Journal articles on the topic 'BRCA testing'
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Parikh, Purvish M., J. Wadhwa, S. Minhas, A. Gupta, S. Mittal, S. Ranjan, P. Mehta, et al. "Practical consensus recommendation on when to do BRCA testing." South Asian Journal of Cancer 07, no. 02 (April 2018): 106. http://dx.doi.org/10.4103/sajc.sajc_112_18.
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Abstract BRCA-mutation associated breast cancer and to future cancer risks and sensitivity to systemic therapies. Now that rapid genetic testing for BRCA1 and BRCA2 mutations is available, BRCA mutation status can be considered when making treatment and prevention decisions for BRCA testing, BRCA mutation carriers with breast cancer. Expert group used data from published literature, practical experience, and opinion of a large group of academic oncologists, to arrive at practical consensus recommendations for use by the community oncologists.
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Sahnane, Nora, Ileana Carnevali, Giorgio Formenti, Jvan Casarin, Sofia Facchi, Raffaella Bombelli, Eleonora Di Lauro, et al. "BRCA Methylation Testing Identifies a Subset of Ovarian Carcinomas without Germline Variants That Can Benefit from PARP Inhibitor." International Journal of Molecular Sciences 21, no. 24 (December 19, 2020): 9708. http://dx.doi.org/10.3390/ijms21249708.
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Homologous Recombination Deficiency (HRD) is a frequent feature of high-grade epithelial ovarian carcinoma (EOC), associated with sensitivity to PARP-inhibitors (PARPi). The best characterized causes of HRD in EOCs are germline or somatic mutations in BRCA1 and BRCA2 genes. Although promoter methylation is a well-known mechanism of gene transcriptional repression, few data have been published about BRCA gene methylation in EOCs. In this retrospective study, we quantitatively analyzed by pyrosequencing a selected series of 90 formalin-fixed (FFPE) primary EOCs without BRCA germline mutations. We identified 20/88 (22.7%) EOCs showing BRCA promoter methylation, including 17/88 (19.3%) in BRCA1 and 4/86 (4.6%) in BRCA2 promoters, one of which showing concomitant BRCA1 methylation. Mean methylation levels were 49.6% and 45.8% for BRCA1 and BRCA2, respectively, with methylation levels ≥50% in 10/20 methylated EOCs. Constitutive BRCA methylation was excluded by testing blood-derived DNA. In conclusion, pyrosequencing methylation analysis of BRCA genes is a robust, quantitative and sensitive assay applicable to FFPE samples. Remarkably, a considerable subset of germline BRCA-negative EOCs showed somatic methylation and, likely, HRD. A subpopulation of women with BRCA methylation, even without BRCA mutations, could potentially benefit from PARP-inhibitors; further clinical studies are needed to clarify the predictive role of somatic BRCA methylation of PARP-therapy response.
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Moore, H. C., R. Wesolowski, T. K. Choueiri, L. Rybicki, A. G. Shealy, G. Casey, and D. Weng. "Therapeutic radiation for breast cancer in BRCA mutation carriers and contralateral breast cancer (CBC) risk." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 611. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.611.
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611 Background: BRCA mutation carriers diagnosed with breast cancer are at high risk for contralateral second primary breast cancers. Mutations in BRCA1 and BRCA2 lead to defects in DNA repair. Radiation treatment for breast cancer is felt to increase risk of CBC, but the interaction between BRCA status and local radiation therapy with respect to their effects on CBC is unclear. Methods: Through an IRB approved database registry at the Cleveland Clinic, breast cancer patients tested for BRCA1 and BRCA2 mutations were identified and evaluated for CBC events and radiation treatment history. Patients with inadequate clinical follow-up, those with bilateral synchronous breast cancer and those undergoing bilateral mastectomy within one year of the original breast cancer diagnosis were excluded from the analysis. Chi-square test was used to compare CBC rates with or without prior radiation separately in patients testing positive and those testing negative for BRCA mutations. Results: Of 115 identified breast cancer patients tested for BRCA mutations, 57 met the inclusion criteria. Twenty-one carried BRCA1 or BRCA2 mutations and 36 tested negative for these mutations. Median follow-up for the two groups was 69.5 months (92 months in BRCA positive group and 51.5 months in BRCA negative group). Median age at diagnosis was 45 years (41 years in BRCA positive group and 48.5 in BRCA negative group). Among the 21 carriers, 9 patients (43%) developed CBC while only 3 of 36 patients (8%) testing negative for BRCA mutations developed CBC. Thirteen of 21 mutation carriers (62%) had received radiation treatment for the original cancer: CBC occurred in 3 of 13 (23%) radiated patients and 6 of 8 (75%) patients who had not received radiation (p= 0.02). Among 36 patients with negative BRCA testing, 30 (83%) had received radiation: CBC occurred in 3 of 30 (10%) mutation negative patients who had received prior radiation and in 0 of the 6 patients who had not received radiation (p = 0.42). Conclusions: CBC incidence was higher among BRCA mutation carriers than a control group suspected of having hereditary breast cancer but testing negative for these mutations. The use of radiation in the presence of a BRCA mutation, however, does not appear to further increase the risk for CBC. No significant financial relationships to disclose.
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Brankovic-Magic, Mirjana, Jelena Dobricic, Radmila Jankovic, Irene Konstantopoulou, Drakoulis Yannoukakos, and Sinisa Radulovic. "Identifying and testing for hereditary susceptibility to breast/ovarian cancer in Serbia: Where are we now?" Archive of Oncology 14, no. 3-4 (2006): 131–35. http://dx.doi.org/10.2298/aoo0604131b.
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About 90% of all breast cancers can be considered as sporadic, without inherited gene alteration. The rest of breast cancers (about 5 to 10%) are considered hereditary, most commonly caused by alterations of BRCA1/2 tumor suppressor genes. Lifetime risks for breast and ovarian cancers are increased among BRCA1/2 mutation carriers - 4 to 8 and 10 to 20 fold higher respectively. Due to the small proportion of hereditary form of disease, as well as to the high cost, BRCA testing is not screening test for general population. It is addressed to selected part of population that fit to recommended criteria. Full coding region sequencing of both genes is "gold standard" for detection of BRCA mutation. Concerning BRCA testing in Serbia, complete or partial sequencing of BRCA1/2 coding region was performed in 60 samples. The presence of 4 BRCA1 known mutations, previously detected elsewhere, has been shown: 185delAG, C61G, 3447del4 and 5382insC (detected twice). In BRCA1 gene, exon 16, an unclassified variant M1652I was found. Polymorphic variants in BRCA1 (8 polymorphisms) and BRCA2 (5 polymorphisms) genes were also detected. The majority of found BRCA1 and BRCA2 polymorphic variants are the missense ones and their influence on breast/ovarian cancer risk in our population has to be proved. Identification of BRCA mutations carriers and establishment of spectra and frequency of BRCA mutations should enable introduction of BRCA1/2 testing into the clinical practice of Serbia. .
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Schwartz, Zachary Phillip, Mae Zakhour, Andrew John Li, Christine S. Walsh, Bj Rimel, Monica Alvarado, Scott E. Lentz, and Ilana Cass. "Comparison of risk-reducing surgery in women with BRCA and non-BRCA ovarian cancer susceptibility genes." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): 1547. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.1547.
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1547 Background: Risk reducing gynecologic surgery (RRSO) is standard of care for women with BRCA mutations. The optimal management for women with non-BRCA ovarian cancer susceptibility mutations remains unclear. We sought to characterize the practice patterns for these women at our two institutions. Methods: Women with germline ovarian cancer susceptibility genes who had a RRSO were identified from 1/2000-1/2019 in an IRB approved study. All patients were asymptomatic with no suspicion for malignancy at time of RRSO. Clinico-pathologic characteristics were extracted from the medical records. Continuous variables were analyzed with Kruskal-Wallis and categorical variables analyzed with chi square and t-tests. Results: 152 BRCA1, 95 BRCA2, and 63 Non-BRCA mutation carriers were identified—50 Lynch (22 MLH1, 13 MSH2, 13 MSH6, 2 PMS2) and 13 Other (6 BRIP1, 2 RAD51C, 5 RAD51D). There was no difference between age at testing, age at RRSO, and interval between testing and RRSO between groups. Genetic counseling was higher in Non-BRCA patients. Family history of ovarian cancer was more common in women with BRCA1 and Other germline mutations compared to BRCA2 and Lynch. Family and personal history of breast cancer was high in all groups except Lynch carriers. Prophylactic mastectomy was seen mostly in BRCA mutation carriers. Concomitant hysterectomy was performed in the majority of women (BRCA1 59%, BRCA2 57%, and Other 62%), with the highest frequency in Lynch carriers (86%, p<.01). Occult cancer was only seen in BRCA mutation carriers: BRCA1 (7%), BRCA2 (2%), Lynch (0%), Other (0%). Conclusions: In this cohort, women with Non-BRCA mutations are managed similarly to women with BRCA mutations. We observed no occult cancers in Non-BRCA patients. The optimal role of surgery as a risk reducing strategy in this group requires further study. [Table: see text]
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Holter, Spring, Ayelet Borgida, Anna Dodd, Robert Grant, Kara Semotiuk, David Hedley, Neesha Dhani, et al. "Germline BRCA Mutations in a Large Clinic-Based Cohort of Patients With Pancreatic Adenocarcinoma." Journal of Clinical Oncology 33, no. 28 (October 1, 2015): 3124–29. http://dx.doi.org/10.1200/jco.2014.59.7401.
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Purpose The main purpose of this study was to determine the prevalence of pathogenic BRCA1 and BRCA2 mutations in a consecutively ascertained clinic-based cohort of patients with pancreatic ductal adenocarcinoma and describe the clinical and family history characteristics. Patients and Methods Unselected, consecutive, incident patients with pancreatic ductal adenocarcinoma were recruited at a single cancer center over a 2-year period. Participants provided blood for DNA analysis and cancer family history, and cancer treatment records were reviewed. DNA from all patients was analyzed by Sanger sequencing and multiplex ligation-dependent probe amplification for germline variants in BRCA1 and BRCA2. Results Three hundred six patients were eligible for analysis. Pathogenic germline BRCA mutations were identified in 14 patients (4.6%; 95% CI, 2.2% to 6.9%), including 11 patients with a BRCA2 mutation and three patients with a BRCA1 mutation. Having a cancer family history that met genetic testing criteria of the National Comprehensive Cancer Network or the Ontario Ministry of Health and Long-Term Care or self-reporting as Ashkenazi Jewish was significantly associated with BRCA mutation carrier status (P = .02, P < .001, and P = .05, respectively). However, the majority of the BRCA mutation–positive patients did not actually meet these genetic testing criteria. Conclusion Pathogenic BRCA mutations were identified in 4.6% of a large cohort of clinic-based patients. Considering the implications for family members of BRCA carriers, and possibly tailored chemotherapeutic treatment of patients, our finding has implications for broader BRCA genetic testing for patients with pancreatic ductal adenocarcinoma.
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Toss, Angela, Eleonora Molinaro, Marta Venturelli, Federica Domati, Luigi Marcheselli, Simonetta Piana, Elena Barbieri, et al. "BRCA Detection Rate in an Italian Cohort of Luminal Early-Onset and Triple-Negative Breast Cancer Patients without Family History: When Biology Overcomes Genealogy." Cancers 12, no. 5 (May 15, 2020): 1252. http://dx.doi.org/10.3390/cancers12051252.
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NCCN Guidelines recommend BRCA genetic testing in individuals with a probability >5% of being a carrier. Nonetheless, the cost-effectiveness of testing individuals with no tumor family history is still debated, especially when BRCA testing is offered by the national health service. Our analysis evaluated the rate of BRCA pathogenic or likely-pathogenic variants in 159 triple-negative breast cancer (TNBC) patients diagnosed ≤60 years, and 109 luminal-like breast cancer (BC) patients diagnosed ≤35 without breast and/or ovarian family histories. In TNBC patients, BRCA mutation prevalence was 22.6% (21.4% BRCA1). Mutation prevalence was 64.2% ≤30 years, 31.8% in patients aged 31–40, 16.1% for those aged 41–50 and 7.9% in 51–60 s. A total of 40% of patients with estrogen receptors (ER) 1–9% were BRCA1 carriers. BRCA detection rate in early-onset BCs was 6.4% (4.6% BRCA2). Mutation prevalence was 0% between 0–25 years, 9% between 26–30 years and 6% between 31–35 years. In conclusion, BRCA testing is recommended in TNBC patients diagnosed ≤60 years, regardless of family cancer history or histotype, and by using immunohistochemical staining <10% for both ER and/PR. In luminal-like early-onset BC, a lower BRCA detection rate was observed, suggesting a role for other predisposing genes along with BRCA genetic testing.
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Shatavi, Seerin Viviane, Lindsay Dohany, Mohammad Muhsin Chisti, Ishmael A. Jaiyesimi, and Dana Zakalik. "Unique genetic characteristics of BRCA mutation carriers in a cohort of Arab American women." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): 1541. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.1541.
