR1, DLL1, TH, ACCS, SPPL3, CCNF, and SRL genes were risky among all three algorithms, while definite candidate genes could not be conclusively determined.ConclusionUsing exome sequencing, we found 7 variants for a breast cancer family without BRCA mutations. Genetic evidence of disease association should be confirmed by future studies.

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.

PCN168 - Cost-Effectiveness Analysis of Testing for Brca Mutations in Women Diagnosed with Ovarian Cancer and their Female First-Degree Relatives: A Uk Health Service Perspective

PCN168 - Cost-Effectiveness Analysis of Testing for Brca Mutations in Women Diagnosed with Ovarian Cancer and their Female First-Degree Relatives: A Uk Health Service Perspective

PCN280 - Current Guidance for Brca Mutation Testing in Ovarian Cancer Patients

PCN280 - Current Guidance for Brca Mutation Testing in Ovarian Cancer Patients

Incidence of germline BRCA mutation in patients with ER-low positive/PR negative/HER-2 neu negative tumors.

2 Background: The 2011 ASCO/CAP guidelines recommend that breast cancers with estrogen receptor (ER) staining as low as 1% on immunohistochemistry be considered ER-positive. In practice, there remains significant variability in what clinicians consider ER-positive versus ER-negative. Current NCCN guidelines recommend that patients under age 60 with triple-negative breast cancer (TNBC) be referred for genetic counseling and consideration of germline BRCA mutation testing. With the 2011 ASCO/CAP guidelines, the definition of TNBC has changed to exclude patients with ER low-positive (1-9%) tumors; hence patients with ER-low positive tumors (formerly considered ER negative) may not be referred for genetic counseling and BRCA testing. This may lead to “undertesting” of appropriate patients. The incidence of BRCA germline mutations in patients with ER-low positive versus ER-negative (0%) tumors is unknown. We sought to identify whether the incidence of BRCA mutation differed between patients with ER-negative/PR-negative/HER-2 neu negative tumors and patients with ER-low positive/PR-negative/HER-2 neu negative tumors. Methods: We performed a review of a prospectively maintained research database of all patients with ER &lt; 10%, PR 0% and HER-2 neu–negative breast cancers who were referred for genetic risk assessment and testing for BRCA mutation at UT MD Anderson Cancer Center. Results: Of 144 patients who underwent BRCA mutation testing, 22 (15%) had ER-low positive tumors while 122 (85%) had ER-negative tumors. Among patients with ER-low positive tumors, 7 of 22 (31.8%) were found to have a deleterious BRCA 1/2 mutation, while 33 of 122 (27%) with ER-negative tumors were found to have a deleterious BRCA 1/2 mutation. The incidence of deleterious BRCA 1/2 mutation in patients with ER-low positive tumors versus those with ER-negative tumors was not statistically significantly different (p = 0.6457). Conclusions: The rate of deleterious BRCA 1/2 germline mutations in ER-negative versus ER-low positive (1-9%) breast cancer is similar. Therefore, we strongly recommend that BRCA testing continue to be offered to women under age 60 with tumors that are ER-low positive/PR-negative/HER-2 neu negative.

BRCA 1 and BRCA 2 mutations in Saudi breast cancer patients (single institution).

