Triple-negative breast cancer (TNBC) is a scary diagnosis, and many patients become resistant to treatment. Results from a study led by Nicholas Navin, PhD, Associate Professor of Genetics at The University of Texas MD Anderson, Houston, indicate breast cancer cell resistance to chemotherapy may be pre-existing and the cells may even adapt to become resistant when confronted by the chemotherapy itself (Cell 2018; https://doi.org/10.1016/j.cell.2018.03.041).
Cancer often begins with a clone—a single mutated cell that either can be destroyed by the immune system, or mutated further as subclones, genetic aberrations resulting in an ever-evolving cellular pathway to cancer.
“Our data showed that resistant genotypes, or genes prone to being cancer-resistant, were pre-existing and adaptively selected by the initial treatment known as neoadjuvant chemotherapy, but also require further changes in gene expression programs to become fully resistant,” Navin noted.
Neoadjuvant chemotherapy (NAC) is the standard of care for many TNBC patients, who lack estrogen and progesterone receptors as well as HER2 receptor, making them ineligible for hormone or anti-HER2 therapy. While NAC is effective in some TNBC patients, approximately half will develop chemotherapy resistance.
“A major gap in knowledge is whether chemoresistance arises due to the selection and expansion of pre-existing subclones, called adaptive resistance, or through new mutations resulting from the chemotherapy, a phenomenon known as acquired resistance,” noted Navin. “Previous genomic studies in other cancers have shown either adaptive or acquired resistance in different cancer types.”
Navin's group studied 20 TNBC patients treated with NAC, looking at genetic changes by deeply sequencing the coding regions of genes across the genome. They sought to understand whether new genetic mutations occurring after chemotherapy erupted spontaneously due to acquired resistance, or whether the mutations already existed at very low levels prior to treatment.
“What we found were two distinct classes of clonal dynamics—extinction and persistence,” said Navin. “In the clonal extinction patients, NAC eliminated the tumor cells, leaving only normal cell types post-treatment. Clonal persistent patients harbored a larger number of residual tumor cells with genotypes and phenotypes that were altered in response to NAC.”
Using single-cell DNA and RNA sequencing, his team performed a detailed analysis of eight clonal persistent patients, measuring miniscule portions of DNA and RNA and found responses to NAC were pre-existing, thus adaptively selected. However, the expression of resistant genes was acquired by subsequent reprogramming as a result of chemotherapy.
Navin's group believes pre-existence of chemoresistant genotypes in tumors indicates there may be diagnostic opportunities for detecting chemoresistant clones in TNBC patients prior to receiving NAC. Their findings that TNBC patients fall into clonal extinction or clonal persistent groups may be applicable to patient outcomes or survival.
“Lastly, our data raise the possibility of therapeutic strategies to overcome chemoresistance by targeting pathways identified in this study,” said Navin.