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1541 Background: Worldwide ethnic variations in the distribution of BRCA1 and BRCA2 mutations of breast cancer patients have been recently recognized. This has led to investigations of the epidemiology, genetics and clinical characteristics of BRCA positive individuals within specific populations. This study aims to describe the findings of BRCA genetic testing in a cohort of Arab American women. Methods: A total of 73 women of Arab ancestry were evaluated in the Beaumont Cancer Genetics Program from Jan 2008 to Jan 2013. Criteria for genetic testing included a personal or family history suggestive of Hereditary Breast and Ovarian Cancer Syndrome (HBOC). Patients underwent comprehensive genetic counseling, followed by full sequence analysis for germline mutations in BRCA1 and BRCA2. Results: 63 women of Arab ancestry underwent genetic testing for BRCA1 and BRCA2. 13 (21%) patients were found to be mutation carriers, of whom 10 (16%) of the 63 had deleterious mutations (7 in BRCA2, and 3 in BRCA1), and 3 (5%) had variants of undetermined significance (VUS) in BRCA2. Of the 10 patients with deleterious mutations, 4 (40%) unrelated individuals had the same mutation, 5804del4, in exon 11 of BRCA2. The remaining patients had deleterious mutations in exon 2, exon 20, and exon 13 of BRCA2; one patient had a BRCA1 and BRCA2 mutation (exon 18). 7 of 10 patients with deleterious mutations had a cancer diagnosis, of which 5 had breast cancer, 1 had ovarian cancer, 1 had pancreatic cancer, and 3 were unaffected. Conclusions: This study demonstrates that BRCA mutations (predominantly in BRCA2) were seen in a significant proportion of Arab American women undergoing genetic testing for HBOC. A mutation in BRCA2, 5804del4, was seen in nearly half (4/10) of the carriers of deleterious mutations. This mutation, in exon 11, has not previously been associated with Arab ethnicity and may represent a founder mutation. Knowledge of the genetic spectrum, frequency, and clinical characteristics of BRCA mutation carriers will lead to greater understanding of hereditary cancer in Arab American women.
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Matsubara, Nobuaki, Johann S. De Bono, David Olmos, Giuseppe Procopio, Satoru Kawakami, Yuksel Urun, Robbert J. van Alphen, et al. "Olaparib efficacy in patients with metastatic castration-resistant prostate cancer (mCRPC) carrying circulating tumor (ct) DNA alterations in BRCA1, BRCA2 or ATM: Results from the PROfound study." Journal of Clinical Oncology 39, no. 6_suppl (February 20, 2021): 27. http://dx.doi.org/10.1200/jco.2021.39.6_suppl.27.
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27 Background: ctDNA testing offers additional opportunities for homologous recombination repair (HRR) gene alteration determination in patients who are not able to access tumor tissue testing. Alteration testing in ctDNA, for BRCA1, BRCA2 and ATM alterations was performed retrospectively in the PROfound study (phase 3 trial of olaparib versus physician’s choice of abiraterone or enzalutamide in men with HRR gene-mutated mCRPC [NCT02987543]). Methods: ctDNA samples were sequenced at FMI, using the FoundationOne Liquid CDx assay for alterations in BRCA1, BRCA2 (BRCA) and ATM, using plasma samples collected during screening in PROfound. Only patients who consented and provided plasma samples from Cohort A (BRCA/ ATM alteration positive by tissue testing) were tested for ctDNA alterations. Radiographic progression-free survival (rPFS) assessed by blinded independent central review (BICR) in patients positive for alterations in ctDNA was analysed via stratified log-rank test. Additional efficacy endpoints (Objective Response Rate [ORR], Overall Survival[OS]) were also assessed. Results: In total, 181/245 (73.9%) Cohort A patients consented and provided a plasma sample for ctDNA testing, of which 139/181 (76.8%) had a ctDNA result reported (either mutation positive or mutation negative) and 42 patient samples failed testing due to insufficient DNA yield or a technical failure of the test.BRCA/ ATM alterations were identified in111/139 (79.9%) patients and 28/139 patients did not report a BRCA/ATM mutation either due to lack of ctDNA shedding from the tumour or ctDNA levels below the sensitivity of the assay. Patients who carried BRCA/ ATM ctDNA alterations had comparable demography, baseline characteristics and proportions of BRCA1, BRCA2 and ATM mutated patients to the overall Cohort A patients. rPFS by BICR results, in patients with BRCA/ ATM alterations in ctDNA, are presented in the Table. Key secondary efficacy endpoints (ORR, OS) will also be reported for ctDNA alteration positive patients. Conclusions: ctDNA testing in patients with mCRPC is feasible and most, but not all patients have concordant results. Patients who were positive for alterations in BRCA1, BRCA2 or ATM showed a consistent rPFS improvement (hazard ratio [HR] 0.33 [0.21, 0.53]) when compared with the ITT population identified by tumor tissue testing (HR 0.34 [0.25, 0.47]). This suggests that using ctDNA to identify patients carrying BRCA1, BRCA2 or ATM alterations who will benefit from olaparib may be beneficial. Clinical trial information: NCT02987543. [Table: see text]
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Murciano-Goroff, Yonina R., Alison M. Schram, Ezra Rosen, Yelena Y. Janjigian, Michael F. Berger, Mark Donoghue, Chaitanya Bandlamudi, and Alexander E. Drilon. "BRCA reversion mutations in a pan-cancer cohort to reveal BRCA-dependence in select noncanonical BRCA-mutant histologies." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): 3012. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.3012.
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3012 Background: Loss of BRCA1/2 function leads to homologous recombination deficiency (HRD) and can enhance platinum and PARP inhibitor sensitivity in breast, pancreas, prostate, and ovarian cancers. In BRCA-associated cancers, resistance can result from the development of BRCA1/2 reversion mutations, which restore BRCA1/2 function. By contrast, a BRCA mutation may be an incidental finding in other tumor histologies. Methods: To determine the distribution of reversion mutations in a pan-cancer cohort, the MSK-IMPACT clinical sequencing cohort was mined to identify patients who had both a germline BRCA1/2 mutation and a frameshift somatic reversion mutation that restored BRCA1/2 function. Whole exome resequencing was used to detect HRD signatures. Chart review enabled collection of data on treatment history in patients consented to germline testing. Results: Of the 33,277 patients with matched tumor and normal sequencing profiled in this study, 861 patients were found to have germline pathogenic BRCA1/2 alterations, including 347 (40%) in BRCA1 and 514 (60%) in BRCA2. Somatic BRCA1/2 driver alterations were also found in tumor tissue from an additional 447 patients, with 156 (35%) having BRCA1 mutations, and the remainder having alterations in BRCA2 (65%) . Among the 1,308 germline or somatic BRCA1/2 mutant tumors, we identified reversion mutations in 12 patients, all of whom were germline carriers of BRCA1/2, comprising 3 BRCA1 and 9 BRCA2 tumors. 7 patients consented to germline testing enabling review of clinical characteristics and treatment history, 5 of whom received PARP inhibitor or platinum-therapy prior to reversion detection. Ten of 12 tumors with reversion mutations were in canonical BRCA-associated cancers. Interestingly, reversion mutations were also found in patients with lung adenocarcinoma (n=1) and gastroesophageal junction adenocarcinoma (n=1). In both these non-canonical histologies, the reversion was detected following progression on platinum-based therapy. Whole exome resequencing of the lung tumor revealed the classic somatic molecular phenotypes of HRD that are characteristic of BRCA-dependent tumors, including in terms of large-scale transitions, HRD-loss of heterozygosity, signature 3, and the number of telomeric allelic imbalance score. Conclusions: Matched tumor and normal sequencing from a large cohort of patients with diverse cancer histologies reveals that reversion mutations are found across BRCA-associated cancer types. In rare cases, reversion mutations in BRCA1/2 following platinum-based therapy may be indicative of prior BRCA-dependence in select non-canonical tumor histologies.
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Sekine, Masayuki, Koji Nishino, and Takayuki Enomoto. "Differences in Ovarian and Other Cancers Risks by Population and BRCA Mutation Location." Genes 12, no. 7 (July 8, 2021): 1050. http://dx.doi.org/10.3390/genes12071050.
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Hereditary breast and ovarian cancer is caused by a germline mutation in BRCA1 or BRCA2 genes. The frequency of germline BRCA1/2 gene mutation carriers and the ratio of germline BRCA1 to BRCA2 mutations in BRCA-related cancer patients vary depending on the population. Genotype and phenotype correlations have been reported in BRCA mutant families, however, the correlations are rarely used for individual risk assessment and management. BRCA genetic testing has become a companion diagnostic for PARP inhibitors, and the number of families with germline BRCA mutation identified is growing rapidly. Therefore, it is expected that analysis of the risk of developing cancer will be possible in a large number of BRCA mutant carriers, and there is a possibility that personal and precision medicine for the carriers with specific common founder mutations will be realized. In this review, we investigated the association of ovarian cancer risk and BRCA mutation location, and differences of other BRCA-related cancer risks by BRCA1/2 mutation, and furthermore, we discussed the difference in the prevalence of germline BRCA mutation in ovarian cancer patients. As a result, although there are various discussions, there appear to be differences in ovarian cancer risk by population and BRCA mutation location. If it becomes possible to estimate the risk of developing BRCA-related cancer for each BRCA mutation type, the age at risk-reducing salpingo-oophorectomy can be determined individually. The decision would bring great benefits to young women with germline BRCA mutations.
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Rahman, Belinda, Anne Lanceley, Rebecca S. Kristeleit, Jonathan A. Ledermann, Michelle Lockley, Mary McCormack, Tim Mould, and Lucy Side. "Mainstreamed genetic testing for women with ovarian cancer: first-year experience." Journal of Medical Genetics 56, no. 3 (March 13, 2018): 195–98. http://dx.doi.org/10.1136/jmedgenet-2017-105140.
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BackgroundOvarian cancer is the fifth most common cause of cancer death for women in the UK. Up to 18% of cases can be attributed to germline mutations in BRCA1 and BRCA2genes. Identifying patients who carry a BRCA mutation provides important information about potential response to treatment and eligibility for therapies such as poly ADP ribose polymerase (PARP) inhibitors. Implementation of systematic genetic testing of patients with ovarian cancer via oncology clinics (mainstreamed genetic testing, MGT) is increasing.Methods and resultsThis service evaluation reports on the first year of MGT at a tertiary oncology centre in London, UK. In total, 122 patients with high-grade non-mucinous ovarian cancer underwent BRCA germline testing via MGT. Eighteen patients (14.8%) were found to carry a deleterious BRCA1/BRCA2 mutation. Four BRCA carriers did not meet previous criteria for genetic testing and would have been missed. Six BRCA carriers accessed PARP inhibitors post-MGT. Only 22% of patients with a variant of unknown significance (VUS) were referred to clinical genetics services.ConclusionsMGT appears to be a feasible way of providing BRCA testing to patients with ovarian cancer. Greater clarity of how oncologists use VUS results is needed, as well as further research on psychosocial implications of MGT for patients with ovarian cancer, which may include somatic testing in the future.
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Kapoor, Nimmi S., Lisa D. Curcio, Carlee A. Blakemore, Amy K. Bremner, Rachel E. McFarland, John G. West, and Kimberly C. Banks. "Benefits and safety of multigene panel testing in patients at risk for hereditary breast cancer." Journal of Clinical Oncology 33, no. 28_suppl (October 1, 2015): 16. http://dx.doi.org/10.1200/jco.2015.33.28_suppl.16.
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16 Background: Recently introduced multi-gene panel testing including BRCA1 and BRCA2 genes (BRCA1/2) for hereditary cancer risk has raised concerns with the ability to detect all deleterious BRCA1/2 mutations compared to older methods of sequentially testing BRCA1/2 separately. The purpose of this study is to evaluate rates of pathogenic BRCA1/2mutations and variants of uncertain significance (VUS) between previous restricted algorithms of genetic testing and newer approaches of multi-gene testing. Methods: Data was collected retrospectively from 966 patients who underwent genetic testing at one of three sites from a single institution. Test results were compared between patients who underwent BRCA1/2testing only (limited group, n = 629) to those who underwent multi-gene testing with 5-43 cancer-related genes (panel group, n = 337). Results: Deleterious BRCA1/2 mutations were identified in 37 patients, with equivalent rates between limited and panel groups (4.0% vs 3.6%, respectively, p = 0.86). Thirty-nine patients had a BRCA1/2 VUS, with similar rates between limited and panel groups (4.5% vs 3.3%, respectively, p = 0.49). On multivariate analysis, there was no difference in detection of either BRCA1/2 mutations or VUS between both groups. Of patients undergoing panel testing, an additional 3.9% (n = 13) had non-BRCA pathogenic mutations and 13.4% (n = 45) had non-BRCA VUSs. Mutations in PALB2, CHEK2, and ATM were the most common non-BRCA mutations identified. Conclusions: Multi-gene panel testing detects pathogenic BRCA1/2 mutations at equivalent rates as limited testing and increases the diagnostic yield. Panel testing increases the VUS rate, mainly due to non-BRCA genes. Patients at risk for hereditary breast cancer can safely benefit from upfront, more efficient, multi-gene panel testing.
