Editor’s Note: HR+/HER2- is the most common subtype of breast cancer, which is not highly sensitive to neoadjuvant therapy. In 2023, clinical trial results from KEYNOTE-756, CheckMate 7FL, and other studies presented at international conferences showed the potential of neoadjuvant immunotherapy for early-stage HR+/HER2- breast cancer patients. At the 2024 North-South Summit, Professor Leiping Wang from Fudan University Cancer Hospital delivered a report titled “HR+/HER2- Breast Cancer: Entering the Era of Neoadjuvant Immunotherapy?” This article reviews the content of her lecture for readers.
Exploration of Neoadjuvant Immunotherapy in Early HER2- Breast Cancer
Professor Leiping Wang began by stating her opinion that HR+/HER2- breast cancer has not yet entered the era of neoadjuvant immunotherapy. She mentioned that HR+/HER2- breast cancer is neither the preferred population for neoadjuvant therapy nor for immunotherapy. However, as more data becomes available, the question of whether HR+/HER2- breast cancer will enter the era of neoadjuvant immunotherapy is worth considering. Professor Wang then delved into an in-depth analysis of this topic.
In breast cancer treatment, TNBC patients were the first to enter the era of neoadjuvant immunotherapy. The 2023 SABCS conference updated the results of the KEYNOTE-522 trial, showing a 9% absolute benefit in 5-year event-free survival (EFS) in the intent-to-treat (ITT) population (81.3% vs. 72.3%) following neoadjuvant immunotherapy. The KEYNOTE-522 trial was inspired by the large neoadjuvant platform trial I-SPY 2. The I-SPY 2 trial results suggested that adding pembrolizumab to standard neoadjuvant chemotherapy in HER2- breast cancer patients (including TNBC and HR+/HER2-) increased the pathological complete response (pCR) rate from 17% to 44%.
The KEYNOTE-522 trial, initiated in 2017, marked the beginning of the era of neoadjuvant immunotherapy for TNBC. Subsequently, the KEYNOTE-756 trial (initiated in 2018) and the Checkmate 7FL trial (initiated in 2019) respectively applied pembrolizumab and nivolumab to the neoadjuvant treatment of HR+/HER2- breast cancer. The 2023 SABCS conference presented data from these two large phase III clinical trials. Could these trials usher in a new era for neoadjuvant immunotherapy in HR+/HER2- breast cancer? Let’s explore this further.
The Necessity of Exploring Neoadjuvant Immunotherapy for HR+/HER2- Breast Cancer
CDK4/6 inhibitors have significantly improved survival in patients with HR+/HER2- advanced breast cancer and are now being used for early-stage breast cancer. The 5-year follow-up data from the MonarchE study showed that adjuvant endocrine therapy combined with abemaciclib provided a 7.6% absolute benefit in invasive disease-free survival (IDFS) in the ITT population (83.6% vs. 76.0%), HR=0.680 (95% CI: 0.599-0.772). However, CDK4/6 inhibitors have not yet been successful in the neoadjuvant setting.
HR+/HER2- is the largest subtype of breast cancer, characterized by high heterogeneity. Among these, Luminal B subtype and histological grade 3 tumors exhibit higher immunogenicity compared to Luminal A and histological grades 1-2. These subtypes proliferate faster, are less differentiated, and have a poorer prognosis, necessitating more aggressive treatment measures. Therefore, it is essential to evaluate the potential of immunotherapy in this population. Compared to advanced stages, early-stage tumors exhibit less immune escape, and neoadjuvant therapy during the tumor-bearing state is more likely to stimulate immune effects than adjuvant therapy, making neoadjuvant treatment a favorable time to explore immunotherapy for HR+/HER2- breast cancer. Additionally, if histological grade 3 HR+/HER2- breast cancer achieves pCR, it could potentially translate into long-term survival, similar to TNBC.
Progress in Neoadjuvant Immunotherapy for HR+/HER2- Breast Cancer
The KEYNOTE-756 trial and Checkmate 7FL trial enrolled 1,278 and 510 patients, respectively, with the majority of patients in both trials having histological grade 3 tumors. Both trials met their primary endpoints, showing improved pCR rates (KEYNOTE-756: 24.3% vs. 15.6%, P=0.00005; Checkmate 7FL: 24.5% vs. 13.8%, P=0.0021).
Professor Wang noted that although neoadjuvant immunotherapy improved pCR rates in HR+/HER2- breast cancer patients, the pCR rate of <25% is insufficient to herald a new era, unlike in TNBC. Therefore, identifying the subpopulation of HR+/HER2- breast cancer patients who benefit most from neoadjuvant immunotherapy is crucial. Currently, pembrolizumab is approved for neoadjuvant treatment in China for early-stage high-risk TNBC patients with a PD-L1 combined positive score (CPS) ≥20. In the KEYNOTE-756 trial, researchers also screened patients based on PD-L1 expression, finding that HR+/HER2- breast cancer patients with CPS ≥20 achieved a pCR rate exceeding 50%, indicating a favorable subgroup. Similar results were observed in the Checkmate 7FL trial.
Researchers also differentiated subpopulations based on ER expression levels. In the KEYNOTE-756 trial, the ER <10% subgroup had a pCR rate exceeding 50%. In the Checkmate 7FL trial, the ER cutoff was raised to 50%, with the ER ≤50% subgroup also achieving a pCR rate over 50%. The long-term EFS and OS results from these trials are highly anticipated.
Professor Wang also pointed out that the pCR rates of Chinese patients in these trials were lower than those of the overall population, indicating the need for more research data on neoadjuvant immunotherapy in HR+/HER2- breast cancer in Chinese patients.
In conclusion, Professor Wang summarized that neoadjuvant treatment for HR+/HER2- breast cancer has not yet entered the immunotherapy era. However, immunotherapy has achieved therapeutic breakthroughs in early-stage HR+/HER2- breast cancer, suggesting that some patients may enter the era of neoadjuvant immunotherapy.
Professor Leiping Wang Fudan University Cancer Hospital, Department of Oncology Member of the Youth Group of the Breast Oncology Committee of the Chinese Medical Association Member of the Breast Cancer Professional Committee of the Chinese Research Hospital Association Young Member of the Breast Cancer Professional Committee of the Chinese Anti-Cancer Association Young Member of the Drug Clinical Research Committee of the Chinese Anti-Cancer Association
