A study led by researchers from City of Hope National Medical Center and the University of Kansas shows how treatment resistance develops in patients with estrogen receptor-positive breast cancer.
In an in-depth study using single-cell RNA sequencing, published in Nature Cancer, the scientists found that the cancer cells that became resistant had switched from estrogen-signaling to alternative methods of proliferation allowing them to resist destruction by the targeted therapy.
“If health care providers are able to identify the development of tumor resistance earlier, then they can quickly switch gears and offer a different treatment regimen that could eventually bring the breast cancer patient into remission rather than continuing on a path that may fail to achieve a positive outcome,” said Andrea Bild, a professor in City of Hope’s Department of Medical Oncology & Therapeutics Research, in a press statement.
“With the current available set of precision medicine tools, medical professionals could measure patient response to treatment earlier to offer treatment options that are more likely to work for each individual patient.”
The vast majority (70-80%) of breast cancers are either estrogen- or progesterone-receptor positive. In patients with estrogen-receptor positive cancer, estrogen activates the receptors and in so doing promotes tumor growth.
Although targeted therapies that block release or activity of estrogen are available to treat estrogen-receptor positive breast cancer, many women (50-90% depending on cancer stage) eventually become resistant to the therapy.
In this study, the researchers studied cell samples taken from post-menopausal women with estrogen-receptor positive breast cancer who underwent treatment with endocrine therapy and/or cyclin-dependent kinase inhibitor therapy, a treatment that stops cancer cells from growing.
The women had six cycles of treatment and had tumor samples taken at the beginning of the trial, at 14 days after first treatment and at the end of their treatment (aprx 180 days after treatment began).
Using single cell RNA sequencing methods to analyze the biopsy samples (taken from 40 women in total), the research team found that resistance occurred widely regardless of treatment type and sometimes as early as 14 days after treatment began.
They found that the resistant tumor cells had managed to alter their internal processes and switch to a non-estrogen dependent pathway of cell proliferation such as via growth receptor and MAPK signaling. This allowed the tumor cells to avoid being targeted by either the endocrine therapy or the cyclin-dependent kinase inhibitor therapy.
The researchers think that understanding more about this process could lead to more effective therapies that are less prone to resistance, or to better therapy combinations to target resistance.
“Early-stage ER+ and PR+ (progesterone receptor positive) breast cancer is often curable, and we need to continue down this line of research to design therapy strategies that provide a positive patient outcome that lasts,” commented Bild.
“I recommend that, when possible, clinicians continue to collect tumor biopsies so we can measure cancer cell responses during treatment to understand how the patient’s tumors are responding. In addition, we need to look at RNA changes and not just DNA modifications, as these changes may more broadly capture resistance mechanisms.”