10 Background: Breast cancer is the commonest malignancy among Saudi females accounting for 25% of all female cancers with a median age at diagnosis of 47 years (1,2). In Saudi, breast cancer showed an increased incidence attributed to many factors such as different lifestyles, reproductive pattern, family history, which was reported to account for 59%, dietary or cultural practice of Saudi women (2,3,4,5). The multifunctional and highly penetrant BRCA 1 and BRCA 2 are the two major breast cancer pre-disposition genes, accounting for about 20% of breast cancer families (6,7). To our knowledge, the prevalence of BRCA 1 and BRCA 2 mutations in native Saudi population is sparse (8,9). Our aim is to describe the findings of BRCA mutation testing in native Saudi patients with breast cancer in a large Ministry of National Guard Health Affairs (NGHA) community-based teaching hospital. Methods: In this study, 75 out of 516 patients with breast cancer who were clinically and histopathologically diagnosed at NGHA from October 2010 to April 2014 were included. Selection criteria: aged ≤ 40 years bilateral breast cancer, triple-negative breast cancer, strongly first degree family history at young age and male breast cancer. Molecular alterations were performed by direct gene sequencing, multiple ligation – dependent probe amplification (MLPA) at Bioscentia human genetic testing in Germany. Results: 75 native Saudi were enrolled and test performed for them. 18 patients (24%) were found to have mutation of which 10 in BRCA One and six in BRCA 2. Two have both BRCA 1 and BRCA 2. Seven patients have the same with deleterious mutations in BRCA 1 gene. Two of them are mother and daughter and other five are unrelated. The mean age of breast cancer diagnosis in the mutation carriers was 38 years. Triple negative breast cancer (TNBC) diagnosed in six patients, bilateral breast cancer diagnosed in one, first-degree family history in eight and second degree in 10 patients and four with no family history. Conclusions: BRCA 1 and BRCA 2 mutations are an important contributor to the etiology of breast cancer in Saudi women. A mutation in BRCA 1, C 1648 &gt; C p, Asn550His in exon 10 has been reported as disease causing (11) and it is found in our study in seven patients. Such mutation might be specific for Saudi, so further studies are highly recommended.

941TiP - Engot-Ov16/Nova: a Phase 3 Randomized Double-Blind Trial of Maintenance with Parp-Inhibitor Niraparib Versus Placebo in Patients with Platinum-Sensitive Ovarian Cancer

ABSTRACT Background: Niraparib is an oral PARP-1/2 inhibitor with efficacy in both germline BRCA mutated (gBRCA) ovarian cancer (OvCa) and high grade serous OvCa (HGSC) patients (pts) who are non-gBRCA. Phase I data established a RP2D of 300 mg. At the recommended dose, 75% platinum sensitive patients achieved RECIST response in phase 1. Trial design: ENGOT-OV16/NOVA study (n = 360) is a double-blind, 2:1 randomized, placebo controlled phase III study of oral niraparib versus placebo in pts with platinum (plat) sensitive recurrent OvCa. Primary objective is to evaluate efficacy of niraparib as maintenance therapy assessed by the prolongation of progression free survival (PFS). PFS will be independently evaluated in a cohort of gBRCA pts and in HGSC pts who are non-gBRCA. Secondary objectives: overall survival in each cohort; bridge the centralized BRCA mutation test method to the candidate companion diagnostic test; patient-reported outcomes; PFS2; chemotherapy free interval; safety/tolerability; QTc in a subset of niraparib-treated pts. Study eligibility includes: histologically confirmed OvCa, HGSC histology or known gBRCA, plat sensitive recurrence, at least 2 prior courses of plat-containing therapy with no/minimal radiological residual disease, and normal CA125 or decrease by 90% after last plat, PS 0-1, and normal organ function. The study is powered to assess PFS and OS in both cohorts (gBRCA & non-gBRCA). The trial is being conducted in 126 sites in collaboration with European Network of Gynaecological Oncological Trials Groups (NSGO Denmark-Norway-Sweden, AGO Austria, AGO Germany, BGOG Belgium, ISGO Israel, GEICO Spain, GINECO France, MaNGO Italy, MITO Italy, NCRI UK), US, Canada, Hungary & Poland. The pt. enrolment is according to the timelines. ClinicalTrials.gov Identifier: NCT01847274 Disclosure: S. Agarwal: Medical Officer, Tesaro Bio Inc. (sponsor of the trial); R.E. Martell: Chief Medical Officer, Tesaro Bio Inc. (Sponsor of the trial). All other authors have declared no conflicts of interest.

The role of testing for BRCA1 and BRCA2 mutations in cancer prevention.

The role of testing for BRCA1 and BRCA2 mutations in cancer prevention.

