Deleterious Germline Mutations In BRCA1 Research Articles

The Landscape of BRCA Mutations among Egyptian Women with Breast Cancer.

Deleterious germline mutations in BRCA1 and BRCA2 genes are associated with a high risk of breast and ovarian cancer. In many developing countries, including Egypt, the prevalence of BRCA1/2 mutations amongwomen with breast cancer (BC) is unknown. We aimed to determine the prevalence of deleterious germline BRCA mutations in Egyptian patients with breast cancer. We report the results of a cohort study of 81 Egyptian patients with breast cancer who were tested for germline BRCA1/2 mutations during routine clinical practice, mostly for their young age of presentation, BC subtype, or presence of family history. In addition, we searched five databases to retrieve studies that reported the prevalence of BRCA1/2 mutation status in Egyptian women with BC. A systematic review of the literature was performed, including prospective and retrospective studies. In our patient cohort study, 12 patients (14.8%) were positive for either BRCA1/2 deleterious mutations. Moreover, 13 (16.1%) patients had a variant of unknown significance (VUS) of BRCA1/2 genes. Twelve studies were eligible for the systematic review, including 610 patients. A total of 19 deleterious germline mutations in BRCA1/2 were identified. The pooled prevalence of BRCA1/2 mutations was 40% (95% confidence interval 1-80%). The reported prevalence was highly variable among the small-sized published studies that adopted adequate techniques. In our patient cohort, there was a high incidence of VUS in BRCA1/2 genes. Accordingly, there is an actual demand to conduct a prospective well-designed national study to accurately estimate the prevalence of BRCA1/2 mutations among patients with BC in Egypt.

Low BRCA1 and BRCA2 Germline Mutation Rates in a French-Canadian Population with a Diagnosis of Epithelial Tubo-Ovarian Carcinoma

ObjectiveUniversal genetic testing has become increasingly important in the management of epithelial tubo-ovarian and peritoneal carcinoma. Worldwide, reported incidences of deleterious BRCA mutations vary between 12% and 15%. We sought to evaluate the incidence in our population, given its specific genetic background (French-Canadian ancestry). MethodMainstream genetic testing was implemented in our service in May 2017 and offered to all patients with epithelial tubo-ovarian or peritoneal carcinomas, except mucinous and borderline tumours. Data were prospectively collected in a database and retrospectively analyzed. ResultsWe tested 222 patients in our centre, of whom 183 (82.4%) had high-grade serous carcinoma (HGSC). Overall, 139 patients had no identified mutation (62.6%). Deleterious BRCA1 and BRCA2 mutations were found in 12 patients (5.4%): 6 had BRCA1, and 6 BRCA2 mutations; 11 of these patients had HGSC. Other non–BRCA mutations (ATM, RAD51C, RAD51D, BRIP1, CDH1, MRE11, MSH6, MUTYH, PALB2, and PMS2) were observed in an additional 20 patients (9.0%), of whom 18 had HGSC. A total of 63 different variants of unknown significance (VUS) were found, of which 4 were in the BRCA1 and BRCA2 genes. Deleterious mutations were not identified in clear cell carcinomas, and only 1 was found in low-grade serous carcinoma. ConclusionIn our French-Canadian population, the incidence of deleterious germline BRCA mutations was surprisingly low at 5.4%—less than half that reported in the literature. This may affect patient response to poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi) therapy. Mainstream genetic testing was successfully implemented in our service and facilitated access to genetic testing in our patient population.

261P Survival outcomes of triple-negative breast cancer (TNBC) patients in the pre-immunotherapy age: An analysis of Gruppo Italiano Mammella (GIM) 14 BIOMETA study with a focus on biological subtypes

TNBC is a subtype of Breast Cancer (BC) associated with an overall survival (OS) of around 19 months (ms). Before immunotherapy, no specific systemic treatment apart from chemotherapy (CT) was available. ER low disease is characterized by low ER and PgR staining (both <10%) and negative Her2. It’s considered as having a survival and a biological behavior comparable to that of TNBC. Deleterious germline BRCA mutations were the only predictive biomarker available in the past years for TNBC.

Genomic profiling of KRAS wide-type pancreatic ductal adenocarcinomas identifies targetable genetic alterations.

