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

Neelam Kumar, Doraid Alrifai, Krishna K. Kolluri, Elizabeth K Sage, Yuki Ishii, Naomi Guppy, Elaine Borg, Mary Falzon, Matthew Nankivell, Andrew G. Nicholson, Sam M. Janes (Corresponding Author)

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)164-166
Number of pages3
JournalLung Cancer
Volume127
Early online date5 Dec 2018
DOIs
Publication statusPublished - Jan 2019

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BRCA1 Protein
Mesothelioma
Drug Therapy
Nuclear Proteins
Neoplasms
Survival
Biomarkers
Vinblastine
Kaplan-Meier Estimate
Mitomycin
Survival Analysis
Microtubules
Cisplatin
Therapeutics
Retrospective Studies

Keywords

  • BRCA-1 associated protein 1
  • Biomarker
  • Mesothelioma
  • Vinorelbine

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Retrospective response analysis of BAP1 expression to predict the clinical activity of systemic cytotoxic chemotherapy in mesothelioma. / Kumar, Neelam; Alrifai, Doraid; Kolluri, Krishna K.; Sage, Elizabeth K; Ishii, Yuki; Guppy, Naomi; Borg, Elaine; Falzon, Mary; Nankivell, Matthew; Nicholson, Andrew G.; Janes, Sam M. (Corresponding Author).

In: Lung Cancer, Vol. 127, 01.2019, p. 164-166.

Research output: Contribution to journalArticle

Kumar, N, Alrifai, D, Kolluri, KK, Sage, EK, Ishii, Y, Guppy, N, Borg, E, Falzon, M, Nankivell, M, Nicholson, AG & Janes, SM 2019, 'Retrospective response analysis of BAP1 expression to predict the clinical activity of systemic cytotoxic chemotherapy in mesothelioma', Lung Cancer, vol. 127, pp. 164-166. https://doi.org/10.1016/j.lungcan.2018.12.004
Kumar, Neelam ; Alrifai, Doraid ; Kolluri, Krishna K. ; Sage, Elizabeth K ; Ishii, Yuki ; Guppy, Naomi ; Borg, Elaine ; Falzon, Mary ; Nankivell, Matthew ; Nicholson, Andrew G. ; Janes, Sam M. / Retrospective response analysis of BAP1 expression to predict the clinical activity of systemic cytotoxic chemotherapy in mesothelioma. In: Lung Cancer. 2019 ; Vol. 127. pp. 164-166.
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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.",
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T1 - Retrospective response analysis of BAP1 expression to predict the clinical activity of systemic cytotoxic chemotherapy in mesothelioma

AU - Kumar, Neelam

AU - Alrifai, Doraid

AU - Kolluri, Krishna K.

AU - Sage, Elizabeth K

AU - Ishii, Yuki

AU - Guppy, Naomi

AU - Borg, Elaine

AU - Falzon, Mary

AU - Nankivell, Matthew

AU - Nicholson, Andrew G.

AU - Janes, Sam M.

N1 - Acknowledgements We would like to thank the Medical Research Council for providing us with data collected as part of the MS01 trial.

PY - 2019/1

Y1 - 2019/1

N2 - 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.

AB - 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.

KW - BRCA-1 associated protein 1

KW - Biomarker

KW - Mesothelioma

KW - Vinorelbine

UR - http://www.mendeley.com/research/retrospective-response-analysis-bap1-expression-predict-clinical-activity-systemic-cytotoxic-chemoth

U2 - 10.1016/j.lungcan.2018.12.004

DO - 10.1016/j.lungcan.2018.12.004

M3 - Article

C2 - 30642545

VL - 127

SP - 164

EP - 166

JO - Lung Cancer

JF - Lung Cancer

SN - 0169-5002

ER -