TY - JOUR
T1 - Comprehensive characterization of pre- and post-treatment samples of breast cancer reveal potential mechanisms of chemotherapy resistance
AU - Hoogstraat, Marlous
AU - Lips, Esther H.
AU - Mayayo-Peralta, Isabel
AU - Mulder, Lennart
AU - Kristel, Petra
AU - van der Heijden, Ingrid
AU - Annunziato, Stefano
AU - van Seijen, Maartje
AU - Nederlof, Petra M.
AU - Sonke, Gabe S.
AU - Zwart, Wilbert
AU - Wesseling, Jelle
AU - Wessels, Lodewyk F. A.
N1 - Funding Information:
We would like to thank the NKI Genomics Core Facility, the NKI Core Facility Molecular Pathology & Biobanking and the NKI High Performance Computing Facility for facilitating and supporting this work. We also want to thank Sjoerd Rodenhuis, Stef van Lieshout, and Peter Bouwman for advice. This research was supported by a Dutch Cancer Society grant (2014-6007).
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12/1
Y1 - 2022/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85129647741&partnerID=8YFLogxK
U2 - 10.1038/s41523-022-00428-8
DO - 10.1038/s41523-022-00428-8
M3 - Article
C2 - 35523804
SN - 2374-4677
VL - 8
JO - npj Breast Cancer
JF - npj Breast Cancer
IS - 1
M1 - 60
ER -