Researchers Identify Mutations that Cause Some Breast Cancers to Resist Treatment

By Jim Stallard

on Friday, November 8, 2013

Pictured: Sarat Chandarlapaty Physician-scientist Sarat Chandarlapaty

Memorial Sloan Kettering researchers have found genetic mutations that cause some breast cancers to develop resistance to hormone therapy.

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.”

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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.”

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If you have the mutation ESR1 what new inhibitor drugs are being investigated and what trials are available?

At least three new drugs are being investigated specifically for these mutations. The most mature trial is of GDC-0810 (learn more about this trial here: Trials of other drugs will open in near future. If you would like to get more information about this or other treatment options, or make an appointment for a consultation with one of our physicians, please call our Physician Referral Service at 800-225-2225. Thank you for reaching out to us.

My daughter, who is now 39 years and was diagnosed with breast cancer in Nov. 2010, which has now metastasized in Liver (detected in February 2014).Since then, she has been on (Abraxane 4 cycles) - (Arimidex 3 months) - Abraxane (3 cycles) - Gem citabine+Carboplatin (4 cycles) - Tamoxifen (3 months) & now on Everolimus + Exemestane (since last 12 days). During this time, her CA 15.3 has been through values 1290-27-21-39-66-38-18-25 (last value on 19th August, 2015). In her case, a strong co-relation between CA15.3 & PET-CT observation has been established.

Last PET-CT done on 22nd August 2015 shows that all lesions & tumors (biggest of them being 7.6 cms X 9 cms. detected in February 2014 has got cleared. But in the same PET-CT it has shown few new lesions - biggest of them being 1.3 X 1.2 cms - have appeared which has taken CA marker from 18 to 25. I have three questions: (1) We are from India. Can she participate in the clinical trial referred to above in response to one of the question, if in next couple of months she meets other inclusion criteria? (2) Her cancer in-spite of being strongly ER/PR positive (>90 % of nuclei being sensitive) hormone therapy not working even for 2 months, can this be termed as patient developing resistance to hormone therapy? (3) Will it be useful & possible to undertake IMPACT test to know the exact mutations (we can send paraffin blocks from latest biopsy & DNA extract from patient's blood to MSKCC) & then to ascertain the applicable drugs?

Once IMPACT test results are ready & if MSKCC's experts find it useful, we can visit MSKCC for consultation & follow-ups.

We are sorry to hear that your daughter's breast cancer has metastasized. Please contact our International Center to discuss your questions further. They may be able to arrange for a review of her medical records my mail, or make an appointment for her to come for a consultation in person. Their email address is or for more information, please visit Thank you for reaching out to us.

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