Findings point to features of therapeutic response and potential biomarkers

  • Clinical trial assesses molecular determinants of response to CDK4/6 inhibitor
  • Changes in cell cycle, estrogen receptor signaling occurred during treatment
  • Hormonal signaling, tumor proliferation noted as potential biomarkers of response

BUFFALO, N.Y. — Initial results from an in-progress Roswell Park Comprehensive Cancer Center clinical trial offer important insights into hormone receptor-positive and HER2-negative (HR+/HER2−) metastatic breast cancer and patient response to CDK4/6 inhibitors. This study, newly published in NPJ Precision Oncology, identifies pathological and biological features associated with therapeutic response in these patients — suggesting possible treatment strategies for this common breast cancer subtype.

HR+/HER2− breast cancer is one the most common subtype of breast cancer, with approximately 300,000 new cases in the United States each year. Treatment typically involves surgery, chemotherapy when indicated, and radiation followed by adjuvant endocrine therapy.
Despite treatment, metastatic disease is a risk for many patients with HR+/HER2- breast cancer. A class of therapeutics known as CDK4/6 inhibitors have been shown to effectively limit the progression of disease. These agents are FDA-approved and widely used for the treatment of metastatic HR+/HER2- breast cancer.

“While CDK4/6 inhibitors have been considered a ‘game-changer’ in the treatment of breast cancer, more work is needed to utilize these agents with precision to further improve quality of life and outcomes for our patients,” says lead author Agnieszka Witkiewicz, MD, Professor of Oncology and Director of the Advanced Tissue Imaging Shared Resource at Roswell Park.

With this goal in mind, Dr. Witkiewicz and Roswell Park colleagues including Ellis Levine, MD, Chief of Breast Medicine, and Erik Knudsen, PhD, Chair of Molecular and Cellular Biology, designed a study to document the changes that occur during progression to metastatic disease and develop an understanding of processes related to the clinical success of CDK4/6 inhibitors.

As of December 2022, the researchers had evaluated more than 250 patients treated with standard-of-care CDK4/6 inhibitor regimens as part of a clinical trial (NCT04526587). Several routine pathological features of breast cancer were associated with the duration of therapeutic response. Gene expression analyses of the tumors indicated that substantial changes occurred during the course of treatment and evolution of the tumors with acquired resistance.

This work uncovered that HR+/HER2- metastatic tumors of the luminal B, HER2, and basal subtypes exhibited shorter progression-free survival with CDK4/6 inhibitor combination therapy. Additionally, cell cycle and estrogen signaling pathways were determinants for therapeutic efficacy. These research findings highlight biological features of HR+/HER2− breast cancer associated to CDK4/6 inhibitor response and suggest that biomarkers could be developed to predict response to CDK4/6 inhibitors and new strategies deployed to target acquired resistance.

“Physicians always welcome information that allows them to target their patients’ cancer using a particular drug to produce a good outcome, not only to celebrate that success with their patients, but also to avoid the frustration of providing a drug that does not work and delays a more efficacious treatment,” says Dr. Levine, noting the overall importance of the study.

Funding for the work was provided by the Roswell Park Alliance Foundation and the National Cancer Institute (CA247362). Dr. Witkiewicz and Knudsen are part of the Acquired Resistance to Therapy Network (ARTNET) which is a National Cancer Institute Moonshot project.