Changes in Expression of Genes Representing Key Biologic Processes after Neoadjuvant Chemotherapy in Breast Cancer, and Prognostic Implications in Residual Disease

Abstract

Purpose: The primary aim was to derive evidence for or against the clinical importance of several biologic processes in patients treated with neoadjuvant chemotherapy (NAC) by assessing expression of selected genes with prior implications in prognosis or treatment resistance. The secondary aim was to determine the prognostic impact in residual disease of the genes' expression. Experimental Design: Expression levels of 24 genes were quantified by NanoString nCounter on formalin-fixed paraffin-embedded residual tumors from 126 patients treated with NAC and 56 paired presurgical biopsies. The paired t test was used for testing changes in gene expression, and Cox regression and penalized elastic-net Cox Regression for estimating HRs. Results: After NAC, 12 genes were significantly up- and 8 downregulated. Fourteen genes were significantly associated with time to recurrence in univariable analysis in residual disease. In a multivariable model, ACACB, CD3D, MKI67, and TOP2A added prognostic value independent of clinical ER−, PgR−, and HER2− status. In ER+/HER2− patients, ACACB, PAWR, and ERBB2 predicted outcome, whereas CD3D and PAWR were prognostic in ER−/HER2− patients. By use of elastic-net analysis, a 6-gene signature (ACACB, CD3D, DECORIN, ESR1, MKI67, PLAU) was identified adding prognostic value independent of ER, PgR, and HER2. Conclusions: Most of the tested genes were significantly enriched or depleted in response to NAC. Expression levels of genes representing proliferation, stromal activation, metabolism, apoptosis, stemcellness, immunologic response, and Ras–ERK activation predicted outcome in residual disease. The multivariable gene models identified could, if validated, be used to identify patients needing additional post-neoadjuvant treatment to improve prognosis. Clin Cancer Res; 22(10); 2405–16. ©2016 AACR.

Competing endogenous RNA network analysis identifies critical genes among the different breast cancer subtypes

“…For example, DCN (decorin) regulates PGR by competing for miR-19b-1-5p and promotes the basal-like subtype (Pearson correlation coefficient =0.54). This supports previous findings that DCN is down-regulated and influences the breast cancer cell motility and invasion, and acts as one of the six-gene signature that adds prognostic value independent of the expression of ER, PR, and HER2 [51, 52]. Therefore, subtype specific expression of 50-gene in PAM50 model can be regulated by other ceRNAs that may influence breast cancer subtype specificity.…”

High levels of serum CA15‐3 and residual invasive tumor size are associated with poor prognosis for breast cancer patients with non‐pathological complete response after neoadjuvant chemotherapy

“…However, the consistently significant associations between LC3B and prognosis were restricted to the luminal B and triple‐negative subtypes. Klintman et al identified 14 genes which were significantly associated with time to recurrence in residual disease after NAC. Of these genes, the 6‐gene signature consisting of genes representing proliferation, metabolism, stromal response, immunologic response and estrogen signaling had additional prognostic significance independent of ER and HER2 status.…”

Chemoresistance and targeted therapies in ovarian and endometrial cancers

“…Par-4 mRNA was upregulated following chemotherapy and Par-4 had a significant impact on prognostic, dependent of the ER status. Indeed, Par-4 level was predictive of a good outcome in ER- patients and the opposite was observed in ER+ patients indicating an important role for hormones and Par-4 [312]. As introduced, few studies demonstrated that estrogen can downregulate Par-4 [177, 178].…”