4121 Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers and the 5-year survival of PDAC patients is below 10%. The oncogenic KRASmutations account for about 90% of PDAC cases. Unfortunately, there is no FDA-approved targeted therapy for KRAS mutations. Therefore, the genomic profiling of KRAS wide-type PDACs can provide invaluable sights to the etiology of these patients and offer them the opportunity of precision therapy trials. Methods: To characterize actionable targets in 521 Chinese PDAC patients, deep sequencing of a 831-gene panel (OncoPanscan, Genetronhealth) was applied to assess somatic mutations of their tumor tissues including SNV, insertions/deletions, CNV and re-arrangements, as well as possible pathogenic germline variants of paired genomic DNA sample. Results: There were 89% (463/521) of patients in our PDAC cohort harbored KRAS mutations. Among the remaining 58 patients in KRAS wild-type subgroup, 33% (19/58) carried activating mutations in the RTK/Ras/MAPK pathway. Targetable BRAF mutations were seen in five (9%) patients: V600E (1/5), G464V (1/5), N486_P490del (2/5) and BRAF fusion (1/5). The frequency of BRAF mutations was 9% (5/58) in KRAS wild-type PDACs but only 0.4% (2/463) in KRAS-mutated PDACs (P &lt; 0.001). We found one classic EGFR activing mutation (L747_A750delinsP) and one MAP2K1 activating mutation (F53_Q58delinsL), which can be targeted by EGFR-TKIs and MEK inhibitor trametinib, respectively. An oncogenic ERBB3 mutation (V104L) was seen in one patient, who was eligible for HER2-targeted therapy clinical trials. We also found STK11/TSC2 inactivating mutations and a dominant-negative mutation of PTEN (R130Q) which could be targeted by mTOR inhibitor everolimus and AKT inhibitor capivasertib, respectively. Additionally, we observed a patient with high level amplification of MET and another patient with the NCOA4-RET fusion gene which can be targeted by MET inhibitor carbozantinib. Interestingly, we also identified two patients with inactivating mutations in ELF3 (one frameshift and one in splicing-site), which is a driver gene of ampullary carcinoma. Lastly, two patients carried deleterious germline mutations in BRCA1 and PALB2, which may be targeted with PARP inhibitors. Overall, at least 29% (17/58) KRAS wide-type patients harbored potentially actionable genomic alterations to currently used anticancer drugs. Conclusions: The mutational landscape of our PDAC cohort provided compelling evidence that targetable driver mutations accounted for a significant portion of KRAS wide-type tumors. Our findings demonstrated that genomic profiling of PDAC patients can enable physicians to optimize their clinical management and enroll them into genomically matched clinical trials.

Abstract PD10-08: Outcomes of germline BRCA carriers versus non-carriers in the french national metastatic breast cancer ESME cohort 2008-2016

