Retrospective response analysis of BAP1 expression to predict the clinical activity of systemic cytotoxic chemotherapy in mesothelioma

Our plain-English summary of Retrospective response analysis of BAP1 expression to predict the clinical activity of systemic cytotoxic chemotherapy in mesothelioma, by N. Kumar, D. Alrifai, K.K. Kolluri, et al (Lung Cancer, 2019).

The study

• Authors: N. Kumar, D. Alrifai, K.K. Kolluri, E.K. Sage, Y. Ishii, N. Guppy, E. Borg, M. Falzon, M. Nankivell, A.G. Nicholson, S.M. Janes
• Journal: Lung Cancer
• Published: 2019;127:164-166
• Cited by: 14 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Introduction BRCA1 associated protein-1 (BAP1) is a key tumor driver in mesothelioma and a potential biomarker predicting response to several targeted therapies in clinical testing. Whether it also modulates response to cytotoxic chemotherapy is undetermined. This study used retrospective response analysis of BAP1 expression in archival tumor biopsies taken from patients in the MS01 trial (NCT00075699). We aimed to determine if BAP1 expression correlated with overall survival within the three treatment arms in this trial, namely active symptom control (ASC); ASC plus mitomycin, vinblastine and cisplatin (MVP); and ASC plus vinorelbine. Materials and methods We used immunohistochemical analysis of tumor samples from the MS01 trial to identify subgroups with and without nuclear BAP1 expression. We performed correlative analysis of clinical characteristics (age at diagnosis, sex and histological subtype) and overall survival within treatment arms with nuclear BAP1 expression. Results 89 tumor samples from the 409 patients originally in the trial were available for analysis. Of these, 60 samples harbored a positive internal control, in the form of positive staining of inflammatory cells for BAP1, and were carried forward for analysis. Correlative analysis suggested no significant association between loss of nuclear BAP1 expression and age at diagnosis, sex and histological subtype. Kaplan Meier survival analysis revealed a small, though non-significant, overall survival disadvantage associated with BAP1 expression in tumors from patients treated with vinorelbine. Discussion This exploratory analysis suggests BAP1 expression may modify response to vinorelbine in MPM, possibly due to prevention of mitotic microtubule formation. We suggest ongoing and planned clinical studies of vinorelbine in MPM assess BAP1 expression as a predictive biomarker of response.

Copyright © 2018. Published by Elsevier B.V.

In plain English

This study re-examined stored tumor samples from MS01, a randomized trial of patients with malignant pleural mesothelioma treated at UK and Australian centers from 2001 to 2006. The trial compared active symptom control (ASC) alone, ASC plus mitomycin, vinblastine and cisplatin (MVP), and ASC plus vinorelbine. Samples existed for 89 of the 409 trial patients, and 60 passed a staining quality check. Of these, 13 tumors showed nuclear BAP1 expression and 47 lacked it. Asbestos exposure was not studied. BAP1 status was not significantly linked to sex, age or tumor subtype. Survival did not differ significantly by BAP1 status among patients given ASC alone or ASC plus MVP. Among patients given vinorelbine, median survival was 5.5 months for 4 patients with BAP1-positive tumors and 11.5 months for 12 patients with BAP1-negative tumors. This was a non-significant trend (p = 0.06; hazard ratio 4.87, 95% confidence interval 0.94 to 25.16). The authors called the analysis exploratory and not powered for these subgroups. They concluded that it suggests BAP1 expression does not modify response to MVP but may modify response to vinorelbine.

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: Exploratory retrospective analysis of archived tumor samples and survival data from a subset of patients in a phase III, three-arm randomized controlled trial (MS01)
• Who was studied: Patients with malignant pleural mesothelioma in the MS01 trial: 409 enrolled at 76 UK centers and two Australian centers between September 17, 2001 and July 31, 2006. Stored tumor samples were available for 89 of them, and 60 were analyzed.
• Exposure: Asbestos exposure was not studied. The factors examined were tumor nuclear BAP1 protein expression, measured by immunohistochemistry, and trial treatment arm: active symptom control (ASC) alone, ASC plus mitomycin, vinblastine and cisplatin (MVP), or ASC plus single-agent vinorelbine.
• Main results:
  • Of 89 available samples from the 409 trial patients, 60 had a positive internal control and were analyzed.
  • Of the 60 analyzed patients, 13 had tumors with nuclear BAP1 expression (BAP1 positive) and 47 had tumors without nuclear BAP1 expression (BAP1 negative).
  • Among the 60 patients, there was no significant difference in gender, age or histological subtype between BAP1-positive and BAP1-negative tumors.
  • For patients with BAP1-positive tumors and for patients with BAP1-negative tumors, overall survival did not differ significantly between any of the treatment arms.
  • Within the ASC arm and within the ASC plus MVP arm, overall survival did not differ significantly between patients with BAP1-positive and BAP1-negative tumors. In the ASC arm, median survival was 10.4 months (n = 4) for BAP1 positive versus 11.6 months (n = 19) for BAP1 negative (p = 0.29). In the ASC plus MVP arm, it was 6.7 months (n = 5) versus 8.3 months (n = 16) (p = 0.55).
  • In the ASC plus vinorelbine arm, median overall survival was 5.5 months for 4 patients with BAP1-positive tumors and 11.5 months for 12 patients with BAP1-negative tumors.
  • In the ASC plus vinorelbine arm, there was a non-significant trend toward shorter overall survival for patients with BAP1-positive tumors compared with BAP1-negative tumors (p = 0.06; hazard ratio 4.87, 95% CI 0.94 to 25.16).
• The authors' conclusion: The authors concluded that this exploratory study suggests BAP1 expression does not modify response to MVP chemotherapy but may modify response to vinorelbine. They encouraged ongoing and planned vinorelbine studies in malignant pleural mesothelioma to assess BAP1 as a predictor of response.
• Limitations the authors state:
  • The sample size was not powered for the subgroup analyses, and the results are exploratory only.
  • Tumor samples had been stored since 2003-4. The authors tried to limit confounding from sample degradation by including only samples with a positive internal control.
  • The limited sample size prevented statistical significance for the survival difference seen with vinorelbine.

Topics

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

Medical terms in this study, explained in our Lexicon: BAP1, Chemotherapy, Mesothelioma, Biomarker, Overall Survival, Cisplatin, Vinorelbine, Histological Subtype.

Related studies

• Loss of BAP1 Expression in Atypical Mesothelial Proliferations Helps to Predict Malignant Mesothelioma — R. Pillappa, J.J. Maleszewski, et al. (2018)
• Loss of expression of BAP1 predicts longer survival in mesothelioma — M. Farzin, C.W. Toon, et al. (2015)
• The epithelioid BAP1-negative and p16-positive phenotype predicts prolonged survival in pleural mesothelioma — A. Chou, C.W. Toon, et al. (2018)
• BAP1 loss is unusual in well-differentiated papillary mesothelioma and may predict development of malignant mesothelioma — H.E. Lee, J.R. Molina, et al. (2018)
• Loss of BRCA1-associated protein 1 (BAP1) expression is rare in non-small cell lung cancer — D. Owen, B.S. Sheffield, et al. (2017)
• Loss of expression of BAP1 is a useful adjunct, which strongly supports the diagnosis of mesothelioma in effusion cytology — J. Andrici, A. Sheen, et al. (2015)

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