Lab Notes Q&A: Genetic Mutations and Breast Cancer

Endocrine News talks to Sarat Chandarlapaty, MD, PhD, about his research on genetic mutations and breast cancer, his methods, and what impact it might have on the field of endocrinology.

Sarat Chandarlapaty, MD, PhD
Sarat Chandarlapaty, MD, PhD

Estrogen-disrupting therapies such as fulvestrant and tamoxifen have achieved great success in treating breast cancer. Such drugs, which block the estrogen receptor and inhibit the production of the hormone, stunt the growth of tumors and prevent the occurrence of breast cancer in at-risk individuals.

Unfortunately, patients frequently develop resistance to these drugs. The reasons remain ambiguous, but metastasis seems to coincide with reduced effectiveness. Researchers set out to find the root of this problem, and two teams simultaneously made a breakthrough.

Medical Cryptanalysts 

Their findings indicated that the genetics of the estrogen receptor a effect both drug resistance and the building blocks of breast cancer.  They discovered that mutations in the encoding endocrine receptor gene ESR1 are likely leading to resistance. With this new information, scientists may soon uncover more e ective therapies for treating patients with these genetic mutations.

A lead researcher on one of the ground-breaking studies was Sarat Chandarlapaty, MD, PhD, at Memorial Sloan-Kettering Cancer Center in New York, N.Y. He and his coauthors tested samples of metastatic tumors in patients with recurring breast cancer after months of hormonal treatment. 

The team recognized a pattern of ESR1 mutations that involved the ligand-binding region of the estrogen receptor. The results have invigorated the field of breast cancer research to pursue related studies.

Chandarlapaty and his colleagues continue to go after the goal of eradicating breast cancer by working to better understand the molecular mechanisms at its root. He took some time to describe to Endocrine News the path that led him to this groundbreaking research, and what he aims to achieve in the future.

Endocrine News: What led you to breast cancer and genetics as your research topics?

Chandarlapaty: When I began my oncology fellowship, the therapeutic benefits of targeting HER2 in breast cancers showing ampli cation of the HER2 gene were just emerging. This was tremendously exciting as one of the early examples of how a deeper understanding of the genetics of a solid tumor like breast cancer was leading to breakthroughs in therapy. And as HER2 was only seen in about 20% of breast cancers, it seemed there might be more such exciting discoveries.

Please describe the activities of your laboratory. How do you conduct your experiments?

Chandarlapaty: We are investigating what causes breast cancers to become resistant to various treatments and then testing newer therapies against the resistant cancers. We rely on cellular models of breast cancer to study the disease. Our experiments principally involve manipulating the genome of breast cancer models so they mirror certain states we see in the clinic; studying how those changes alter the cellular response to drugs; and evaluating how newer drugs perturb the cell.

What resources and equipment do you rely on the most?

Chandarlapaty: [We rely upon] cells derived from human breast cancer and drugs developed by both pharmaceutical companies and academic labs.

How has your research influenced, or is influencing, medicine? How is it influencing endocrinology specifically?

Chandarlapaty: I hope that we are influencing the design of clinical trials of newer therapies, specifically for the subtypes of breast cancer that are driven by the estrogen receptor as well as those driven by HER2. For endocrinology, I think our work on how breast cancers develop resistance to antiestrogen therapy will help the field to develop even better drugs for preventing or treating ER+ breast cancer.

If you had unlimited funding, how would you use it to upgrade your laboratory and advance your research?

Chandarlapaty: One [way] — develop more models of breast cancer from patients. By obtaining specimens from patients whose tumors have become resistant, we might be able to make better models of breast cancer for the lab to study the disease. This is a costly process.

Where do you see your scientific work heading in the future? How do you hope to affect change with your projects?

Chandarlapaty: I think we are just beginning in terms of understanding resistance to antiestrogens and the optimal strategies to deal with more treatment refractory cancers.

The Next Steps

In the months since Chandarlapaty’s study was published, pharmaceutical companies have been in a race to  nd an effective anti-resistance drug. While clinical trials are still a ways off, novel approaches with old therapies have begun to emerge.

According to Bioscience Technology, one example includes the use of an oral selective estrogen receptor down-regulator (SERD), ARN810, which is being administered in a trial at Memorial Sloan-Kettering Cancer Center, Massachusetts General Hospital, and Vanderbilt Ingram Cancer Center. Oncologists seem to view this study as an example with great potential.

Researchers expect that current drugs such as fulvestrant and tamoxifen will be found to perform better in higher concentrations. If studies that are underway support this hypothesis, the prescription of these hormonal therapies will include larger doses of the estrogen blockers until new medications based around ESR1 mutations are available.

The question remains of how to identify patients who may develop these mutations. Chandarlapaty’s research focused on the metastatic tumors, within which the genetic deviance has appeared prevalent. Primary tumors seem to make for trickier subject matter. If physicians can find a way to screen patients with primary tumors for the mutation, they may be able to improve treatment plans and avoid metastasis.

With more patient samples, as Chandarlapaty suggested, researchers will be able to further refine their understanding of the mutation and its influence. One thing is for sure: Antiestrogens will continue to play a crucial role in breast cancer research and treatments.

—Mapes is a Washington D.C.-based freelance writer and a regular contributor to Endocrine News. She wrote about improving customer service in in the March issue

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