Abstract BACKGROUND: Approximately 5% of breast cancer (BC) patients (pts) carry a deleterious germline BRCA mutation (gBRCAm). Retrospective studies suggest that overall survival (OS) is equivalent between gBRCAm carriers and non-carriers with metastatic BC (MBC). We aimed to use the large ESME multicentre national MBC database to compare outcomes of gBRCAm carriers, gBRCA wild-type (WT) and not tested (NT) pts. METHODS: We used the large ESME MBC database (NCT03275311), a unique national cohort of all consecutive pts who initiated a first-line treatment for MBC between 2008 and 2016 in one of the 18 French Comprehensive Cancer Centers. All pts with data available regarding gBRCA testing were selected for the present analysis. 26 pts with non-BRCA germline mutations were classified in the WT group. The primary endpoint was OS from date of treatment initiation in the 3 groups of patients: gBRCAm, gBRCA WT and gBRCA NT.Secondary endpoints were progression-free survival under first line treatment (PFS1), clinical and biological characteristics of the 3 groups and prognostic factors for OS. Multivariable analyses included the main known prognostic factors (age at MBC, MBC subtype, disease-free interval, presence of visceral disease, number of metastatic sites). They were conducted using Cox proportional analyses. RESULTS: 20624 pts were included in this analysis (414 gBRCAm, 1710 WT, 18500 gBRCA NT). Pts and disease characteristics are summarized in table 1. As expected, patients with gBRCAm were younger and had a higher rate of TNBC and G3 tumors. Median follow-up was 50.5 months (95%CI 49.7-51.5). Non-adjusted median OS was 30.6 months [21.9-34.3] in the gBRCAm group, 35.8 [32.2-37.8] in the WT and 39.3 [38.3-40.3] in NT groups. Median PFS1 was 7.9 months [6.6-9.3] in the gBRCAm group, 7.8 [7.3-8.5] in the WT and 9.7 months [ 9.5-10.0] in the NT groups. In multivariable analyses, OS and PFS were not significantly different between MBC patients with gBRCA and others (respective HRs 1.01 [0.88;1.17], p=0.87 and 0.94 [0.84;1.06], p=0.31). CONCLUSION: In this large scale real-life ESME MBC database analysis, outcomes of gBRCAm carriers with MBC do not differ from non carriers or not tested subgroups, when adjusted for other prognostic factors. Table 1: characteristics of patients and diseasegBRCAm. gBRCA WT. gBRCA NT Pvalue (chi-2)N = 414 N = 1710 N = 18500 Age (years) median [range]45 [23-82]48 [20- 88]61 [22-103]p&amp;lt;0.0001Grade 3 N (%) Missing data202 (57.7) 64598 (41.1) 2545337 (34.5)3036p&amp;lt;0.0001Triple negative breast cancer N (%)158 (38.2)370 (21.6)2331 (12.6)p&amp;lt;0.0001De novo MBC N (%)74 (17.9)359 (21)5914 (32)p&amp;lt;0.0001Disease-free interval (months) median [range]39.0 [-1.5- 425.7]36.3 [-2.1- 549.6]31.8 [-2.9- 657.8]p&amp;lt;0.0001Metastatic sites ≥3 N (%)113 (27.3)349 (20.4)3943 (21.3)p=0.008Visceral metastases N (%)279 (67.4)964 (56.4)10659(57.6)p=0.0002Central Nervous System Metastases N (%)66 (15.9)132 (7.7)1145 (6.2)p&amp;lt;0.0001 Citation Format: Audrey Mailliez, Veronique D'Hondt, Amelie Lusque, Olivier Caron, Luc Cabel, Antony Goncalves, Marc Debled, Laurence Gladieff, Jean-Marc Ferrero, Thierry Petit, Marie-Ange Mouret-Reynier, Jean-Christophe Eymard, Jean-Sébastien Frenel, Thibault De La Motte Rouge, Gaëtane Simon, Suzette Delaloge. Outcomes of germline BRCA carriers versus non-carriers in the french national metastatic breast cancer ESME cohort 2008-2016 [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD10-08.

Innovations in targeted therapies for triple negative breast cancer.

Triple negative breast cancer (TNBC) is defined by a lack of targets, namely hormone receptor (HR) expression and human epidermal growth factor receptor 2 amplification. Cytotoxic chemotherapy remains the mainstay of treatment. Though TNBC constitutes approximately 10-15% of breast cancer, it is disproportionally lethal, but it is hoped that outcomes will improve as targetable oncogenic drivers are identified. Translational work in TNBC has focused on subsets defined by defects in homologous recombination repair, immune cell infiltration, or programmed death ligand receptor 1 expression, an over-active phosphoinositide-3 kinase pathway, or expression of androgen receptors. Though not specific to TNBC, the novel cell surface antigen trophoblast antigen 2 has also been identified and successfully targeted. This work has led to Food and Drug Administration approvals for small molecule poly-ADP-ribosyl polymerase inhibitors in patients with deleterious germline mutations in BRCA1 or BRCA2, the combination of nab-paclitaxel with immune checkpoint inhibitor antibodies in the first-line metastatic setting for programmed death ligand receptor 1+ TNBC, and use of the antibody-drug conjugate sacituzumab govitecan in the later-line metastatic setting. Identification of targetable oncogenic drivers in TNBC is an area of intense cancer biology research, hopefully translating to new therapies and improved outcomes.

The DNA damaging revolution.

Poly(ADP-ribose) polymerase (PARP) is a nuclear enzyme that plays a critical role in the repair of single-strand DNA damage via the base excision repair pathway. PARP inhibitors have substantial single-agent antitumor activity by inducing synthetic lethality. They have also emerged as promising anticancer targeted therapies, especially in tumors harboring deleterious germline or somatic breast cancer susceptibility gene (BRCA) mutations. PARP inhibition produces single-strand DNA breaks, which may be repaired by homologous recombination, a process partially dependent on BRCA1 and BRCA2. The PARP inhibitors olaparib, veliparib, talazoparib, niraparib, and rucaparib have predominantly been studied in patients with breast or ovarian cancers associated with deleterious germline mutations in BRCA1 and BRCA2. Ongoing clinical trials are evaluating the role of PARP inhibitors alone and in combination with other therapies, including selective inhibitors against key targets involved in the DNA damage response. In this review we summarize the use of PARP inhibitors in various tumor types, as well as possible approaches for overcoming resistance to PARP inhibitors.

Pathology of Hereditary Breast and Ovarian Cancer.