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Trainer, Alison H., Bettina Meiser, Kaaren Watts, Gillian Mitchell, Kathy Tucker, and Michael Friedlander. "Moving Toward Personalized Medicine: Treatment-Focused Genetic Testing of Women Newly Diagnosed With Ovarian Cancer." International Journal of Gynecologic Cancer 20, no. 5 (June 2010): 704–16. http://dx.doi.org/10.1111/igc.0b013e3181dbd1a5.
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Objectives:The presence of a germline BRCA mutation defines a genotype-specific group of women whose invasive ovarian cancer is associated with an increasingly well-defined prognostic and chemosensitivity biological profile. To determine the criteria that may be used to select patients for BRCA treatment-focused genetic testing, we performed a systemic literature search of studies that assessed BRCA1 and BRCA2 mutation frequency in women with ovarian cancer unselected for family history. The results are discussed with regard to the added clinical value gained by identifying a germline BRCA mutation at the time of the ovarian cancer diagnosis.Methods:BRCA-related studies were identified in the CD-ROM databases PubMed (including MEDLINE), PsychINFO, and CINAHL and included in the review if they met the following criteria: they (a) assessed mutation frequency in women with ovarian cancer who were unselected for family history and ethnicity, (b) were published in a peer-review journal, (c) between January 1997 and October 2009, and (d) in the English language.Results:Studies investigating the prevalence of BRCA1 or BRCA2 mutations in ovarian cancer patients unselected for family history or ethnicity have found a pathological BRCA mutation rate of approximately 3% to 17%. Without a significant family history, specific features that may be used to target treatment-focused BRCA testing in the ovarian cancer setting include young age at onset (<50 years), high-grade serous tumor histology, and specific ethnicity associated with known BRCA founder mutations.Conclusions:We believe that given the growing appreciation of the prognostic significance of BRCA mutations and the differential chemosensitivity shown by these tumors, as well as the potential of novel agents such as poly(ADP-ribose) polymerase inhibitors, the identification of a germline BRCA mutation concurrent with a new diagnosis of ovarian cancer will significantly impact on tailoring personalized ovarian management in the future.
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Salo-Mullen, Erin E., Eileen Mary O'Reilly, David Paul Kelsen, Maeve Aine Lowery, Kenneth H. Yu, Rohini Rau-Murthy, Beth Siegel, et al. "Identification of germline genetic mutations in patients with pancreatic adenocarcinoma." Journal of Clinical Oncology 31, no. 4_suppl (February 1, 2013): 159. http://dx.doi.org/10.1200/jco.2013.31.4_suppl.159.
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159 Background: The emergence of PARP-inhibitors for potential treatment of BRCA-associated cancers highlights the importance of identifying germline mutations in individuals with pancreatic adenocarcinoma (PAC) (NCT 01585805 for PARP-i in PAC). Optimal selection of PAC patients for genetic testing remains to be determined. Our objective was to investigate prevalence of germline mutations in our PAC patients. Methods: MSKCC Clinical Genetics database was reviewed for PAC patients offered germline testing from 1/1/2011 to present. Clinical data was extracted from records. Pedigrees were reviewed to verify NCCN (PAC at any age with ≥2 close relatives with breast/ovarian/PAC at any age) and/or other testing criteria. Results: 70 PAC patients (33 males, 40 Ashkenazi Jewish (AJ)) were seen; 36 met NCCN criteria and 16 were AJ with 1 close relative with breast/ovarian/PAC. Of 18 not meeting these criteria, 7 were AJ, 3 were early-onset, and 7 were non-AJ with at least 1 additional BRCA-associated cancer in either themselves or a close relative. 63 patients accepted BRCA testing: 6 (9.5%) had a BRCA1 (n=2) or BRCA2 (n=4) mutation. Only 2 of these met NCCN criteria; 3 were AJ with 1 close relative with a BRCA-associated cancer; and 1 was non-AJ descent with 1 close relative with early-onset breast cancer. 36 AJ patients pursued BRCA testing: 4 (11.1%) had a BRCA1 (n=1) or BRCA2 (n=3) mutation; all were founder mutations. Additional genetic testing, based on family history, identified 1 MSH2 mutation, 1 MSH6 mutation, and 1 p16 mutation. Overall mutation detection rates were 13.6% (9/66) in total cohort who pursued any genetic testing and 15.8% (6/38) in tested AJ group. 6 patients with PAC before age 50 were tested: 1 non-AJ patient had a BRCA1 mutation and 1 (with history of melanoma) had a p16 mutation. Conclusions: With mutation detection rates of nearly 14% in total tested population & 16% in AJ cohort, germline genetic testing is important for PAC patients with potential implications for treatment and for relatives. By limiting BRCA testing to patients who meet current NCCN testing criteria, 66.7% (4/6) of our patients with BRCA mutations would not have been identified. Reassessment of testing criteria is needed for optimal care of PAC patients.
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Imyanitov, Yevgeniy, Aleksey Belyaev, Aleksandr Shcherbakov, Lev Bershteyn, Aleksandr Bessonov, Petr Krivorotko, Tatyana Gorodnova, et al. "PRESENCE OF BRCA1 AND BRCA2 IN HEALTHY WOMEN AND MEN: DNA TESTING, DIAGNOSTIC ACTIVITIES AND CANCER PREVENTION." Problems in oncology 63, no. 2 (February 1, 2017): 190–98. http://dx.doi.org/10.37469/0507-3758-2017-63-2-190-198.
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BRCA1 and BRCA2 germ-line mutations are associated in increased cancer risk both in women and in men. This article summarizes clinical recommendation of European Society for Medical Oncology (ESMO), National Comprehensive Cancer Network (NCCN) and other professional societies regarding inclusion criteria for BRCA-testing, diagnostic activities aimed to detect early cancers in BRCA1/2 mutation carriers as well as approaches to prevention of BRCA-driven cancers. The adjustment of existing clinical recommendations to health care realities in Russian Federation is discussed
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Jung, J., E. Kang, J. M. Gwak, A. N. Seo, S. Y. Park, A. S. Lee, H. Baek, S. Chae, E. K. Kim, and S. W. Kim. "Association between basal-like phenotype and BRCA1/2 germline mutations in Korean breast cancer patients." Current Oncology 23, no. 5 (October 26, 2016): 298. http://dx.doi.org/10.3747/co.23.3054.
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Introduction BRCA mutation testing allows index patients and their families to be provided with appropriate cancer risk-reduction strategies. Because of the low prevalence of BRCA mutations in unselected breast cancer patients and the high cost of genetic testing, it is important to identify the subset of women who are likely to carry BRCA mutations. In the present study, we examined the association between BRCA1/2 germline mutations and the immunohistochemical features of breast cancer.Methods In a retrospective review of 498 breast cancer patients who had undergone BRCA testing at Seoul National University Bundang Hospital between July 2003 and September 2012, we gathered immunohistochemical information on estrogen receptor (er), progesterone receptor (pr), her2 (human epidermal growth factor receptor 2), cytokeratin 5/6, egfr (epidermal growth factor receptor), and p53 status.Results Among the 411 patients eligible for the study, 50 (12.2%) had germline mutations in BRCA1 or BRCA2. Of the 93 patients with triple-negative breast cancer (tnbc), 25 with BRCA1/2 mutations were identified (BRCA1, 20.4%; BRCA2, 6.5%). On univariate analysis, er, pr, cytokeratin 5/6, egfr, and tnbc were found to be related to BRCA1 mutations, but on multivariate analysis, only tnbc was significantly associated with BRCA1 mutations. Among patients with early-onset breast cancer or with a family history of breast or ovarian cancer, BRCA1 mutations were significantly more prevalent in the tnbc group than in the non-tnbc group.Conclusions In the present study, tnbc was the only independent predictor of BRCA1 mutation in patients at high risk of hereditary breast and ovarian cancers. Other histologic features of basal-like breast cancer did not improve the estimate of BRCA1 mutation risk.
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Mullai, N. "The importance of variants of unknown significance (VUS) in BRCA mutation." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): e22507-e22507. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e22507.
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e22507 Background: Genetic testing of patients for BRCA mutation may report variants of unknown significance (VUS). The use of multi-gene panels in clinical care has been increasing. Consequently, the reporting of variants of unknown significance has also increased. More than two decades of research and testing have elevated the status of BRCA1 and BRCA2 genes as the most well characterized genes. However, VUS are found even in BRCA1/2 testing. This raises many ethical and policy issues including communicating the significance of the results and possible clinical management options to patients. The practicing physicians would face the ethical and potential legal burden of contacting and explaining to patients, when any role of VUS changes and gets reclassified as potentially harmful. Methods: Data were collected retrospectively from medical records of patients tested for BRCA mutations. The results of fifty-two patients were analyzed. Eight patients had BRCA1 and BRCA2 mutations and twelve patients had variants of unknown significance. Results: When the results of thirteen patients with BRCA mutations with VUS were analyzed further, the variants included POLE, CHEK2, PALB2, MUTHYH, BR1P1, MSH3, ATM, RAD51C, GALNT12, etc. The age of these patients ranged from 39 years to 69 years. Four patients had ovarian cancer and eight patients had breast cancer, and one patient had both breast and ovarian cancers. The number of patients with stage IV, III, II, and I diseases were six, one, two, and two respectively. One patient had bilateral breast cancer and one patient had carcinoma in-situ. Eight patients had family histories of various cancers, including cancers of the breast, uterine, and prostate cancer. All patients were treated appropriately and three patients died due to their disease. Conclusions: Based on patients’ age, family histories, and disease characteristics BRCA mutation analyses were done. All patients tested positive for BRCA mutations and VUS were informed about their results. Variants of BRCA1 and BRCA2 occur in 2%-4% of tests depending on the laboratories, where the tests were performed. There is no concordance as to how VUS results were reported. There is conflicting evidence regarding the pathogenicity of VUS. These make clinical recommendations very complex. Based on existing guidelines, physicians can explain the details of the significance of BRCA! And BRCA2 mutations to patients with clarity. However, it is difficult and unclear to give recommendations regarding prophylactic measures, specific treatment options for BRCA mutation positive breast and ovarian cancer, follow-ups, and family testing in patients with VUS. Therefore, during BRCA testing, when VUS are reported routinely along with mutations of known significance, the treating physicians would need a better guidance to advise their patients without unduly increasing their anxiety, fear, and potential for misunderstanding.
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Atchley, Deann P., Constance T. Albarracin, Adriana Lopez, Vicente Valero, Christopher I. Amos, Ana Maria Gonzalez-Angulo, Gabriel N. Hortobagyi, and Banu K. Arun. "Clinical and Pathologic Characteristics of Patients With BRCA-Positive and BRCA-Negative Breast Cancer." Journal of Clinical Oncology 26, no. 26 (September 10, 2008): 4282–88. http://dx.doi.org/10.1200/jco.2008.16.6231.
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Purpose Mutations in the BRCA1 and BRCA2 genes confer greater risk of developing breast cancer. We determined whether tumor pathologic features and clinical features differ in patients with and without BRCA mutations. Patients and Methods Tumor pathologic features and clinical characteristics were examined in 491 women with breast cancer who underwent genetic testing for BRCA mutations between 1997 and 2006. A retrospective review of medical records was conducted to determine clinical characteristics including ethnicity, age and clinical stage at diagnosis, age at parity, number of full-term pregnancies, use of oral contraceptives and hormone replacement therapy, and BRCA mutation status. Tumor pathology was reviewed to determine histologic type, tumor grade, and estrogen receptor, progesterone receptor, and HER-2/neu status. Results Of the 491 patients with identified breast cancers, 391 patients were BRCA negative, and 86 patients were BRCA positive. Triple-negative breast cancer (ie, those with negative estrogen receptor, progesterone receptor, and HER-2/neu status) was diagnosed in 57.1% of the BRCA1-positive patients, 23.3% of the BRCA2-positive patients, and 13.8% of the BRCA-negative patients. BRCA1 mutation carriers had higher nuclear grade tumors than the other two groups (P < .001). Of the triple-negative cancer patients, BRCA2 mutation carriers were older when diagnosed than BRCA1 mutation carriers and noncarriers (P < .01). Conclusion These results suggest that tumors associated with BRCA1 mutations may be divided into two distinct groups, triple-negative and non–triple-negative groups. Future studies should seek to determine whether patients with BRCA1 mutations and triple-negative breast cancer respond to treatment better than BRCA-negative patients with similar tumor pathology.
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Neveling, Kornelia, Arjen R. Mensenkamp, Ronny Derks, Michael Kwint, Hicham Ouchene, Marloes Steehouwer, Bart van Lier, et al. "BRCA Testing by Single-Molecule Molecular Inversion Probes." Clinical Chemistry 63, no. 2 (February 1, 2017): 503–12. http://dx.doi.org/10.1373/clinchem.2016.263897.
