Search

In the OlympiA study, 1 year of adjuvant olaparib significantly extended invasive disease-free survival and overall survival. The benefit was consistent across subgroups, and this regimen is now recommended after chemotherapy for germline BRCA1/2 mutation (g BRCA1/2 m) carriers with high-risk, HER2-negative early breast cancer. However, the integration of olaparib in the landscape of agents currently available in the post(neo)adjuvant setting—ie, pembrolizumab, abemaciclib, and capecitabine—is challenging, as there are no data suggesting how to select, sequence, and/or combine these therapeutic approaches. Furthermore, it is unclear how to best identify additional patients who could benefit from adjuvant olaparib beyond the original OlympiA criteria. Since it is unlikely that new clinical trials will answer these questions, recommendations for clinical practice can be made through indirect evidence. In this article, we review available data that could help guide treatment decisions for g BRCA1/2 m carriers with high-risk, early-stage breast cancer. [ABSTRACT FROM AUTHOR]

Abstract Background To analyze the effects of BRCA1/2 mutations on chemotherapy response scores (CRS) and survival in a cohort of patients with advanced-stage ovarian cancer who were treated with neoadjuvant chemotherapy (NAC) followed by interval debulking surgery (IDS). Methods We retrospectively reviewed the medical records of 169 high-grade serous ovarian cancer patients who underwent a germline BRCA1/2 test and received three cycles of NAC at the Yonsei Cancer Center from 2006 to 2018. Chemotherapy response scores were compared in patients with and without BRCA1/2 mutations. The effects of BRCA1/2 mutations and CRS on survival were evaluated. Results BRCA1/2 mutations were detected in 47 (28.1%) of the 169 patients. Overall, 16 (34.0%) patients with BRCA1/2 mutations had a CRS 3 to chemotherapy compared to scores of 43 in patients (35.2%) without a mutation. Response scores of 3 in patients with BRCA1/2 mutations were not significantly associated with either improved progression-free survival (PFS) (P = 0.949) or overall survival (OS) (P = 0.168). However, CRS 3 in patients without BRCA mutations was significantly associated with both improved PFS (P = 0.030) and OS (P = 0.039). In patients with CRS1/2, carriers of BRCA1/2 mutations had better PFS (P = 0.0344) and OS (P = 0.043) than wild-type BRCA genotype patients. Conclusion In ovarian cancer patients treated with NAC, CRS did not predict survival for BRCA 1/2 mutation carriers but did for BRCA wild-type patients.

Background: To analyze the effects of BRCA1/2 mutations on chemotherapy response scores (CRS) and survival in a cohort of patients with advanced-stage ovarian cancer who were treated with neoadjuvant chemotherapy (NAC) followed by interval debulking surgery (IDS).Methods: We retrospectively reviewed the medical records of 169 high-grade serous ovarian cancer patients who underwent a germline BRCA1/2 test and received three cycles of NAC at the Yonsei Cancer Center from 2006 to 2018. Chemotherapy response scores were compared in patients with and without BRCA1/2 mutations. The effects of BRCA1/2 mutations and CRS on survival were evaluated.Results: BRCA1/2 mutations were detected in 47 (28.1%) of the 169 patients. Overall, 16 (34.0%) patients with BRCA1/2 mutations had a CRS 3 to chemotherapy compared to scores of 43 in patients (35.2%) without a mutation. Response scores of 3 in patients with BRCA1/2 mutations were not significantly associated with either improved progression-free survival (PFS) (P = 0.949) or overall survival (OS) (P = 0.168). However, CRS 3 in patients without BRCA mutations was significantly associated with both improved PFS (P = 0.030) and OS (P = 0.039). In patients with CRS1/2, carriers of BRCA1/2 mutations had better PFS (P = 0.0344) and OS (P = 0.043) than wild-type BRCA genotype patients.Conclusion: In ovarian cancer patients treated with NAC, CRS did not predict survival for BRCA 1/2 mutation carriers but did for BRCA wild-type patients. [ABSTRACT FROM AUTHOR]