Preoperative genetic testing affects surgical decision making in breast cancer patients

ObjectivesOur aim was to determine if BRCA mutation status changes surgical decision making in women who undergo genetic testing after the diagnosis of breast cancer. MethodsThis is a retrospective cohort study of breast cancer patients who had BRCA mutation testing performed prior to surgery. We compared surgical choice and change in surgical choice in women who tested positive for a BRCA mutation with those who tested negative. Surgery was considered the most definitive surgery within a year of diagnosis. Other data collected included age, race, stage, histology, receptor status, adjuvant treatment, gravity, parity, and family history. Variables were compared by BRCA status using Fisher's exact test and logistic regression. ResultsThree hundred and two women were included. Thirty-two (10.6%) were identified as carrying a BRCA mutation. Most women had early stage disease (55.6% T1 lesions, 72.8% node negative); 55.6% had breast-conserving surgery, and the remaining had unilateral or bilateral mastectomy. BRCA mutation carriers were more likely to have both a personal history of breast cancer (RR 2.74, 95% CI=1.08–6.98) and hormone receptor-negative tumors (56.0% vs. 26.2%, p=0.002). BRCA mutation carriers were more likely to choose bilateral mastectomy with reconstruction (56.3% vs. 15.9%, p<0.0001); 71.9% of BRCA mutation carriers opted for a different surgery than what was initially planned by their surgeon as compared to 29% of mutation-negative patients (p<0.0001). ConclusionsBRCA mutation testing strongly influences surgical decision making in newly diagnosed breast cancer patients. For women who meet NCCN referral guidelines, genetic evaluation should be performed prior to surgical intervention.

Evaluation of BRCA1/2 mutation status among women with triple-negative breast cancer.

1119 Background: Testing for BRCA1 and BRCA2 mutations in breast cancer patients is used to identify risk of second primary cancers and risk of cancer in the patients’ family. A high proportion of BRCA1 mutation positive patients have triple-negative breast cancer (TNBC). TNBC shows a poor prognosis and no effective treatment strategies against TNBC are available to date. However, BRCA-related cancers are sensitive to platinum chemotherapy as well as to drugs targeting poly (ADP-ribose) polymerase enzymes, which are under development so far. Women with TNBC are thought to be more likely to be BRCA mutation carriers, but there have only been limited numbers of studies investigating BRCA1- and BRCA2-mutation status among Caucasian patients with TNBC. Methods: We determined the prevalence of BRCA1 and BRCA2 mutations within a cohort of 88 unselected TNBC cases including patients from Germany and Austria. Double-stranded Sanger sequencing of all exons of BRCA1 and BRCA2, respectively, was performed. Results: ...

Risk Assessment, Genetic Counseling, and Genetic Testing for BRCA-Related Cancer in Women: U.S. Preventive Services Task Force Recommendation Statement

Update of the 2005 U.S. Preventive Services Task Force (USPSTF) recommendation on genetic risk assessment and BRCA mutation testing for breast and ovarian cancer susceptibility. The USPSTF reviewed the evidence on risk assessment,genetic counseling, and genetic testing for potentially harmful BRCA mutations in asymptomatic women with a family history of breast or ovarian cancer but no personal history of cancer or known potentially harmful BRCA mutations in the family. The USPSTF also reviewed interventions aimed at reducing the risk for BRCA-related cancer in women with potentially harmful BRCA mutations, including intensive cancer screening, medications, and risk-reducing surgery. This recommendation applies to asymptomatic women who have not been diagnosed with BRCA-related cancer. The USPSTF recommends that primary care providers screen women who have family members with breast, ovarian, tubal, or peritoneal cancer with 1 of several screening tools designed to identify a family history that may be associated with an increased risk for potentially harmful mutations in breast cancer susceptibility genes (BRCA1 or BRCA2). Women with positive screening results should receive genetic counseling and, if indicated after counseling, BRCA testing. (B recommendation)The USPSTF recommends against routine genetic counseling or BRCA testing for women whose family history is not associated with an increased risk for potentially harmful mutations in the BRCA1 or BRCA2 genes. (D recommendation).

High-Risk Women Should Have BRCA Testing

The U.S. Preventive Services Task Force released new guidelines recommending BRCA mutation testing be limited to high-risk women who have received genetic counseling.

