Researchers at Memorial Sloan Kettering Cancer Center (MSK) have made an important discovery about how genetic mutations in breast cancer patients interact to promote resistance to certain drugs called CDK4/6 inhibitors. This discovery is naturepropose a new strategy to predict and prevent resistance to specific therapies based on a tumor’s genetic profile.
This represents a major advance in understanding and predicting cancer behavior in response to treatment. ”
Pedram Razavi, MD, Physician Scientist, Memorial Sloan Kettering Cancer Center
Razavi co-led the study with physician and scientist Sarat Chandarlapati, MD. The study’s lead author was Dr. Anton Safonov, a physician-scientist in the MSK Breast Translational Program.
“To our knowledge, this is the first example to show that complete genomic analysis of breast cancer, including both genetic and tumor-specific changes, can predict the precise biological mechanisms of resistance before treatment begins,” Dr. Razavi added.
Gene loss and prediction of breast cancer treatment resistance
Many breast cancer patients eventually develop resistance to CDK4/6 inhibitor combinations. But about 10% do so in a particular way. Their cancer cells are RB1. A new study found two warning signs that patients may develop resistance before treatment.
- DNA repair problems, particularly ones called homologous recombination defects (HRD), prevent cancer cells from properly repairing broken DNA.
- Early genetic makeup of the tumor. This helps doctors predict which cancers are likely to lose genes. RB1 gene.
These findings provide a pathway to identify high-risk tumors and guide more personalized treatment decisions.
Based on this discovery, a global randomized phase 3 clinical trial called EvoPAR-Breast01 is currently enrolling patients to test a new approach that uses HRD-targeted therapies instead of CDK4/6 inhibitors as the first treatment. Patients in this study were newly diagnosed with ER-positive, HRD-positive metastatic breast cancer.
“Cancer does not have infinite ways to escape treatment,” Dr. Razavi says. “They’re ponies with a trick or two, and those tricks are often determined by genetics or tumor-specific genetic characteristics. If we can predict their ability, we can stop resistance before it develops. That’s what we’re trying to do with this trial: predict mechanisms of resistance and hopefully improve outcomes for patients.”
Main findings
The study involved analyzing data from more than 5,800 MSK breast cancer patients to understand how inherited (germline) and acquired (somatic) genetic changes influence breast tumor growth and response to treatment. This analysis revealed the following:
- Patients born with the mutation are BRCA2 The gene is more likely to have additional mutations in another gene called. RB1.
- These patients have poor outcomes even with standard CDK4/6 inhibitor-based therapy.
- tumors that carry only one copy of RB1 Full progression is much more likely if the gene is present before starting treatment with a CDK4/6 inhibitor. RB1 loss.
- Underlying DNA repair defects, particularly HRD, further promote resistance mechanisms.
- In preclinical models supported by clinical data, drugs called PARP inhibitors produced better outcomes than CDK4/6 inhibitors in tumors with HRD.
- Importantly, some tumors developed “back mutations” that restored DNA repair function. Once HRD is restored, these tumors may regain sensitivity to CDK4/6 inhibitors. This suggests that early use of PARP inhibitors not only improves early outcomes but may later restore responsiveness to CDK4/6 inhibitors.
Research background and results
This study is part of MSK’s broader efforts to predict and combat breast cancer treatment resistance, led by Dr. Razavi, Dr. Chandarlapati, and many other MSK experts.
Since 2018, research efforts led by Dr. Chandarlapati and Dr. Razavi have uncovered multiple mechanisms by which breast cancer acquires resistance to CDK4/6 inhibitors. RB1 functions and changes in different tumor suppressors; TP53.
In this latest study, researchers BRCA2 Mutations, and certain other genes associated with HRD, can cause DNA problems, RB1 Genes also mutate. This explains why these patients do not respond well to CDK4/6 inhibitors. Losing both tumor suppressor genes is like a car with faulty brakes crashing through a barrier.
Additionally, researchers showed that defective DNA repair by HRD independently increases the likelihood of infection. RB1 change. To extend the analogy, this is similar to a car with frayed brake lines. Although it appears to be working at first, it is especially prone to failure under stress.
