Editor’s Note:
The primary goal for early-stage breast cancer patients is cure, and numerous studies have explored treatment strategies based on this objective. In this edition of the ESMO conference, updates on studies such as monarchE, NATALEE, and KEYNOTE-522 in the field of early breast cancer treatment were presented. Data from the KEYNOTE-756 study suggested that incorporating immunotherapy into neoadjuvant/adjuvant treatment for early breast cancer could provide additional benefits for patients. Professor Man Li from Dalian Medical University Affiliated Second Hospital, a special guest in the field of oncology, provides insights into the advancements in early breast cancer treatment for our readers.
Professor Man Li: In this edition of the ESMO conference, several studies in the treatment of HR+/HER2- early breast cancer and triple-negative breast cancer were presented, shedding light on various evidence-based medical approaches on the path to achieving a cure.
For HR+/HER2- early breast cancer, we observed the frequent emergence of augmented treatment strategies in this conference. The release of data from the monarchE study, with a median follow-up of 4.5 years, once again confirmed the significant role of CDK4/6 inhibitors combined with endocrine therapy in the adjuvant enhanced treatment of HR+ early breast cancer patients.
At the 2020 SABCS conference, the monarchE study presented results with a median follow-up of 19.1 months, achieving the expected primary endpoint. Subsequently, data from the 3-year and 4-year follow-ups of the monarchE study have been continuously disclosed, allowing us to observe the sustained benefits for patients receiving abemaciclib treatment. The data from the 4.5-year follow-up, released at this conference, demonstrates that in the intention-to-treat (ITT) population, patients in the abemaciclib group continue to experience a persistent improvement in invasive disease-free survival (iDFS). The 5-year iDFS rate is 7.6% higher in the abemaciclib group compared to the control group, with a significant 32% reduction in the iDFS event risk (83.6% vs. 76.6%, HR 0.680, 95% CI: 0.599–0.772). The Kaplan-Meier curves for iDFS in both groups continue to diverge, indicating a sustained separation trend, and the absolute difference in iDFS rates expands each year. Subgroup analysis reveals that patients in different subgroups consistently benefit from abemaciclib treatment in terms of iDFS.
The 5-year Distant Recurrence-Free Survival (DRFS) rate in the abemaciclib group is 6.7% higher compared to the control group, with a significant 32.5% reduction in the risk of DRFS events (86.0% vs. 79.2%, HR 0.675, 95% CI: 0.588–0.774).
The disclosure of these data results allows us to see that the addition of abemaciclib (a CDK4/6 inhibitor) in HR+/HER2- early high-risk breast cancer patients can further enhance the long-term survival benefits for patients. Simultaneously, we now have more data on the road to cure for early HR+/HER2- breast cancer, warranting greater expectations for the use of CDK4/6 inhibitors in the treatment of early breast cancer patients.
For early HR+/HER2- breast cancer, positive primary endpoint results from the pivotal Phase III trial NATALEE were presented at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting. The data indicates that, compared to single-agent endocrine therapy, the combination of ribociclib with endocrine therapy significantly reduces the risk of tumor recurrence in stage II and III HR+/HER2- early breast cancer patients. The 3-year invasive Disease-Free Survival (iDFS) rates for the two groups were 90.4% vs. 87.1%, and the combination of ribociclib with endocrine therapy resulted in a 25.2% reduction in the 3-year iDFS event risk (HR 0.748; 95% CI: 0.618–0.906; P=0.0014) and a 26% reduction in the 3-year Distant Disease-Free Survival (DDFS) event risk (HR 0.739; 95% CI: 0.603–0.905; P=0.0017). Additionally, benefits were observed in all prespecified key subgroups.
At this ESMO conference, exploratory subgroup analysis results for the prespecified iDFS of enrolled patients in the NATALEE study were disclosed. As of January 11, 2023, this analysis included a total of 5,101 patients, with a median follow-up time of 27.7 months for both groups. Overall, in all clinically relevant subgroups, the iDFS benefit of ribociclib combined with endocrine therapy compared to single-agent endocrine therapy was consistent, aligning with the results observed in the overall population.
With our deepening understanding of adjuvant enhanced therapy for HR+/HER2- breast cancer, we can see that CDK4/6 inhibitors have made significant contributions to the path to cure for early HR+/HER2- breast cancer. Additionally, we look forward to the possibility of more novel CDK4/6 inhibitors in the future to help achieve a cure for early HR+/HER2- breast cancer patients.