Hereditary breast and ovarian cancer (HBOC) syndrome is most commonly characterized by deleterious germline mutations in BRCA1 and BRCA2. HBOC patients are prone to the development of malignant neoplasms in multiple organs including the breast, ovary, and fallopian tube. From a pathological perspective, a number of morphological features have been described in BRCA-associated breast and tubo-ovarian cancers. For example, breast cancers diagnosed in BRCA1-mutation carriers are frequently of a high Nottingham grade and display medullary morphology and a triple-negative and/or a basal-like immunophenotype. In contrast, breast cancers in BRCA2-mutation carriers are similar to sporadic luminal-type tumors that are positive for hormone receptors and lack expression of human epidermal growth factor receptor 2. Cancers arising in the fallopian tube and ovary are almost exclusively of a high-grade serous histotype with frequent Solid, pseudo-Endometrioid, and Transitional cell carcinoma-like morphology (“SET features”), marked nuclear atypia, high mitotic index, abundant tumor infiltrating lymphocytes, and necrosis. In addition, pushing or infiltrative micropapillary patterns of invasion have been described in BRCA-associated metastases of tubo-ovarian high-grade serous carcinomas. Besides BRCA1 and BRCA2 mutations, alterations in a number of other homologous recombination genes with moderate penetrance, including PALB2, RAD51C, RAD51D, BRIP1, and others, have also been described in HBOC patients with varying frequency; however, distinct morphological characteristics of these tumors have not been well characterized to date. In this review, the above pathological features are discussed in detail and a focus is placed on how accurate pathologic interpretation plays an important role in allowing HBOC patients to receive the best possible management.

Pregnancy After Breast Cancer in Patients With Germline BRCA Mutations.

Young women with germline BRCA mutations have unique reproductive challenges. Pregnancy after breast cancer does not increase the risk of recurrence; however, very limited data are available in patients with BRCA mutations. This study investigated the impact of pregnancy on breast cancer outcomes in patients with germline BRCA mutations. This is an international, multicenter, hospital-based, retrospective cohort study. Eligible patients were diagnosed between January 2000 and December 2012 with invasive early breast cancer at age ≤ 40 years and harbored deleterious germline BRCA mutations. Primary end points were pregnancy rate, and disease-free survival (DFS) between patients with and without a pregnancy after breast cancer. Pregnancy outcomes and overall survival (OS) were secondary end points. Survival analyses were adjusted for guarantee-time bias controlling for known prognostic factors. Of 1,252 patients with germline BRCA mutations (BRCA1, 811 patients; BRCA2, 430 patients; BRCA1/2, 11 patients) included, 195 had at least 1 pregnancy after breast cancer (pregnancy rate at 10 years, 19%; 95% CI, 17% to 22%). Induced abortions and miscarriages occurred in 16 (8.2%) and 20 (10.3%) patients, respectively. Among the 150 patients who gave birth (76.9%; 170 babies), pregnancy complications and congenital anomalies occurred in 13 (11.6%) and 2 (1.8%) cases, respectively. Median follow-up from breast cancer diagnosis was 8.3 years. No differences in DFS (adjusted hazard ratio [HR], 0.87; 95% CI, 0.61 to 1.23; P = .41) or OS (adjusted HR, 0.88; 95% CI, 0.50 to 1.56; P = .66) were observed between the pregnancy and nonpregnancy cohorts. Pregnancy after breast cancer in patients with germline BRCA mutations is safe without apparent worsening of maternal prognosis and is associated with favorable fetal outcomes. These results provide reassurance to patients with BRCA-mutated breast cancer interested in future fertility.

Impact of Taxanes, Endocrine Therapy, and Deleterious Germline BRCA Mutations on Anti-müllerian Hormone Levels in Early Breast Cancer Patients Treated With Anthracycline- and Cyclophosphamide-Based Chemotherapy.

