Molecular prediction of adjuvant cisplatin efficacy in Non-Small Cell Lung Cancer (NSCLC)—validation in two independent cohorts

Buhl, Ida Kappel; Santoni-Rugiu, Eric; Ravn, Jesper; Hansen, Anker; Christensen, Ib Jarle; Jensen, Thomas E.; Pratt, Bruce M.; Askaa, Jon; Jensen, Peter Buhl; Knudsen, Steen; Sørensen, Jens Benn

doi:10.1371/journal.pone.0194609

Cited by 12 publications

(13 citation statements)

References 48 publications

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“…A similar DRP for fulvestrant has been shown to predict benefit of fulvestrant in the DBCG cohort and retrospectively in a neoadjuvant trial with fulvestrant (32,47). As the DRP system has previously been found to be predictive in settings with multiple drugs (48,49), this system could then potentially point to which antihormonal treatment would be preferable: fulvestrant or AIs in the first line setting of combinations with CDK4/6 inhibitors.…”

Section: Discussionmentioning

confidence: 82%

Evaluation of drug-specific multigene markers to predict aromatase inhibitor efficacy in advanced breast cancer: a cohort study from Danish Breast Cancer Cooperative Group

Buhl¹,

Christensen

Buhl³

et al. 2019

Preprint

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Background Even with positive oestrogen receptor (ER+) status some advanced breast cancer (ABC) patients fail to benefit from endocrine therapy (ET). A method that previously predicted other drugs in various cancers was evaluated. Here multigene markers based on aromatase inhibitor (AI) effect in vitro were used for prediction of AI benefit in ER+ ABC patients. Simultaneously effects of long-term ET on predictive efficacy was evaluated. Methods The Drug Response Predictors (DRPs) are based on correlations between baseline gene expression and growth inhibition patterns of exemestane, anastrozole and letrozole, respectively, in the National Cancer Institute 60 cell lines. The genes were controlled for expression in 3,500 tumours. In a Danish Breast Cancer Cooperative Group cohort of 695 ABC patients with complete gene expression and time-to-progression (TTP) data, 414 received an AI as monotherapy. Hereof, 57 received anastrozole, 166 received exemestane, and 327 received letrozole. mRNA was isolated from archival formalin-fixed paraffin embedded tumour tissue and run on microarray and 60% of the tumours were from time of primary diagnosis. Medical records of the patients were assessed for TTP for all treatments given for ABC. Results The DRPs were tested in subsets 1) with no adjuvant ET and 2) with adjuvant ET. In 1) the anastrozole DRP predicted benefit of anastrozole (hazard ratio (HR) was 0.21 upper 95%-confidence interval limit (CI) 0.76, p=0.023) but not in 2). Dichotomised by a DRP of 50, the anastrozole DRP did predict benefit (HR=0.16, upper 95%-CI 0.75, p=0.026). Only in 1) the exemestane DRP predicted benefit of exemestane (HR=0.57, upper 95%-CI 1.00, p=0.0497). The letrozole DRP had no predictive value. Additionally, we tested each DRPs ability to predict other AIs. Only the anastrozole DRP predicted benefit of overall AI treatment, in 1)with an HR of 0.76 (upper 95%-CI 0.99, p=0.044) and in 2) with an HR of 0.71 (upper 95%-CI 0.92, p=0.015). The anastrozole DRP did though not predict benefit of letrozole. All tests are one-sided, alpha=5%. Conclusions Among the DRPs for AIs, the anastrozole DRP was strongest with clinically relevant prediction of TTP in AI treated ER+ ABC patients. Trial registration: ClinicalTrials.gov NCT01861496. BackgroundApproximately 70% of women with advanced breast cancer (ABC) have oestrogen-receptor positive

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Section: Discussionmentioning

confidence: 82%

Evaluation of drug-specific multigene markers to predict aromatase inhibitor efficacy in advanced breast cancer: a cohort study from Danish Breast Cancer Cooperative Group

Buhl¹,

Christensen

Buhl³

et al. 2019

Preprint

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“…Tumour biomarker analysis A novel, tumour-agnostic, molecular biomarker, 2X-121 DRP, was developed to identify responders and non-responders using 61 cell lines as previously described. 21,22 In these tumour cell lines, 414 genes were found to predict response to E7449: 172 genes were found to be positively correlated with sensitivity to E7449, and 242 genes were negatively correlated. Among these 414 genes predictive of the response to E7449, 111 were found to be associated in the literature with DNA damage response or Wnt/βcatenin pathways (Supplementary Table 2).…”

Section: Serum Biomarker Analysismentioning

confidence: 94%

“…Matching baseline transcriptome and growth inhibition data were available for 61 of the 74 cell lines, and were used to develop a DRP as previously described. 21 , 22 Briefly, IC 50 values in the 61 cell lines were correlated to gene-expression levels in the same cell lines; 172 genes with a Pearson correlation above 0.25 were retained as potential markers of sensitivity, while 242 genes with a Pearson correlation below −0.25 were retained as potential markers of resistance. The 414 genes were searched in PubMed for known associations to DNA damage response or Wnt/β-catenin pathways.…”

