gBRCA Testing Research Articles

The first Japanese nationwide multicenter study of BRCA mutation testing in ovarian cancer: CHARacterizing the cross-sectionaL approach to Ovarian cancer geneTic TEsting of BRCA (CHARLOTTE)

IntroductionBRCA gene mutations are associated with hereditary ovarian cancer. BRCA plays a key role in genome integrity, and mutations result in an increased risk for ovarian cancer. Although various guidelines...

Dose-dense early postoperative intraperitoneal chemotherapy in ovarian cancer: Randomized, phase II trial.

5514 Background: Dose-dense early postoperative intraperitoneal chemo (DD-EPIC) had been carried out in advanced ovarian cancer (OC) pts in China over the past three decades but it was not proved by a prospective study. This trial was designed to confirm the benefit of DD-EPIC in delaying progression and improving survival. Methods: In a multicenter, phase 2 trial, pts with FIGO IIIC-IV OC and optimal debulking surgery (residual disease ≤1cm) were randomly allocated to receive 4 doses of weekly DD-EPIC with cisplatin (50mg/m2) and etoposide (100mg/m2) followed by 6 cycles of intravenous (iv) chemo with carboplatin and taxane every 3 weeks (DD-EPIC group), or standard iv chemo alone (iv group). (ClinicalTrials.gov, NCT01669226). Results: Between 2009 and 2015, 218 pts were randomized, of whom 215 initiated treatment (106 to DD-EPIC and 109 to iv; for efficacy analyses). Totally, 36 pts (16·7%) were received neoadjuvant chemo. With a median of 61·9 mos follow-up, 122 pts died (54 in DD-EPIC and 68 in iv group). Remarkable OS benefit of DD-EPIC was recorded (67·5 mos for DD-EPIC vs. 46·3 mos for iv; HR 0·70, 95% CI 0·49-1·00, P=0·047). Pts in DD-EPIC had a significantly increased median PFS compared with those in iv group (21·7 vs. 16·8 mos; HR 0·64, 95% CI 0·47-0·86, P=0·003). Median TFST was 25·1 vs. 18·0 mos in favor of DD-EPIC (HR 0·62, 95%CI 0·46-0·83, P=0·002). Similar findings were detected in TSST (42·2 vs. 29·3 mos; HR 0·66, 95%CI 0·47-0·94, P=0·019). Grade 3 and 4 Leucopenia (53·8% vs. 35·2%), anemia (23·6% vs. 5·6%) and gastrointestinal events (10·4% vs. 1·9%) were more common in DD-EPIC ( P=0·006, P<0·001 and P=0·010, respectively). Ninety-one pts were detected by gBRCA testing, with 25·3% of cases carrying deleterious BRCAm, but PFS and OS benefit were observed in patients with BRCA-wild type (HR 0·46 and 0·55, 95%CI 0·27-0·81 and 0·27-1·11, respectively). Conclusions: DD-EPIC with a higher completion rate and acceptable treatment burden was associated with longer OS than standard iv alone. Owing to the benefit of relatively long-term OS, DD-EPIC may be considered as a valuable option for OC, particularly in developing countries and BRCA-wild type pts. Clinical trial information: NCT01669226. [Table: see text]

FLABRA, frontline approach for BRCA testing in ovarian cancer (OC) treatment naïve population: A Latin America (LA) epidemiologic study.

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.

A systematic review of international guidelines and recommendations for the genetic screening, diagnosis, genetic counseling, and treatment of BRCA-mutated breast cancer.

PurposeTo conduct a systematic review of international guidelines on screening and management of patients with BRCA-mutated breast cancer (BC).MethodsMajor electronic databases (MEDLINE and Embase; N=8) and gray literature sources were searched (January 2007 to February 2018). Latest guideline recommendations on genetic screening, counseling, and BC treatment of BRCA mutation carriers were summarized. Guidelines specific to germline BRCA (gBRCA) mutation were captured where available.ResultsA total of 3,775 records were retrieved and 32 guidelines were included; Europe (n=16), USA (n=11), Canada (n=3), Australia (n=1), and Japan (n=1) were included. Across and within guidelines, genetic counseling was recommended at multiple points in the care pathway, though the format was not always clearly defined. US guidelines emphasized that BRCA mutation testing should occur after specialized genetic counseling; other European guidelines are less prescriptive. BRCA testing eligibility criteria differed, with some guidelines being less restrictive; US National Comprehensive Cancer Network (NCCN) BC guidelines specified that HER2-negative BC patients eligible for single-agent therapy are eligible for gBRCA testing. Fast-track BRCA testing is recommended in the Netherlands if treatment choice will affect survival, but in the UK only as part of clinical trials. More recent European (European School of Oncology–European Society for Medical Oncology 3rd International Consensus Guidelines for Breast Cancer in Young Women 2017, Arbeitsgemeinschaft Gynäkologische Onkologie 2017 in Germany) and US (NCCN) guidelines have updated recommendations regarding gBRCA-targeted poly(ADP-ribose) polymerase (PARP) inhibitor therapy in BC.ConclusionRegional and organizational guidelines differ for genetic screening, counseling, and treatment of patients with BRCA-mutated BC. Guideline harmonization would optimize identification and management of these patients.