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Abstract BACKGROUND Despite advances in next generation DNA sequencing (NGS), NGS-based single gene tests for diagnostic purposes require improvements in terms of completeness, quality, speed, and cost. Single-molecule molecular inversion probes (smMIPs) are a technology with unrealized potential in the area of clinical genetic testing. In this proof-of-concept study, we selected 2 frequently requested gene tests, those for the breast cancer genes BRCA1 and BRCA2, and developed an automated work flow based on smMIPs. METHODS The BRCA1 and BRCA2 smMIPs were validated using 166 human genomic DNA samples with known variant status. A generic automated work flow was built to perform smMIP-based enrichment and sequencing for BRCA1, BRCA2, and the checkpoint kinase 2 (CHEK2) c.1100del variant. RESULTS Pathogenic and benign variants were analyzed in a subset of 152 previously BRCA-genotyped samples, yielding an analytical sensitivity and specificity of 100%. Following automation, blind analysis of 65 in-house samples and 267 Norwegian samples correctly identified all true-positive variants (>3000), with no false positives. Consequent to process optimization, turnaround times were reduced by 60% to currently 10–15 days. Copy number variants were detected with an analytical sensitivity of 100% and an analytical specificity of 88%. CONCLUSIONS smMIP-based genetic testing enables automated and reliable analysis of the coding sequences of BRCA1 and BRCA2. The use of single-molecule tags, double-tiled targeted enrichment, and capturing and sequencing in duplo, in combination with automated library preparation and data analysis, results in a robust process and reduces routine turnaround times. Furthermore, smMIP-based copy number variation analysis could make independent copy number variation tools like multiplex ligation-dependent probes amplification dispensable.
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Liu, Ying L., Julia Lindsay Boland, Karen Anne Cadoo, Claire Frances Friedman, Jason A. Konner, Roisin Eilish O'Cearbhaill, Carol Aghajanian, and Dmitriy Zamarin. "Response to immune checkpoint inhibition and survival in BRCA-associated recurrent ovarian cancer." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): 2615. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.2615.
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2615 Background: Alterations in the DNA mismatch repair pathway increase susceptibility to immune checkpoint inhibition (ICI). Tumors with BRCA-related DNA repair defects may have increased antigenicity, which could drive response to ICI. Responses to ICI in ovarian cancer (OC) have been modest. We seek to evaluate the association of BRCA mutations with response to ICI and survival in recurrent OC. Methods: A single-center, retrospective review identified 103 women with recurrent OC and known BRCA mutation status (90 germline and 33 somatic testing) who received ICI between 1/2013-7/2018 (98 on study). Clinical characteristics and duration of ICI (Long > = 24 vs. Short < 24 weeks) were compared by BRCA status. Kaplan Meier survival analysis was used to calculate progression-free (PFS) and overall survival (OS) from start of ICI, and CoxPH models/logrank test were used to assess survival differences by BRCA status. Results: Deleterious germline (g) or somatic (s) BRCA 1/2 mutations were present in 29 (28%) women (12 g BRCA1, 9 g BRCA2, 3 s BRCA1, 5 s BRCA2, 1 g BRCA1/s BRCA1, 3 g BRCA2/s BRCA2, and 1 g BRCA2/s BRCA1). Patients (pts) with BRCA mutations had more lines of treatment prior to ICI (median 5 vs. 4, p = 0.03) and a longer time from diagnosis to ICI (median 54 vs. 38.5 months (mo), p = 0.01), but there were no significant differences in other variables including histology (86% high grade serous), stage at diagnosis (96% Stage III/IV), and platinum status (83% resistant), p > 0.05. Four pts (15%) with BRCA mutations had long duration of ICI as compared with 20 pts (27%) in those without mutations, p = 0.20. Median PFS was 2.2 mo (95% CI 1.7-2.7) in those with BRCA mutations and 3.4 mo (95% CI 2.1-4.0) in those without mutations, HR 1.22 (95% CI 0.78-1.91, p = 0.38). At a median follow-up of 23.3 mo, median OS was 21.3 mo (95% CI 13.7-31.8) in those with BRCA mutations and 19.8 mo (95% CI 13.8-25.3) in those without. This was not significantly different, HR 1.00 (95% CI 0.54-1.87, p = 0.99), after adjustment for prior lines and time from diagnosis to ICI. Conclusions: In our study of heavily pretreated OC pts receiving ICI, BRCA 1/2 mutations were not associated with improved response or survival. These findings should be validated in larger studies.
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Spizzo, Gilbert, Alberto Puccini, Joanne Xiu, Richard M. Goldberg, Axel Grothey, Anthony Frank Shields, Sukeshi Patel Arora, et al. "Frequency of BRCA mutation in biliary tract cancer and its correlation with tumor mutational burden (TMB) and microsatellite instability (MSI)." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): 4085. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.4085.
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4085 Background: Biliary tract cancers constitute ~3% of cancers worldwide with incidence increasing, especially for intrahepatic cholangiocarcinoma (IHC). The prognosis of these tumors remains dismal and novel treatment strategies are needed to improve overall survival. BRCA mutations occur in biliary tract cancers but their frequency in distinct sites of biliary tract cancer is unknown. Moreover, no data are available correlating BRCA mutation with immunogenic markers such as TMB, MSI, or PD-L1 expression. Methods: Tumor samples from 1288 primary biliary tract cancers, comprising IHC (n = 746), extrahepatic cholangiocarcinoma (EHC) (n = 189), gallbladder (GBC) (n=353) were profiled at Caris Life Sciences, Phoenix, AZ. Testing included NextGen SEQ (MiSeq on 47 genes, NextSeq on 592 genes) and PD-L1 IHC (SP142). TMB was calculated based on somatic nonsynonymous missense mutations, and MSI was evaluated by NGS of known MSI loci. Results: BRCA mutations were detected in 3.6% (N = 46) of samples ( BRCA1 0.6%, BRCA2 3%), no differences were seen based on the site of the tumor. In GBC and IHC BRCA2 mutations (4.0% and 2.7%) were more frequent than BRCA1 (0.3% and 0.4, p < 0.05) while in EHC, similar frequency was observed ( BRCA1: 2.1%; BRCA2: 2.6%). There was no significant association with gender or age. In BRCA-mutant biliary tract cancer the most frequently mutated genes were TP53 (55.6%), ARID1A (52.2%) and KRAS (26.1%), KMT2D/C (20%, 13%) and CDKN2A(13%). Overall, BRCA mutations were associated with a higher rate of MSI-H (19.5% vs 1.7%, p = 0.001) and higher TMB in both MSI-H and MSS tumors (p<0.05). When investigated separately, BRCA association with elevated TMB was seen in IHC and EHC, but not in GBC. No correlation was seen with PD-L1 expression. TP53, KMT2D/C, RB1, PTEN, KDM6A mutations and FGFR1 amplifications were significantly higher in BRCA mutated tumors (p < 0.05). Conclusions: BRCA mutations are found in a significant subgroup of biliary tract tumors and are associated with an immunogenic tumor profile. These data provide rationale for trials testing PARP inhibitors in combination with immunotherapy and targeted therapies in patients with BRCA-mutant biliary tract cancers that are MSS.
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Oktay, Kutluk, Ja Yeon Kim, David Barad, and Samir N. Babayev. "Association of BRCA1 Mutations With Occult Primary Ovarian Insufficiency: A Possible Explanation for the Link Between Infertility and Breast/Ovarian Cancer Risks." Journal of Clinical Oncology 28, no. 2 (January 10, 2010): 240–44. http://dx.doi.org/10.1200/jco.2009.24.2057.
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Purpose Germline mutations in BRCA genes are associated with breast and ovarian cancer susceptibility. Because infertility is associated with breast and ovarian cancer risks, we hypothesized that the mutations in the BRCA gene may be associated with low response to fertility treatments. Methods We performed ovarian stimulation in 126 women with breast cancer by using letrozole and gonadotropins for the purpose of fertility preservation by embryo or oocyte cryopreservation. As surrogates of ovarian reserve, the oocyte yield and the incidence of low response were compared with ovarian stimulation according to BRCA mutation status. Results Of the 82 women who met the inclusion criteria, 47 women (57%) had undergone BRCA testing, and 14 had a mutation in BRCA genes, of which two were of clinically undetermined significance. In BRCA mutation–positive patients, low ovarian response rate was significantly higher compared with BRCA mutation–negative patients (33.3 v 3.3%; P = .014) and with BRCA-untested women (2.9%; P = .012). All BRCA mutation–positive low responders had BRCA1 mutations, but low response was not encountered in women who were only BRCA2 mutation positive. Compared with controls, BRCA1 mutation– but not BRCA2 mutation–positive women produced lower numbers of eggs (7.4 [95% CI, 3.1 to 17.7] v 12.4 [95% CI, 10.8 to 14.2]; P = .025) and had as many as 38.3 times the odds ratio of low response (95% CI, 4.1 to 353.4; P = .001). Conclusion BRCA1 mutations are associated with occult primary ovarian insufficiency. This finding may, at least in part, explain the link between infertility and breast/ovarian cancer risks.
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Arun, Banu, Angelica Gutierrez Barrera, Rachel M. Layman, Stephen K. Gruschkus, Isabelle Bedrosian, Constance T. Albarracin, Carlos Hernando Barcenas, Vicente Valero, Jennifer Keating Litton, and Debu Tripathy. "Outcome of patients with breast cancer and a germline BRCA mutation in a prospective cohort." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): 1544. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.1544.
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1544 Background: There are limited large prospective single institution studies on outcome of breast cancer in patients with germline BRCA1 and BRCA2 mutation. The primary aim of this study was to determine the effect of a germline BRCA1 or BRCA2 mutation on recurrence-free survival (RFS) and overall survival (OS) in patients with breast cancer. Methods: This is a prospective cohort study of patients with invasive breast cancer recruited from the UT MD Anderson Cancer Center Breast Medical Oncology and Clinical Cancer Genetics Center. For the purpose of this analysis, newly diagnosed breast cancer patients who have had germline BRCA1 and BRCA2 testing within 12 months were included. Clinical and pathological data, and data regarding outcomes were collected in this prospective cohort. The Kaplan-Meier method and corresponding log-rank test were used to estimate OS and RFS and to compare survival by mutation status. Results: Between 1996 and 2015, 3026 patients were recruited. Median age at diagnosis was 45 (19-87) years. A germline BRCA mutation was detected in 361 (11.9%) patients (207 with BRCA1, 154 with BRCA2). After a median follow-up time of 5.3 (0.04-20.7) years, 437 (14.4%) patients recurred and 340 (11.2%) were deceased. At median follow-up time 5 years, 79.3% of BRCA1, 91.4% of BRCA2 and 89.6% of BRCA negative patients were disease free; this difference was significant (p = 0.0001). Difference in OS between BRCA1/2-positive and BRCA-negative patients was also significant (p = 0.0001), with 81.2% of BRCA1, 93.4% of BRCA2 and 90% of BRCA negative patients being alive at 5 years. Amongst 600 patients with triple negative breast cancer (TNBC) patients, DFS and OS were not significantly different between the 3 groups. Of those patients diagnosed under 40 years (n = 937), RFS and OS was significantly different between 3 groups at 5 years (0.001 for RFS and OS); 75% BRCA1, 92% BRCA2 and 86% BRCA negative patients were disease free and 77% BRCA1, 94% BRCA2 and 88% BRCA negative patients were alive. Conclusions: Patients with BRCA1 or BRCA2 mutations have different survival outcomes. The prognosis of the first cancer needs to be taken into consideration when deciding for preventive surgeries to prevent second primary breast cancers in these patients. Furthermore, for BRCA1 mutation carriers more effective therapy strategies need to be evaluated to improve outcome.
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Akaev, Iolia, Siavash Rahimi, Olubukola Onifade, Francis John Edward Gardner, David Castells-Rufas, Eleanor Jones, Shyamika Acharige, and Chit Cheng Yeoh. "Tumour Versus Germline BRCA Testing in Ovarian Cancer: A Single-Site Institution Experience in the United Kingdom." Diagnostics 11, no. 3 (March 19, 2021): 547. http://dx.doi.org/10.3390/diagnostics11030547.
