Why Some Breast Cancer Becomes Resistant to Hormone Therapy

Alexander M. Castellino, PhD

March 20, 2018

An unexpected finding in women with estrogen receptor (ER)–positive (ER+) metastatic breast cancer (MBC) is the emergence of acquired mutations in HER2.

These mutations explain some of the resistance to hormone-directed therapy that is seen in these patients, and the new finding could offer a new approach to clinical management, researchers said at a media preview for the American Association for Cancer Research (AACR) 2018 Annual Meeting. 

Utthara Nayar, PhD, a research fellow in medicine at the Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, shared some of the data in advance of her presentation at the meeting.  

"Resistant ER-positive metastatic breast cancer remains the most common cause of breast cancer death because patients invariably develop resistance and stop responding to these drugs," Nayar commented in an AACR news release.  

These hormone-directed therapies include aromatase inhibitors, tamoxifen, and selective ER degraders.

Resistance to such ER-directed therapy is explained in approximately 25% of patients, she said, but for most patients (~75%), the resistance is unexplained.

Nayar and her colleagues used whole-genome sequencing to study metastatic tumor biopsy specimens from 168 patients with ER+ MBC. They found mutations in the HER2 gene in 12 patients, and 8 of these patients had activating mutations. 

For five of these patients with activating mutations, the researchers had tissue available from the treatment-naive primary tumors, and this revealed no evidence of pre-existing mutations in four of the five patients. This finding suggests that these four mutations were acquired under the selective pressure of ER-directed therapy

"It was surprising to discover that HER2 mutations can be acquired in the metastatic setting, suggesting that these tumors evolve," commented senior author, Nikhil Wagle, MD, deputy director of the Center of Cancer Precision Medicine at the Dana-Farber Cancer Institute.

The researchers identified the HER2 mutations (S653C, L755S, V777L, and L869R) and showed that cells harboring these were viable in a medium containing fulvestrant or neratinib (an irreversible epidermal growth factor receptor/human epidermal growth factor receptor 2/human epidermal growth factor receptor 4 kinase inhibitor).

However, this viability decreased in a medium containing both fulvestrant and neratinib, which suggests that the combination of these two drugs may be a way to target the acquired resistance.

Nayar reported that the patient who had acquired the HER2 V777L mutation was initially diagnosed with ER+HER– breast cancer. After 4 years of tamoxifen therapy, she developed metastatic disease, which progressed while she received letrozole and palbociclib. She was then entered into a clinical trial evaluating the combination of fulvestrant and neratinib.

"The discovery of the acquired HER2 mutation in one person's metastatic biopsy prompted enrollment into a phase 2 clinical trial of fulvestrant plus neratinib, resulting in a partial response lasting 6 months, consistent with our in vitro findings showing neratinib-induced resensitization to ER-directed therapy," Nayar commented.

Nayar pointed out that it was important to profile resistant metastatic tumors. "Currently, only the initial tumor is profiled in most cases," she said. Precision medicine in ER+ MBC means that patients with acquired HER2 mutations should be directed to clinical trials testing strategies to overcome the mechanism of resistance, she noted.

"Repeated sequencing of tumors can pinpoint new genetic changes that cause resistance to therapies. This in turn can enable physicians to personalize therapy depending on the specific genetic changes in a patient's tumor over time," Wagle said.

The researchers acknowledge that the small number of patients identified with HER2 mutations (12 of 168 tested) was a limitation of the study, but they emphasized that these were real-world samples — patients had different stages of cancer initially, received different treatments, and had different tumor features.

Elaine Mardis, PhD, program chair of the 2018 AACR Annual Meeting and co-executive director of the Institute for Genomic Medicine at the Nationwide Children's Hospital in Columbus, Ohio, acted as a co-moderator of the presscast.

She explained that the importance of the study lies in its use of next-generation sequencing technology and its ability to look at pre- and postresistance samples to reveal a new mechanism by resistance to ER agonists. "These HER2 mutations have effective therapies, such as small-molecule inhibitors like neratinib," she said.

Nayar has disclosed no relevant financial relationships. Wagle is a stockholder in Foundation Medicine.

American Association for Cancer Research (AACR) 2018 Annual Meeting. Abstract 4952. To be presented April 17, 2018.

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