Nadia Harbeck, MD, PhD
Invited discussant Nadia Harbeck, MD, PhD, Head of the Breast Center of the University of Munich (LMU), Germany, said the UNICANCER-NeoPAL trial points toward the future of endocrine therapy in early breast cancer—using cyclin-dependent kinase 4/6 (CDK4/6) inhibitors as a means of “enhancing” this approach in patients who need more than an endocrine agent alone.
This study, along with the LORELEI trial—in which the addition of the phosphoinositide 3-kinase inhibitor taselisib to letrozole improved response rates in the neoadjuvant setting1—showed that “potent agents are already available” that can challenge the role of chemotherapy in estrogen receptor–positive disease, she said.
UNICANCER-NeoPAL is not yet practice-changing, but “it’s a very interesting hypothesis-generating trial,” she commented, although she acknowledged a few possible limitations of the study. For one thing, the choice of endpoint—residual cancer burden—may not be the best outcome measure. It is not routinely done and also may not be appropriate for many estrogen receptor–positive patients, she said.
“We know from the U.S. Food and Drug Administration meta-analysis2 that we see differences in luminal tumors, with regard to pathologic complete responses—whether you achieve this or not doesn’t matter much in luminal subtypes,” she said.
In the current study, response rates were low in all patients, independent of the treatment arm. Chemotherapy led to more responses; however, 19 weeks may be too short a time to see the full potential of an endocrine-based approach such as letrozole/palbociclib (Ibrance), Dr. Harbeck pointed out.
Paving the Way for a Third Option
The main message from the trial is a third treatment option may be emerging, and it might be the best choice for a subset of patients with estrogen receptor–positive/HER2-negative tumors, she concluded. “Currently, we look at risk and decide whether endocrine therapy or chemotherapy followed by endocrine therapy is the way forward. This work paves the way for a third option that is not endocrine therapy, and not chemotherapy, but enhanced endocrine therapy, which could be given to some of our patients.”
The WSG-ADAPT trial may be informative on this question. In this study, more than 4,000 patients are being treated with a brief (3‑week) course of preoperative endocrine therapy, with the selection of adjuvant treatment (endocrine therapy alone or with chemotherapy) based on response.
“The problematic cohort includes the intermediate-risk patients who do not respond well to 3 weeks of endocrine therapy. For them, enhanced endocrine therapy may be better than chemotherapy,” she said. “Also, patients with luminal tumors but more than three involved nodes, who now receive chemotherapy, may be good candidates for enhanced endocrine therapy, either replacing chemotherapy or in addition to it…. The challenge remains to identify patients with luminal early breast cancer for whom an endocrine-based approach will improve outcomes,” she commented.
In short, Dr. Harbeck believes the full potential of endocrine-based therapy in the early breast cancer setting has not yet been reached. “Visionary trials are needed to optimally position these new therapy concepts in patient management.” ■
DISCLOSURE: Dr. Harbeck has received honoraria for consulting and lectures from Lilly, Novartis, and Pfizer.
1. Saura C, de Azambuja E, Hlauschek D, et al: Primary results of LORELEI: A phase II randomized, double-blind study of neoadjuvant letrozole plus taselisib versus letrozole plus placebo in postmenopausal patients with ER+/HER2-negative early breast cancer. 2017 ESMO Congress. Abstract LBA10_PR. Presented September 8, 2017.
2. Cortazar P, Zhang L, Untch M, et al: Pathological complete response and long-term clinical benefit in breast cancer: The CTNeoBC pooled analysis. Lancet 384:164-172, 2014.