Breast cancer (BC) remains a significant health challenge for women in the United States, but advancements in treatment are markedly improving outcomes. Joyce O’Shaughnessy, MD, a hematology and oncology specialist at Texas Oncology, presented recent data at the National Community Oncology Dispensing Association Fall Summit, highlighting progress in treating both early and metastatic BC. These advancements include the use of CDK4/6 inhibitors, checkpoint inhibitors, and targeted therapies, offering more personalized and effective treatment strategies.
HR+/HER2- Breast Cancer Treatment Strategies
Hormone receptor–positive, human epidermal growth factor receptor 2–negative (HR+/HER2–) breast cancer is the most common subtype, accounting for approximately 70% of new cases. A significant challenge in treating early-stage HR+/HER2– BC is determining which patients benefit from chemotherapy (CT). The RxPONDER trial evaluated the role of endocrine therapy (ET) with or without CT in women with HR+/HER2–, axillary lymph-node–negative BC.
The RxPONDER trial randomized 5083 pre- and postmenopausal women and found that premenopausal women with 1 to 3 positive lymph nodes and a recurrence score of 25 or lower experienced longer invasive disease–free survival and distant relapse–free survival with chemo-ET compared to endocrine-only therapy. However, postmenopausal women with similar characteristics did not benefit from adjuvant CT. According to O’Shaughnessy, this raises the question of whether CT primarily acts as an endocrine therapy in postmenopausal patients, suggesting that LHRH agonists may be a more appropriate treatment option.
Further analysis of the RxPONDER trial indicated that anti-Mullerian hormone (AMH) levels, which indicate ovarian function, can predict which patients will benefit from CT. Patients with low AMH levels did not benefit from CT, suggesting that CT may work through ovarian function suppression. Preliminary data from the FLEX trial also suggest a potential benefit of anthracycline-based CT for patients with high AMH levels in HR-positive, HER2-negative EBC.
CDK4/6 Inhibitors in Early Breast Cancer
Adjuvant CDK4/6 inhibitors have shown success in treating patients with high-risk, HR+/HER2–, node-positive EBC. These inhibitors, such as abemaciclib (Verzenio; Eli Lilly) and ribociclib (Kisqali; Novartis), target CDK4/6 proteins, which promote cancer cell growth. The monarchE trial demonstrated a 5-year 7.6% absolute improvement in IDFS with abemaciclib, while the NATALEE trial showed a 4.9% absolute IDFS improvement with ribociclib. Importantly, dose reduction in these studies did not compromise efficacy and improved patient adherence.
Checkpoint Inhibitors in High-Risk Breast Cancer
Checkpoint inhibitors like pembrolizumab (Keytruda; Merck) and nivolumab (Opdivo; Bristol Myers Squibb) are also being used to treat high-risk, HR+/HER2– breast cancer. Trials such as KEYNOTE-756 and CheckMate 7FL have shown that the benefit from checkpoint inhibitors is more pronounced in patients with high PDL1 expression and low estrogen receptor expression.
Advancements in Metastatic Breast Cancer Treatment
Metastatic BC (MBC) remains a significant concern, with 1 in 3 women diagnosed with BC developing MBC. The first-line standard of care for MBC includes CDK4/6 inhibitors such as palbociclib (Ibrance; Pfizer), ribociclib, or abemaciclib, combined with an aromatase inhibitor. For patients who progress after first-line CDK4/6 inhibitor therapy, abemaciclib plus fulvestrant (Faslodex; AstraZeneca) is suggested, based on data from the postMONARCH trial.
In the phase 3 KEYNOTE 522 trial, patients with previously untreated stage 2 or stage 3 triple-negative BC receiving neoadjuvant therapy with pembrolizumab plus paclitaxel and carboplatin showed an absolute improvement in event-free survival of 9% and a statistically significant improvement in overall survival of 4.9% after 5 years.
Data from the DESTINY-Breast04 trial showed that patients with HER2-low, HR+/HER2–, stage 4 MBC experienced improved progression-free survival when adding trastuzumab deruxtecan (Enhertu: AstraZeneca) to CT. This was also observed for patients with stage 2 and 3 diseases in the DESTINY-Breast06 trial, highlighting the agent’s potential efficacy across various stages of disease.
The Path Forward
The advancements in BC treatment, particularly in targeted therapies, CDK4/6 inhibitors, and checkpoint inhibitors, are revolutionizing approaches in both early and metastatic disease. As research continues to uncover more effective combinations and therapies, patients benefit from improved survival rates and enhanced quality of life. However, with ongoing challenges in treating high-risk populations, precision medicine remains essential in delivering optimal outcomes for BC patients, and continued clinical research is key to optimizing health outcomes.