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The aim of this audit was to evaluate the usefulness and serviceability of testing for pathogenic mutations in BRCA1 or BRCA2 (BRCA1/2) genes in ovarian cancer (OC) patients. One hundred and thirty-five patients with more common histological sub-types of OC were retrospectively identified between 2011 and 2019. The fail rate of the molecular analysis was 7.4% (10/135). One hundred and twenty-five records were evaluated: 99 (79.2%) patients had wild-type BRCA (both somatic and germline); tumour BRCA1/2 (tBRCA1/2) pathogenic mutations were found in 20 (16%) patients with distribution between BRCA1 and BRCA2 being 40% and 60%, respectively; 13 (10.4%) patients with pathogenic variants had germline mutations; and tBRCA1/2 with variant of unknown significance (VUS), in the absence of pathogenic BRCA1 or BRCA2 variants, was detected in 6 (4.8%) patients. Our data show that expanding the molecular service to the routine first-tumour testing for patients with OC will potentially increase the detection rate of BRCA mutations, thereby providing early benefits of PARP inhibitors therapy. The tumour testing service should continue to be offered to newly diagnosed patients with high-grade epithelial cancers, including high-grade serous carcinoma, but also with carcinosarcomas and poorly-differentiated metastatic adenocarcinomas of unknown origin.
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Smith, Wesley, Kayla Smith, William Sessions, Connor Evins, Michael Baker, and Mary Blumer. "An evaluation of gender discrepancies in genetic referrals for BRCA testing for indicated malignancies." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): 10584. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.10584.
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10584 Background: Tumor suppressing genes BRCA1 and BRCA2 were discovered in 1990 and 1994, respectively, with mutations linked to hereditary breast-ovarian cancer syndromes (HBOCs). The discovery of these mutations has led to screening of at-risk patient populations and their family members. Women with BRCA1 or BRCA2 mutations are generally recommended to have prophylactic bilateral mastectomies and oophorectomies to decrease their future risk of cancer. While the initial discovery mostly focused on cancers in women, research has shown that BRCA mutations increase the risk of other cancers such as prostate cancer and pancreatic cancer, that also affect men. Previous research suggests that men are three times less likely to receive genetic testing in cancer driven by a 10:1 disparity in HBOC genetic testing. This was thought to be due to the lack of information on the importance of HBOC testing along with social roles in health. We wanted to evaluate the magnitude of the potential gender gap in BRCA testing in men compared to women. Methods: This was an IRB-approved, single center retrospective study to evaluate the rate of referrals to genetics for BRCA testing. Eligible patients had a personal history of cancer meeting criteria for BRCA testing per NCCN recommendations. Chart review was performed for patients with ovarian cancer, female breast cancer 45 years and younger, female triple negative breast cancer 60 years and younger, metastatic prostate cancer, all male breast cancer that have made an office visit since 2017, and pancreatic cancer since 2019. Rates of referral for genetic testing was the primary outcome and the groups were compared via the Chi-Square test. Results: 1,320 patients were included in the study, of which 664 were men and 656 were women. 128/664 (19.3%) of men were referred to genetics for screening compared to 527/656 (80.3%) for women ( p <.001). Additionally, 42/128 (32.8%) men who were referred for screening did not complete genetic screening compared to 72/527 (13.7%) women ( p <.001). A total of 62/541 (11.5%) patients who completed screening had either a BRCA1 or BRCA2 mutation. Conclusions: In our study, men were referred for BRCA testing significantly less than women for primary cancers, despite recommendation from the NCCN. In addition, men were also more than twice as likely not to complete genetic screening even if referred. The integration of genetics and oncology will continue to grow as personalized medicine continues to drive more treatment options. Closing this gender gap is important not only for familial screening purposes but also for treatment implications as patients with germline BRCA mutations are eligible for poly ADP ribose polymerase (PARP) inhibitors (e.g. olaparib) in both metastatic prostate cancer and pancreatic cancer. Further quality improvement initiatives are needed in order to close this gap by increasing education of the importance of BRCA testing in men.
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Oktay, K., J. Kim, D. Barad, N. Gleicher, and S. Babayev. "Association of BRCA1 mutations with diminished ovarian reserve: A common genetic mechanism for breast/ovarian cancer, and infertility?" Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): 11039. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.11039.
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11039 Background: 25% of all breast cancers (BC) occur prior to menopause and preservation of fertility is an important quality of life issue for these women. We recently reported an ovarian stimulation (OS) protocol utilizing letrozole for women with BC who wish to preserve their fertility by embryo freezing. Because BRCA+ young women are highly represented among those undergoing fertility preservation, and because knock out models showed a relationship between DNA repair genes and germ cell development, we hypothesized that women with BRCA mutations have diminished oocyte reserve (DOR). Methods: We analyzed the letrozole-OS data to assess the association between BRCA mutations and number of oocytes retrieved, which is the most direct non-invasive method of assessing ovarian reserve. Women with infertility history and age>37 were excluded. Results: Of 125 BC patients who underwent OS between 5/03 and 11/08, 82 met the criteria, of which 47 (57%) had BRCA testing. Of those, 14 (30%) were BRCA+; 9 BRCA1+, 4 BRCA2+, and 1 + for both. Mean ages of those untested, BRCA-, and + women were similar (33.0±2.9 vs 32.8±2.9 vs 33.0±2.8; p=0.97)). Age-adjusted poor response (PR) rate (<4 oocytes retrieved) was significantly higher in BRCA+ (28.6%; 4/14) compared to BRCA- (3%;1/33, p=0.009) and untested (2.9%; 1/35, p=0.007). All poor responders were BRCA1+ with one also having a mutation in BRCA2. A BRCA mutation was associated with 17.7 times the relative risk (RR) of PR (95% CI 1.4–214; p=0.024). The mean number of oocytes was significantly lower in BRCA1+ but not BRCA2+ compared to BRCA- and untested (p=0.05). BRCA1 but not BRCA2 mutations were associated with PR with a RR of 24.0 (95% CI 1.9–298; p=0.013). When only mutations of known clinical significance were included, the RR for PR further increased (RR=36, 95% CI 2.5–503; p=0.008) suggesting a common mechanism between BRCA-induced cancer and premature diminishment of oocyte reserve. Conclusions: Because women with BRCA1 mutations may have DOR prematurely, they should be counseled for possible higher risk of ovarian failure and infertility after chemotherapy, and referred for fertility preservation. Diminished ovarian reserve may be a new component of the Hereditary Breast Ovarian Cancer Syndrome. No significant financial relationships to disclose.
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Metcalfe, Kelly A., Aletta Poll, Robert Royer, Marcia Llacuachaqui, Anna Tulman, Ping Sun, and Steven A. Narod. "Screening for Founder Mutations in BRCA1 and BRCA2 in Unselected Jewish Women." Journal of Clinical Oncology 28, no. 3 (January 20, 2010): 387–91. http://dx.doi.org/10.1200/jco.2009.25.0712.
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Purpose There are two mutations in BRCA1 and one mutation in BRCA2 that are present in up to 2.5% of Ashkenazi Jewish women. Current guidelines for testing stipulate that a personal or family history of cancer be present to be eligible for testing. To date, population screening in this population has not been suggested. However, this may be rational. Little is known about the appropriateness of testing guidelines for the Jewish population or the level of interest in testing. Methods Eligible subjects were women who self-identified as Jewish, who were between the ages of 25 and 80 years, and who resided in Ontario. Subjects were recruited through an article in a national newspaper. Women were asked to complete a study questionnaire and a family history questionnaire and to provide a blood or saliva sample. The risk of carrying a BRCA mutation was estimated for each woman. Results A total of 2,080 women were enrolled onto the study. The overall mutation prevalence was 1.1% (0.5% for BRCA1 and 0.6% for BRCA2). Among the 22 mutation carriers, the mean estimate of carrying a BRCA mutation was 3.9%. Ten (45%) of the 22 women met the current Ontario Ministry of Health Guidelines criteria for testing. Conclusion There is considerable interest for genetic testing among Jewish women at low risk of carrying a mutation. However, many women with mutations are ineligible for genetic testing under current guidelines. Approximately 1% of Jewish women carry a BRCA mutation, and these women should be considered to be candidates for genetic testing.
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Lindsey, Heather. "BRCA Testing." Oncology Times 26, no. 3 (February 2004): 12. http://dx.doi.org/10.1097/01.cot.0000291728.63654.be.
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Mirza, M. A., A. Sehbai, T. Nestor, V. Brown, and J. Abraham. "BRCA mutations: An Appalachian experience." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 20111. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.20111.
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20111 Background: BRCA1 and 2 mutations are rare in general population and women with these mutations confer a significantly increased risk of invasive breast and ovarian cancer (65% to 85%, and 15% to 65% cumulative lifetime risk, respectively). A few of these are variant mutations also known as Variant of unknown significance (VUS). Methods: Observational study of 155 patients who presented to MBRCC, WVU for genetic counseling between November 2001 and March 2005. Patients underwent genetic testing after detailed genetic counseling. Clinical data, such as patient’s age, ethnic origin, follow up period, Myriad risk of mutation, clinical outcome i.e., Mastectomy versus Bilateral Salpingo-oophorectomy versus Surveillance, total numbers of patients screened, tested and reason for not testing, and other data, were available for statistical analysis. Results: In out patient population who underwent genetic counseling, 46% (71 out of 155) underwent genetic testing. A large number of patients (54%; 84 out of 155) who underwent genetic counseling could not undergo the genetic testing. Total number of patients not genetically tested were 84, out of which, 27 were low risk, 35 had insurance denial, 7 were not interested, 14 were awaiting results or insurance approval and 1 was deceased. 27 out of 71 patients (38%) who underwent genetic testing were positive for a mutation. Among these patients (n = 27), 8 had BRCA 1; 3 had BRCA1 VUS; 7 had BRCA 2 and 9 had BRCA2 VUS. The average age for patients who had a genetic mutation was 42 years. The most prevalent genetic mutation in our study population was BRCA2 VUS (33%; 9 out of 27) followed by BRCA 1 mutation (29%; 8 out of 27). 11 out of 27 (40%) who had a mutation underwent mastectomy. 13 out of 27 patients (48%) who had a mutation underwent bilateral salpingo-oophorectomy. 7 out of 27 patients (26%) who had a mutation underwent total abdominal hysterectomy. 4 out of 27 patients (15%) who had a germline mutation were lost to followup. Conclusion: We report the prevalence and the clinical outcomes in patients with BRCA mutations in the state of West Virginia, which is comparable to the national database. High number of patients could not undergo genetic testing because of insurance denial. No significant financial relationships to disclose.
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Poon, Kok-Siong, Lily Chiu, and Karen Mei-Ling Tan. "Laboratory Verification of a BRCA1 and BRCA2 Massively Parallel Sequencing Assay from Wet Bench to Bioinformatics for Germline DNA Analysis." Global Medical Genetics 08, no. 02 (March 16, 2021): 062–68. http://dx.doi.org/10.1055/s-0041-1726338.
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Abstract Introduction A robust genetic test for BRCA1 and BRCA2 genes is necessary for the diagnosis, prognosis, and treatment of patients with hereditary breast and ovarian cancer. We evaluated a commercial amplicon-based massively parallel sequencing (MPS) assay, BRCA MASTR Plus on the MiSeq platform, for germline BRCA genetic testing. Methods This study was performed on 31 DNA from cell lines and proficiency testing samples to establish the accuracy of the assay. A reference cell line DNA, NA12878 was used to determine the reproducibility of the assay. Discordant MPS result was resolved orthogonally by the current gold-standard Sanger sequencing method. Results The analytical accuracy, sensitivity, and specificity for variant detection were 93.55, 92.86, and 100.00%, respectively. Both sequencing depth and variant allele frequencies were highly reproducible by comparing the NA12878 DNA tested in three separate runs. The single discordant result, later confirmed by Sanger sequencing was due to the inability of the MASTR Reporter software to identify a 40-bp deletion in BRCA1. Conclusion The BRCA MASTR Plus assay on the MiSeq platform is accurate and reproducible for germline BRCA genetic testing, making it suitable for use in a clinical diagnostic laboratory. However, Sanger sequencing may still serve as a confirmatory method to improve diagnostic capability of the MPS assay.
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Hwang, E. Shelley, Jane L. McLennan, Dan H. Moore, Beth B. Crawford, Laura J. Esserman, and John L. Ziegler. "Ductal Carcinoma In Situ in BRCA Mutation Carriers." Journal of Clinical Oncology 25, no. 6 (February 9, 2007): 642–47. http://dx.doi.org/10.1200/jco.2005.04.0345.
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Purpose The current literature suggests that ductal carcinoma in situ (DCIS) of the breast is infrequently diagnosed in patients with BRCA germline mutations. We studied women at high risk of hereditary breast cancer syndromes who underwent testing for BRCA1 and BRCA2 to estimate DCIS prevalence and incidence in known BRCA-positive women compared with high-risk women who were mutation negative. Methods We analyzed breast event outcomes in a retrospective cohort of 129 BRCA-positive and 269 BRCA-negative women undergoing genetic testing for a BRCA mutation between September 1996 and December 2003 at University of California, San Francisco. We estimated the frequency of DCIS and invasive cancer and time to breast events from birth using a Cox proportional hazard model for competing risks. Histologic grade of DCIS was also compared between groups. Results Among BRCA carriers, 48 (37%) had DCIS (with or without invasive cancer) compared with 92 noncarriers (34%). Univariate analysis showed that both DCIS and invasive cancer had an earlier onset in mutation carriers than in noncarriers, although on a per-woman basis, this difference was not statistically significant. High-grade DCIS was more common in BRCA1 mutation carriers than in patients without a mutation (P = .02). Conclusion DCIS is equally as prevalent in patients who carry deleterious BRCA mutations as in high familial-risk women who are noncarriers, but occurs at an earlier age. Our results argue for the consideration of DCIS as a criterion for BRCA risk assessments with appropriate weighting in prediction models such as BRCAPRO.
