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Durable clinical benefit from PARP inhibition in a platinum-sensitive, BRCA2-mutated pancreatic cancer patient after earlier progression on placebo treatment on the POLO trial: a case report.

ABSTRACT: Metastatic pancreatic adenocarcinoma is a deadly malignancy with limited treatment options. Based on the results of the phase 3 POLO trial, the PARP inhibitor olaparib was approved by the Food and Drug Administration as a maintenance therapy in germline BRCA1- and BRCA2-mutated metastatic pancreatic cancer patients whose cancers had not progressed on first-line platinum-based chemotherapy. While this approval was a step forward, there have been criticisms of the POLO study leaving doubts in the field about the effectiveness of PARP inhibition in pancreatic cancer. Here, we describe a patient with a germline BRCA2-mutated, metastatic pancreatic cancer who was randomized to the placebo-arm of the POLO trial. After progressing on the placebo-arm of the POLO study, her cancer again responded to platinum-based chemotherapy and has since been successfully treated for 4 years with off-protocol maintenance olaparib. The presence of placebo treatment in this case serves as an internal control demonstrating the efficacy of PARP inhibition in this patient. This case highlights the potential of PARP inhibitor maintenance therapy in appropriately selected metastatic pancreatic cancer patients.

SUBMITTER: Rubinson D

PROVIDER: S-EPMC8748075 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:IntroductionBRCA-mutated breast cancer cells lack the DNA-repair mechanism homologous recombination that is required for error-free DNA double-strand break (DSB) repair. Homologous recombination deficiency (HRD) may cause hypersensitivity to DNA DSB-inducing agents, such as bifunctional alkylating agents and platinum salts. HRD can be caused by BRCA mutations, and by other mechanisms. To identify HRD, studies have focused on triple-negative (TN) breast cancers as these resemble BRCA1-mutated breast cancer closely and might also share this hypersensitivity. However, ways to identify HRD in non-BRCA-mutated, estrogen receptor (ER)-positive breast cancers have remained elusive. The current study provides evidence that genomic patterns resembling BRCA1- or BRCA2-mutated breast cancers can identify breast cancer patients with TN as well as ER-positive, HER2-negative tumors that are sensitive to intensified, DSB-inducing chemotherapy.MethodsArray comparative genomic hybridization (aCGH) was used to classify breast cancers. Patients with tumors with similar aCGH patterns as BRCA1- and/or BRCA2-mutated breast cancers were defined as having a BRCA-likeCGH status, others as non-BCRA-likeCGH. Stage-III patients (n?=?249) had participated in a randomized controlled trial of adjuvant high-dose (HD) cyclophosphamide-thiotepa-carboplatin (CTC) versus 5-fluorouracil-epirubicin-cyclophosphamide (FE90C) chemotherapy.ResultsAmong patients with BRCA-likeCGH tumors (81/249, 32%), a significant benefit of HD-CTC compared to FE90C was observed regarding overall survival (adjusted hazard ratio 0.19, 95% CI: 0.08 to 0.48) that was not seen for patients with non-BRCA-likeCGH tumors (adjusted hazard ratio 0.90, 95% CI: 0.53 to 1.54) (P?=?0.004). Half of all BRCA-likeCGH tumors were ER-positive.ConclusionsDistinct aCGH patterns differentiated between HER2-negative patients with a markedly improved outcome after adjuvant treatment with an intensified DNA-DSB-inducing regimen (BRCA-likeCGH patients) and those without benefit (non-BRCA-likeCGH patients).

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Durable clinical benefit from PARP inhibition in a platinum-sensitive, BRCA2-mutated pancreatic cancer patient after earlier progression on placebo treatment on the POLO trial: a case report.

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