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Study Examines Mechanisms of Resistance in Early-Stage Breast Cancer After Endocrine Plus CDK4/6 Therapy


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About 80% of breast cancer cases are hormone receptor–positive, according to the American Cancer Society. Patients with estrogen receptor–positive breast cancer generally are treated using therapy that inhibits both estrogen levels and cell-cycle activity, but about 90% of patients with metastatic disease and 50% of patients with stage II and III breast cancer eventually develop resistance. In a recent study published in Nature Cancer, researchers have identified how cancer cells in patients with early-stage breast cancer change and become resistant to hormone or combination therapies.

A research team led by Andrea Bild, PhD, Professor in the Department of Medical Oncology & Therapeutics Research at City of Hope, used single-cell RNA sequencing to identify resistant traits cancer cells acquire. The team also identified when these resistant traits are acquired and found them as early as 2 weeks after the start of a treatment regimen, which is months faster than current methods used to measure treatment response.

“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,” Dr. Bild said. “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.”

Study Details

Dr. Bild and colleagues studied the evolution of the DNA and RNA in breast tumor cells of postmenopausal women with estrogen receptor–positive breast cancer who were enrolled in the FELINE trial. These patients were treated with endocrine therapy (letrozole) alone and in combination with the cyclin-dependent kinase (CDK) inhibitor ribociclib. Patients were treated with targeted therapy in a neoadjuvant setting to assess response. Biopsies from more than 40 patients’ tumors were processed and analyzed from cells taken prior to, 2 weeks after, and 6 months from the start of endocrine and combination treatments.

The researchers found that resistant cells that persist even after endocrine and cell-cycle (CDK4/6) inhibition therapy tend to shift their growth engine from using estrogen signaling to using alternative growth factor receptors and to rewiring cell-cycle pathways. For example, resistant cells bypass the blocked pathways by turning on alternative signaling pathways such as growth receptors and MAPK signaling; this rewiring enables cancer cells to continue growing despite the estrogen and cell-cycle drug inhibitors. Targeting these acquired resistance pathways with appropriate therapies may help physicians in the future treat patients with resistant estrogen receptor–positive early-stage breast cancer.

Clinical Implications

“The study is impressive in its scope, presenting comprehensive genomic profiling of the longitudinal samples from multiple patients,” said Suwon Kim, PhD, who was not involved in the research and is Associate Professor at the Translational Genomics Research Institute, an affiliate of City of Hope, and a faculty member of the University of Arizona College of Medicine. “The results are significant, revealing the emergence of the alternate specific pathways in single tumor cells as they become resistant to CDK inhibitors and endocrine therapy. The study findings offer opportunities for evidence-guided therapeutic intervention for therapy-resistant breast cancer.”

Understanding how tumor cells quickly change and rewire signaling pathways so they can persist after combination neoadjuvant cancer treatment will enable scientists to design novel treatment regimens that target tumor resistance. Dr. Bild and her colleagues are now identifying drugs that block the traits found specifically in resistant cancer cells.

“Early-stage estrogen receptor–positive and 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,” Dr. Bild said. “I recommend that, when possible, clinicians continue to collect tumor biopsies, so we can measure cancer cell responses during treatment to understand how patients' 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.”

Dr. Bild is the corresponding author of the Nature Cancer article.

Disclosure: For full disclosures of the study authors, visit www.nature.com.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
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