Background: Limited evidence exists on the impact of adding a taxane, using endocrine therapy and carrying a deleterious germline BRCA mutation on ovarian reserve measured by anti-müllerian hormone (AMH) levels of young breast cancer patients receiving (neo)adjuvant cyclophosphamide- and anthracycline-based chemotherapy.Methods: This is a biomarker analysis including young (≤ 40 years) early breast cancer patients with known germline BRCA mutational status and available prospectively collected frozen plasma samples before and after chemotherapy. Chemotherapy consisted of either six cycles of FEC (5 fluorouracil 500 mg/m2, epirubicin 100 mg/m2, cyclophosphamide 500 mg/m2) or three cycles of FEC followed by three cycles of docetaxel (D, 100 mg/m2). Endocrine therapy consisted of tamoxifen (±GnRH agonists). AMH levels at baseline, 1 and 3 years after diagnosis were compared according to type of chemotherapy (FEC only vs. FEC-D), use of endocrine therapy (yes vs. no) and deleterious germline BRCA mutations (mutated vs. negative).Results: Out of 148 included patients, 127 (86%) received D following FEC chemotherapy, 90 (61%) underwent endocrine therapy, and 35 (24%) had deleterious germline BRCA mutations. In the whole cohort, AMH levels drastically dropped 1 year after diagnosis (p < 0.0001) with a slight but significant recovery at 3 years (p < 0.0001). One year after diagnosis, patients treated with FEC only had higher median AMH levels than those who received FEC-D (0.22 vs. 0.04 μg/L, p = 0.0006); no difference was observed at 3 years (0.06 and 0.18 μg/L, p = 0.47). Patients under endocrine therapy had significantly higher AMH levels than those who did not receive this treatment 1 year after diagnosis (0.12 vs. 0.02 μg/L; p = 0.008), with no difference at 3 years (0.11 and 0.20 μg/L, p = 0.22). AMH levels were similar between BRCA-mutated and BRCA-negative patients at baseline (1.94 vs. 1.66 μg/L, p = 0.53), 1 year (0.09 vs. 0.06 μg/L, p = 0.39) and 3 years (0.25 vs. 0.16 μg/L; p = 0.43) after diagnosis.Conclusions: In breast cancer patients receiving FEC chemotherapy, adding D appeared to negatively impact on their ovarian reserve in the short-term; no further detrimental effect was observed for endocrine therapy use and presence of a deleterious germline BRCA mutation.

Benchmarking of a checklist for the identification of familial risk for breast and ovarian cancers in a prospective cohort.

The detection of deleterious germline mutations in BRCA1 and BRCA2 considerably influences the clinical management of healthy and diseased carriers. Therefore, the identification of persons at risk who could uptake genetic counseling and testing is pivotal. We developed a checklist with validated criteria to improve the identification, and prospectively evaluate the incidence, of familial cancer history in 5091 breast cancer patients. The rate of 30.4% of patients at high genetic risk underpins the demand for care in risk identification and counseling. The easy-to-use instrument promotes the implementation and dissemination of risk counseling by physicians.

Advances in the use of PARP inhibitors for BRCA1/2-associated breast cancer: talazoparib.

Poly-ADP-ribosyl polymerase (PARP) enzymes PARP-1 and PARP-2 recognize DNA damage and set off a cascade of cellular mechanisms required for multiple types of DNA damage repair. PARP inhibitors are small molecule mimetics of nicotinamide which bind to PARP's catalytic domain to inhibit poly-ADP-ribosylation (PARylation) of target proteins, including PARP-1 itself. PARP inhibitors olaparib, veliparib, talazoparib, niraparib and rucaparib have predominantly been studied in women with breast or ovarian cancers associated with deleterious germline mutations in BRCA1 and BRCA2 (gBRCA1/2+). The BRCA1 and BRCA2 proteins are involved in DNA repair by homologous recombination. This review will focus on talazoparib, a PARP inhibitor approved by the US FDA for the treatment of metastatic gBRCA1/2+ breast cancers in October 2018.

Retrospective Survival Analysis of Patients With Advanced Pancreatic Ductal Adenocarcinoma and Germline BRCA or PALB2 Mutations.

Germline mutations in the homologous recombination (HR) genes BRCA1, BRCA2, and PALB2 confer an increased risk for pancreatic ductal adenocarcinoma (PDAC). Tumors associated with mutations in HR genes are sensitive to DNA-damaging agents, such as platinum chemotherapies. We hypothesized that patients with PDAC with germline BRCA1, BRCA2, or PALB2 mutations may benefit preferentially from platinum-based chemotherapy. Twenty-nine individuals with deleterious germline mutations in BRCA1, BRCA2, or PALB2 and a diagnosis of advanced PDAC (mut-positive) were matched 2:1 to patients who were noncarrier or untested (control) by age at diagnosis, year of diagnosis, stage, and sex. Patients were identified via one of two available databases at the University of Pennsylvania: the Basser Center for BRCA Registry or the University of Pennsylvania Electronic Medical Patient Record. Treatment history, including exposure to platinum-based chemotherapy, was ascertained. Primary objective was overall survival (OS). Patients who were mut-positive had an OS of 21.8 months; control patients had an OS of 8.1 months (hazard ratio [HR], 0.35; 95% CI, 0.2 to 0.62; P< .001). With platinum exposure, patients who were mut-positive had an undefined OS (median follow-up, 20.1 months), versus an OS of 15.5 months in the control patients (HR, 0.25; 95% CI, 0.1 to 0.61; P = .002). In patients not treated with platinum, there was no significant difference in OS between groups (HR, 0.54; 95% CI, 0.25 to 1.17; P = .12). When treated with platinum therapy, patients who were mut-positive had a 1-year OS of 94%, compared with a 1-year OS of 60% in control patients. Platinum-based therapy may confer a survival benefit in patients with advanced PDAC who carry a deleterious germline BRCA1, BRCA2, or PALB2 mutation.

