Novel Clinical Trial to Test Combining Successful Drugs for Metastatic Breast Cancer with Radiation Therapy to Treat Women with Less Severe Disease

Project at UH Seidman Cancer Center part of first-ever SPORE grant awarded by the NIH for radiotherapy

UH Clinical Update | December 2022

Women with estrogen receptor-positive (ER+) breast cancer that has spread to multiple lymph nodes have 10-year disease-free survival rates between 60 and 70 percent.

“Those women still have particularly poor outcomes, and our standard approaches for managing those women are insufficient,” says Corey Speers, MD, PhD, Hennessy Hyland Master Clinician in Immunotherapy and New Drug Development at University Hospitals Seidman Cancer Center. “There is reason to believe that we can do better.”

Corey Speers, MD

Dr. Speers is also Vice Chair of Research and Director of the Phase I Clinical Trials Program, Department of Radiation Oncology and Co-director of the Breast Oncology Program, UH Seidman Cancer Center. He also holds the position of Clinical Professor of Medicine at Case Western Reserve University School of Medicine. 

A New Option

Now, a novel new clinical trial led by Dr. Speers, to launch in 2023 at UH Seidman Cancer Center, is looking to improve the odds for these women. The trial will explore whether radiation therapy can be combined with modern targeted therapies that are successful in lengthening survival in women with metastatic breast cancer to improve outcomes for women with locally advanced disease.

The trial is part of a joint effort between UH Seidman Cancer Center, Case Western Reserve University School of Medicine and the University of Michigan, funded by a prestigious Specialized Program of Research Excellence (SPORE) grant from the National Institutes of Health (NIH). The University of Michigan will be using the SPORE funding to conduct research and clinical trials centered on pancreatic cancer and glioblastoma, while the funds at Case Western Reserve University and UH Seidman will be used to study breast cancer.

The radiotherapy SPORE grant is the first ever awarded by the NIH devoted to the treatment modality of radiation therapy and not to a specific disease site. It’s an idea whose time has come, Dr. Speers says.

“About 70 percent of patients with cancer will get radiation as part of their treatment,” he says. “Because it plays such an important role, I think that understanding how we can leverage that treatment modality more effectively was of interest to the NIH. We had a group assembled of individuals and groups who are thought leaders in understanding radiation, biology, and radiation response. Leveraging that made sense for the NIH to invest in.”

Trial Details

As part of the larger SPORE project, Dr. Speers and his colleagues will launch a clinical trial in 2023. The upcoming trial, funded by Novartis, will enroll women with ER+ breast cancer with spread to four or more lymph nodes at the time of surgery. The research team will test the CDK4/6 inhibitor ribociclib (Kisqali) in combination with radiation therapy. Targeted therapies in this class of drugs, which also include palbociclib (Ibrance) and abemaciclib (Verzenio), interrupt the CDK4/6 proteins, found both in healthy cells and cancer cells, that can become overactive and cause the cells to grow and divide uncontrollably.

Dr. Speers says that he and his colleagues have gathered preliminary evidence that makes them hopeful expanding the use of CDK4/6 inhibitors to women with locally advanced breast cancer will be effective.

“CDK4/6 inhibitors, which have really only been available clinically for about the last five years or so, have been very effective in women with metastatic breast cancer, but until recently hadn't been used in women with non-metastatic breast cancer, and so far with only one drug (abemaciclib),” he says. “We made some of the first observations that when you combine these agents with ionizing radiation, you can make the systemic targeted therapy with the CDK4/6 inhibitors more effective and you can make the radiation more effective. There's a kind of synergy between the two therapies. So our whole aim is really expanding the use of the CDK4/6 inhibitors from women who have metastatic, incurable breast cancer to women who have curable breast cancer, but are at higher risk for disease and progression of metastasis.”

Other Research Aims

As part of the SPORE research, Dr. Speers and his colleagues will also be conducting studies with animal models to determine the ideal sequencing for delivering the systemic CDK4/6 inhibitor along with radiation therapy. The studies will resolve the issue of which should come first, and whether both therapies should be given at the same time, he says.

They’ve also identified a biomarker – retinoblastoma protein – that appears to be an important part of the picture in predicting which women with breast cancer, both ER+ and triple negative (TNBC), will respond well to the combined approach.

“We think it’s really important in identifying who’s going to respond,” Dr. Speers says. “One important aim of our work will be to determine whether radiotherapy resistance due to aberrant cell cycle control and activated DNA repair can be targeted in tumor cells with intact retinoblastoma protein using CDK4/6 inhibitors.”

Dr. Speers and his colleagues, in fact, were the first to show that CDK4/6 proteins play a previously undescribed role in the DNA damage response pathway. This fact, he says, helps explain why the combination of radiotherapy and CDK4/6 inhibitors is so potentially powerful.

“CDK4/6 inhibitors, by themselves, stop proliferation because of their cell cycle effects,” he says. “But they also have a previously undescribed role in DNA damage repair. When cancer cells can’t repair their DNA as effectively, and you add on top of that something really toxic to DNA like ionizing radiation, the cancer cells get a “double hit” and die. You’re hitting them with different weapons.”

Next Steps

If pre-clinical studies and clinical trial results in women with locally advanced ER+ positive are encouraging, Dr. Speers says there are plans to expand the trial to women with triple negative breast cancer – also a group where better outcomes are urgently needed.

“The drug does not have an FDA indication for triple negative disease,” he says. “It only has an indication for ER+ cancer. This will give us a sense of whether it's safe to deliver radiation and the drug together, and then we can move forward. We think it will be.”