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Keung, Yi-Kong, Adriana Hu, Annie Yeung, Amy Chan, and Eddie Hu. "Higher prevalence of BRCA2 mutations among Chinese breast cancer patients in a community oncology clinic." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): e12017-e12017. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.e12017.
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e12017 Background: According to a large US population-based study, BRCA1 and 2 mutations occur in about 6 and 4% breast cancer cases age <45. Asians have the lowest prevalence of BRCA1 mutation among five US racial groups. The prevalence of BRCA1 and BRCA2 mutations was reported as 8.1% and 2.7% among pts with family history in Shanghai, compared to 4.9% and 7.5% respectively in Hong Kong. We would like to explore the BRCA mutations in a clinic located in an Asian-majority community in California. Methods: Consecutive female breast cancer pts selected for BRCA testing according to NCCN guidelines are retrospectively studied from 10/2009 to 10/2011. Sequencing of all translated exons and immediately adjacent intronic regions of the BRCA1 and BRCA2 was performed on the peripheral blood (Myriad, Utah). Results: Twenty-six pts were included in this study. Six pts have bilateral breast cancers; 2 synchronous and 4 metachronous with intervals of 11-13 years. Nine pts (34.6%) had BRCA2 germline mutations, of which 5 were considered deleterious and 4 of uncertain significance. Eleven pts (42.3%) had no BRCA mutation. BRCA results were unavailable in six pts because they were either not yet done or denied by health insurance. Conclusions: 1. High prevalence of BRCA2 mutation is seen in our pts selected according to NCCN guidelines. The presence of BRCA2 but not BRCA1 mutation in our study is intriguing. 2. Triple negative breast cancer is not more prevalent in BRCA2 mutation carriers. 3. Similar frequency of family history of breast/ovarian cancer is noted among pts with or without BRCA2 mutation, deleterious or of uncertain significance. The role of the BRCA2 mutation of uncertain significance needs to be further elucidated. 4. Due to the small sample size, further study is required to confirm our findings. [Table: see text]
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Randall, Megan, Kelly Burgess, Lela Buckingham, and Lydia Usha. "Exceptional Response to Olaparib in a Patient With Recurrent Ovarian Cancer and an Entire BRCA1 Germline Gene Deletion." Journal of the National Comprehensive Cancer Network 18, no. 3 (March 2020): 223–28. http://dx.doi.org/10.6004/jnccn.2019.7378.
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PARP inhibitors are known to be effective in patients with ovarian cancer (OC) and germline mutations in BRCA1 and BRCA2 genes (BRCA mutations). Little is known, however, about any correlation between the deletion size and location of the BRCA mutation and the response to PARP inhibitors. Women with OC commonly undergo genetic testing because the presence of a germline BRCA mutation impacts therapeutic decisions and is important for cancer surveillance in patients and their family members. This report presents a case of a rare entire germline BRCA1 gene deletion and an exceptional response to a PARP inhibitor, olaparib, in a heavily pretreated patient with OC. Her disease course was also remarkable for complete responses to platinum-based chemotherapy and long chemotherapy-free intervals. Interestingly, the deletion of the entire BRCA1 gene was found after previously negative BRCA test results and is associated with a deletion of 6 adjacent genes without known clinical significance. She has remained progression-free and asymptomatic for >3 years on olaparib, with an overall survival of >12 years. We postulate that this unusually favorable response and prolonged overall survival is related to the cancer cells’ inability to reverse the entire gene deletion to wild-type (a common mechanism of resistance to PARP inhibition). This case shows the value of genetic testing for patients with OC and highlights the utility of additional testing with previously negative results and limited genetic testing. It also provides insight into a potential mechanism of an exceptional response to PARP inhibition.
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Arun, Banu, Soley Bayraktar, Diane D. Liu, Angelica M. Gutierrez Barrera, Deann Atchley, Lajos Pusztai, Jennifer Keating Litton, et al. "Response to Neoadjuvant Systemic Therapy for Breast Cancer in BRCA Mutation Carriers and Noncarriers: A Single-Institution Experience." Journal of Clinical Oncology 29, no. 28 (October 1, 2011): 3739–46. http://dx.doi.org/10.1200/jco.2011.35.2682.
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Purpose To compare the pathologic complete response (pCR) rate and relapse-free survival (RFS) and overall survival (OS) after neoadjuvant systemic chemotherapy (NST) in patients with breast cancer with and without deleterious BRCA1 and BRCA2 mutations. Patients and Methods A total of 317 women who underwent BRCA genetic testing and were treated with NST for breast cancer between 1997 and 2009 were included in the study. The Kaplan-Meier product-limit method was used to estimate RFS and OS rates. Logistic regression models were fit to determine the associations between BRCA status, pCR, and survival. Results Fifty-seven (18%) and 23 (7%) patients had BRCA1 and BRCA2 mutations, respectively. Twenty-six (46%) of 57 BRCA1 carriers achieved a pCR, compared with three (13%) of 23 BRCA2 carriers and 53 (22%) of 237 BRCA noncarriers (P < .001). In the multivariate logistic model, BRCA1 status (odds ratio [OR] = 3.16; 95% CI, 1.55 to 6.42; P = .002), estrogen receptor (ER) negativity (OR = 1.96; 95% CI:1.05 to 3.65; P = .03) and concurrent trastuzumab use (OR = 4.18; 95% CI, 2.04 to 8.57; P < .001) remained as independent significant predictors for a pCR. At a median follow-up of 3.2 years, 69 patients (22%) experienced a disease recurrence or death. No significant differences were noted in survival outcomes with respect to BRCA status and type of NST received. However, among BRCA1 carriers, patients who achieved a pCR had better 5-year RFS (P = .001) and OS (P = .01) rates than patients who did not. Conclusion BRCA1 status and ER negativity are independently associated with higher pCR rates in patients with breast cancer. Overall prognosis of breast cancer in BRCA carriers is similar to sporadic breast cancers.
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Manchanda, Ranjit, Li Sun, Shreeya Patel, Olivia Evans, Janneke Wilschut, Ana Carolina De Freitas Lopes, Faiza Gaba, et al. "Economic Evaluation of Population-Based BRCA1/BRCA2 Mutation Testing across Multiple Countries and Health Systems." Cancers 12, no. 7 (July 17, 2020): 1929. http://dx.doi.org/10.3390/cancers12071929.
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Clinical criteria/Family history-based BRCA testing misses a large proportion of BRCA carriers who can benefit from screening/prevention. We estimate the cost-effectiveness of population-based BRCA testing in general population women across different countries/health systems. A Markov model comparing the lifetime costs and effects of BRCA1/BRCA2 testing all general population women ≥30 years compared with clinical criteria/FH-based testing. Separate analyses are undertaken for the UK/USA/Netherlands (high-income countries/HIC), China/Brazil (upper–middle income countries/UMIC) and India (low–middle income countries/LMIC) using both health system/payer and societal perspectives. BRCA carriers undergo appropriate screening/prevention interventions to reduce breast cancer (BC) and ovarian cancer (OC) risk. Outcomes include OC, BC, and additional heart disease deaths and incremental cost-effectiveness ratio (ICER)/quality-adjusted life year (QALY). Probabilistic/one-way sensitivity analyses evaluate model uncertainty. For the base case, from a societal perspective, we found that population-based BRCA testing is cost-saving in HIC (UK-ICER = $−5639/QALY; USA-ICER = $−4018/QALY; Netherlands-ICER = $−11,433/QALY), and it appears cost-effective in UMIC (China-ICER = $18,066/QALY; Brazil-ICER = $13,579/QALY), but it is not cost-effective in LMIC (India-ICER = $23,031/QALY). From a payer perspective, population-based BRCA testing is highly cost-effective in HIC (UK-ICER = $21,191/QALY, USA-ICER = $16,552/QALY, Netherlands-ICER = $25,215/QALY), and it is cost-effective in UMIC (China-ICER = $23,485/QALY, Brazil−ICER = $20,995/QALY), but it is not cost-effective in LMIC (India-ICER = $32,217/QALY). BRCA testing costs below $172/test (ICER = $19,685/QALY), which makes it cost-effective (from a societal perspective) for LMIC/India. Population-based BRCA testing can prevent an additional 2319 to 2666 BC and 327 to 449 OC cases per million women than the current clinical strategy. Findings suggest that population-based BRCA testing for countries evaluated is extremely cost-effective across HIC/UMIC health systems, is cost-saving for HIC health systems from a societal perspective, and can prevent tens of thousands more BC/OC cases.
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Weitzel, Jeffrey N., Jessica Clague, Arelis Martir-Negron, Raquel Ogaz, Josef Herzog, Charité Ricker, Chelsy Jungbluth, et al. "Prevalence and Type ofBRCAMutations in Hispanics Undergoing Genetic Cancer Risk Assessment in the Southwestern United States: A Report From the Clinical Cancer Genetics Community Research Network." Journal of Clinical Oncology 31, no. 2 (January 10, 2013): 210–16. http://dx.doi.org/10.1200/jco.2011.41.0027.
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PurposeTo determine the prevalence and type of BRCA1 and BRCA2 (BRCA) mutations among Hispanics in the Southwestern United States and their potential impact on genetic cancer risk assessment (GCRA).Patients and MethodsHispanics (n = 746) with a personal or family history of breast and/or ovarian cancer were enrolled in an institutional review board–approved registry and received GCRA and BRCA testing within a consortium of 14 clinics. Population-based Hispanic breast cancer cases (n = 492) enrolled in the Northern California Breast Cancer Family Registry, negative by sequencing for BRCA mutations, were analyzed for the presence of the BRCA1 ex9-12del large rearrangement.ResultsDeleterious BRCA mutations were detected in 189 (25%) of 746 familial clinic patients (124 BRCA1, 65 BRCA2); 21 (11%) of 189 were large rearrangement mutations, of which 62% (13 of 21) were BRCA1 ex9-12del. Nine recurrent mutations accounted for 53% of the total. Among these, BRCA1 ex9-12del seems to be a Mexican founder mutation and represents 10% to 12% of all BRCA1 mutations in clinic- and population-based cohorts in the United States.ConclusionBRCA mutations were prevalent in the largest study of Hispanic breast and/or ovarian cancer families in the United States to date, and a significant proportion were large rearrangement mutations. The high frequency of large rearrangement mutations warrants screening in every case. We document the first Mexican founder mutation (BRCA1 ex9-12del), which, along with other recurrent mutations, suggests the potential for a cost-effective panel approach to ancestry-informed GCRA.
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Howarth, Dt R., Sharon S. Lum, Pamela Esquivel, Carlos A. Garberoglio, Maheswari Senthil, and Naveenraj L. Solomon. "Initial Results of Multigene Panel Testing for Hereditary Breast and Ovarian Cancer and Lynch Syndrome." American Surgeon 81, no. 10 (October 2015): 941–44. http://dx.doi.org/10.1177/000313481508101006.
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Multigene panel testing for hereditary cancer risk has recently become commercially available; however, the impact of its use on patient care is undefined. We sought to evaluate results from implementation of panel testing in a multidisciplinary cancer center. We performed a retrospective review of consecutive patients undergoing genetic testing after initiating use of multigene panel testing at Loma Linda University Medical Center. From February 13 to August 25, 2014, 92 patients were referred for genetic testing based on National Comprehensive Cancer Network guidelines. Testing was completed in 90 patients. Overall, nine (10%) pathogenic mutations were identified: five BRCA1/2, and four in non-BRCA loci. Single-site testing identified one BRCA1 and one BRCA2 mutation. The remaining mutations were identified by use of panel testing for hereditary breast and ovarian cancer. There were 40 variants of uncertain significance identified in 34 patients. The use of panel testing more than doubled the identification rate of clinically significant pathogenic mutations that would have been missed with BRCA testing alone. The large number of variants of uncertain significance identified will require long-term follow-up for potential reclassification. Multigene panel testing provides additional information that may improve patient outcomes.
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Chandrasekaran, Dhivya, Monika Sobocan, Oleg Blyuss, Rowan E. Miller, Olivia Evans, Shanthini M. Crusz, Tina Mills-Baldock, et al. "Implementation of Multigene Germline and Parallel Somatic Genetic Testing in Epithelial Ovarian Cancer: SIGNPOST Study." Cancers 13, no. 17 (August 27, 2021): 4344. http://dx.doi.org/10.3390/cancers13174344.
