Comprehensive characterization of pre- and post-treatment samples of breast cancer reveal potential mechanisms of chemotherapy resistance

Abstract

When locally advanced breast cancer is treated with neoadjuvant chemotherapy, the recurrence risk is significantly higher if no complete pathologic response is achieved. Identification of the underlying resistance mechanisms is essential to select treatments with maximal efficacy and minimal toxicity. Here we employed gene expression profiles derived from 317 HER2-negative treatment-naïve breast cancer biopsies of patients who underwent neoadjuvant chemotherapy, deep whole exome, and RNA-sequencing profiles of 22 matched pre- and post-treatment tumors, and treatment outcome data to identify biomarkers of response and resistance mechanisms. Molecular profiling of treatment-naïve breast cancer samples revealed that expression levels of proliferation, immune response, and extracellular matrix (ECM) organization combined predict response to chemotherapy. Triple negative patients with high proliferation, high immune response and low ECM expression had a significantly better treatment response and survival benefit (HR 0.29, 95% CI 0.10–0.85; p = 0.02), while in ER+ patients the opposite was seen (HR 4.73, 95% CI 1.51–14.8; p = 0.008). The characterization of paired pre-and post-treatment samples revealed that aberrations of known cancer genes were either only present in the pre-treatment sample (CDKN1B) or in the post-treatment sample (TP53, APC, CTNNB1). Proliferation-associated genes were frequently down-regulated in post-treatment ER+ tumors, but not in triple negative tumors. Genes involved in ECM were upregulated in the majority of post-chemotherapy samples. Genomic and transcriptomic differences between pre- and post-chemotherapy samples are common and may reveal potential mechanisms of therapy resistance. Our results show a wide range of distinct, but related mechanisms, with a prominent role for proliferation- and ECM-related genes.

Immune landscape of breast tumors with low and intermediate estrogen receptor expression

“…2a, i ). Using pre-treatment gene expression data from an independent validation cohort of stage I-III breast cancer patients treated with neo-adjuvant chemotherapy 41 , we also observed higher levels of the CD8 + T-cell signature and IFN-γ signature in breast tumors with 0%, 1–9% and 10–50% ER expression, as compared to tumors with ER expression >50% (Supplementary Fig. 4A–D ).…”

“…Gene expression data and clinical characteristics of the validation cohort were obtained directly from the primary investigators 41 . Briefly, microarray experiments (GEO accession number GSE34138) or RNA-sequencing (GEO accession number GSE192341) were performed on pre-treatment biopsies from patients with stage I-III HER2-negative breast cancer in the Netherlands Cancer Institute, treated with neo-adjuvant chemotherapy.…”

“…Briefly, microarray experiments (GEO accession number GSE34138) or RNA-sequencing (GEO accession number GSE192341) were performed on pre-treatment biopsies from patients with stage I-III HER2-negative breast cancer in the Netherlands Cancer Institute, treated with neo-adjuvant chemotherapy. Data from these experiments were pooled and normalized as previously described 41 . There was no overlap between samples of this independent validation cohort and the main cohort studied in this manuscript.…”

Transcriptome Meta-Analysis of Triple-Negative Breast Cancer Response to Neoadjuvant Chemotherapy

“…In breast cancer, CCND1 is frequently overexpressed due to gene amplification or other mechanisms, and its overexpression has been associated with the development and progression of the disease [ 53 , 54 , 55 , 56 ]. CCND1 is associated with luminal breast cancers and amplifications have been found in chemoresistant post-treatment ER+ tumors [ 57 ].…”

Web-Based Dynamic Nomograms for Predicting Overall Survival and Cancer-Specific Survival in Breast Cancer Patients with Lung Metastases

“…The ER pathway can be used as a bypass activation mechanism for downstream signals of the HER2 pathway [ 21 ]. Activating the HER2 signaling pathways could further promote the activity of the ER pathway, leading to impaired endocrine therapy response and possibly changing the tumor’s response to HER2-targeted therapy [ 22 ]. Some neoadjuvant clinical studies targeting anti-HER2 have shown that, compared with HER2+/ER- patients, HER2+/ER+ patients have a lower pathological complete response rate (pCR) [ 23 ].…”