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

Abstract

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.

Acquired resistance to PRMT5 inhibition induces concomitant collateral sensitivity to paclitaxel

“…Importantly, the TCGA data were not limited to LUAD but instead included all tumor types that received taxane treatment and reported outcomes, such that breast cancer was the majority tumor type. Taxanes are primarily used in the treatment of breast cancer, NSCLC, and prostate cancer, which together make up an estimated 30 to 40% of new cancer cases in the United States (48). Our findings raise the possibility that STMN2 levels might serve as a predictive biomarker for either taxane response or cotreatment with PRMT5i and taxanes, upon Food and Drug Administration approval, and certainly provide clear rationale for investigating STMN2's role in cancer.…”

Predictive markers based on transcriptome modules for vinorelbine-based adjuvant chemotherapy for lung adenocarcinoma patients

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