Figuring out how to outsmart breast cancer — preventing it from spreading or coming back after treatment — is a relentless challenge for oncologists. Now researchers at Memorial Sloan Kettering Cancer Center (MSK) have embarked on a bold new effort to predict ahead of time how breast cancer cells will evolve to resist therapies. The goal of this research is to block a tumor’s mechanism of resistance to breast cancer targeted therapy before the resistance develops.
“In the past, we’ve always been reactive — we give a treatment, the cancer adapts to survive, and then we give a drug that blocks that path of resistance,” says physician-scientist Pedram Razavi, MD, PhD. “But the next line of therapy generally does not work as well as the first. Now we are trying to develop ways to predict the behavior of cancer and stay ahead of it.”
Think of it as playing poker with cancer and being able to see most of its cards.
Dr. Razavi, in collaboration with physician-scientist Sarat Chandarlapaty, MD, PhD, and other MSK experts, is on a quest to predict which resistance mechanisms the cancer cells are likely to use. The researchers are using cutting-edge technologies, including artificial intelligence (AI) programs and supersensitive blood tests that can detect tumor DNA at levels that previously have been invisible.
The key to preventing breast cancer recurrence is in selecting the right treatment to nip it in the bud, Dr. Razavi explains.
“The good news is we have a lot of new treatments and new combinations of treatments,” he says. “It’s not like when I started, and we had just a few targeted therapies for breast cancer. Now we have so many effective treatments to choose from. The question is how can we select and use them better, and even begin to think about eradicating a subset of metastatic breast cancers?”
HERizon-Breast Clinical Trial for Metastatic HER2-positive Breast Cancer Using a Liquid Biopsy
Dr. Razavi, in collaboration with breast cancer specialist and clinical trialist Shanu Modi, MD, and other MSK experts, is launching a clinical trial that could open the possibility of eliminating breast cancer in certain patients with disease long considered incurable. The new trial, called HERizon-Breast, will enroll patients with newly diagnosed HER2-positive metastatic breast cancer. Although highly effective therapies are now available, HER2-positive breast cancer tends to develop resistance, grow, and spread rapidly.
Seeking to stop resistance at the very first sign, researchers will monitor patients closely using PET scans and a next-generation, ultrasensitive blood test that can detect tiny DNA fragments released by cancer cells into the bloodstream — called circulating tumor DNA (ctDNA).
The blood test, also known as a “liquid biopsy,” is so sensitive it can detect just a few bits of tumor DNA out of a million normal DNA fragments. Because the liquid biopsy finds breast cancer cells just beginning to resist treatment, it enables oncologists to intervene much earlier, stopping the recurrence before it takes hold.
“This unique study brings together experts from many disciplines who make up what we call the MSK Breast Cancer Cure Team,” says Dr. Razavi, who is also Director of Liquid Biopsy & Genomics. “It is truly groundbreaking.”
There will be more information available about this clinical trial and how to participate when it opens later this year. The study is just beginning but MSK experts are hopeful this could be the future of breast cancer care.
“We are using drugs that are already FDA-approved — the big difference in this trial is how we are using them,” Dr. Razavi says. “We think adapting these treatments, based on molecular evidence of disease in the blood, can potentially prevent the tumor from evolving into mostly resistant cancer cells.”
How MSK Currently Treats Breast Cancer Targeted Therapy Resistance
This new strategy to intervene earlier is the latest development in MSK’s efforts over the past decade to combat drug resistance in breast cancer patients. All MSK breast cancer patients have their tumors analyzed by MSK-IMPACT®, which looks for cancer-driving mutations. MSK also uses a liquid biopsy test called MSK-ACCESS® to identify tumor mutations in the blood.
By taking multiple samples from a patient at different points in their treatment, researchers can identify mutations that arise as the cancer changes to try to outsmart and resist the treatment. The continuous sampling makes it possible to match the evolving mutations to the most effective therapies that will block them.
These findings have led to major advances, including therapies that target specific cancer-promoting pathways. (Read more about the history of these discoveries at the end of the story, below.)