Section: Methodsmentioning

confidence: 99%

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First-in-human study of the PARP/tankyrase inhibitor E7449 in patients with advanced solid tumours and evaluation of a novel drug-response predictor

et al. 2020

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BACKGROUND: This phase 1 study examined the safety, maximum-tolerated dose (MTD) and antitumour activity of E7449, a novel PARP 1/2 and tankyrase 1/2 inhibitor. METHODS: E7449 was orally administered once daily in 28-day cycles to patients with advanced solid tumours (50-800-mg doses). Archival tumour samples from consenting patients were evaluated for the expression of 414 genes in a biomarker panel (2X-121 drug-response predictor [DRP]) found to be predictive of the response to E7449 in cell lines. RESULTS: Forty-one patients were enrolled (13 pancreatic, 5 ovarian, 4 each with breast, lung or colorectal cancer and 11 with other tumour types). The most common grade ≥3 treatment-related adverse event was fatigue (n = 7, 17.1%). Five patients experienced a dose-limiting toxicity (fatigue, n = 4, 800 mg; anaphylaxis, n = 1, 600 mg) for an MTD of 600 mg. E7449 exhibited antitumour activity in solid tumours, including 2 partial responses (PRs), and stable disease (SD) in 13 patients, which was durable (>23 weeks) for 8 patients. In 13 patients, the 2X-121 DRP identified those achieving PR and durable SD. E7449 showed good tolerability, promising antitumour activity and significant concentration-dependent PARP inhibition following 50-800-mg oral dosing. CONCLUSION: The results support further clinical investigation of E7449 and its associated biomarker 2X-121 DRP. CLINICAL TRIAL REGISTRATION: www.ClinicalTrials.gov code: NCT01618136.

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“…Panels that consist of several biomarkers may prove more informative and reflect the complex heterogeneity of tumours. Recently, several gene expression panels have been published that are both prognostic and predictive of benefit from adjuvant chemotherapy in patients with NSCLC 13–19. Of these panels, only four13 15 16 18 were derived from genome-wide mRNA expression profiling (GEP).…”

Section: Introductionmentioning

confidence: 99%

Immunohistochemical validation study of 15-gene biomarker panel predictive of benefit from adjuvant chemotherapy in resected non-small-cell lung cancer: analysis of JBR.10

Grieve

Ding²,

Moore

et al. 2020

ESMO Open

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ObjectiveThere are no validated approaches to predict benefit from adjuvant chemotherapy for resected patients with non-small-cell lung cancer (NSCLC). The aim of this study was to translate a 15-gene mRNA expression profile published by Zhu et al, shown to be prognostic and predictive of benefit, into a readily applicable immunohistochemistry (IHC) panel.MethodsFor seven of the genes in the gene expression profile (GEP) for which suitable commercial antibodies were available, we semiquantitatively assessed the IHC expression and prognostic significance for 173 patients treated at the Saint John Regional Hospital (SJRH). Cut-offs for high and low expression were defined for each marker and applied to IHC scores from 291 of the 482 patients in JBR.10, including patients on both the adjuvant chemotherapy and observation arms. The prognostic and predictive value of these markers on overall survival (OS) or recurrence-free survival (RFS) was assessed by Cox regression models.ResultsIn the SJRH cohort, in 62 patients with resected stage II–III NSCLC, the prognostic significance of IHC assays for four proteins were concordant with Zhu’s GEP results. Low FOSL2 (OS, HR=0.15; p=0.0001; RFS, HR=0.14; p<0.0001) and high STMN2 (RFS, HR=2.501; p=0.0197) were adverse prognostic factors. Low ATP1B1 and low TRIM14 expression trended toward worse OS and RFS. Validation of these markers with JBR.10 patients failed to show prognostic significance either individually or in combined risk classifications. Additionally, the interaction between these markers and chemotherapy treatment in predicting OS (FOSL2, p=0.52; STMN2 p=0.14; ATP1B1, p=0.33; TRIM14, p=0.81) or RFS (FOSL2, p=0.63; STMN2, p=0.12; ATP1B1, p=0.66; TRIM14, p=0.57) did not reach significance, individually or in combination panels.ConclusionsZhu’s GEP could not be translated into an IHC panel predictive of benefit from adjuvant chemotherapy. Future predictive biomarker analysis in the adjuvant NSCLC setting may need to focus on novel therapies.

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Molecular prediction of adjuvant cisplatin efficacy in Non-Small Cell Lung Cancer (NSCLC)—validation in two independent cohorts

Cited by 12 publications

References 48 publications

Evaluation of drug-specific multigene markers to predict aromatase inhibitor efficacy in advanced breast cancer: a cohort study from Danish Breast Cancer Cooperative Group

Evaluation of drug-specific multigene markers to predict aromatase inhibitor efficacy in advanced breast cancer: a cohort study from Danish Breast Cancer Cooperative Group

First-in-human study of the PARP/tankyrase inhibitor E7449 in patients with advanced solid tumours and evaluation of a novel drug-response predictor

Immunohistochemical validation study of 15-gene biomarker panel predictive of benefit from adjuvant chemotherapy in resected non-small-cell lung cancer: analysis of JBR.10

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