Newer Generation Breast Cancer Drugs Increase Tumor’s Vulnerability to Radiation Therapy, UH Seidman Research Shows

Innovations in Cancer | January 2025

Approach being tested in patients in clinical trial at UH Seidman Cancer Center

More than 280,000 American women receive a diagnosis of breast cancer each year, and more than 100,000 have cancer that has spread to three or more lymph nodes or have triple-negative disease – a particularly virulent form of breast cancer. This unfortunate fact puts their risk of the cancer recurring after treatment at between 20 and 25%.

Corey Speers, MD

“A 25% risk of recurrence in this number of potentially curable women represents a greater mortality risk than many other cancers,” says Corey Speers, MD, PhD. Dr. Speers is Hennessy Hyland Master Clinician in Immunotherapy and New Drug Development at University Hospitals Seidman Cancer Center. He is also Vice Chair of Research and Co-director of the Breast Oncology Program at UH Seidman Cancer Center, as well as being a tenured Clinical Professor of Medicine at Case Western Reserve University School of Medicine. 

However, Dr. Speers is leading a research team that hopes to help change these challenging numbers and improve outcomes for women with breast cancer. With funding from the National Institutes of Health through a prestigious Specialized Program of Research Excellence (SPORE) grant, he and his colleagues are exploring how a certain class of breast cancer drugs can make tumors more vulnerable to radiation therapy.

These drugs, known as CDK4/6 inhibitors, interrupt the CDK4/6 proteins found both in healthy cells and cancer cells. These are proteins that can become overactive and cause cancer cells to grow and divide uncontrollably. Drugs to combat this include ribociclib (Kisqali), palbociclib (Ibrance) and abemaciclib (Verzenio).

“These are drugs that target a certain pathway that has been shown to improve outcomes for women with metastatic, ER+ breast cancer,” Dr. Speers says. “Now they're starting to be used in women who have non-metastatic cancer, but which has gone to the lymph nodes that are at higher risk of it going somewhere else in the body. This class of medications was thought to work by slowing down the growth of cells by inhibiting the cell cycle proliferation of those cancer cells.”

Already, Dr. Speers and his team have shown that all three drugs make cancer cell lines and animals in the lab similarly more sensitive to radiation therapy.

“It's a novel observation that we made that the two together actually makes the radiation work better,” he says. “There was no reason before our studies to think necessarily that that would be the case. But we uncovered a new role for the CDK4/6 proteins that influence response to radiation. What we were able to demonstrate is that that those CDK4/6 proteins that are targeted by these medications actually have other functions that people didn't really appreciate before. One of those functions includes helping cells withstand radiation treatment and survive radiation. As a result, what we're trying to demonstrate is that combining these drugs with radiation makes the radiation more effective.”

Building on this work, Dr. Speers and his colleagues have launched a Phase 1 clinical trial at UH Seidman Cancer Center of ribociclib administered concurrently with postoperative radiation therapy. Women eligible for the trial are those with high-risk, node-positive, HR+/HER2- breast cancer. Once enrolled in the study, patients will begin treatment with ribociclib 400 mg daily at the same time as they initiate standard of care adjuvant radiation therapy. Patients will continue treatment with ribociclib for up to six weeks.

Dr. Speers says that while he’s pleased with the progress on the project, many questions are still unanswered – answers he believes will come from continued study with SPORE resources.

“Although we have demonstrated that all three CDK4/6 inhibitors lead to the radiosensitization of ER+ breast cancer, the full mechanism of this radiosensitization remains unclear as does the utility of this approach in women with triple negative breast cancer,” he says. “Our data suggests a novel association between CDK 4/6 inhibition and the DNA damage response. Indeed, we have demonstrated that short term CDK4/6 inhibition leads to a decrease in expression of DNA repair proteins like CHK1 and RAD51 that play a role in homologous recombination and leads to radiosensitization in ER+ breast cancer models. This has not, however, ever been demonstrated in triple negative breast cancer. We're also planning to figure out who this combination therapy helps most. We don't think that it works in every woman, but there may be certain types of tumors for whom this combination therapy may be more effective. Plus, we're trying to figure out the sequencing of that therapy – drug first then radiation, or the opposite. That's one of the goals of this study.”

If the project proves successful and difficult-to-treat breast cancers become more vulnerable to radiation, Dr. Speers says, it could change protocols for radiation therapy and perhaps even lead to shorter radiation therapy sequences for women in the future.

“Part of the next generation of studies we're trying to do is examining whether we can get away with doing less radiation,” he says. “That would be the next step in how this research will evolve. It may allow women to be cured with less radiation in the future.”

The Kathy and Les Coleman Clinical Trials Center at UH Seidman Cancer Center offers more than 400 clinical trials for cancer patients. To learn more, visit: UHhospitals.org/CancerClinicalTrials.

Contributing Expert:
Corey Speers, MD, PhD
Hennessy Hyland Master Clinician in Immunotherapy and New Drug Development
Vice Chair of Research
Co-director, Breast Oncology Program
UH Seidman Cancer Center
Clinical Professor of Medicine
Case Western Reserve University School of Medicine