Targeting ER, HER2, and RB1 Shows Promise in HER2/ER+ Breast Cancer

A combined approach targeting estrogen receptor (ER), HER2, and RB1 yielded promising results in terms of Ki-67 expression in an exploratory study of women with HER2-positive, ER-positive breast cancer.

“HER2-positive, ER-positive tumors have molecular features distinct from those of HER2-positive, ER-negative cancers, suggesting that the two types of tumors should be treated with differently tailored approaches,” wrote study authors led by Luca Gianni, MD, of San Raffaele Scientific Institute in Milan. Previous work has suggested that a combined approach targeting HER2, ER, and RB1 may improve outcomes.

The phase II open-label study tested a combination of palbociclib to block RB1, fulvestrant to block ER, and trastuzumab along with pertuzumab to block HER2. It enrolled 36 patients, 1 of whom was ineligible and 5 of whom were found to be HER2-negative on retrospective analysis, leaving 35 for the safety analysis and 30 for the efficacy analysis. The primary endpoint was change in Ki-67 expression at 2 weeks of treatment and at surgery (16 weeks after treatment); this marker is considered a good measure of the effects of neoadjuvant endocrine treatment in hormone receptor–positive breast cancer. The results of the study were published in Lancet Oncology.

At baseline, the geometric mean of Ki-67 expression was 31.9 compared with 4.3 at week 2 (P < .0001), and 12.1 at the time of surgery (P = .013). A clinical objective response was observed immediately before surgery in 29 of 30 patients (97%). At surgery, 8 patients (27%) had a pathologic complete response in breast and axillary nodes; none had this response in breast only.

There were no grade 4 or serious adverse events seen in the study. The most frequent adverse events of any grade included diarrhea (74% of patients) and neutropenia (69%). Grade 3 neutropenia was reported in 29% of patients, and grade 3 diarrhea was reported in 14%. There was one case each (3%) of grade 3 stomatitis, increased alanine aminotransferase levels, and hypersensitivity reactions.

The change in Ki-67 expression, as well as a change in a measure of apoptosis, suggests that the regimen is worthy of further study, the authors wrote. “The small sample size and absence of controls means the observation is promising but limited,” they noted.