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We present findings of a cancer multidisciplinary-team (MDT) coordinated mainstreaming pathway of unselected 5-panel germline BRCA1/BRCA2/RAD51C/RAD51D/BRIP1 and parallel somatic BRCA1/BRCA2 testing in all women with epithelial-OC and highlight the discordance between germline and somatic testing strategies across two cancer centres. Patients were counselled and consented by a cancer MDT member. The uptake of parallel multi-gene germline and somatic testing was 97.7%. Counselling by clinical-nurse-specialist more frequently needed >1 consultation (53.6% (30/56)) compared to a medical (15.0% (21/137)) or surgical oncologist (15.3% (17/110)) (p < 0.001). The median age was 54 (IQR = 51–62) years in germline pathogenic-variant (PV) versus 61 (IQR = 51–71) in BRCA wild-type (p = 0.001). There was no significant difference in distribution of PVs by ethnicity, stage, surgery timing or resection status. A total of 15.5% germline and 7.8% somatic BRCA1/BRCA2 PVs were identified. A total of 2.3% patients had RAD51C/RAD51D/BRIP1 PVs. A total of 11% germline PVs were large-genomic-rearrangements and missed by somatic testing. A total of 20% germline PVs are missed by somatic first BRCA-testing approach and 55.6% germline PVs missed by family history ascertainment. The somatic testing failure rate is higher (23%) for patients undergoing diagnostic biopsies. Our findings favour a prospective parallel somatic and germline panel testing approach as a clinically efficient strategy to maximise variant identification. UK Genomics test-directory criteria should be expanded to include a panel of OC genes.
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Metcalfe, Kelly A., Aletta Poll, Andrea Eisen, Jordan Lerner-Ellis, and Steven Narod. "Outcomes associated with rapid genetic testing for BRCA1 and BRCA2 at time of breast cancer diagnosis." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): 1577. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.1577.
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1577 Background: Bilateral mastectomy improves survival for women with BRCA-associated breast cancer. Most women do not know their BRCA status at the time of BC diagnosis when making surgical decisions. Rapid genetic testing (RGT) allows a woman to have genetic test results prior to treatment decision making, but it is unclear if RGT has an impact on treatment choices. It is also unclear if there are psychosocial implications associated with genetic testing at the time of breast cancer diagnosis. The objective of the current study was to assess the impact of RGT at the time of BC diagnosis on surgical decision-making and psychosocial functioning. Methods: Eligible women were referred from participating surgeons at BC diagnosis. Women completed baseline questionnaires assessing treatment preferences, cancer related distress, anxiety, and depression. All participants received in-person pre-test genetic counselling and genetic test results were given within 10 days. Participants completed surveys at 1 week and 1 year post-genetic testing to assess treatments and psychosocial functioning. Results: 1010 women consented to participate and 60 (5.9%) were identified with a BRCA mutation. 15% of those identified with a BRCA mutation did not meet provincial eligibility criteria for genetic testing, and 20% were eligible prior to a breast cancer diagnosis but had not received testing. Mean levels of cancer-related distress, anxiety and depression declined significantly from baseline to 1 year for all women (all p < .05), and there were no differences at any time point between those with and without a BRCA mutation. Of those identified with a BRCA mutation, 67.3% reported that their surgery choice changed. 73.7% of BRCA carriers had a bilateral mastectomy, compared to 20.2% of BRCA negative (p < 0.001). Most women used genetic testing results for surgical decision making (96.1% of BRCA positive and 86.4% for negative). Conclusions: Rapid genetic testing for BRCA1 and BRCA2 at the time of BC diagnosis does not have a negative impact on psychosocial functioning. There are no differences in cancer-related distress, anxiety or depression between women who receive a positive result compare to a negative genetic test result. Furthermore, surgical choice changed for many women identified with a BRCA mutation, with the majority electing for bilateral mastectomy.
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Abida, Wassim, David Campbell, Akash Patnaik, Brieuc Sautois, Jeremy David Shapiro, Nicholas J. Vogelzang, Alan Haruo Bryce, et al. "Genomic characteristics associated with clinical activity of rucaparib in patients (pts) with BRCA1 or BRCA2 (BRCA)-mutated metastatic castration-resistant prostate cancer (mCRPC)." Journal of Clinical Oncology 38, no. 6_suppl (February 20, 2020): 178. http://dx.doi.org/10.1200/jco.2020.38.6_suppl.178.
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178 Background: The phase 2 TRITON2 study (NCT02952534) is evaluating the PARP inhibitor rucaparib in pts with mCRPC and a deleterious germline or somatic alteration in BRCA ( BRCA pts) or 1 of 13 other DNA damage repair (DDR) genes. Methods: Eligible pts had progressed on 1–2 lines of androgen receptor-directed therapy and 1 taxane-based chemotherapy. Deleterious DDR gene alterations were identified from central testing of plasma and/or tissue samples by Foundation Medicine or from local testing. Results: As of Jul 2, 2019 (visit cutoff), 98 BRCA pts had received rucaparib; median (range) duration of follow-up was 13.0 (4.1–25.8) mo. Confirmed objective response rate (ORR) in BRCA pts (with investigator-assessed measurable disease) and PSA response rates (in pts with and without measurable disease) are shown in the Table. A biallelic alteration was observed in 81.4% (35/43) of BRCA pts for whom zygosity could be determined, and pts with homozygous BRCA loss (20.4%; 20/98) demonstrated high ORR (66.7% [95% CI, 38.4-88.2]; 10/15) and PSA response rates (75.0% [95% CI, 50.9-91.3]; 15/20). The safety profile in BRCA pts was consistent with the overall TRITON2 pt population. Conclusions: Results from TRITON2 showed antitumor activity with rucaparib in pts with mCRPC and a deleterious BRCA alteration. Responses were observed in patients with germline or somatic alterations in BRCA1 or BRCA2. The activity of rucaparib in these and additional genomic subgroups (e.g., based on zygosity, plasma genomic testing, or co-occurring alterations) will be reported. Clinical trial information: NCT02952534. [Table: see text]
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Pal, Tuya, Deborah Cragun, Xuefeng Wang, Sean J. Yoder, Tania MESA, Marilin Rosa, Ann Tezak, Anne Weidner, Susan Thomas Vadaparampil, and Catherine Phelan. "Characterization of germline and tumor genomic profile in unselected young black breast cancer patients." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): e13090-e13090. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e13090.
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e13090 Background: Young black women bear a disproportionate burden of breast cancer (BC), yet there is limited characterization of these cancers based on BRCA1 and BRCA2 ( BRCA) status and tumor genomics. In this pilot study, we characterized: tumor and clinical characteristics based on BRCA carrier status and overlap of basal-like (BL) and triple negative (TN) BC. Methods: A population-based sample of 481 black women diagnosed with invasive BC < age 50 were recruited through the Florida Cancer Registry (FCR). BRCA status was determined based on germline testing. TN status was determined based on pathology reports and FCR data. Among a subset of 90 participants, gene expression profiling (GEP) was conducted on tumor samples through PAM50 analyses to classify intrinsic subtypes and risk of recurrence (ROR) scores. Results: Mean age at BC diagnosis was 41.9 (range: 25-50) and mean ROR score was 49.6 (range: 8.7-80.7). Participants included 7 BRCA1 carriers, 5 BRCA2 carriers, 67 non-carriers (NC), and 11 with no confirmed testing. Of 46 BL tumors, 33 were TN (71.7%) constituting 94.3% of TN tumors (the remaining 5.7% were Luminal A). All BRCA1 carriers had BL tumors, of which 5 were TN. Sensitivity, positive predictive value, and negative predictive value in identifying BRCA1 carrier was higher based on BL compared to TN status (Table 1). BRCA2-associated tumors included 3 Luminal A, 1 Luminal B, and 1 BL. Mean ROR score was highest among BRCA1 carriers (57.7), followed by NC (50.5) and BRCA2 carriers (41.5). Conclusions: Study findings suggest BL status predicted BRCA1 positivity better than TN status. BRCA2- (compared to BRCA1-) associated tumors were more heterogeneous with over half being Luminal A, which may explain the lower ROR among BRCA2 carriers. Additional follow-up and expansion of this cohort with collection of clinical outcomes will be useful in assessing the predictive utility of ROR scores among young black women with BC. [Table: see text]
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Bahsi, Taha, and Haktan Bağış Erdem. "Spectrum of BRCA1/BRCA2 variants in 1419 Turkish breast and ovarian cancer patients: a single center study." Turkish Journal of Biochemistry 45, no. 1 (December 24, 2019): 83–90. http://dx.doi.org/10.1515/tjb-2019-0424.
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Abstract Objectives Hereditary breast and ovarian cancer syndrome is chacterized with multiple cases of breast cancer and/or ovarian cancer on the same side of the family. BRCA1/BRCA2 genes are associated with 20–25% of all patients. For developing national health policies for genetic testing, it is important to determine the range of pathogenic mutations in susceptibility genes and to identify recurrent founder mutations. Materials and methods All the patients were provided BRCA testing criteria according to National Comprehensive Cancer Network. QIAseq multiplex amplicon panel, BRCA MASTR™ Dx and Ion AmpliSeq Panel were used for BRCA1/BRCA2 coding regions. SALSA® MLPA® was performed for negative patients. Results Of 1419 patients, 134 (9.4%) were found to carry a pathogenic and 5 (0.3%) were found to carry a likely pathogenic mutation. Of those, 58 patients were found to carry a mutation in BRCA1 and 64 in BRCA2. Variant of uncertain significance was detected in 91 patients (6.4%). Conclusion The spectrum of BRCA1/2 mutations in Turkish population has been shown in the largest patient group to date. The thesis that founder mutations show diversity in different populations has been confirmed in our study, and the mutations that are common in Turkish population have been presented in this study.
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Goncalves, Susana Beatriz, Gonzalo Giornelli, Marcelo Horacio Pereira, Dolores Gallardo-Rincon, and Maria Del Pilar Estevez-Diz. "FLABRA, frontline approach for BRCA testing in ovarian cancer (OC) treatment naïve population: A Latin America (LA) epidemiologic study." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): e17050-e17050. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e17050.
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e17050 Background: The majority of OC cases are sporadic, but it is estimated that in 17%, germline mutations in BRCA1 or BRCA2 genes can be identified. BRCA mutated OC has distinct clinical characteristics, increased sensitivity to platinum and non-platinum agents, and to DNA damage repair (DDR) targeting agents like PARP inhibitors. Additionally, somatic BRCA mutations could be identified in tumor tissue. The prevalence of germline BRCA mutations (gBRCAm) and somatic mutations (sBRCAm) has been not been characterized in Latin-american population, which is a paradigm of poly-ethnicity, where prevalence of germline, but especially somatic BRCA mutations in OC, has not been studied. Furthermore, tumor testing as first step may be a new option in BRCA testing algorithm that could avoid the necessity for double testing (gBRCA, then sBRCA testing), in case of gBRCAm negative result. Methods: FLABRA is a cross-sectional, multi-center, study designed to determine the prevalence of sBRCAm in newly diagnosed OC patients versus gBRCAm, and to describe different treatment approaches at front line in LA, as well as current OC genetic counselling. We enrolled 400 consecutive patients from 40 institutions in Argentina, Brazil, Colombia, Mexico, Peru and Panama, diagnosed with OC. Tumor blocks were tested for sBRCA (Myriad Tumor BRACAnalysis CDx™). In sBRCA positive patients, blood samples were analyzed to confirm if the mutation was germline or somatic in origin. In gBRCAm, genetic counseling was advised. Medical records were reviewed for data relevant to medical history, surgery results, treatment approach and genetic counseling. Results: We present the preliminary results with 291 patients already tested. For this first subset of patients, 85/291 (29%) had BRCA mutations identified in their tumors. Preliminary results confirm that starting with tumor testing enlarges the population eligible for PARP inhibitors, by identifying additional patients with somatic mutations only detectable in the tumor. Although preliminary, our data confirms the possibility of identifying additional patients with sBRCA mutations by testing in tumor, with a more cost-effective approach, avoiding a second round of gBRCA testing in patients with BRCA negative results in tumor. Conclusions: In this preliminary analysis we found that somatic BRCA mutations account for a significant proportion from total BRCA mutations within LA population studied.
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Abida, Wassim, Alan Haruo Bryce, Nicholas J. Vogelzang, Robert J. Amato, Ivor John Percent, Jeremy David Shapiro, Raymond S. McDermott, et al. "Genomic characteristics of deleterious BRCA1 and BRCA2 alterations and associations with baseline clinical factors in patients with metastatic castration-resistant prostate cancer (mCRPC) enrolled in TRITON2." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): 5031. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.5031.