Prevalence and Spectrum of Breast Cancer Inherited Mutations in Uganda and Cameroon Women

Background: Breast cancer among indigenous Africans is characterized by higher prevalence of triple-negative disease and poor prognosis. A previous study in Nigeria reported a strikingly high prevalence of deleterious germline mutations in BRCA1 and BRCA2 among Nigerian women with breast cancer. It is unknown if this is true in other sub-Saharan African countries. Aim: The objective of this study is to determine the frequency of germline mutations among an unselected sample of women in Africa. Methods: We conducted a case-control study of breast cancer in Uganda and Cameroon to investigate genetic and nongenetic risk factors for breast cancer. Breast cancer cases were enrolled in two tertiary hospitals in the two countries, unselected for age at diagnosis and family history. Controls who were free of breast cancer were enrolled in the same hospitals and matched to cases on age. A 24-gene sequencing panel was used to test germline mutations in cases and controls. Results: There were 176 cases and 177 controls with a mean age at diagnosis of 46.2 years for cases and mean age at interview of 46.7 years for controls. Among cases, 18.2% carried a pathogenic mutation in a breast cancer gene: 6.3% in BRCA1, 6.3% in BRCA2, 1.7% in ATM, 1.1% in PALB2, 0.6% in BARD1, 0.6% in CDH1, 0.6% in TP53, and 1.2% in any of 17 other genes. Among controls, 2.3% carried a pathogenic mutation in one of the 24 susceptibility genes. Cases were 9.6-fold more likely to carry a mutation compared with controls (odds ratio=9.61, 95% confidence interval: 3.28-38.1; P &lt; 0.001). The mean age of breast cancer cases with pathogenic BRCA1 mutations was 38.3 years compared with 46.7 years among other cases without such mutations ( P = 0.03). There was a trend that cases with a positive family history had higher chance of carrying a mutation (33.3%) than cases without (17.1%), but few cases reported a positive family history. Conclusion: Our findings confirm the earlier report of a high proportion of deleterious mutations in BRCA1 and BRCA2 among breast cancer patients in sub-Saharan Africa. As most of these women present with advanced breast cancer, there is an urgent need to improve access to genomic testing and life saving cancer medicines including chemotherapy and clinical trials of novel agents like PARP inhibitors. Given the high burden of inherited breast cancer, genetic risk assessment should be integrated into cancer control plans in sub-Saharan Africa.

242P - Impact of deleterious germline BRCA mutations, addition of taxanes and use of adjuvant endocrine therapy (ET) on anti-müllerian hormone (AMH) levels in early breast cancer (EBC) patients treated by adjuvant chemotherapy (CT)

242P - Impact of deleterious germline BRCA mutations, addition of taxanes and use of adjuvant endocrine therapy (ET) on anti-müllerian hormone (AMH) levels in early breast cancer (EBC) patients treated by adjuvant chemotherapy (CT)

Phase I Trial of Veliparib, a Poly ADP Ribose Polymerase Inhibitor, Plus Metronomic Cyclophosphamide in Metastatic HER2-negative Breast Cancer

