Exceptional Responders to Metastatic Breast Cancer Treatment Characterized

Response to treatment for metastatic breast cancer (MBC) can vary widely. While the five-year survival rate in patients with MBC is only 29%, some patients experience a long-lasting treatment response. “Characterizing these exceptional responders may help to guide personalized treatments and avenues for future research,” says Shimoli V. Barot, MD, a breast medical oncologist at Cleveland Clinic Cancer Institute.

Using electronic medical records, Dr. Barot and her colleagues have identified clinical, pathologic, genetic and genomic characteristics of MBC exceptional responders from an analysis of outcomes from MBC patients diagnosed and treated at Cleveland Clinic from 2000 to 2023. The investigation revealed 27 patients who were considered to be exceptional responders (defined as a partial or complete response to treatments that are effective in fewer than 10% of patients with similar-stage disease) at three years. Their research was selected for presentation at the recent San Antonio Breast Cancer Symposium.

Shared factors among exceptional responders

Exceptional responders were mostly White females with a median age of 53 years, had never smoked and had early-stage disease prior to metastases.

“Because there were very few exceptional responders, we can’t definitively prove that these are causative associations, but by identifying potential factors shared by exceptional responders, it may help us to improve treatment responses in patients similar to these,” says Dr. Barot. Multi-institutional collaborations in the future may expand the cohort of exceptional responders available to study in order to better define the characteristics that contribute to deep and durable responses.

Another characteristic that defined exceptional responders was a history of early-stage breast cancer before the development of metastases, most often the bones (59.3%), distant lymph nodes (59.3%, and lungs (48.1%). The most common breast cancer subtype was hormone receptor-positive, HER2-negative subtype.

The average duration of response among the cohort was four years. More than one-third (34.3%) of the exceptional responders were treated with an aromatase inhibitor alone, 21% with a CDK 4/6 inhibitor plus an aromatase inhibitor or fulvestrant and 15% with capecitabine alone or in combination with HER2-directed therapies. Exceptional responders also received treatment with other combinations of HER2-directed therapies.

Of the exceptional responders, 90.6% had a partial response and 9.3% had a complete response.

“Newer drugs approved in the past few years are not represented because patients treated with these agents have not met the criteria for exceptional response as yet, namely a complete or partial response at three years,” says Dr. Barot. “Whether these newer drugs will change outcomes is a work in progress.”

Germline mutations were present in 51.8% of patients, and included a BRCA2 mutation in 7.4% and a BRCA1 mutation in 3.7% of patients. Other germline genetic mutations in 11 other exceptional responders included CDKN2, MSH2, MSH3 and MSH6.

May guide personalized treatment

Only a small proportion of the exceptional responders had a significant family history of breast cancer, but several genomic alterations were identified in nine patients in the cohort of 27. “Because of the limited number of patients in the cohort, we were not able to identify a recurrent mutation that is particularly associated with an exceptional response,” says Dr. Barot.

“In the future, if we are able to narrow it down to a couple of mutations, it may be important information to have in order to personalize treatments. The way practice is now, the use of next-generation sequencing for circulating tumor DNA testing is routine with almost every progression, and in the future, it may even be used at the first diagnosis of metastatic disease.”

The germline and somatic mutations observed offer opportunities for translational research.