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

Our plain-English summary of Clinical-pharmacogenetic models for personalized cancer treatment: application to malignant mesothelioma, by K. Goričar, V. Kovač, V. Dolžan (Scientific Reports, 2017).

The study

• Authors: K. Goričar, V. Kovač, V. Dolžan
• Journal: Scientific Reports
• Published: 2017;7:46537
• Cited by: 13 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

In plain English

This Slovenian study tested whether clinical features and inherited gene variants predict chemotherapy outcome in malignant mesothelioma (MM); asbestos exposure was not studied. The authors genotyped blood DNA from 189 MM patients and built and tested scores for gemcitabine/cisplatin and pemetrexed/cisplatin. The gemcitabine/cisplatin score used CRP (C-reactive protein), tumor type, performance status and four gene variants. For progression-free survival above or below 8 months in 71 training patients, its sensitivity and specificity were 0.615 and 0.812; for above or below 6 months in 66 validation patients, they were 0.667 and 0.641. Higher scores were linked to shorter progression-free survival. The pemetrexed/cisplatin score used CRP and two gene variants; sensitivity and specificity were 0.750 and 0.607 in the 57-patient training group, and 0.889 and 0.500 in the 20-patient validation group, from which one patient was excluded. Among 159 patients with genetic data for both models, the authors estimated that 85.5% could get an effective regimen, including 21.4% predicted to do equally well on either; they said this needs prospective confirmation. They noted the small pemetrexed validation group and the large role of CRP.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Development and validation of clinical-pharmacogenetic prediction models (scores combining clinical factors and gene variants), each built in a training group and tested in a separate validation group of chemotherapy-treated patients
• Who was studied: 189 patients with histologically proven malignant mesothelioma who started gemcitabine/cisplatin or pemetrexed/cisplatin chemotherapy at the Institute of Oncology Ljubljana, Slovenia, between March 2002 and September 2013, plus pemetrexed/cisplatin patients who started between 2014 and 2016. Gemcitabine/cisplatin: 71 training and 66 validation patients. Pemetrexed/cisplatin: 57 training and 20 validation patients.
• Exposure: Not asbestos. The study examined chemotherapy with gemcitabine/cisplatin or pemetrexed/cisplatin, and inherited genetic variants (polymorphisms) in genes for drug metabolism, transport and drug targets and in DNA repair pathways.
• Main results:
  • In the gemcitabine/cisplatin training group, longer survival was associated with CRP below 23 mg/l, better performance status or non-sarcomatoid histology, and four of the gene variants studied.
  • In the gemcitabine/cisplatin training group (71 patients), the area under the curve (AUC) for predicting progression-free survival above or below 8 months was 0.732 for the clinical-pharmacogenetic model.
  • In the gemcitabine/cisplatin training group, a cutoff score of 0.75 had sensitivity 0.615, specificity 0.812, positive predictive value 0.800 and negative predictive value 0.634.
  • In the gemcitabine/cisplatin training group, patients with scores above the 0.75 cutoff had shorter progression-free survival (HR 2.75; 95% CI 1.75–4.32) and shorter overall survival (HR 2.77) than patients with lower scores.
  • In the gemcitabine/cisplatin validation group (66 patients), the model was evaluated for progression-free survival above or below 6 months (not 8 months as in training). Its positive predictive value was 0.735.
  • In the gemcitabine/cisplatin validation group, sensitivity was 0.667 and specificity was 0.641.
  • In the gemcitabine/cisplatin validation group, patients with scores above the 0.75 cutoff had shorter progression-free survival (HR 1.52; 95% CI 1.07–2.17) and shorter overall survival than patients with lower scores.
  • The pemetrexed/cisplatin model included two gene variants (MTHFD1 rs2236225 and ABCC2 rs2273697) and CRP level.
  • In the pemetrexed/cisplatin training group (57 patients), a cutoff score of 2.7 had sensitivity 0.750 and specificity 0.607 for predicting progression-free survival longer or shorter than 6 months. Response rate was also worse in patients with higher scores.
  • In the pemetrexed/cisplatin validation group (20 patients), sensitivity was 0.889 and specificity 0.500.
  • From the pemetrexed/cisplatin validation analysis of observed versus predicted outcomes, one patient was excluded.
  • In the pemetrexed/cisplatin validation group, patients with scores above the 2.7 cutoff had shorter progression-free survival (HR 4.81; 95% CI 1.16–19.91).
  • The combined treatment algorithm was applied to the 159 patients with genotyping data for both models.
  • Among those 159 patients, the algorithm recommended a more favorable regimen for 64.2%: gemcitabine/cisplatin for 28.3% and pemetrexed/cisplatin for 35.9%. It predicted that 21.4% would respond equally well to both treatments and that 14.5% would probably respond well to neither.
  • Altogether, the authors estimated that 85.5% of patients could be treated with an effective regimen, compared with a predicted 57.3% if all patients received standard pemetrexed/cisplatin.
• The authors' conclusion: The authors concluded that they had developed models predicting gemcitabine/cisplatin and pemetrexed/cisplatin outcome, and that with their algorithm effective chemotherapy could be recommended for 85.5% of MM patients. They added that this needs to be confirmed in a prospective study.
• Limitations the authors state:
  • In the gemcitabine/cisplatin groups, validation patients were older, had worse performance status and higher CRP, and were generally not amenable to surgery. The authors called this difference a limitation.
  • Patients given pemetrexed/cisplatin as second-line treatment had worse response and shorter survival in general, which the authors called a limitation.
  • Only twenty pemetrexed/cisplatin patients, with shorter follow-up, could be included in the validation group. The authors said the results should be considered preliminary.
  • CRP made a large contribution to the model.
  • Before clinical use, issues remain beyond validation in an independent population, such as methodology, availability of approved tests, and cost-effectiveness of genotyping.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Mesothelioma, Chemotherapy, Gemcitabine, Cisplatin, Pemetrexed (Alimta), Performance Status, Overall Survival.

Related studies

• Comparison of cisplatin plus pemetrexed and cisplatin plus gemcitabine for the treatment of malignant pleural mesothelioma in Japanese patients — T. Shukuya, T. Takahashi, et al. (2014)
• Pharmacogenetics of pemetrexed combination therapy in lung cancer: pathway analysis reveals novel toxicity associations — A. Corrigan, J.L. Walker, et al. (2014)
• A Tumor-Specific Neo-Antigen Caused by a Frameshift Mutation in BAP1 Is a Potential Personalized Biomarker in Malignant Peritoneal Mesothelioma — J. Lai, Z. Zhou, et al. (2016)
• DNA repair polymorphisms and treatment outcomes of patients with malignant mesothelioma treated with gemcitabine-platinum combination chemotherapy — N. Erčulj, V. Kovač, et al. (2012)
• Resveratrol and cisplatin in a malignant mesothelioma cell model — S. Chirumbolo, G. Bjørklund (2016)
• Malignant peritoneal mesothelioma in a child: chemotherapy with gemcitabine and platinum was effective for the disease unresponsive to other treatments — S. Kobayashi, T. Waragai, et al. (2014)

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