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5031 Background: The phase 2 TRITON2 study (NCT02952534) is evaluating the PARP inhibitor rucaparib in patients with mCRPC who have a deleterious germline or somatic alteration in BRCA ( BRCA1 or BRCA2) or 1 of 13 other DNA damage repair genes. Here we present analyses of tumor genomics and baseline clinical characteristics in mCRPC patients with a deleterious alteration in BRCA. Methods: Plasma (baseline) and tissue (archival or baseline) samples from patients with a deleterious alteration in BRCA were analyzed using Foundation Medicine next-generation sequencing assays. The alterations and zygosity of the alterations that were detected, as well as the somatic/germline status from Color Genomics testing, were summarized. Associations between genomic alterations, DNA yield, allele frequency, and baseline clinical characteristics were investigated. Results: Results are shown in the Table for a cohort of 40 BRCA2 and 5 BRCA1 patients enrolled in TRITON2 (Abida W et al. Presented at ESMO 2018. Abst 793PD). A biallelic alteration was observed in 21 of the 22 BRCA2 patients (95%) for whom alteration zygosity could be determined. Among the 5 BRCA1 patients, 1 alteration was monoallelic and 4 were of unknown zygosity. Co-occurring alterations in cancer-related or DNA damage repair genes were observed in many patients with BRCA alterations. At baseline, cell-free DNA (cfDNA) yield correlated positively with the sum of target lesions (STL; P= 0.04), but not with prostate-specific antigen (PSA) levels ( P= 0.86). No correlation was observed between allele frequency of the BRCA alteration baseline STL ( P= 0.68) or PSA levels ( P= 0.97). Conclusions: Patients with a BRCA mutation enrolled in TRITON2 demonstrate a profile of genomic alterations consistent with that of prior studies of patients with mCRPC. Plasma cfDNA profiling showed a correlation between baseline cfDNA yield and measurable tumor burden, but not baseline PSA. Clinical trial information: NCT02952534. [Table: see text]
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Toss, Angela, Marta Venturelli, Eleonora Molinaro, Stefania Pipitone, Elena Barbieri, Isabella Marchi, Elena Tenedini, et al. "Hereditary Pancreatic Cancer: A Retrospective Single-Center Study of 5143 Italian Families with History of BRCA-Related Malignancies." Cancers 11, no. 2 (February 7, 2019): 193. http://dx.doi.org/10.3390/cancers11020193.
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The identification of BRCA mutations plays a crucial role in the management of hereditary cancer prevention and treatment. Nonetheless, BRCA-testing in pancreatic cancer (PC) patients is not universally introduced in clinical practice. A retrospective analysis was conducted, firstly, to evaluate the rate of BRCA-positive families among those presenting a family history of PC besides breast and/or ovarian cancer. Secondly, the relationship between BRCA pathogenic variants and PC risk was evaluated. Finally, the characteristics of PC developed in BRCA families were described. Among 5143 family trees reporting breast and/or ovarian cancer cases, 392 showed a family history of PC. A total of 35 families (24.5% selected by the Modena Criteria and 21.3% by the NCCN Criteria) were positive to BRCA testing. Among the BRCA1 mutations, 36.8% were found within a region defined by c.3239–c.3917, whilst 43.7% of BRCA2 mutations were located within c.7180–c.8248. This study confirmed that an increase in the rate of positive tests in families with PC when associated to breast and/or ovarian tumors. Moreover, this analysis indicated two possible Pancreatic Cancer Cluster Regions that should be verified in future research. Finally, PC in families with breast and/or ovarian cancer history, particularly in BRCA families, were diagnosed at younger age and showed better one-year overall survival.
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Di Brino, Eugenio, Matteo Ruggeri, Stefania Boccia, Nicoletta Cerana, Domenica Lorusso, Dario Sacchini, Antonella Savarese, Liliana Varesco, and Americo Cicchetti. "A cost-minimization analysis of a preventive testing strategy for relatives of patients with BRCA mutated ovarian cancer." Global & Regional Health Technology Assessment 7, no. 1 (April 4, 2020): 1–8. http://dx.doi.org/10.33393/grhta.2020.557.
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Purpose: This study aims to estimate the cost-minimization strategy of a preventive testing strategy destined to relatives of patients with BRCA mutated cancer versus a no test strategy in Italia.
Methods: A BRCA testing pathway was designed by a panel of experts based on the MSTM Excel (2010) tool; the analysis was carried out considering the perspective of the Italian National Health Service. Two alternatives were considered: 1) preventive BRCA testing for relatives of patients affected by ovarian cancer carrying a BRCA1/BRCA2 mutation; 2) no test. Cost and effectiveness data, derived from literature and published sources validated by a Board of experts, were discounted using a discount factor equal to 3%. Probabilistic sensitivity analysis was performed.
Results: Considering an average cost of therapy for breast and ovarian cancer major of €90,000.00 per case, the economic impact related to the preventive testing strategy are equal to –€17,814,767.25. The sensitivity analysis confirms these results in the totality of the simulations performed.
Conclusions: Preventive genetic testing in relatives of patients affected by ovarian cancer is cost-effective and represents a sustainable cost for the National Healthcare System in Italia, also in the light of its reference values.
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Lipton, Joseph H., Mahdi Zargar, Ellen Warner, Ellen E. Greenblatt, Esther Lee, Kelvin K. W. Chan, and William W. L. Wong. "Cost effectiveness of in vitro fertilisation and preimplantation genetic testing to prevent transmission of BRCA1/2 mutations." Human Reproduction 35, no. 2 (February 2020): 434–45. http://dx.doi.org/10.1093/humrep/dez203.
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Abstract STUDY QUESTION Is it cost-effective to use in vitro fertilisation and preimplantation genetic testing of monogenic defects (IVT/PGT-M) to prevent transmission of BRCA1/2 mutations to second-generation new births in comparison with naturally conceived births? SUMMARY ANSWER In this cost-effectiveness analysis, we found that IVF/PGT-M is cost-effective for BRCA1 and BRCA2 mutation carriers if using a willingness to pay of $50 000 per quality-adjusted life-year (QALY). WHAT IS KNOWN ALREADY Carriers of a BRCA1 or BRCA2 mutation have a significantly increased risk of several types of cancer throughout their lifetime. The cost of risk reduction, screening and treatment of cancer in this population is high. In addition, there is a 50% chance of passing on this genetic mutation to each child. One option to avoid transmission of an inherited deleterious gene to one’s offspring involves in vitro fertilisation with preimplantation genetic testing. STUDY DESIGN, SIZE, DURATION We implemented a state transition model comparing the healthcare impact of a cohort of healthy children born after IVF/PGT-M, who have a population risk of developing cancer, to a cohort of naturally conceived live-births, half of whom are carriers of the BRCA mutation. Transition probabilities are based on published sources, a lifetime horizon and a perspective of a provincial Ministry of Health in Canada. PARTICIPANTS/MATERIALS, SETTING, METHODS The target population is the second-generation new births who have at least one parent with a known BRCA1 or BRCA2 mutation. MAIN RESULTS AND THE ROLE OF CHANCE At a willingness-to-pay threshold of $50 000 per QALY, IVF/PGT-M is a cost-effective intervention for carriers of either BRCA mutation. For BRCA1, the incremental cost-effectiveness ratio (ICER) for IVF/PGT-M is $14 242/QALY. For BRCA2, the ICER of intervention is $12 893/QALY. Probabilistic sensitivity analysis results show that IVF/PGT-M has a 98.4 and 97.3% chance of being cost-effective for BRCA1 and BRCA2 mutation carriers, respectively, at the $50 000/QALY threshold. LIMITATIONS, REASONS FOR CAUTION Our model did not include the short-term negative effect of IVF/PGT-M on the woman’s quality of life; in addition, our model did not consider any ethical issues related to post-implantation genetic testing. WIDER IMPLICATIONS OF THE FINDINGS In countries in which the healthcare of a large segment of the population is covered by a single payer system such as the government, it would be cost-effective for that payer to cover the cost of IVF/PGT-M for couples in which one member has a BRCA mutation, in order to avoid the future costs and disutility of managing offspring with an inherited BRCA mutation. STUDY FUNDING/COMPETING INTEREST(S) Dr Wong’s research program was supported by the Canadian Institutes of Health Research (CIHR), the Natural Sciences and Engineering Research Council (NSERC), the Canadian Liver Foundation and an Ontario Ministry of Research, Innovation and Science Early Researcher Award. All authors declared no conflict of interests.
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Spizzo, Gilbert, Alberto Puccini, Joanne Xiu, Richard M. Goldberg, Axel Grothey, Anthony F. Shields, Sukeshi Patel Arora, et al. "Molecular profile of BRCA-mutated biliary tract cancers." ESMO Open 5, no. 3 (June 2020): e000682. http://dx.doi.org/10.1136/esmoopen-2020-000682.
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IntroductionPrognosis of biliary tract cancers (BTC) remains dismal and novel treatment strategies are needed to improve survival. BRCA mutations are known to occur in BTC but their frequency and the molecular landscape in which they are observed in distinct sites of BTC remain unknown.Material and methodsTumour samples from 1292 patients with BTC, comprising intrahepatic cholangiocarcinoma (IHC, n=746), extrahepatic cholangiocarcinoma (EHC, n=189) and gallbladder cancer (GBC, n=353), were analysed using next-generation sequencing (NGS). Tumour mutational burden (TMB) was calculated based on somatic non-synonymous missense mutations. Determination of tumour mismatch repair (MMR) or microsatellite instability (MSI) status was done by fragment analysis, immunohistochemistry and the evaluation of known microsatellite loci by NGS. Programmed death ligand 1 expression was analysed using immunohistochemistry.ResultsOverall, BRCA mutations were detected in 3.6% (n=46) of samples (BRCA1: 0.6%, BRCA2: 3%) with no significant difference in frequency observed based on tumour site. In GBC and IHC, BRCA2 mutations (4.0% and 2.7%) were more frequent than BRCA1 (0.3% and 0.4%, p<0.05) while in EHC, similar frequency was observed (2.6% for BRCA2 vs 2.1% for BRCA1). BRCA mutations were associated with a higher rate in subjects with MSI-H/deficient mismatch repair (19.5% vs 1.7%, p<0.0001) and tumours with higher TMB, regardless of the MMR or MSI status (p<0.05).ConclusionsBRCA mutations are found in a subgroup of patients with BTC and are characterised by a distinct molecular profile. These data provide a rationale testing poly(ADP-ribose)polymeraseinhibitors and other targeted therapies in patients with BRCA-mutant BTC.
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Hart, Lowell L., Kai Treuner, Li Ma, Jenna Wong, Catherine A. Schnabel, and James Andrew Reeves. "Integration of molecular cancer classification and next-generation sequencing to identify metastatic patients eligible for PARP inhibitors." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): e15080-e15080. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e15080.
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e15080 Background: Olaparib, rucaparib, and niraparib are 3 poly-ADP-ribose polymerase inhibitors (PARPi) approved by the FDA for ovarian, breast, pancreatic, prostate, fallopian tube and peritoneal cancers with BRCA mutations. Several ongoing clinical trials aim to determine the efficacy of PARPi in various other cancer types, including specific cancer subtypes, such as clear cell renal cell carcinoma and cholangiocarcinoma either as monotherapy or combination therapy; however, eligibility for PARPi therapy requires the identification of the primary tumor type and confirmation of BRCA mutation. The 92-gene assay (CancerTYPE ID) is a validated gene expression classifier of 50 tumor types and subtypes for metastatic patients with unknown or uncertain diagnoses. Multimodal biomarker testing, including next-generation sequencing (NGS), enables identification of actionable biomarkers to guide targeted therapy selection. In the current study, a database of metastatic cases that integrates tumor type with biomarker analysis was characterized to identify those eligible for PARPi treatment. Methods: MOSAIC (Molecular Synergy to Advance Individualized Cancer Care) is an IRB-approved, de-identified database of cases submitted for CancerTYPE ID testing with tissue-guided multimodal biomarker testing by NGS, including tumor mutational burden (TMB) fluorescent in situ hybridization (FISH), and microsatellite instability (MSI), and immunohistochemistry (IHC) (NeoTYPE profiles, Neogenomics). For the current study, metastatic cancers classified as ovarian, breast, pancreatic, or prostate were identified in the database, followed by NGS analysis to detect mutations in BRCA1 or BRCA2. Results: The current analysis included 2151 CancerTYPE ID cases, from which 71 ovarian, 47 breast, 12 pancreatic and 15 prostate cancer cases were identified. Out of 46 cases of ovarian cancer with molecular biomarker results, NGS identified 7 (15.3%) cases with BRCA1 mutation and 4 (8.7%) cases with BRCA2 mutation. Additionally, 4 (10.5%) cases with BRCA1 mutation and 1 (2.6%) case with BRCA2 mutation out of 38 cases of breast cancer with BRCA results were detected. No cases of prostate cancer or pancreatic cancer with mutations in BRCA1 or BRCA2 were detected. Conclusions: These findings in metastatic patients demonstrate the clinical utility of tumor type identification combined with molecular biomarker profiling, leading to additional options for patients with advanced disease. Specifically, analysis of the MOSAIC database identified a subset of patients with metastatic cancers eligible for PARPi therapy based on tumor type and BRCA mutation status. As new and approved PARPi are evaluated for efficacy in additional tumor types, patients can be identified that may be eligible for these targeted cancer drugs.