Chemotherapy toxicity and activity in patients with pancreatic ductal adenocarcinoma and germline BRCA1-2 pathogenic variants (gBRCA1-2pv): a multicenter survey

Abstract

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.

Multimodal treatment with curative intent in a germline BRCA2 mutant metastatic ampullary adenocarcinoma: a case report

“…This encouraged us to take advantage of a profound response and consider a personalized surgical approach with potential curative intent both on primary and metastatic lesions. Second, germline BRCA1/2 mutations have been associated, even though not univocally, with enhanced toxicity to platinum compounds [19][20][21]. This case is consistent with some of these previous reports, since we observed the occurrence of a G4 neutropenia despite granulocyte stimulating factor (G-CSF) support given as secondary prophylaxis.…”

Antitumoral Agent-Induced Constipation: A Systematic Review

“…The antitumoral treatment was not mentioned in 28 studies; those studies referred to chemotherapy, without specifying which chemotherapy. From those who specifically mentioned any antitumoral treatment, the most frequent antitumoral treatments mentioned were carboplatin [ 14 , 20 , 21 ], oxaliplatin [ 13 , 22 , 23 , 24 , 25 ], bevacizumab [ 23 , 24 ], vinca alkaloids [ 14 , 26 , 27 ], and lenalidomide, thalidomide, and bortezomib [ 11 , 22 , 28 , 29 ].…”

“…As far as the severity of constipation is concerned, previous studies explain that the burden related to constipation is more severe as death approaches [ 65 ]. In this systematic review, the severity of constipation is only mentioned in 13 of the 54 studies [ 1 , 11 , 14 , 25 , 29 , 30 , 34 , 35 , 36 , 47 , 48 , 68 , 69 ].…”

Olaparib as a single agent treatment in pre-treated metastatic pancreatic cancer patient harboring BRCA2 mutation: What could we expect?

“…Germline variants in cancer susceptibility genes, in particular BRCA1/2, are clinically relevant targets in metastatic pancreatic ductal adenocarcinoma (PDAC), both for the first-line and maintenance therapy. The patients harboring BRCA1/2 mutations are more responsive to platinum-based chemotherapy agents and poly (ADP-ribose) polymerase (PARP) inhibitors, 1,2 adding a new therapeutic chance for this small subset of PDAC population. Generally, sensitivity to platinum-based chemotherapy is expected to predict the sensitivity to PARP inhibitors, although platinum chemotherapy elicits cell death through both homologous recombination (HR) dependent and non-HR-dependent mechanisms, thus reducing predictive power.…”