Written by Victoria Lee, Science Writer at Front Line Genomics
In the fight against breast cancer, it’s useful to be able to prepare for the next move and see as far ahead as possible. Chemotherapy-resistant and recurring breast cancer cells are a challenge to clinicians and patients, but hope exists in new research into mechanisms of, and biomarkers for, chemotherapy resistance.
Researchers in the Netherlands have identified new biomarkers and mechanisms of chemotherapy resistance in breast cancer cells. In a study published recently in NPJ Breast Cancer, Marlous Hoogstraat and colleagues have reported findings that (in both triple-negative (TN) and oestrogen receptor-positive (ER+) breast cancer tumours, as well as matched pre- and post-treatment tumour cells) proliferation rate, immune response, and extracellular matrix (ECM) organisation jointly predicted the response to neoadjuvant chemotherapy (NAC), with implications for prognosis and treatment planning.
Chemotherapy resistance and recurrence risk in breast cancer
Chemotherapy is the standard of care for breast cancers with high recurrence risk. Neoadjuvant treatment can improve tissue conservation and downsize the tumour and allows for the in vivo assessment of tumour response to treatment, and thereby a more accurate prognosis and targeting of adjuvant therapy.
Pathological complete response (pCR) to chemotherapy is prognostically positive, while partial or non-response often results in recurrences of tumours. A partial pathological response to chemotherapy could indicate that part of the tumour is resistant to treatment, or a resistance mechanism has occurred as a cellular stress response.
Post-treatment proliferation of tumour cells is prognostic of the treatment outcome, as is immune system activation. Most tumours show at least partial non-response to chemotherapy, and the extent of this non-responsiveness is predictive of recurrence-free survival. Studies comparing pre- and post-treatment tumour samples have revealed resistance mechanisms to targeted cancer drugs, but this has not been replicated to a large extent for different chemotherapy regimens.
Biomarkers for pathological response and identification of the mechanisms of resistance to chemotherapy in breast cancer cells are thus extremely valuable to the treatment of non-HER+ breast cancer.
Searching for markers of chemotherapy resistance
Hoogstraat and colleagues performed RNA sequencing on 317 pre-NAC tumour biopsy samples, as well as deep DNA and RNA characterisation of 22 matched pre- and post- treatment chemotherapy-resistant TN and ER+ tumours. They also used the quantitative Neoadjuvant Response Index (NRI) as the primary outcome. The use of both sample sets allowed the researchers to study both pre-treatment factors and resistance mechanisms, and validate them over two datasets.
Proliferation rate, immune response, and extracellular matrix (ECM) organisation co-predicted response to NAC in both TN and ER+ tumour samples in the pre-NAC biopsies. The decrease in proliferation and enrichment in stem-cell related signatures in the post-treatment samples was most prominent in ER+ tumours.
Perhaps surprisingly, decreased proliferation rates following chemotherapy did not predict improved survival rates in patients with ER+ tumours. ER+ tumours mostly had a mild to strong decrease in proliferation following chemotherapy. While the prognostic factor of low tumour cell proliferation following treatment could not be validated in this study, Hoogstraat et al. hypothesise that some highly proliferative ER+ cells may enter a dormant or senescent state under the stress of chemotherapy, only to re-enter the cell cycle after treatment completion. This behaviour may confer increased drug resistance and be indicative of a poor prognosis, but this will need further studies to investigate.
Proliferation predicts chemotherapy response
High proliferation levels in TN samples in this study were associated with an increased chance of a positive response to chemotherapy. The authors also found associations between chemotherapy response and genes related to immune response and ECM organisation. Whole exome sequencing data revealed associations between established cancer genes and chemotherapy response. CCND1 overexpression was associated with chemotherapy resistance in both ER+ and TN breast tumours, with significant enrichment of CCND1-amplified tumours in chemotherapy-resistant samples and overexpression of the gene in tumours that did not achieve a pCR in the validation cohort. CCND1 amplification is present in a high proportion of ER+ cases and is associated with poor prognosis.
Finding the underlying mechanisms for chemotherapy resistance in locally-advanced breast cancer is an undeniably valuable tool in selecting treatments that maximise efficacy while minimising toxicity for patients. Hoogstraat’s study, comparing pre- and post-treatment samples, has identified a range of distinct mechanisms and a prominent role in proliferation-related genes, particularly CCND1.
