Preventing breast cancer resistance to CDK4/6 inhibitors using genomic findings

(Press-News.org) Researchers at Memorial Sloan Kettering Cancer Center (MSK) have made an important discovery about how genetic mutations in breast cancer patients can interact and drive resistance to certain drugs called CDK4/6 inhibitors. This finding, published in Nature, suggests a new strategy for predicting and preventing resistance to specific therapies based on the tumor’s genetic profile. 

“This represents a major advance in understanding and predicting cancer behavior in response to treatment,” says physician-scientist Pedram Razavi, MD, PhD, who led the study with physician-scientist Sarat Chandarlapaty, MD, PhD. The study’s first author was Anton Safonov, MD, a physician-scientist in the MSK Breast Translational Program. 

“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,” Dr. Razavi adds.

Predicting Gene Loss and Breast Cancer Therapy Resistance Many patients with breast cancer eventually develop resistance to CDK4/6 inhibitor combinations. But about 10 percent do so in a specific way: Their cancer cells lose a protective gene called RB1. The new study found two warning signs before treatment that a patient may develop resistance:

DNA repair problems, especially one called homologous recombination deficiency (HRD), where cancer cells can’t fix broken DNA properly. The initial genetic makeup of the tumor, which can help doctors predict which cancers might lose the RB1 gene.  These findings provide a path toward identifying high-risk tumors and guiding more personalized treatment decisions. 

Based on the discovery, a global, randomized phase 3 clinical trial called EvoPAR-Breast01 is now enrolling patients to test the new approach for their first treatment, which replaces CDK4/6 inhibitors and instead uses therapies targeting HRD. Patients in the trial have newly diagnosed ER-positive, HRD-positive metastatic breast cancer.

“Cancers don’t have endless ways to escape treatment,” Dr. Razavi says. “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.”

Key Findings The research involved analyzing data from more than 5,800 MSK breast cancer patients to understand how inherited (germline) and acquired (somatic) genetic changes affect how a breast tumor grows and responds to therapy. This analysis revealed:

Patients born with mutations in the BRCA2 gene are more likely to have additional mutations in another gene called RB1.  These patients do poorly when they are treated with the standard CDK4/6 inhibitor–based therapy.  Tumors carrying only a single copy of the RB1 gene before starting CDK4/6 inhibitor treatment are much more likely to develop complete RB1 loss. Underlying DNA repair defects — especially HRD — further drive the resistance mechanism.  In preclinical models supported by clinical data, drugs called PARP inhibitors resulted in better outcomes than CDK4/6 inhibitors in tumors with HRD.  Importantly, some tumors developed “reversion mutations” that restore DNA repair function. Once HRD is reversed, these tumors may regain sensitivity to CDK4/6 inhibitors. This suggests that using PARP inhibitors early may not only improve initial outcomes, but also potentially restore responsiveness to CDK4/6 inhibitors later. Research Background and Results The research is part of a broader effort at MSK to anticipate and counteract breast cancer treatment resistance, led by Dr. Razavi, Dr. Chandarlapaty, and other MSK experts from many disciplines. 

Since 2018, research efforts led by Dr. Chandarlapaty and Dr. Razavi have uncovered multiple mechanisms by which breast cancers develop resistance to CDK4/6 inhibitors, including loss of RB1 function and alterations in another tumor suppressor, TP53.

In this latest study, the researchers found that inheriting a BRCA2 mutation — and certain other genes linked to HRD — can cause DNA problems that make it more likely for the RB1 gene to mutate as well. This explains why these patients don’t respond well to CDK4/6 inhibitors — losing both tumor suppressor genes is like a car with failed brakes smashing through a barrier.

In addition, the researchers showed that defective DNA repair through HRD independently increases the likelihood of acquiring RB1 alterations. To extend the analogy, this is akin to a car with a frayed brake line: It may appear functional at first but is particularly vulnerable to failing under stress.

“This study gives us the opportunity to address drug resistance proactively, rather than reactively,” Dr. Safonov says. “This will allow us to stay one step ahead of breast cancer by gaining the ability to peek at its ‘battle plans.” 

In a series of lab experiments conducted in Dr. Chandarlapaty’s laboratory, co-first author Minna Lee, MD, used patient-derived xenograft models from BRCA2-mutant breast cancers. She found that CDK4/6 inhibitors did not work as well on these tumors, which were prone to losing the RB1 gene during treatment. 

These laboratory results confirmed and explained what doctors were seeing in patients: There was a biological reason why these treatments failed. Importantly, collaborating with international research partners, the team showed that PARP inhibitors consistently worked better than CDK4/6 inhibitors in HRD-positive tumors.

The lab evidence strongly supported giving patients with DNA repair problems (HRD-positive) PARP inhibitors first instead of CDK4/6 inhibitors.

The convergence of genomic, laboratory, and clinical evidence led to quick approval to launch the global phase 3 EvoPAR-Breast01 clinical trial. 

“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,” Dr. Razavi says. “There aren’t many examples where translational data were compelling enough to move directly into a phase 3 study without developing earlier clinical evidence.” 

“This study underscores how critical it is to integrate clinical observations with rigorous laboratory modeling,” Dr. Chandarlapaty says. “The ability to test hypotheses generated from data in patient-derived models and engineered cell lines allows us to move beyond correlation and establish biological causality. This gives us the confidence to design trials that meaningfully change patient care.”

The trial will evaluate whether the combination of the highly selective PARP inhibitor drug saruparib and the hormonal therapy camizestrant is more effective than treatments with standard-of-care CDK4/6 inhibitors and hormonal therapy. 

Essential Research Partners Dr. Razavi and the MSK team expressed sincere appreciation to the thousands of patients who have participated in MSK’s translational research programs. Their willingness to contribute clinical and genomic data made this work possible and allowed investigators to translate biological discoveries into more informed treatment approaches.

The team is especially grateful to one patient who participated through MSK’s Last Wish Program, a rapid research autopsy program that collects and stores tissue samples to advance scientific discovery. 

“One of my patients called me to the hospital near the end of her life to discuss something important,” Dr. Razavi recalls. “Unfortunately, by the time I arrived, she was already unconscious, but her parents told me she had said, ‘I know he’s doing research on this, and I want to help, even after my death.’ The tumor samples she ultimately provided — and the models derived from them — turned out to be critical for validating our findings and making this study a reality.” 

Dr. Razavi also emphasized that strong academic–industry collaboration is essential for success. “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 says. “Partnerships like this are critical to bringing our scientific discoveries to patients efficiently and responsibly.”

Key Takeaways Research conducted by MSK has revealed significant insights into how certain inherited and tumor-specific genetic alterations can drive resistance to CDK4/6 inhibitors in metastatic breast cancer. Patients with inherited mutations in the BRCA2 gene are more likely to develop additional mutations in the RB1 gene. These patients often do not respond well to CDK4/6 inhibitors.  Tumors carrying a single copy of RB1 before treatment are much more likely to develop complete RB1 loss from CDK4/6 inhibitor therapy. Based on these findings, the researchers propose that breast cancer patients with HRD-positive tumors, including many with BRCA1, BRCA2, or PALB2 mutations should be treated with PARP inhibitors instead of CDK4/6 inhibitors as their initial therapy to delay or even prevent resistance. The EvoPAR-Breast01 trial, now enrolling patients, aims to test this new frontline strategy.  END