BackgroundPoly-ADP-ribose-polymerase is an essential nuclear enzyme, involved in base-excision repair of damaged DNA. Poly-ADP-ribose-polymerase inhibition sensitizes tumor cells to cytotoxic agents, which induce DNA damage, including cyclophosphamide (C), and metronomic dosing of C may optimize potential for synergy. MethodsThe primary objective of this phase I trial was to determine the safety and identify the recommended phase II dose of the combination of low-dose oral C (50, 75, 100, and 125 mg) once daily in combination with veliparib (V) (100, 200, and 300 mg) administered twice a day (BID) for 21-day cycles using a standard 3 + 3 design in patients with metastatic human epidermal growth factor receptor 2/neu-negative breast cancer. Dose-limiting toxicity was defined as any grade 3 non-hematologic toxicity or grade 4 thrombocytopenia/neutropenia occurring during cycle 1. ResultsA total of 31 patients were enrolled; 19 were treated with 50 mg of C and 12 were treated at higher doses (75, 100, or 125 mg), with V doses ranging from 50 to 300 mg BID. The recommended phase II dose of the combination was V 200 mg orally BID plus C 125 mg orally daily, with nausea and headache dose-limiting at higher V dose levels. Objective response or stable disease for at least 24 weeks occurred in 3 (43%) of 7 patients with known deleterious germline BRCA mutations and 2 (11%) of 19 patients with negative/unknown mutation status (P = .1). ConclusionThe combination of oral continuous dosing of V (200 mg orally BID) with metronomic C (50, 75, 100, and 125 mg daily) is well-tolerated and shows antitumor activity in patients with BRCA–mutation-associated metastatic human epidermal growth factor receptor 2/neu-negative breast cancer.

Targeted sequencing of BRCA1 and BRCA2 across a large unselected breast cancer cohort suggests that one-third of mutations are somatic

A mutation found in the BRCA1 or BRCA2 gene of a breast tumor could be either germline or somatically acquired. The prevalence of somatic BRCA1/2 mutations and the ratio between somatic and germline BRCA1/2 mutations in unselected breast cancer patients are currently unclear. Paired normal and tumor DNA was analyzed for BRCA1/2 mutations by massively parallel sequencing in an unselected cohort of 273 breast cancer patients from south Sweden. Deleterious germline mutations in BRCA1 (n = 10) or BRCA2 (n = 10) were detected in 20 patients (7%). Deleterious somatic mutations in BRCA1 (n = 4) or BRCA2 (n = 5) were detected in 9 patients (3%). Accordingly, about 1 in 9 breast carcinomas (11%) in our cohort harbor a BRCA1/2 mutation. For each gene, the tumor phenotypes were very similar regardless of the mutation being germline or somatically acquired, whereas the tumor phenotypes differed significantly between wild-type and mutated cases. For age at diagnosis, the patients with somatic BRCA1/2 mutations resembled the wild-type patients (median age at diagnosis, germline BRCA1: 41.5 years; germline BRCA2: 49.5 years; somatic BRCA1/2: 65 years; wild-type BRCA1/2: 62.5 years). In a population without strong germline founder mutations, the likelihood of a BRCA1/2 mutation found in a breast carcinoma being somatic was ∼1/3 and germline 2/3. This may have implications for treatment and genetic counseling.

Abstract P3-13-01: Lurbinectedin (PM01183) activity in BRCA1/2-associated or unselected metastatic breast cancer. Interim results of an ongoing phase II trial

