Trastuzumab May Enhance Durability of Response to Fulvestrant

Mahmoud Charif, MD

HER2 blockade may enhance the duration of response to fulvestrant, according to researchers from the University of Cincinnati College of Medicine who found that patients with metastatic breast cancer who received both trastuzumab and fulvestrant maintained a much longer treatment response than patients with HER2-negative disease who did not receive trastuzumab.

At the 2014 ASCO Breast Cancer Symposium, researcher Mahmoud Charif, MD, described the study in patients with hormone receptor-positive breast cancer receiving fulvestrant. The study’s objective was to determine factors associated with a prolonged response to fulvestrant and to investigate whether or not blocking HER2 improves response durability.

“Anecdotally, in practice we see that some patients stay on fulvestrant a long time. In this study, some were on the drug for more than 7 years [more than 2800 days], whereas the median time on treatment was 425 days,” Charif said in an interview. “We are trying to identify factors associated with improved responses. These factors are currently unknown.”

Study Details

The median age of the subjects was 58 years. Out of 85 women, 60 had received hormone therapy and 56 received chemotherapy. Primary tumors were HER2-positive in 11 patients (13%), and all these women received trastuzumab.

The analysis found no difference in the duration of response to fulvestrant according to age, sites of metastases, or use of adjuvant endocrine therapy or chemotherapy. Differences were observed, however, according to HER2 status, Charif reported.

“We looked at several factors. What stood out is that HER2-positive patients who received trastuzumab concurrently with fulvestrant turned out to be the longest responders to fulvestrant,” he said.

Median duration of fulvestrant therapy for HER2-positive patients was 772 days, compared with 360 days for HER2-negative patients (P = .059). Of the 11 patients with HER2-positive disease receiving fulvestrant plus trastuzumab, 9 patients remained on treatment past the median treatment duration. Among the 74 patients with HER2-negative disease, 33 patients, or fewer than half, were treated longer than 425 days (odds ratio 5.45; P = .0484).

Possible Synergy

“The median number of days that the HER2-positive patients stayed on fulvestrant is twice the number for HER2-negative patients,” Charif noted. “When you take fulvestrant, if you have HER2-positive disease you are 5 times more likely to beat the median than if you have HER2-negative disease.”Charif and colleagues hypothesize that there is synergy between these 2 agents. Interestingly, overexpression of HER2 is normally associated with endocrine therapy resistance, he noted.

“HER2 blockade may enhance the duration of response,” he suggested. The apparent synergism between trastuzumab and fulvestrant may be due to the effect of trastuzumab inhibiting the transcriptional coactivator MED1, a recently discovered key crosstalk point between HER2 and estrogen receptor signaling pathways in mediating endocrine resistance.

“MED1 interacts with how the estrogen receptor works. When it is overactive, it is associated with resistance to hormonal therapy. Down-regulating MED1 makes tumors responsive to tamoxifen and fulvestrant,” he said.

In this case, trastuzumab may be down-regulating MED1, he suggested. In a future subset of patients, the investigators plan to compare MED1 expression in the primary tumor versus metastatic disease, and in HER2-positive versus HER2-negative tumors.

“We expect levels in HER2-positive tumors may be elevated, and this would be how trastuzumab may be affecting MED1 and reversing some of the resistance to hormonal therapy. We will be looking at larger numbers of patients, to have more robust data and to determine how MED1 plays into this issue,” Charif said.

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