Abstract P6-06-06: Family history and young breast cancer patients in the UK: The POSH study

Abstract Background Approximately 4% of breast cancer cases occur in women under 40 years. Young age at diagnosis is associated with inferior survival compared to older patients. It is unclear whether an increased incidence of adverse biological features fully explains this. An underlying genetic pre-disposition to breast cancer is characterised by young age of disease onset, yet even at a very young age of diagnosis most individuals do not have an identifiable mutation in a known high risk breast cancer gene. Genome wide association studies have identified low penetrance genetic variants which may account for unexplained family histories of breast cancer. The effect of a BRCA 1/2 mutation on breast cancer prognosis remains controversial with retrospective studies reporting inconsistent outcomes for mutation carriers compared to sporadic tumours. The prognostic effect of low penetrance breast cancer susceptibility genes is under investigation. POSH is a prospective observational cohort study designed to investigate prognostic factors in young breast cancer patients. Here we report pathology, treatment and outcome of these patients according to their family history of breast cancer. Methods 2956 patients aged ≤40 at breast cancer diagnosis were recruited from 126 UK hospitals between 2001 and 2007. Details of personal characteristics, tumour pathology and treatment were collected. Family history details were collected using a questionnaire completed by participants at recruitment. BRCA mutation testing is in progress. Follow-up data were collected at 6 and 12 months and then annually. Results Family history data were available for 2850 patients. 1878 (65.9%) reported no family history of breast/ ovarian malignancies and 972 (34.1%) reported breast/ ovarian cancer in one or more 1st or 2nd degree relative. Patients with a positive family history were significantly more likely to have a surveillance detected breast cancer than those without a family history (3.0% vs. 0.1% p&amp;lt;0.001) and patients with an affected 1st degree relative had a higher incidence of surveillance detected tumours than those with an affected 2nd degree relative (6.0% vs. 0.7% p&amp;lt;0.001). Patients with a positive family history were significantly more likely to have a grade 3 tumour than patients with a negative family history (63.3% vs. 58.9% p = 0.04). There were no significant differences in median tumour diameter, incidence of nodal involvement or presence of metastases between the positive and negative family history groups. The frequency of ER and PR overexpressing tumours did not vary significantly between family history groups. Patients with a negative family history were significantly more likely to have a HER2 positive tumour than those with a positive family history (28.8% vs.24.7% p = 0.031). There were no significant differences in tumour grade, size, nodal status, and ER, PR or HER2 status between patients with 1st degree or 2nd degree affected relatives. Conclusions Our data indicates that having a first or second degree relative with a breast/ ovarian cancer is associated with an increased frequency of grade 3 and HER2 negative breast tumours but not with other pathological features. Further analyses will investigate the independent effect of family history on breast cancer survival and recurrence rates. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-06-06.

Abstract P2-07-06: Detection of germline mutations in 196 genes in Chinese breast cancer families using targeted capture and next-generation sequencing

Abstract Background: Germline mutations in BRCA1, BRCA2 and other genes predispose to high risks of breast cancer. Genetic testing for germline mutations in BRCA1 and BRCA2 has been widely used in women with severe family history of breast or ovarian cancer in many western countries. However, in China, hereditary breast cancer associated genes and their mutation types remain unclear. So far, there's no recommended guidelines for high-risk populations. Next-Generation Sequencing (NGS) technology has been proved to detect all classes of mutations cost-effectively. Here we describe the first study of germline mutations in 196 genes in Chinese breast cancer families using NGS. Methods: Breast cancer patients were consecutively enrolled at diagnosis in our hospital between 2011-2012. Inclusion criteria were as follows: Firstly, breast cancer patients are Shanghai natives; secondly, breast cancer patients aged 35 or younger had at least another family member with any type of cancer or those between 35 and 50 years had ≥2 family members with cancer on same side of family or those above 50 years had ≥3 family members with cancer on same side of family. A total of 196 genes were tested and they included two parts. One hundred and twenty-two genes selected were associated with 54 hereditary cancer syndromes and another 74 genes were cancer susceptibility genes proved by researches published on Pubmed up to 2012. Blood samples were collected and genomic DNA were subjected to targeted capture using the Agilent SureSelect DNA kit and sequencing of exons and flanking regions corresponding to 196 genes using the Illumina HiSeq 2000 platform. All classes of genomic alterations were detected. The study was approved by the Scientific and Ethical Committee of the Cancer Hospital of Fudan University. All participants provided informed consent. Results: Eighty-six breast cancer patients met our inclusion criteria were enrolled in our study. The 86 families totally harbored 456 cancers, mainly including 206(45.2%) breast cancers, 45(9.9%) colorectal carcinomas, 38(8.3%) lung cancers, 36(7.9%) gastric cancers, 28(6.1%) hepatic carcinomas and 17(3.7%) ovarian cancers. A total of 66 germline mutations were detected in 29 genes of 46 probands, including 18 BRCA1 or BRCA2 mutations and one recurrent mutation in each gene, one novel TP53 mutations, one germline mutation in RAD50, PALB2, FANCD2, FANCI, RAD51C, SLX4/FANCP, etc. All of these genes were previously reported in hereditary breast cancer. Of women with germline mutations, the mean age at first primary breast cancer diagnosis was 39.6 y and 10(21.7%) of them had bilateral breast cancer. As for all genomic rearrangements, bioinformatics analysis is in process. Conclusion: This is the first study to report the spectrum of germline mutations in 196 hereditary cancer associated genes in Chinese familial breast cancer patients regardless of cancer types of family members. It will give us a reference for carrying out genetic counseling in Chinese breast cancer families. At the same time, NGS is an effective method to test many genes simultaneously at low cost. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-07-06.