Abstract P1-09-14: Demographic, clinical/disease characteristics, and treatment of patients with germline mutated metastatic breast cancer: A CancerLinQ study

Abstract Objective: To describe the demographics, clinical/disease characteristics and treatment patterns of patients with germline BRCA mutated (gBRCAm) metastatic breast cancer (mBC) as compared to those with gBRCA wild type (wt) and those who are untested for gBRCA mutations. Methods: The CancerlinQ Discovery Database (CLQ), launched by the American Society of Clinical Oncology (ASCO) in 2016, consists of longitudinal, demographic and geographic diverse data aggregated from oncology practice electronic health record (EHR) databases. Natural language processing and technology-enabled curation are utilized to identify records of most interest, followed by manual curation to abstract information from unstructured EHR fields. This cohort consists of 7,889 patients diagnosed with mBC between 1982 and 2018, and is enriched for patients with gBRCA testing through the curation process. Results: Overall most patients were female (99.0%), white (55.3%), and the median age at mBC diagnosis was 63 years (yrs). The majority were not tested for gBRCA mutation (88.4%); 2.0% were gBRCAm, 9.2% were gBRCAwt, 0.4% had an undetermined test result, and 0.1% had a variant of unknown significance. Among those tested for estrogen-receptor (ER) (n=6,700) and progesterone-receptor (PR) (n=6,737) status, 76.6% were ER positive (+) and 62.2% were PR+. Among those tested for human epidermal growth factor receptor 2 (HER2) (n=6,696), 21.7% were HER2+. Among those with known results for ER, PR, and HER2 (n=6,063), 10.1% were hormone receptor (HR)+/HER2+, 10.6% were HR negative (-)/HER2+, 65.0% were HR+/HER2-, and 14.3% were HR-/HER2-. The median age at mBC diagnosis was 50 yrs for gBRCAm, 51 yrs for gBRCAwt and 64 yrs among the gBRCA untested group. A similar proportion of patients were diagnosed with metastatic disease among the gBRCAm and gBRCAwt groups (25.3% and 20.3%, respectively), while the proportion was higher among the gBRCA untested group (38.0 %). The most common site of metastasis for all groups was bone (35.1% for gBRCAm, 41.7% for gBRCAwt, and 36.5 % for gBRCA untested), followed by liver (16.2% for gBRCAm, 13.3% for gBRCAwt, and 8.5% for gBRCA untested). The most common first-line therapies for gBRCAm patients were tamoxifen (7.7%), letrozole (7.0%), cyclophosphamide+doxorubicin (6.3%), and paclitaxel (6.3%); for gBRCAwt patients they were cyclophosphamide+doxorubicin (6.6%), paclitaxel (6.4%), and tamoxifen (6.4%); and for gBRCA untested patients they were letrozole (11.1%), fulvestrant (9.3%), and tamoxifen (4.6%). The mean number of lines of therapy (including lines of chemotherapy and hormone therapy) were 3.5, 3.8, and 3.4 for the gBRCAm, gBRCAwt, and gBRCA untested groups, respectively. Conclusions: Patients with gBRCAm were younger than the gBRCA untested group, and more patients had metastatic disease at diagnosis in the gBRCA untested group. Further analyses accounting for HR and HER2 status will be conducted and presented. This is the first example of research using curated breast cancer data from ASCO's CLQ. Citation Format: Dalvi T, Herr I, Maclachlan S, Briceno J, Bennett J, McLaurin K, Hettle R, McCutcheon S. Demographic, clinical/disease characteristics, and treatment of patients with germline mutated metastatic breast cancer: A CancerLinQ study [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-09-14.

Clinical Outcomes, Treatment Patterns, and Health Resource Utilization Among Metastatic Breast Cancer Patients with Germline BRCA1/2 Mutation: AReal-World Retrospective Study.