Furthermore, at this year’s ESMO conference, we also noted bold attempts at immunotherapy in early breast cancer patients. The KEYNOTE-756 study aimed to compare the pathologic complete response (pCR) rates between the pembrolizumab/chemotherapy + endocrine therapy (ET) neoadjuvant treatment group and the placebo/chemotherapy + ET adjuvant treatment group in high-risk, ER+/HER2- early breast cancer. The study results showed that the pCR rate for the pembrolizumab combination with chemotherapy group vs. the placebo combination with chemotherapy group was 24.3% vs. 15.6%, with a treatment difference of 8.5%, 95% CI: 4.2–12.8; P=0.00005. In pre-specified subgroups, the pCR benefit was generally consistent, including tumor PD-L1 status (CPS≥1 vs. ＜1), lymph node involvement (positive vs. negative), and estrogen receptor (ER) positivity (≥10% vs. ＜10%).
With the announcement of the KEYNOTE-756 study results, we see that the use of immunotherapy in neoadjuvant/adjuvant treatment for HR+/HER2- breast cancer patients can increase the pathologic complete response (pCR) rate. Currently, the primary endpoint results for event-free survival (EFS) in this study are still immature, but it raises expectations for the future treatment outcomes of combining immunotherapy with neoadjuvant/adjuvant therapy. We look forward to this approach providing both short-term and long-term survival benefits.
For the treatment of HR+/HER2- early breast cancer patients, there are still many unknowns, such as whether to use CDK4/6 inhibitors for enhanced therapy in adjuvant treatment or to incorporate immunotherapy into neoadjuvant/adjuvant treatment. The relative merits and drawbacks of these approaches lack sufficient evidence-based medical data. We anticipate the release of more results from large randomized controlled clinical studies to guide HR+/HER2- early breast cancer patients on the path to cure.
At this year’s ESMO conference, in the field of early breast cancer treatment, there have been significant advances not only for HR+/HER2- subtype patients but also for triple-negative breast cancer patients. The KEYNOTE-522 study indicates that adding pembrolizumab to chemotherapy for early triple-negative breast cancer patients results in statistically and clinically significant improvements in pCR and EFS. The latest EFS results with a median follow-up of 63.1 months were updated at this conference.
As of March 23, 2023, with a median follow-up of 63.1 months, once again confirming the sustained benefits of neoadjuvant pembrolizumab combined with chemotherapy, the KEYNOTE-522 study demonstrated a continuous improvement in 60-month event-free survival (EFS) compared to the control group, with an increase of 9% (81.3% vs. 72.3%). Regardless of the pathologic complete response (pCR) results, the use of neoadjuvant pembrolizumab plus chemotherapy, followed by adjuvant treatment with palbociclib after surgery, provides sustained EFS benefits for stage II-III triple-negative breast cancer patients compared to neoadjuvant chemotherapy alone.
This informs us that for patients achieving a pathologic complete response (pCR), immunotherapy is necessary in both neoadjuvant and adjuvant treatments. In the future, using immunotherapy for patients who achieve pCR may lead to earlier and higher rates of cure. For patients who do not achieve pCR, the addition of immunotherapy in both neoadjuvant and adjuvant treatments is hoped to contribute to achieving a cure. Our efforts in enhancing treatment for early breast cancer patients continue, and we look forward to the emergence of more evidence-based medical data in the future to truly enable a cure for this patient population.
Doctor of Medicine, Professor, PhD Supervisor
Director of Oncology Department, Second Affiliated Hospital of Dalian Medical University
Liaoning Province Hundred, Thousand, Ten Thousand Talents Program – Hundred Talents Level
Director of the Chinese Society of Clinical Oncology
Executive Committee Member of the Breast Cancer Expert Committee, Chinese Society of Clinical Oncology (CSCO)
Member of the Breast Cancer Professional Committee, Chinese Anti-Cancer Association
Vice Chairman of the Oncology Branch, Liaoning Medical Association
Vice Chairman of the Breast Cancer Professional Committee, Liaoning Anti-Cancer Association
Nominee Chairman of the Tumor Metastasis Committee, Liaoning Anti-Cancer Association
Chairman of the Oncology Branch, Dalian Medical Association
