MSK uncovers how interacting mutations shield breast cancer

· News-Medical

"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

  • 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. 

"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

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.

"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."

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.

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. 

Source:

Memorial Sloan Kettering Cancer Center

Journal reference:

Safonov, A., et al. (2026). Homologous recombination deficiency and hemizygosity drive resistance in breast cancer. Nature. DOI: 10.1038/s41586-026-10197-0. https://www.nature.com/articles/s41586-026-10197-0.