With evolving treatment guidelines for germline BRCA1/2 mutation (gBRCAm) in breast cancer, we present the latest gBRCA testing rates among metastatic breast cancer (mBC) patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) or triple-negative breast cancer (TNBC). Among these patients with gBRCAm, we analyzed clinical outcomes, treatment patterns, and health resource utilization (HRU). The Flatiron Health electronic health record database was used to assess gBRCA testing rates in a real-world retrospective analysis of US patients at least 18years old with HR+/HER2- or TNBC, and with mBC diagnosed from January 2011 to February 2018. Outcomes were compared between gBRCAm patients with HR+/HER2- vs TNBC, adjusting for imbalances utilizing inverse probability treatment weighting; effects of HR+/HER2- vs TNBC on overall survival (OS) were assessed, antineoplastic treatments summarized, and HRU analyzed using t tests. The study included 12,021 mBC patients (HR+/HER2-, 10,291; TNBC, 1730). Results for gBRCA testing were available for 2005 (16.7%) patients (HR+/HER2-, 1587; TNBC, 418). A total of 229 (1.9%) patients (HR+/HER2-, 165; TNBC, 64) had gBRCAm. Significantly worse OS in gBRCAm mBC was observed in TNBC vs HR+/HER2- [hazard ratio (95% confidence interval), 0.45 (0.27-0.74); p = 0.002]. Estimated median and 4-year OS rates for gBRCAm mBC patients with either HR+/HER2- or TNBC were 38.0months, 23.4months and 35.6%, 21.2% respectively. The most common first-line treatment post diagnosis for gBRCAm HR+/HER2- was letrozole (8%) vs capecitabine (14%) for gBRCAm TNBC. The number of HRU treatment visits per patient per year was significantly (p < 0.05) higher among gBRCAm mBC patients with TNBC vs HR+/HER2-. Among HER2- mBC patients, gBRCA testing rates are low. Among gBRCAm HER2- mBC patients, the poor OS and HRU burden observed, especially in patients with TNBC, demonstrate an unmet need for more efficacious, targeted, and less HRU-intensive treatment options. Pfizer.

Abstract P3-04-11: Implications of somatic TP53 and PIK3CA mutations in patients with metastatic breast cancer who underwent germline BRCA testing

Abstract Background: TP53 and PIK3CA are the most frequently mutated genes in breast cancer. However, there is limited data evaluating the impact of somatic mutations in TP53 and/or PIK3CA patients (pts) with metastatic breast cancer (MBC) who have undergone germline testing for BRCA mutations. Here, we report the frequency of somatic TP53 and PIK3CA mutations in MBC pts who previously underwent germline BRCA (gBRCA) testing and evaluate their impact on long-term outcomes. Methods: We identified pts with MBC from our prospectively maintained high risk genetics database who underwent gBRCA testing and had somatic mutation testing performed for TP53 and/or PIK3CA through hotspot sequencing of single genes or as part of a next generation sequencing panel. Univariable logistic regression was used to evaluate associations between clinicopathological characteristics, including gBRCA status, and the presence of somatic TP53 and PIK3CA mutations. Overall survival (OS) was defined as the time from diagnosis to death from any cause. Multivariable cox regression analysis was used to identify independent predictors of OS. Results: 104 pts met all inclusion criteria. Somatic mutations in TP53 and PIK3CA were found in 46% (39/84) and 23% (24/104) of tested pts, respectively. Associations between clinicopathological characteristics and somatic TP53 and PIK3CA mutation status are summarized in Table 1. Pts with hormone receptor positive (HR+) disease were less likely to have TP53 mutations (odds ratio [OR]: 0.28, 95% confidence interval [CI]: 0.11-0.70, p=0.007) but more likely to harbor PIK3CA mutations (OR: 3.27, 95% CI: 1.11-9.62, p=0.031). There were no significant associations between gBRCA mutation status and somatic TP53 or PIK3CA mutations. On multivariable analysis, somatic TP53 mutations (adjusted hazard ratio [aHR]: 1.98, 95% CI: 1.10-3.58, p=0.023) and de novo metastatic disease (aHR=2.88, 95% CI: 1.26-6.58, p=0.012) independently predicted poorer OS, while HR+ disease (aHR: 0.40, 95% CI: 0.21-0.74, p=0.004) and HER2+ disease (aHR: 0.33, 95% CI: 0.13-0.83, p=0.019) were significantly associated with improved OS. PIK3CA mutations (aHR: 1.20, 95% CI: 0.59-2.44, p=0.62) and gBRCA mutations (aHR: 0.78, 95% CI: 0.33-1.83, p=0.57) did not significantly impact OS in this study. Conclusion: In this study, somatic TP53 mutations independently predicted worse OS in pts with MBC after adjusting for significant covariates, including gBRCA mutation status. These findings should be validated in a larger cohort of pts. Table 1: Association between patient characteristics and somatic TP53 and PIK3CA mutation status TP53 PIK3CA TP53 mutant (n=39)TP53 wild type (n=45)p valuePIK3CA mutant (n=24)PIK3CA wild type (n=80)p valueMedian Age – years (Interquartile Range)37 (33-47)39 (36-44)0.93739 (34-46)38 (34-43)0.494gBRCA mutant – n(%)3 (8)11 (24)0.0511 (4)15 (19)0.116ER/PR positive - n(%)17 (44)33 (73)0.00719 (79)43 (54)0.031HER2 positive - n(%)8 (21)6 (13)0.3827 (29)10 (13)0.060De Novo Metastatic – n(%)6 (15)8 (18)0.7693 (13)16 (20)0.409Visceral Disease – n(%)23 (59)26 (58)0.91215 (63)47 (59)0.743 Citation Format: Yam C, Gutierrez Barrera A, Huang D, Lin X, Litton JK, Arun B. Implications of somatic TP53 and PIK3CA mutations in patients with metastatic breast cancer who underwent germline BRCA testing [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-04-11.