Background: BRCA1 and BRCA2 (BRCA1/2)-deficient tumors display impaired homologous recombination repair (HRR) and enhanced sensitivity to DNA damaging agents or to poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi). Their efficacy in germline BRCA1/2 (gBRCA1/2)-mutated metastatic breast cancers has been recently confirmed in clinical trials. Numerous mechanisms of PARPi resistance have been described, whose clinical relevance in gBRCA-mutated breast cancer is unknown. This highlights the need to identify functional biomarkers to better predict PARPi sensitivity. Patients and methods: We investigated the in vivo mechanisms of PARPi resistance in gBRCA1 patient-derived tumor xenografts (PDXs) exhibiting differential response to PARPi. Analysis included exome sequencing and immunostaining of DNA damage response proteins to functionally evaluate HRR. Findings were validated in a retrospective sample set from gBRCA1/ 2-cancer patients treated with PARPi. Results: RAD51 nuclear foci, a surrogate marker of HRR functionality, were the only common feature in PDX and patient samples with primary or acquired PARPi resistance. Consistently, low RAD51 was associated with objective response to PARPi. Evaluation of the RAD51 biomarker in untreated tumors was feasible due to endogenous DNA damage. In PARPi-resistant gBRCA1 PDXs, genetic analysis found no in-frame secondary mutations, but BRCA1 hypomorphic proteins in 60% of the models, TP53BP1-loss in 20% and RAD51-amplification in one sample, none mutually exclusive. Conversely, one of three PARPi-resistant gBRCA2 tumors displayed BRCA2 restoration by exome sequencing. In PDXs, PARPi resistance could be reverted upon combination of a PARPi with an ataxia-telangiectasia mutated (ATM) inhibitor. Conclusion: Detection of RAD51 foci in gBRCA tumors correlates with PARPi resistance regardless of the underlying mechanism restoring HRR function. This is a promising biomarker to be used in the clinic to better select patients for PARPi therapy. Our study also supports the clinical development of PARPi combinations such as those with ATM inhibitors. [ABSTRACT FROM AUTHOR]