Using Artificial Intelligence To Improve HR-Positive, HER2-Negative Breast Cancer Treatment
Dr. Razavi and colleagues at MSK have already taken the first step toward using AI to improve hormone receptor-positive, HER2-negative breast cancer treatment that prevents resistance. They developed a machine-learning model that incorporates both clinical and tumor genomic features to predict outcomes.
They used this model to predict which patients with HR-positive, HER2-negative metastatic breast cancer would have better or worse outcomes if they were giving CDK4/6 inhibitors in addition to hormone therapy as their first treatment.
This tool proved more accurate than previous methods of determining the risk of resistance. The researchers reported the results in December 2024 at the general session of the San Antonio Breast Cancer Symposium (SABCS).
Dr. Razavi says these results signal the promise of artificial intelligence to transform breast cancer treatment.
“This approach moves us closer to the promise of precision oncology in breast cancer,” he says. “We will be able to identify patients at high risk of progression much earlier and improve their outcomes with more intense therapies. It also will enable us to spare lower-risk patients from the side effects of unnecessary treatments.”
MSK’s History of Discoveries To Prevent Breast Cancer Resistance:
- In 2013, the laboratory of Sarat Chandarlapaty, MD, PhD, discovered how mutations in the ESR1 gene cause resistance to hormone therapy, which led to FDA approval in 2023 of a drug, elacestrant (Orserdu™) for certain patients. Elacestrant is part of a promising new class of drugs called selective estrogen receptor degraders (SERDs). Another SERD, imlunestrant (Inluriyo®) was approved by the FDA in September 2025 based on a clinical trial led by MSK medical oncologist Komal Jhaveri, MD.
- In 2018, Dr. Razavi and colleagues were among the first to map the genomic landscape of metastatic breast cancer, showing how tumors can develop different strategies to resist hormone therapy. They published the results in Cancer Cell.
- In 2018, Dr. Chandarlapaty, Dr. Razavi, and others discovered important insights into why a new class of breast cancer drugs called CDK4/6 inhibitors sometimes don’t work or trigger resistance. They identified two genes that are a critical cause of this resistance: FAT1 and RB1.
- In 2020, Dr. Razavi, Dr. Chandarlapaty, and colleagues used serial liquid biopsy samples from patients who received alpelisib (a class of drug targeting the PI3K protein coded by the PIK3CA gene) and discovered that mutations in the PTEN gene are a major mechanism of acquired resistance to this class of drugs.
- In 2024, Dr. Razavi and breast medical oncologist Anton Safonov, MD, discovered that germline BRCA mutations can drive resistance to CDK4/6 inhibitors. They also showed for the first time that certain genomic features of breast cancers can predict which resistance mechanisms a tumor is likely to develop to evade treatment. The findings have resulted in the design and development of the EvoPAR-Breast01 phase III clinical trial, which aims to learn if treatment with saruparib (a drug called a PARP1 inhibitor) and camizestrant (a new hormonal therapy) works better than standard treatments with CDK4/6 inhibitors and hormone therapy for metastatic breast cancer.
- Dr. Jhaveri has led clinical trials showing combination therapies can target the PIK3CA resistance pathway. Imlunestrant was very effective when combined with a second drug called abemaciclib. Another drug, inavolisib, was approved by the FDA in 2024 for use with two older breast cancer drugs — the hormone therapy fulvestrant (Faslodex®) and the targeted therapy palbociclib (Ibrance®).
- In 2024, Dr. Chandarlapaty, Dr. Razavi, and colleagues discovered that TP53 mutations can help cancer cells resist CDK4/6 inhibitors by finding a way to keep dividing instead of stopping their growth. They published these results in Cancer Cell.
- In 2025, Dr. Chandarlapaty and others identified certain mutational processes called APOBEC3 that can help breast cancer develop resistance to many treatments faster. They reported these findings in Nature Genetics. They are now trying to find ways to intercept this resistance.
Key Takeaways:
- Breast cancer often develops resistance to targeted therapies.
- MSK experts are on a quest to predict which resistance mechanisms breast cancer cells are likely to use.
- They are using cutting-edge technologies, including artificial intelligence (AI) and supersensitive blood tests.
-
A groundbreaking clinical trial called HERizon-Breast will open soon for people with newly diagnosed HER2-positive metastatic breast cancer.
