Post hoc analyses of GOG 9923: Does BRCA status affect toxicities?: An NRG oncology study

Gillen, J.; Miller, Austin; Bell‐McGuinn, Katherine M.; Schilder, Russell J.; Walker, Joan L.; Mathews, Cara; Duska, Linda R.; Guntupalli, Saketh R.; O’Cearbhaill, Roisin E.; Hays, John L.; Hagemann, Andrea R.; Gray, Heidi J.; Gordon, Sarah W.; Armstrong, Deborah K.; Chen, Alice; Fracasso, Paula M.; Aghajanian, Carol; Moore, Kathleen N.

doi:10.1016/j.ygyno.2021.01.037

Cited by 4 publications

(6 citation statements)

References 22 publications

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“…30 Other retrospective investigations including 31-150 patients addressed chemotherapy toxicity in other types of gBRCA1-2pv neoplasms. [23][24][25][26][36][37][38][39] Albeit mostly not reporting information on dose-intensity or treatment duration, these series apparently confirm our findings. Patients with breast cancer receiving anthracycline-and taxane-based chemotherapy had no difference in toxicity as opposed to wild-type patients.…”

Section: Esmo Opensupporting

confidence: 84%

Section: Discussionmentioning

confidence: 99%

“…24,36 By contrast, in patients with ovarian cancer receiving platinum-based chemotherapy, hematological toxicity was more serious among those harboring gBRCA1-2pv in the majority of series, 26,38 with a few exceptions in smaller surveys 23 or without separately reported data for patients receiving either intravenous or intraperitoneal platinum salts. 39 The unique data about chemotherapy toxicity in PDAC patients with gBRCA1-2pv can be derived from the phase II trial by O'Reilly and colleagues, 21 which investigated the activity of gemcitabine plus cisplatin with or without veliparib in patients with gBRCA1-2 or PALB2pv. 21 In the 23 patients treated with gemcitabine plus cisplatin, grade 3-4 neutropenia and anemia were 30% and 35%, respectively.…”

Section: Esmo Openmentioning

confidence: 99%

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

et al. 2021

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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.

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Section: Esmo Opensupporting

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Section: Esmo Openmentioning

confidence: 99%

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

et al. 2021

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“…The presence of BRCA1/2 or other germline mutations has been evaluated as a toxicity-predisposition factor. In a post-hoc analysis of the GOG9923 trial, germline BRCA1/2 mutated patients treated with carboplatin, paclitaxel and veliparib with or without bevacizumab did not display an increased risk of AEs compared to wild-type subjects [ 137 ]. Previous evidence suggests that inherited mutations, including BRCA1/2 , PALB2 , TP53 and CHEK2 , are frequent among pre-treated cancer survivors with therapy-related MDS/AML [ 138 , 139 , 140 ].…”

Section: Future Challenges and Perspectivesmentioning

confidence: 99%

Everything Comes with a Price: The Toxicity Profile of DNA-Damage Response Targeting Agents

Martorana

Silva

Sessa

et al. 2022

Cancers

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Targeting the inherent vulnerability of cancer cells with an impaired DNA Damage Repair (DDR) machinery, Poly-ADP-Ribose-Polymerase (PARP) inhibitors have yielded significant results in several tumor types, eventually entering clinical practice for the treatment of ovarian, breast, pancreatic and prostate cancer. More recently, inhibitors of other key components of DNA repair, such as ATR, CHK1 and WEE1, have been developed and are currently under investigation in clinical trials. The inhibition of DDR inevitably induces on-target and off-target adverse events. Hematological and gastrointestinal toxicities as well as fatigue are common with all DDR-targeting agents, while other adverse events are drug specific, such as hypertension with niraparib and transaminase elevation with rucaparib. Cases of pneumonitis and secondary hematological malignancies have been reported with PARP inhibitors and, despite being overly rare, they deserve particular attention due to their severity. Safety also represents a crucial issue for the development of combination regimens incorporating DDR-targeting agents with other treatments, such as chemotherapy, anti-angiogenics or immunotherapy. As such, overlapping and cumulative toxicities should be considered, especially when more than two classes of drugs are combined. Here, we review the safety profile of DDR-targeting agents when used as single agents or in combination and we provide principles of toxicity management.

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“…We previously reported that breast cancer patients with gBRCA1 have a higher incidence of febrile neutropenia and grade 4 neutropenia under chemotherapy [ 17 ]. Post-hoc subgroup analyses on randomized trials suggested that breast cancer patients carrying g BRCA [ 18 ], but not ovarian cancer patients [ 19 , 20 ], showed a higher incidence of acute hematologic toxicities under taxanes. Long-term follow-up of gBRCA carriers treated with poly-(ADP-ribose) polymerase (PARP) inhibitors suggested an increased incidence of therapy-related myeloid neoplasms, i.e.…”

Section: Introductionmentioning

confidence: 99%

Hematologic toxicities of chemotherapy in breast and ovarian cancer patients carrying BRCA1/BRCA2 germline pathogenic variants. A single center experience and review of the literature

et al. 2023

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BRCA1 and BRCA2 play a central role in DNA repair and their germline pathogenic variants (gBRCA) confer a high risk for developing breast and ovarian cancer. Standard chemotherapy regimens for these cancers include DNA-damaging agents. We hypothesized that gBRCA carriers might be at higher risk of developing chemotherapy-related hematologic toxicity and therapy-related myeloid neoplasms (t-MN). We conducted a retrospective study of women newly diagnosed with invasive breast or ovarian cancer who were screened for gBRCA1/gBRCA2 at Geneva University Hospitals. All patients were treated with (neo-)adjuvant chemotherapy. We evaluated acute hematologic toxicities by analyzing the occurrence of febrile neutropenia and severe neutropenia (grade 4) at day 7–14 of the first cycle of chemotherapy and G-CSF use during the entire chemotherapy regimen. Characteristics of t-MN were collected. We reviewed medical records from 447 patients: 58 gBRCA1 and 40 gBRCA2 carriers and 349 non-carriers. gBRCA1 carriers were at higher risk of developing severe neutropenia (32% vs. 14.5%, p = 0.007; OR = 3.3, 95% CI [1.6-7], p = 0.001) and of requiring G-CSF for secondary prophylaxis (58.3% vs. 38.2%, p = 0.011; OR = 2.5, 95% CI [1.4–4.8], p = 0.004). gBRCA2 carriers did not show increased acute hematologic toxicities. t-MN were observed in 2 patients (1 gBRCA1 and one non-carrier). Our results suggested an increased acute hematologic toxicity upon exposure to chemotherapy for breast and ovarian cancer among gBRCA1 but not gBRCA2 carriers. A deeper characterization of t-MN is warranted with the recent development of PARP inhibitors in frontline therapy in gBRCA breast and ovarian cancer.

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Post hoc analyses of GOG 9923: Does BRCA status affect toxicities?: An NRG oncology study

Cited by 4 publications

References 22 publications

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

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

Everything Comes with a Price: The Toxicity Profile of DNA-Damage Response Targeting Agents

Hematologic toxicities of chemotherapy in breast and ovarian cancer patients carrying BRCA1/BRCA2 germline pathogenic variants. A single center experience and review of the literature

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