Background: Germline BRCA1-2 pathogenic variants (gBRCA1-2pv)-related pancreatic ductal adenocarcinoma (PDAC) showed increased sensitivity to DNA cross-linking agents. This study aimed at exploring safety profile, dose intensity, and activity of different chemotherapy regimens in this setting., Patients and Methods: gBRCA1-2pv PDAC patients of any age and clinical tumor stage who completed a first course of chemotherapy were eligible. A descriptive analysis of chemotherapy toxicity, dose intensity, response, and survival outcomes was performed., Results: A total of 85 gBRCA1-2pv PDAC patients treated in 21 Italian centers between December 2008 and March 2021were enrolled. Seventy-four patients were assessable for toxicity and dose intensity, 83 for outcome. Dose intensity was as follows: nab-paclitaxel 72%, gemcitabine 76% (AG); cisplatin 75%, nab-paclitaxel 73%, capecitabine 73%, and gemcitabine 65% (PAXG); fluorouracil 35%, irinotecan 58%, and oxaliplatin 64% (FOLFIRINOX). When compared with the literature, grade 3-4 neutropenia, thrombocytopenia, and diarrhea were increased with PAXG, and unmodified with AG and FOLFIRINOX. RECIST responses were numerically higher with the three- (81%) or four-drug (73%) platinum-containing regimens that outperformed AG (41%) and oxaliplatin-based doublets (56%). Carbohydrate antigen 19.9 (CA19.9) reduction >89% at nadir was reported in two-third of metastatic patients treated with triplets and quadruplets, as opposed to 33% and 45% of patients receiving oxaliplatin-based doublets or AG, respectively. All patients receiving AG experienced disease progression, with a median progression-free survival (mPFS) of 6.4 months, while patients treated with platinum-containing triplets or quadruplets had an mPFS >10.8 months. Albeit still immature, data on overall survival seemed to parallel those on PFS., Conclusions: Our data, as opposed to figures expected from the literature, highlighted that platinum-based regimens provoked an increased toxicity on proliferating cells, when dose intensity was maintained, or an as-expected toxicity, when dose intensity was reduced, while no change in toxicity and dose intensity was evident with AG. Furthermore, an apparently improved outcome of platinum-based triplets or quadruplets over other regimens was observed., Competing Interests: Disclosure MN reports travel expenses from Celgene; speaker honorarium from Accademia della Medicina; and consultant honoraria from EMD Serono. IG serves on the advisory board of Amgen, Takeda, and Eisai. GT reports travel expenses and personal honoraria for advisory boards from Celgene, Merck, AstraZeneca, Servier, and BMS. SC reports travel expenses and personal honoraria for the following companies: Amgen, Bayer, Eli Lilly, and Servier (as speaker); Amgen, Eli Lilly, Bayer, Baxter, Merck Sharp & Dohme (MSD), Servier (on advisory boards). Amgen, Baxter, Eli Lilly, Celgene, Novartis, and MSD (as consultant); receiving research grant from Celgene and Eisai. MM reports personal honoraria as speaker or consultant for the following companies: AstraZeneca, MSD, Boehringer Ingelheim, Pfizer, EUSA Pharma, Merck-Serono, Novartis, Roche, Ipsen, and Mylan. MR reports travel expenses and personal honoraria for advisory boards from Celgene, Merck, AstraZeneca, Baxalta (2016), Baxter, Sanofi (2017), Servier, Shire, Eli Lilly, Pfizer (2016), Novocure (2016), and Novartis (2016); personal honoraria for steering committee work for AstraZeneca, and nonremunerated steering committee activities for Boston Pharmaceuticals. All other authors have declared no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: Germline BRCA1-2 pathogenic variants (gBRCApv) increase the risk of pancreatic cancer and predict for response to platinating agents and poly(ADP-ribose) polymerase inhibitors. Data on worldwide gBRCApv incidence among pancreatic ductal adenocarcinoma (PDAC) patients are sparse and describe a remarkable geographic heterogeneity. The aim of this study is to analyze the epidemiology of gBRCApv in Italian patients., Materials and Methods: Patients of any age with pancreatic adenocarcinoma, screened within 3 months from diagnosis for gBRCApv in Italian oncologic centers systematically performing tests without any selection. For the purposes of our analysis, breast, ovarian, pancreas, and prostate cancer in a patient's family history was considered as potentially BRCA-associated. Patients or disease characteristics were examined using the χ 2 test or Fisher's exact test for qualitative variables and the Student's t-test or Mann-Whitney test for continuous variables, as appropriate., Results: Between June 2015 and May 2020, 939 patients were tested by 14 Italian centers; 492 (52%) males, median age 62 years (range 28-87), 569 (61%) metastatic, 273 (29%) with a family history of potentially BRCA-associated cancers. gBRCA1-2pv were found in 76 patients (8.1%; 9.1% in metastatic; 6.4% in non-metastatic). The gBRCA2/gBRCA1 ratio was 5.4 : 1. Patients with gBRCApv were younger compared with wild-type (59 versus 62 years, P = 0.01). The gBRCApv rate was 17.1% among patients <40 years old, 10.4% among patients 41-50 years old, 9.2% among patients 51-60 years old, 6.7% among patients aged 61-70 years, and 6.2% among patients >70 years old (none out of 94 patients >73 years old). gBRCApv frequency in 845 patients <74 years old was 9%. Patients with/without a family history of potentially BRCA-associated tumors had 14%/6% mutations., Conclusion: Based on our findings of a gBRCApv incidence higher than expected in a real-life series of Italian patients with incident PDAC, we recommend screening all PDAC patients <74 years old, regardless of family history and stage, due to the therapeutic implications and cancer risk prevention in patients' relatives., Competing Interests: Disclosure MR reports travel expenses and personal honoraria for Advisory Boards from Celgene, Merck, Astra-Zeneca, Baxalta (2016), Baxter, Sanofi (2017), Servier, Shire, Eli Lilly, Pfizer (2016), Novocure (2016), and Novartis (2016), personal honoraria for steering committee work for AstraZeneca, and non-remunerated steering committee activities for Boston Pharmaceuticals. MF reports travel expenses and personal honoraria for Advisory Boards from Celgene, Novartis, Advanced Accelerators Applications, and Ipsen. SC reports travel expenses and personal honoraria for the following companies. Speaker: Amgen, Bayer, Eli Lilly, Servier. Advisory Boards: Amgen, Eli Lilly, Bayer, Baxter, Merck Sharp & Dohme (MSD), Servier. Consultant: Amgen, Baxter, Eli Lilly, Celgene, Novartis, MSD. Research grant: Celgene, Eisai. GT: Travel expenses and personal honoraria for Advisory Boards from Celgene, Merck, Astra-Zeneca, Servier. LS reports travel expenses and personal honoraria for Advisory Boards from Merck-Serono, Celgene, Roche, Sanofi, Servier, Bayer, Astra-Zeneca, Amgen. DM reports research grants and personal fees for consulting from Incyte Corporation; research grants and personal fees for consulting from Shire, Evotec, and iOnctura; research grants from Celgene, and personal fees for consulting from Eli Lilly and Baxter. FDV reports travel expenses and personal honoraria for Advisory Boards: Roche, Amgen, Celgene, Eli Lilly, Servier. MDM reports travel expenses and personal honoraria for Advisory Boards from Celgene. GG reports travel expenses and personal honoraria for Advisory Boards from Celgene (2016–2017–2018), Sanofi (2016–2018), Servier (2019). FDB reports personal honoraria for: Consultant Advisory Board: Ignyta, Bristol-Myers Squibb (BMS), Daiichi Sankyo, Pfizer, Octimet Oncology, Incyte, Teofarma, Pierre Fabre, Roche, EMD Serono, Sanofi, NMS Nerviano Medical Science, Pharm Research Associated (UK) Ltd; Speaker: BMS, Roche, MSD, Ignyta, Bayer, ACCMED, Dephaforum S.r.l., Nadirex, Merck, Biotechspert Ltd, PriME Oncology, Pfizer, Servier, Celgene, Tesaro, Loxo Oncology Inc., Sanofi, Healthcare Research & Pharmacoepidemiology. MN reports travel expenses from Celgene and personal honoraria for Advisory Board from EMD Serono. All the other authors have declared no conflicts of interest. Patient consent Before testing, all patients signed an informed consensus statement that was revised and approved by a local ethics committee and allowed, for genetic testing, and data collection, and analysis and elaboration. Data were irreversibly anonymized before entering into the database. Data availability statement Data are available upon reasonable request., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)