Should platinum-based chemotherapy be preferred for germline BReast CAncer genes (BRCA) 1 and 2-mutated pancreatic ductal adenocarcinoma (PDAC) patients? A systematic review and meta-analysis

Rebelatto, Taiane Francieli; Falavigna, Maicon; Pozzari, Marta; Spada, Francesca; Cella, Chiara Alessandra; Laffi, Alice; Pellicori, Stefania; Fazio, Nicola

doi:10.1016/j.ctrv.2019.101895

Cited by 36 publications

(28 citation statements)

References 37 publications

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“…In this setting, 18 F-flurorodeoxyglucose PET [27][28][29] imaging was helpful, but the utility has to be validated in large prospective cohorts. Second, the tolerance to induction chemotherapy should be kept in mind, considering the presence of germline mutations [30,31]. Third, the number of cycles administered: our results showed that patients might benefit from at least 8 cycles of chemotherapy before CRT, similar to the results of other studies [20].…”

Section: Continuing With Chemotherapy or Crt At Restagingsupporting

confidence: 81%

Outcomes of patients with initially locally advanced pancreatic adenocarcinoma who did not benefit from resection: a prospective cohort study

et al. 2020

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Background: The current study aimed to evaluate the outcomes of patients with unresectable non-metastatic locally advanced pancreatic adenocarcinoma (LAPA) who did not benefit from resection considering the treatment strategy in the clinical settings. Methods: Between 2010 and 2017, a total of 234 patients underwent induction chemotherapy for LAPA that could not be treated with surgery. After oncologic restaging, continuous chemotherapy or chemoradiation (CRT) was decided for patients without metastatic disease. The Kaplan-Meier method was used to determine overall survival (OS), and the Wilcoxon test to compare survival curves. Multivariate analysis was performed using the stepwise logistic regression method. Results: FOLFIRINOX was the most common induction regimen (168 patients, 72%), with a median of 6 chemotherapy cycles and resulted in higher OS, compared to gemcitabine (19 vs. 16 months, hazard ratio (HR) = 1.2, 95% confidence interval: 0.86-1.6, P = .03). However, no difference was observed after adjusting for age (≤75 years) and performance status score (0-1). At restaging, 187 patients (80%) had non-metastatic disease: CRT was administered to 126 patients (67%) while chemotherapy was continued in 61 (33%). Patients who received CRT had characteristics comparable to those who continued with chemotherapy, with similar OS. They also had longer progression-free survival (median 13.3 vs. 9.6 months, HR = 1.38, 95% confidence interval: 1-1.9, P < .01) and limited short-term treatment-related toxicity. Conclusions: The median survival of patients who could not undergo surgery was 19 months. Hence, CRT should not be eliminated as a treatment option and may be useful as a part of optimised sequential chemotherapy for both local and metastatic disease.

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Section: Continuing With Chemotherapy or Crt At Restagingsupporting

confidence: 81%

Outcomes of patients with initially locally advanced pancreatic adenocarcinoma who did not benefit from resection: a prospective cohort study

et al. 2020

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“…Physicians must focus on restaging to determine the appropriate treatment for each patient, including CT, liver MRI 26 (27)(28)(29) imaging was helpful, but the utility has to be validated in large prospective cohorts. Second, the tolerance to induction chemotherapy should be kept in mind, considering the presence of germline mutations (30,31). Third, the number of cycles administered: our results showed that patients might benefit from at least 8 cycles of chemotherapy before CRT, similar to the results of other studies (20).…”

Section: Perspectives In Patients With Non-metastatic Lapa At Restagingsupporting

confidence: 81%

Outcomes of Patients with Initially Locally Advanced Pancreatic Adenocarcinoma who did not Benefit from Resection: A Prospective Cohort Study