Preventing ovarian cancer through genetic testing: a population‐based study

Genetic testing for BRCA1 and BRCA2 gene mutations, in conjunction with preventive salpingo-oophorectomy for mutation carriers, may be used to prevent a proportion of invasive ovarian cancers ('personalized medicine'). We evaluated the potential utility of this approach at a population level by reviewing the pedigree information and genetic test results from 1342 ovarian cancer patients in Ontario. Of the 1342 patients tested, 176 patients had a BRCA1 or BRCA2 mutation; of these, 48 women would have qualified for testing prior to the development of cancer based on the eligibility criteria in place for the province of Ontario. In summary, 48 of 1342 unselected cases of ovarian cancer (3.6%) might have been prevented if genetic testing criteria were universally applied to all women in Ontario at risk for ovarian cancer.

Translating Genomics in Cancer Care

There is increasing enthusiasm for genomics and its promise in advancing personalized medicine. Genomic information has been used to personalize health care for decades, spanning the fields of cardiovascular disease, infectious disease, endocrinology, metabolic medicine, and hematology. However, oncology has often been the first test bed for the clinical translation of genomics for diagnostic, prognostic, and therapeutic applications. Notable hereditary cancer examples include testing for mutations in BRCA1 or BRCA2 in unaffected women to identify those at significantly elevated risk for developing breast and ovarian cancers, and screening patients with newly diagnosed colorectal cancer for mutations in 4 mismatch repair genes to reduce morbidity and mortality in their relatives. Somatic genomic testing is also increasingly used in oncology, with gene expression profiling of breast tumors and EGFR testing to predict treatment response representing commonly used examples. Health technology assessment provides a rigorous means to inform clinical and policy decision-making through systematic assessment of the evidentiary base, along with precepts of clinical effectiveness, cost-effectiveness, and consideration of risks and benefits for health care delivery and society. Although this evaluation is a fundamental step in the translation of any new therapeutic, procedure, or diagnostic test into clinical care, emerging developments may threaten this standard. These include "direct to consumer" genomic risk assessment services and the challenges posed by incidental results generated from next-generation sequencing (NGS) technologies. This article presents a review of the evidentiary standards and knowledge base supporting the translation of key cancer genomic technologies along the continuum of validity, utility, cost-effectiveness, health service impacts, and ethical and societal issues, and offers future research considerations to guide the responsible introduction of NGS technologies into health care. It concludes that significant evidentiary gaps remain in translating genomic technologies into routine clinical practice, particularly in efficacy, health outcomes, cost-effectiveness, and health services research. These caveats are especially germane in the context of NGS, wherein efforts are underway to translate NGS results despite their limited accuracy, lack of proven efficacy, and significant computational and counseling challenges. Further research across these domains is critical to inform the effective, efficient, and equitable translation of genomics into cancer care.