In 2013, breast cancer specialist Sarat Chandarlapaty discovered the link between mutations in the ESR1 gene and resistance to hormone therapy. It led to FDA approval of a new breast cancer drug this year. Several similar drugs are in clinical trials.
Earlier this year, the U.S. Food and Drug Administration (FDA) approved the drug elacestrant (Orserdu™) for certain people with advanced or metastatic breast cancer (stages 3 and 4). Elacestrant was effective in patients whose tumors were ER-positive, HER2-negative; had continued to grow after hormone therapy; and had a mutation (change) in a gene called ESR1.
Elacestrant is part of a new class of drugs called selective estrogen receptor degraders (SERDs). Taken orally in pill form, they could be a promising treatment option for many people with breast cancer.
The approval of elacestrant capped a decade of pivotal research led by Memorial Sloan Kettering Cancer Center (MSK) medical oncologist and breast cancer specialist Sarat Chandarlapaty, MD, PhD. Beginning in 2013, his laboratory made pioneering discoveries showing how ESR1 gene mutations cause resistance to hormone therapy.
“This is an example of the great things that can follow from the science done here at MSK,” says Mark Robson, MD, Chief of the Breast Medicine Service. “The benefit this will provide to patients would not have been possible without Dr. Chandarlapaty’s work first published 10 years ago.”
Here, Dr. Chandarlapaty discusses the discoveries that led to this new therapy for people with breast cancer.
What was the first step in finding a treatment for hormone therapy-resistant breast cancer?
About three-fourths of breast cancers depend at least partly on the hormone estrogen to fuel their growth. These cancers are called estrogen receptor (ER)-positive because the cancer cells bear a receptor that activates when estrogen binds to it. We had been trying to understand why many people with ER-positive breast cancers respond well at first to hormone therapy, but then later — in some cases, years — their tumors develop resistance, start growing, and spread.
Most breast cancer research had focused on the primary tumor. But that assumes the cancer doesn’t evolve after it is exposed to therapy. We wanted to collect samples from metastatic sites, after patients had developed resistance. We found patients were big proponents of our idea, and they were willing to provide biopsies. We gathered many metastatic samples taken from MSK patients from 2007 to 2013.
What enabled you to zero in on the ESR1 gene mutation as the cause of resistance?
I teamed with [MSK Co-Director of the The Marie-Josée and Henry R. Kravis Center for Molecular Oncology] Michael Berger, PhD, to analyze metastatic tumor samples using MSK-IMPACT®. This is a tumor-sequencing test we now use for all MSK patients. We looked at hundreds of genes to see if any had mutations that could be linked to resistance. Two mutations kept popping up in a gene called ESR1, which carries the instructions for building the estrogen receptor. These mutations were absent in tumors collected before the patients had hormone therapy, suggesting they were the cause of resistance. But we had to prove it.
We tested the theory by implanting human breast tumors in mice. Some had the ESR1 mutations, and others did not. When the mice were given estrogen, both types of tumors grew. When the estrogen was removed, the normal tumors shrank but the mutated ESR1 tumors continued to grow. We published these findings in Nature Genetics in 2013.
How exactly do the ESR1 mutations cause resistance?
We discovered that ESR1 gene mutations convert the estrogen receptor into a shape that mimics the form the receptor takes when binding to estrogen. That means that even in the absence of the estrogen signal, the receptor’s “on” switch is flipped to make the cancer grow. The research showed us the estrogen receptor was the right target. We just needed better drugs. It can be hard to get pharmaceutical companies interested in a specific target unless there is a big enough potential market, but we soon discovered that ESR1 mutations were very common in tumors that had grown resistant to hormone therapy.
How did you learn the ESR1 mutations were so common?
In 2016, we did a study using liquid biopsies, which involved studying blood plasma samples taken from more than 500 people with metastatic breast cancer that had grown resistant to hormone therapy. We analyzed cell-free DNA — the bits of DNA that tumors shed into the bloodstream. As we reported in JAMA Oncology, about 30% of patients had one of two common ESR1 mutations. This patient group had more aggressive cancer and shorter overall survival. The discovery that these mutations are very prevalent gave a clear message to drug companies that ESR1-focused therapies could help a lot of patients. Now, seven years later, we are seeing a lot of these therapies far along in the pipeline.
How do oral SERD drugs work? How do they target breast cancer tumors with mutated ESR1 genes?
These drugs — called selective estrogen receptor degraders, or SERDs — bind with estrogen receptors to stop estrogen from attaching to cancer cells. SERDs also reduce the number of estrogen receptors and change the receptors that remain so they don’t work as well. One SERD, fulvestrant (Faslodex), was approved in 2002 and has been given to patients whose cancer became resistant to hormone therapy. But many times, the tumors begin to grow resistant to fulvestrant as well. There was a strong need to develop oral SERDs that would work better.
In 2017, we looked deeper into ESR1 to see if we could find more clues about how to make SERDs more effective. We analyzed breast cancer samples from more than 900 patients. This uncovered additional ESR1 mutations that can cause fulvestrant to be only partially effective. We also demonstrated that other, newer SERDs targeted the specific mutations more precisely. The findings, published in Cancer Discovery, highlighted the potential for next-generation SERDs to overcome resistance. This finding provided another incentive for drug companies to jump in.
How is your 2013 discovery in the laboratory impacting breast cancer treatment 10 years later?
Elacestrant is likely just the first approval of multiple SERDs for treating metastatic, hormone-resistant breast cancer. At MSK, Komal Jhaveri, MD, FACP, is leading testing of two different SERDs — imlunestrant and giredestrant — which are in phase 3 trials. Other SERDs are in testing at other institutions, either alone or in combination with other drugs. Unlike fulvestrant, the new generation of SERDs can be taken in pill form rather than injection [shot] in a doctor’s office, which itself is an important benefit for patients.
None of this would have been possible without new technology being developed at MSK at critical times, including MSK-IMPACT and the specific liquid biopsy tests. We also were uniquely positioned to have access to extensive patient samples to make these findings. Early on, we depended a great deal on philanthropic donations, especially from The Shen Family Foundation, to run the sequencing tests that helped us identify the ESR1 mutations.
It’s always been exciting to be at a place so singularly focused on a major problem. With exceptionally brilliant colleagues, you’re challenged to be able to think creatively in the lab and help people down the road.
