Clinical-pharmacogenetic models for personalized cancer treatment: application to malignant mesothelioma

Abstract

Large interindividual differences in treatment outcome are observed in cancer patients undergoing chemotherapy. Our aim was to develop and validate clinical-pharmacogenetic prediction models of gemcitabine/cisplatin or pemetrexed/cisplatin treatment outcome and develop an algorithm for genotype-based treatment recommendations in malignant mesothelioma (MM). We genotyped 189 MM patients for polymorphisms in gemcitabine, pemetrexed and cisplatin metabolism, transport and drug target genes and DNA repair pathways. To build respective clinical-pharmacogenetic models, pharmacogenetic scores were assigned by rounding regression coefficients. Gemcitabine/cisplatin model was based on training group of 71 patients and included CRP, histological type, performance status, RRM1 rs1042927, ERCC2 rs13181, ERCC1 rs3212986, and XRCC1 rs25487. Patients with higher score had shorter progression-free (PFS) and overall survival (P < 0.001). This model’s sensitivity was 0.615 and specificity 0.812. In independent validation group of 66 patients the sensitivity and specificity were 0.667 and 0.641, respectively. Pemetrexed/cisplatin model was based on 57 patients and included CRP, MTHFD1 rs2236225, and ABCC2 rs2273697. Patients with higher score had worse response and shorter PFS (P < 0.001). This model’s sensitivity was 0.750 and specificity 0.607. In independent validation group of 20 patients the sensitivity and specificity were 0.889 and 0.500, respectively. The proposed algorithm based on these models could enable the choice of the most effective chemotherapy for 85.5% of patients and lead to improved treatment outcome in MM.

Translational Knowledge Discovery Between Drug Interactions and Pharmacogenetics

“…Patients with ABCC2 rs2273697 (AA or AG genotype) were reported to have improved overall and progression-free survival when treated with cisplatin and pemetrexed compared with patients with the ABCC2 GG genotype. 38 The synergistic PD DDI between cisplatin and pemetrexed has been demonstrated in in vitro studies over multiple cancer cell lines (MCF7, A549, and PA1 cells). 39 In particular, when MCF7 cells were incubated with pemetrexed for 24 hours followed by cisplatin for 24 hours, synergistic inhibition of cell proliferation was noted.…”

New Perspectives on Diagnosis and Therapy of Malignant Pleural Mesothelioma

“…Due to the rapidly evolving field of precision medicine, identification of novel biomarkers is promising as it may provide the best therapeutic options for each patient, considered the genetic background and the specific characteristics of the tumor. This hope is supported by a recent study on polymorphisms in gemcitabine, pemetrexed, and cisplatin metabolism, transport and other drug target genes and DNA repair pathways, which has led to a clinical-pharmacogenetic model that could predict the best chemotherapeutic treatment for a specific MPM patient ( 177 ). Furthermore, oncogene-targeted depth sequencing on a tumor sample and paired peripheral blood DNA from a patient with malignant mesothelioma of the peritoneum revealed a mutation leading to 13-amino acids neo-peptide of the truncated BAP1 protein, which is predicted to be present on this examined patient’s HLA-B protein.…”

“…Despite progresses, survival time and response rate to cytotoxic agents used for MPM treatment are still not satisfactory ( 176 ), plus a high degree of variability in treatment outcome in cancer patients undergoing chemotherapy has been observed ( 177 ). Furthermore, the cancer is still diagnosed at an advanced stage.…”

Matrix Metalloproteinases Polymorphisms as Prognostic Biomarkers in Malignant Pleural Mesothelioma

“…The influence of platinum pathway and folate pathway polymorphisms on treatment outcome and toxicity has been studied extensively in the Slovenian MPM population [ 5 , 6 ]. The most recent study proposes an algorithm based on clinical-pharmacogenetic models for stratification of MPM patients and personalized cancer treatment [ 7 ]. Newer treatment options, including targeted treatments and immunotherapy, are being researched and implemented in clinical trials [ 8 , 9 ], with the aim of further improving treatment outcome in MPM.…”