By Mary Ellen Schneider
In patients with estrogen receptor (ER)-positive, HER2-negative breast cancer that is resistant to neoadjuvant endocrine therapy, the use of salvage neoadjuvant chemotherapy is not likely to induce a complete or near complete response, according to findings presented at the 2020 San Antonio Breast Cancer Symposium.
The results come from the phase 3 ALTERNATE trial, which examines the use of anastrozole, fulvestrant, or both in postmenopausal women with clinical stage II and III ER-positive, HER2-negative breast cancer that is resistant to endocrine therapy. In the current analysis, researchers looked specifically at a subgroup of patients with a Ki67 greater than 10% at 4 or 12 weeks following neoadjuvant endocrine therapy who were triaged to neoadjuvant chemotherapy or weekly paclitaxel, followed by surgery and adjuvant therapy of physician’s choice (Abstract GS4-05).
“Salvage neoadjuvant chemotherapy induced a very low [pathologic complete response] rate of approximately 5% in patients with neoadjuvant endocrine therapy-resistant ER-positive, HER2-negative breast cancer,” said Cynthia X. Ma, MD, PhD, of Washington University School of Medicine in St. Louis, who presented the study findings.
In total, 1,362 patients were randomized in the trial and 286 (22%) had Ki67 greater than 10% at week 4 or 12. A total of 168 patients chose to switch to neoadjuvant chemotherapy. The remainder either underwent immediate surgery (32 patients) or discontinued protocol-directed therapy (86 patients).
Among patients undergoing neoadjuvant chemotherapy, more than two-thirds had a presenting clinical T stage of T2 and most patients had a clinical N stage of either N0 or N1. Central ER testing was performed on pre-treatment biopsies and confirmed ER Allred score 6-8 in 92% of patients. More than 80% were ER-positive, progesterone receptor (PR)-positive. More than half of patients were tumor grade G2.
Neoadjuvant chemotherapy regimens administered included doxorubicin and cyclophosphamide followed by paclitaxel (36%); weekly paclitaxel (33%); docetaxel and cyclophosphamide (20%), another doxorubicin and/or taxane-containing regimen (10%), and cyclophosphamide, methotrexate, and fluorouracil (1%). Overall, 21% of patients did not complete the planned course of neoadjuvant chemotherapy due to toxicity or refusal. In total, 154 patients underwent mastectomy or breast conserving surgery.
Among the intent-to-treat population of 168 patients, there were eight patients (4.8%) with pathologic complete responses (95% CI, 2.1-9.2). Most patients fell into a residual cancer burden category of RCB2 (49%) or RCB3 (25%). Similarly, in patients who received weekly paclitaxel, the pathologic complete response rate was 1.8% (95% CI, 0.05-9.6) and more than 70% had RCB 2 or RCB3.
“In this endocrine therapy resistant group, there was no obvious association of Ki67 at diagnosis with residual cancer burden category,” Dr. Ma said. “Likewise, there was no obvious association between RCB category and baseline tumor grade or clinical T stage. There was a trend in achieving [pathologic complete response] or RCB1 in clinical N0 disease, but this did not reach statistical significance.”
The study does not establish the clinical utility of Ki67 assessment in week 4, said Lajos Pusztai, MD, of Yale University, who was the discussant for the ALTERNATE trial presentation. “It’s quite clear that Ki67 greater than 10% is far from the optimal threshold to predict higher levels of pathological [complete response],” he said. “In fact, pathological [complete response] rates of 25% or above are only seen in patients with Ki67 levels greater than 40%.”
However, Dr. Pusztai said the lack of pathologic complete response does not necessarily imply a lack of invasive disease-free survival benefit from chemotherapy among these patients.