Abstract Background: Metastatic breast cancer (MBC) is a clinically heterogeneous disease in which selective approaches are needed to identify patients (pts) who will benefit the most from available therapies and avoid unnecessary toxicities. Lurbinectedin (PM01183) is a new anticancer drug that binds to the DNA minor groove inducing double-strand breaks and blocking transcription. It has significant in vitro and in vivo antitumor activity, particularly in breast cancer models. PM01183 is more active against homologous recombination-deficient cell lines. Hence, MBC pts with deleterious germline BRCA mutations might be more sensitive to PM01183 than those with sporadic tumors. PM1183 activity was shown in different tumor types in clinical trials, especially in pts with platinum-resistant ovarian cancer (objective response rate [ORR]: 30%). Methods: MBC pts &amp;lt; 75-years-old with ductal or lobular carcinoma pretreated with ≤ 3 chemotherapy regimens for MBC, measurable disease per RECIST v1.1, performance status (PS) ≤1 and adequate major organ function are being treated with PM01183 7.0 mg flat dose i.v. every 3 weeks. The primary aim is to evaluate the clinical efficacy of PM01183 in two cohorts of MBC pts: cohort A: BRCA+ (known germline BRCA1/2 mutation) and cohort B: unselected (BRCA1/2 wild type or unknown mutation status). The primary endpoint is confirmed ORR by RECIST v1.1. A futility analysis was planned when 20 and 30 pts were recruited in cohort A and B, respectively. If at least 4 pts in cohort A and 3 pts in cohort B, achieve a response, recruitment in that cohort will continue up to 53 and 64 total pts, respectively. Results: As of June 2014, 56 pts had been enrolled. Cohort A/B (n: 21/35): Median age 40/52-years-old; Cohort A(%)/B(%): PS 0: 48/66; &amp;gt;2 metastatic sites: 58/40; most common sites of metastasis: lymph node 79/33, liver 48/60 and bone 42/48; triple negative: 57/46; hormonal receptor +: 38/49; prior anthracyclines: 95/91, taxanes: 100/94, platinum: 52/26, PARPi: 29/0; cohort A: BRCA 1/2 (%): 52/48. Cohort A-BRCA 1/2+ (n=21)Cohort B-unselected (n=35)Median cycles (range)4 (1-20)3 (1-14)Best overall response(n= 17 evaluable)(n= 34 evaluable)CR1 (6%)0PR6 (35%)3 (9%)SD6 (35%)16 (47%)PD4 (24%)15 (44%)ORR (95%CI)41% (18-67%)9% (1.9-23.7%)Median duration of response Monts (95%CI)5.0 (0.1-12.8)3.3 (1.4-5.1) In an exploratory analysis, ORR in cohort A was higher in PARPi naïve pts: 64% (7/11 pts). Grade (G) 3-4 related adverse events occurred in &amp;gt;5% pts were myelosuppression (neutropenia 69%, febrile neutropenia 7%, thrombocytopenia 14%); G3 fatigue 7%, transient transaminase increase 19% (G4: 2%), nausea 6% and dyspnea 6% (3 pts, 2 of them due to pneumonitis). One patient with massive liver involvement and impaired function died on C1D4 due to multiorgan failure possibly related to the study drug. Conclusions: PM01183 has promising activity in pretreated MBC pts with BRCA mutation. Safety profile appears to be mostly predictable and with non-cumulative toxicity. Treatment-related neutropenia was manageable with G-CSF and/or dose reduction. After futility analysis, targeted activity has been met in cohort A (BRCA+), and recruitment will continue up to 53 evaluable BRCA+ pts. Citation Format: Judit Balmaña, Cristina Cruz, Judy Garber, Jose A Perez Fidalgo, Ana Lluch, Nadine Tung, Silvia Antolin, Cristian Fernandez, Carmen Kahatt, Sergio Szyldergemajn, Arturo Soto Matos, Sonia Extremera, Jose Baselga, Steven J Isakoff. Lurbinectedin (PM01183) activity in BRCA1/2-associated or unselected metastatic breast cancer. Interim results of an ongoing phase II trial [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-13-01.

Poly (ADP-ribose) polymerase inhibitors: recent advances and future development.

Poly (ADP-ribose) polymerase (PARP) inhibitors have shown promising activity in epithelial ovarian cancers, especially relapsed platinum-sensitive high-grade serous disease. Consistent with preclinical studies, ovarian cancers and a number of other solid tumor types occurring in patients with deleterious germline mutations in BRCA1 or BRCA2 seem to be particularly sensitive. However, it is also becoming clear that germline BRCA1/2 mutations are neither necessary nor sufficient for patients to derive benefit from PARP inhibitors. We provide an update on PARP inhibitor clinical development, describe recent advances in our understanding of PARP inhibitor mechanism of action, and discuss current issues in the development of these agents.

Germline mutation in BRCA1 or BRCA2 and ten-year survival for women diagnosed with epithelial ovarian cancer.

To analyze the effect of germline mutations in BRCA1 and BRCA2 on mortality in patients with ovarian cancer up to 10 years after diagnosis. We used unpublished survival time data for 2,242 patients from two case-control studies and extended survival time data for 4,314 patients from previously reported studies. All participants had been screened for deleterious germline mutations in BRCA1 and BRCA2. Survival time was analyzed for the combined data using Cox proportional hazard models with BRCA1 and BRCA2 as time-varying covariates. Competing risks were analyzed using Fine and Gray model. The combined 10-year overall survival rate was 30% [95% confidence interval (CI), 28%-31%] for non-carriers, 25% (95% CI, 22%-28%) for BRCA1 carriers, and 35% (95% CI, 30%-41%) for BRCA2 carriers. The HR for BRCA1 was 0.53 at time zero and increased over time becoming greater than one at 4.8 years. For BRCA2, the HR was 0.42 at time zero and increased over time (predicted to become greater than 1 at 10.5 years). The results were similar when restricted to 3,202 patients with high-grade serous tumors and to ovarian cancer-specific mortality. BRCA1/2 mutations are associated with better short-term survival, but this advantage decreases over time and in BRCA1 carriers is eventually reversed. This may have important implications for therapy of both primary and relapsed disease and for analysis of long-term survival in clinical trials of new agents, particularly those that are effective in BRCA1/2 mutation carriers.