“This study gives us the opportunity to proactively address drug resistance rather than reactively,” Safonov says. “This gives us a peek into the ‘battle plan’ of breast cancer and allows us to stay one step ahead of it.”
In a series of laboratory experiments conducted in Dr. Chandarlapati’s laboratory, co-lead author Minna Lee, MD, used the following patient-derived xenograft models: BRCA2-Mutant breast cancer. She found that CDK4/6 inhibitors were less effective against these tumors, and these tumors tended to lose tumor mass. RB1 Genes under treatment.
These test results confirmed and explained what the doctor was observing the patient for. In other words, there was a biological reason why these treatments failed. Importantly, the team, in collaboration with international research partners, showed that PARP inhibitors were consistently more effective than CDK4/6 inhibitors in HRD-positive tumors.
Laboratory evidence strongly supports the initial administration of PARP inhibitors instead of CDK4/6 inhibitors in patients with DNA repair problems (HRD positive).
Convergence of genomic, laboratory, and clinical evidence led to rapid approval to begin the global Phase 3 EvoPAR-Breast01 clinical trial.
“This highlights the strength of our program and how our discoveries can be translated very quickly into clinical trials that have the potential to change medicine,” Dr. Razavi says. “There are not many cases where translational data is compelling enough to move directly into a Phase 3 trial without developing early clinical evidence.”
“This study highlights how important it is to integrate clinical observations with rigorous laboratory modeling,” says Dr. Chandarlapati. “The ability to test hypotheses generated from patient-derived models and engineered cell line data allows us to go beyond correlation and establish biological causation. This gives us confidence to design trials that meaningfully transform patient care.”
This trial will assess whether the combination of the highly selective PARP inhibitor sarparib and the hormone therapy camidestrant is more effective than the standard of care CDK4/6 inhibitor and hormone therapy.
important research partner
Dr. Razavi and the MSK team expressed their sincere gratitude to the thousands of patients who have participated in MSK’s translational research programs. Their willingness to provide clinical and genomic data made this study possible, allowing researchers to translate biological discoveries into more informed therapeutic approaches.
The team is especially grateful to one patient who participated in MSK’s Last Wish program. MSK’s Last Wish program is a rapid research dissection program that collects and archives tissue samples to advance scientific discoveries.
“One of my patients, near the end of his life, called me at the hospital to discuss something important,” Dr. Razavi recalls. “Unfortunately, she was already unconscious when I arrived, but her parents said she said, ‘I know he’s working on this and I want to help him after I die.'” The tumor sample she ultimately provided, and the model derived from it, proved crucial in validating our findings and making this research a reality. ”
Dr. Razavi also emphasized that strong academic and industry collaboration is essential for success. “We are grateful to our collaborators at AstraZeneca who recognize the strength of our scientific evidence and are determined to move this strategy forward into global Phase 3 trials,” he says. “Partnerships like this are essential to delivering our scientific discoveries to patients efficiently and responsibly.”
Important points
- Research conducted by MSK has revealed important insights into how specific genetic and tumor-specific genetic alterations promote resistance to CDK4/6 inhibitors in metastatic breast cancer.
- Patients with inherited mutations BRCA2 Genes are more likely to undergo further mutations. RB1 gene. These patients often do not respond well to CDK4/6 inhibitors.
- Tumors that carry a single copy RB1 Full progression is much more likely before treatment RB1 loss with CDK4/6 inhibitor treatment.
- Based on these findings, researchers propose that breast cancer patients with HRD-positive tumors include many breast cancer patients with HRD-positive tumors. BRCA1, BRCA2or PALB2 Mutations should be treated with PARP inhibitors rather than CDK4/6 inhibitors as initial therapy to delay or prevent resistance.
- The EvoPAR-Breast01 trial, currently enrolling patients, aims to test this new front-line strategy.
sauce:
Memorial Sloan Kettering Cancer Center
Reference magazines:
Safonov, A. Others. (2026). Homologous recombination defects and hemizygosity enhance breast cancer resistance. Nature. DOI: 10.1038/s41586-026-10197-0. https://www.nature.com/articles/s41586-026-10197-0.