Abstract 2726: Guidance by molecular selection improves the outcome of early phase treatment for gynecological (GYN) cancers

Abstract Background: Patients (pts) with advanced gynecological (GYN) cancers have limited therapeutic options and the prognosis is poor. Early phase trials may be a suitable option for pts with good performance status. Increasingly, molecular characterisation guides pt selection for early phase trials. We sought to determine the outcome of GYN pts treated in a phase 1 unit and examined the role of molecular selection to inform therapeutic decision making. Methods: Medical records of all pts with a GYN malignancy treated within an early phase trial between 2010 and 2016 were reviewed. Data comprising patient and tumor characteristics, prior treatment, trial therapy and outcome were analysed. Results: 81 pts with a median age of 60 years (range 20-75) with a diagnosis of ovarian (OC, 54), endometrial (EC, 15) or cervical/vulval (CC, 12) cancer were identified. The median number of prior therapies for advanced disease was 3 (OC) and 2 (EC and CC) (overall range 1-6). 9 pts (11%) entered a second and 1 pt a third phase 1 study on disease progression. Next Generation Sequencing (NGS) using a targeted panel was performed in 32 pts (40%) with an actionable mutation identified in 9 including; KRAS (3pts), PIK3CA (2pts) and EGFR (2pts). Germline BRCA (gBRCA) testing was performed in 35 OC pts (65%) with 24 gBRCA mutations identified. Pts were allocated, in order of priority, where available, to (1) a trial selected on the basis of NGS or gBRCA (‘genomic’ 35%), (2) a ‘tumor specific’ cohort within an early phase trial (15%) or (3) a ‘generic’ study (51%). For the whole cohort there was an overall response rate (ORR) of 18% with 41% stable disease (SD) and median progression free survival (PFS) and overall survival (OS) of 13 and 46 weeks respectively. Outcomes were best for pts in the genomic group. Both PFS and OS were significantly longer with genomic selection (p &amp;lt; 0.01 for both, Mantel-cox test) with median PFS of 29.7, 14.2, 8.0 weeks and OS of 84.1, 69.7, 33.6 weeks for genomics, tumor specific and generic studies respectively. The ORR was also greatest for the genomic cohort (32%) compared to the tumour specific (7%) and generic (11%) groups. Within the heavily pre-treated EC and CC cohorts there was an OS of 30 and 42 weeks respectively. 24% of EC pts had an ORR with a further 24% with stable disease (SD). There was only 1 response (9%) in the CC cohort, however SD was seen in 64%. The OS for the OC was 55 weeks with an ORR of 20% and 46% SD. Conclusions: Early phase trials represent a good option for pts with advanced GYN malignancies. Whilst applicable to all GYN cancers, this is particularly relevant for EC and CC pts as standard treatment options are limited. For OC patients (median 3 prior lines of chemotherapy in this cohort) where standard treatment options exist, early access to phase 1 genomic trials may result in improved response rates and allow further standard options to be given subsequently. NGS is feasible in real time and may have a positive impact on outcome. Citation Format: Rowan E. Miller, Michael John Devlin, Nicholas Brown, Kin Woo, Tami Grunewald, Arran Speirs, Miriam Mitchison, Michelle Lockley, Mary McCormack, Jonathan Ledermann, Martin Forster, Tim Meyer, Rebecca Kristeleit. Guidance by molecular selection improves the outcome of early phase treatment for gynecological (GYN) cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2726. doi:10.1158/1538-7445.AM2017-2726