Researchers at Memorial Sloan Kettering Cancer Center (MSK) have identified how certain genetic mutations in breast cancer can interact and cause resistance to CDK4/6 inhibitors, a class of drugs used in treatment. The study, published in Nature, provides insight into predicting which patients may not respond to these therapies and suggests new strategies for personalizing treatment.
The research was led by Dr. Razavi and physician-scientist Sarat Chandarlapaty, MD, PhD. Anton Safonov, MD, served as the first author. According to Dr. Razavi: "To our knowledge, this is the first example showing that a complete genomic analysis of breast cancer, including both inherited and tumor-specific alterations, can predict the precise biological mechanism of resistance before therapy even begins."
About 10 percent of breast cancer patients who develop resistance to CDK4/6 inhibitors do so through loss of the RB1 gene. The study identified two warning signs before treatment that could indicate a higher risk for this type of resistance.
The findings are expected to help identify high-risk tumors and guide more tailored treatment decisions for patients.
A global phase 3 clinical trial called EvoPAR-Breast01 has begun enrolling patients based on these discoveries. This trial will test whether replacing CDK4/6 inhibitors with therapies targeting homologous recombination deficiency (HRD) improves outcomes for newly diagnosed ER-positive, HRD-positive metastatic breast cancer patients.
Dr. Razavi explained: "Cancers don't have endless ways to escape treatment. They are one- or two-trick ponies, and those tricks are often determined by their inherited or tumor-specific genetic features. If we can predict what they're capable of, we can intercept it before the resistance happens. That's what we're trying to do in this trial - forecast the mechanism of resistance and hopefully improve the outcomes for our patients."
The team analyzed data from over 5,800 MSK breast cancer patients to understand how inherited (germline) and acquired (somatic) genetic changes influence tumor growth and response to therapy.
Since 2018, Drs. Chandarlapaty and Razavi have led efforts at MSK to uncover mechanisms behind breast cancer's resistance to CDK4/6 inhibitors—including loss of RB1 function and changes in another tumor suppressor gene called TP53.
In this recent work, researchers found that inheriting a BRCA2 mutation—or other genes linked with HRD—can create DNA repair issues that make RB1 mutations more likely during treatment with CDK4/6 inhibitors. Losing both genes makes tumors especially resistant to these drugs.
Further laboratory experiments using patient-derived models showed that CDK4/6 inhibitors were less effective on BRCA2-mutant tumors prone to losing RB1 during therapy. International collaborations confirmed that PARP inhibitors performed better than CDK4/6 inhibitors in HRD-positive tumors.
Based on converging evidence from genomics, lab studies, and clinical observations, regulators quickly approved launching the EvoPAR-Breast01 phase 3 trial without prior early-phase trials—a rare step highlighted by Dr. Razavi: "This highlights the strength of our program and how we are able to very quickly translate our findings to a potentially practice-changing clinical trial," he said. "There aren't many examples where translational data were compelling enough to move directly into a phase 3 study without developing earlier clinical evidence."
Dr. Chandarlapaty added: "This study underscores how critical it is to integrate clinical observations with rigorous laboratory modeling... This gives us the confidence to design trials that meaningfully change patient care."
The ongoing trial will compare a combination of PARP inhibitor saruparib plus hormonal therapy camizestrant against standard-of-care treatments involving CDK4/6 inhibitors combined with hormonal therapy.
MSK researchers expressed gratitude toward thousands of participating patients whose contributions made these advances possible—especially one individual who participated posthumously through MSK's Last Wish Program by donating tissue samples critical for validating findings.
Dr. Razavi also acknowledged industry partners: "We are grateful to our collaborators at AstraZeneca for recognizing the strength of our scientific evidence and for their willingness to advance this strategy decisively into a global phase 3 trial," he said. "Partnerships like this are critical to bringing our scientific discoveries to patients efficiently and responsibly."
