Update: On January 27, 2023, the FDA approved the drug elacestrant (Orserdu) for people whose advanced or metastatic breast cancer have ESR1 mutations. The approval, and the benefit it will provide to patients, was made possible by Dr. Chandarlapaty’s research.
About 75 percent of breast cancers depend at least partly on the hormone estrogen to fuel their growth. This type of cancer is called estrogen receptor (ER) positive because the cancer cells bear a receptor that becomes activated when estrogen binds to it.
ER-positive patients are usually treated with aromatase inhibitors, drugs that prevent production of estrogen and thereby starve the cancer of this fuel. Although this approach — called hormone therapy — is usually effective, some ER-positive patients initially respond but then relapse as their cancer develops resistance to the drugs and spreads, or metastasizes, elsewhere in the body.
Now Memorial Sloan Kettering researchers studying metastatic breast tumors have found that this resistance is caused by mutations in the gene that produces the estrogen receptor. They also demonstrated that these mutations convert the receptor into a shape that mimics the form it takes when binding to estrogen. This alteration enables the cancer to progress even in the absence of the estrogen signal.
The finding, reported online November 3 in Nature Genetics, helps explain why this subset of patients become resistant to hormonal therapy. It also suggests that more potent drugs targeting the ER receptor could foil this resistance and stop cancer growth.
“Our findings show us that the estrogen receptor remains the key target despite the tumor becoming resistant,” says Memorial Sloan Kettering physician-scientist Sarat Chandarlapaty, who led the study. “Even in the presence of mutations, a new drug could bind to the receptor differently or more tightly than current drugs and prevent it from changing shape and triggering cancer growth.”
Focus on Tumors After Resistance
Dr. Chandarlapaty, a member of Memorial Sloan Kettering’s Human Oncology and Pathogenesis Program, explains that the finding arose from a concerted effort by researchers to study breast cancer tumors after they had demonstrated resistance. He worked with several Memorial Sloan Kettering colleagues to examine tumor samples that were collected with patient consent after the cancer had metastasized.
“The majority of cancer research focuses on the primary tumor, not those that develop in other parts of the body after metastatic spread,” Dr. Chandarlapaty says. “We wanted to look at these tumors after resistance has occurred and learn what has changed. How did they respond or evolve to elude a therapy that originally was working?”
Dr. Chandarlapaty teamed with Michael Berger, a genomics researcher in the Department of Pathology, to genetically analyze these post-resistance tumors for mutations. They looked at hundreds of genes to see if there were mutations in any of them that could be linked to resistance. Two mutations kept appearing in a gene called ESR1, which carries the instructions for building the estrogen receptor.
“When you see mutations in the drug target, that tells you it’s very likely to be important,” Dr. Chandarlapaty says. “But we had to definitively prove it.”
Growth Independent of Fuel
To demonstrate the mutations’ link to resistance, the researchers implanted human breast tumors in mice. Some tumors had the ESR1 mutations, and others did not. When the mice were given estrogen, both types of tumor grew. When the estrogen was removed, the normal tumors shrank but the mutated ESR1 tumors continued to grow.
“The two pieces of evidence together make a very strong story: the mutations exist in patients with resistance and they confer resistance in our experimental systems,” he says. “This tells us to develop more powerful drugs against the ER receptor rather than turning away from it and looking for a fundamentally different processes to target.”
Dr. Chandarlapaty says a new generation of estrogen receptor inhibitors that are currently being investigated look very promising for preventing this type of resistance. He also emphasizes the value of studying biopsies taken after resistance develops to gain further insights about what causes these tumors to stop responding to the drugs.
“It’s something that Memorial Sloan Kettering is really trying to take the lead on,” he says. “[Memorial Hospital Physician-in-Chief] José Baselga has really championed the idea of taking these later biopsies as a way to understand how tumors evolve and what the best avenues are for newer and more effective therapies.”