Garnier

Ewald

Marchese

et al. 2020

Preprint

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Background: The current study aimed to evaluate the outcomes of patients with unresectable non-metastatic locally advanced pancreatic adenocarcinoma (LAPA) who did not benefit from resection considering the treatment strategy in the clinical settings. Methods: Between 2010 and 2017, a total of 234 patients underwent induction chemotherapy for LAPA that could not be treated with surgery. After oncologic restaging, continuous chemotherapy or chemoradiation (CRT) was decided for patients without metastatic disease. The Kaplan–Meier method was used to determine overall survival (OS), and the Wilcoxon test to compare survival curves. Multivariate analysis was performed using the stepwise logistic regression method. Results: FOLFIRINOX was the most common induction regimen (168 patients, 72%), with a median of 6 chemotherapy cycles and resulted in higher OS, compared to gemcitabine (19 vs. 16 months, hazard ratio (HR)=1.2, 95% confidence interval: 0.86–1.6, P =.03). However, no difference was observed after adjusting for age (≤75 years) and performance status score (0–1). At restaging, 187 patients (80%) had non-metastatic disease: CRT was administered to 126 patients (67%) while chemotherapy was continued in 61 (33%). Patients who received CRT had characteristics comparable to those who continued with chemotherapy, with similar OS. They also had longer progression-free survival (median 13.3 vs. 9.6 months, HR=1.38, 95% confidence interval: 1–1.9, P <.01) and limited short-term treatment-related toxicity. Conclusions: The median survival of patients who could not undergo surgery was 19 months. Hence, CRT should not be eliminated as a treatment option and may be useful as a part of optimised sequential chemotherapy for both local and metastatic disease.

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“…At the same time, the authors called for more and higher-quality trials in this setting. 23 Further studies are desirable to evaluate PARP inhibitors in different treatment settings in DDR-altered PDACs.…”

Section: Discussionmentioning

confidence: 99%

Molecular characteristics of BRCA1/2 and PALB2 mutations in pancreatic ductal adenocarcinoma

et al. 2020

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IntroductionPoly-(ADP)-ribose polymerase (PARP) inhibitors are successfully used for treatment of BRCA-mutated (mut) breast cancers and are under extensive evaluation for BRCA- and PALB2-mutated pancreatic ductal adenocarcinoma (PDAC). However, the optimal treatment regimen for BRCA/PALB2-mutated PDCA has yet to be established. Moreover, limited data are available on the association of BRCA/PALB2 gene alterations with other comutations and immunological biomarkers.Material and methodsTumour samples of 2818 patients with PDAC were analysed for BRCA1/2 PALB2 mutations and other genes by next-generation sequencing (NGS) (MiSeq on 47 genes, NextSeq on 592 genes). TMB was calculated based on somatic non-synonymous missense mutations. MSI-H/dMMR was evaluated by NGS, and PD-L1 expression was determined using immunohistochemistry.ResultsIn 4.2% (n=124) of all PDAC samples BRCA mutations have been detected. BRCA2 mutations were more commonly observed than BRCA1 mutations (3.1%(n=89) vs 1.1% [n=35], p<0.0001). BRCA2 mutation was associated with an older age (64 vs 61 years for wild-type (wt), p=0.002) and PALB2 mutation was observed more frequently in female than in male patients. BRCA and PALB2 mutations were associated with MSI-H/dMMR compared with wt (BRCA: 4.8% vs 1.2%, p=0.002; PALB2: 6.7% vs 1.3 %, p=0.18), PD-L1 expression of >1.0% (BRCA: 21.8% vs wt 11.2%, p<0.001, PALB2: 0.0% vs 12.4 %, p=0.38) and high TMB (BRCA: mean 8.7 vs 6.5 mut/MB, p<0.001; PALB2: 10.6 mut/Mb vs 6.6 mut/Mb, p=0.0007). Also, PD-L1 expression and TMB differed between BRCA and PALB2 mutation and wt samples in MSS tumours (p<0.05). BRCA-mutated and PALB2-mutated PDACs were characterised by a different mutational profile than was observed in wt tumours.ConclusionsBRCA and PALB2 mutations were found in a significant subgroup of PDACs. These mutations were associated with a distinct molecular profile potentially predictive for response to immune-checkpoint inhibitor therapy. Therefore, these data provide a rationale to evaluate PARP inhibitors in combination with immune-checkpoint inhibitors in patients with BRCA/PALB2-mutated PDAC.

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Should platinum-based chemotherapy be preferred for germline BReast CAncer genes (BRCA) 1 and 2-mutated pancreatic ductal adenocarcinoma (PDAC) patients? A systematic review and meta-analysis

Cited by 36 publications

References 37 publications

Outcomes of patients with initially locally advanced pancreatic adenocarcinoma who did not benefit from resection: a prospective cohort study

Outcomes of patients with initially locally advanced pancreatic adenocarcinoma who did not benefit from resection: a prospective cohort study

Outcomes of Patients with Initially Locally Advanced Pancreatic Adenocarcinoma who did not Benefit from Resection: A Prospective Cohort Study

Molecular characteristics of BRCA1/2 and PALB2 mutations in pancreatic ductal adenocarcinoma

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