Recent advancements in sequencing and targeted therapies are transforming the management of hormone receptor (HR)-positive, HER2-negative metastatic breast cancer. According to Francisco J. Esteva, MD, PhD, next-generation sequencing (NGS) plays a pivotal role in tailoring treatment strategies for these patients. All patients with metastatic disease should undergo NGS to identify specific mutations that can inform treatment decisions.
The Role of NGS in Metastatic Breast Cancer
NGS helps identify genetic alterations in the PIK3CA kinase pathway, including mutations in PIK3CA, AKT, and P10. These mutations are particularly relevant as they can be targeted with new therapies. For patients without actionable mutations, CDK 4/6 inhibitors like palbociclib, ribociclib, or abemaciclib in combination with an aromatase inhibitor or fulvestrant remain a standard approach. However, the presence of PIK3CA mutations opens the door to novel treatment options.
SOLAR-1 Trial: Alpelisib and Fulvestrant
The phase 3 SOLAR-1 trial investigated alpelisib, a PIK3CA inhibitor, in combination with fulvestrant in postmenopausal women with HR-positive, HER2-negative metastatic breast cancer who had progressed on or after prior AI therapy. The study revealed that patients with PIK3CA mutations experienced improved progression-free survival (PFS) compared to those receiving placebo. However, the use of alpelisib was limited by a high incidence of hyperglycemia, rash, and other adverse effects.
INAVO120 Trial: Inavolisib, Palbociclib, and Fulvestrant
The phase 3 INAVO120 trial focused on patients with PIK3CA-mutated HR-positive, HER2-negative, locally advanced or metastatic breast cancer. Patients were randomized to receive palbociclib and fulvestrant with either placebo or inavolisib, a PIK3CA kinase inhibitor. The study demonstrated a significant improvement in progression-free survival with the inavolisib combination. The findings, presented at the San Antonio Breast Cancer Symposium and the ASCO Annual Meeting, and published in the New England Journal of Medicine, highlighted the potential to prolong PFS and delay the need for chemotherapy. The treatment was generally well-tolerated, with mostly grade 1 or 2 hyperglycemia, diarrhea, rash, and stomatitis.
CAPItello-291 Trial: Capivasertib and Fulvestrant
The CAPItello-291 trial involved patients with HR-positive, HER2-negative metastatic disease who had progressed on or after a prior CDK 4/6 inhibitor. Patients were randomized to receive capivasertib and fulvestrant or fulvestrant and placebo. The study showed that patients treated with capivasertib and fulvestrant had a longer PFS, particularly those with PI3K, AKT, or P10 alterations. The adverse events were generally acceptable, with most being grade 1 or 2, and the quality of life was maintained. Blood sugar levels were not significantly elevated in patients treated with capivasertib compared to placebo, suggesting a tolerable treatment option.
Antibody-Drug Conjugates in HER2-Low Breast Cancer
Another area of interest is the use of antibody-drug conjugates (ADCs) in HER2-low breast cancer. Patients with low levels of HER2, previously considered triple-negative, can now be treated with agents like fam-trastuzumab deruxtecan-nxki (Enhertu) or sacituzumab govitecan-hziy (Trodelvy). Further research is needed to determine the optimal sequencing of these therapies to maximize patient benefit.
Implications for Clinical Practice
The key takeaway is the importance of NGS in all patients with HR-positive, HER2-negative metastatic breast cancer to identify PI3K/AKT mutations. This information guides treatment decisions in both the first-line and second-line settings. Studies are also exploring the use of capivasertib in the frontline setting after AI therapy, further expanding treatment options.
