PIK3CA and MAP3K1 alterations imply luminal A status and are associated with clinical benefit from pan-PI3K inhibitor buparlisib and letrozole in ER+ metastatic breast cancer

Abstract

Clinical trials have demonstrated the efficacy of combining phosphoinositide 3-kinase (PI3K) inhibitors with endocrine therapies in hormone therapy-refractory breast cancer. However, biomarkers of PI3K pathway dependence in ER+ breast cancer have not been fully established. Hotspot mutations in the alpha isoform of PI3K (PIK3CA) are frequent in ER+ disease and may identify tumors that respond to PI3K inhibitors. It is unclear whether PIK3CA mutations are the only biomarker to suggest pathway dependence and response to therapy. We performed correlative molecular characterization of primary and metastatic tissue from patients enrolled in a phase Ib study combining buparlisib (NVP-BKM-120), a pan-PI3K inhibitor, with letrozole in ER+, human epidermal growth factor-2 (HER2)-negative, metastatic breast cancer. Activating mutations in PIK3CA and inactivating MAP3K1 mutations marked tumors from patients with clinical benefit (≥6 months of stable disease). Patients harboring mutations in both genes exhibited the greatest likelihood of clinical benefit. In ER+ breast cancer cell lines, siRNA-mediated knockdown of MAP3K1 did not affect the response to buparlisib. In a subset of patients treated with buparlisib or the PI3Kα inhibitor alpelisib each with letrozole where PAM50 analysis was performed, nearly all tumors from patients with clinical benefit had a luminal A subtype. Mutations in MAP3K1 in ER+ breast cancer may be associated with clinical benefit from combined inhibition of PI3K and ER, but we could not ascribe direct biological function therein, suggesting they may be a surrogate for luminal A status. We posit that luminal A tumors may be a target population for this therapeutic combination.

Intrinsic Genetic and Transcriptomic Patterns Reflect Tumor Immune Subtypes Facilitating Exploring Possible Combinatory Therapy

“…PIK3CA and MAP3K1 gene is significantly mutated in Luminal A subtypes (Supplementary Figure S2H), while Luminal A subtypes are significantly enriched in C3 immune subtype (Supplementary Figure S2C), which is consistent with the results that PIK3CA and MAP3K1 gene mutated significantly in C3 immune subtypes. Previous study also suggested that PIK3CA and MAP3K1 alterations imply luminal A status in breast cancer and are associated with clinical benefits from PI3K inhibitors (Nixon et al, 2019). GATA3 gene is significantly mutated in Luminal B subtypes (Supplementary Figure S2H), while Luminal B subtypes are significantly enriched in C4 immune subtypes (Supplementary Figure S2D), which is consistent with the result that GATA3 gene mutated significantly in C4 immune subtypes.…”

Role of PI3K/AKT pathway in cancer: the framework of malignant behavior

“…Hence, dual blockade of the Her2 and ER pathways is necessary for the treatment of ER+/Her2 mutant BCs [168]. Moreover, PIK3CA and MAP3K1 alterations reveal Luminal A status in ER+ metastatic BCs and the patients are likely to clinically benefit from BKM120 [169]. On the other hand, top to 70% of patients with breast cancer brain metastases (BCBM) show the activated PI3K pathway [170], and GDC-0084 induces apoptosis of PIK3CA-mutant BCBM cells by suppressing activation of AKT and p70 S6 kinase [171].…”

Genomic Signatures in Luminal Breast Cancer

“…PIK3CA is recurrently mutated in about 30-40% of ER+ breast tumors and it is therefore one of the most fre-quent genetic aberrations in luminal breast cancer [55]. This suggests a dependency of ER+ breast cancer cells on the PI3K/AKT/mTOR signaling pathway and provides a promising therapeutic target [83]. Alpelisib is a p110α isoform specific oral PIK3CA inhibitor, and results from the SOLAR I trial showed a benefit from treatment with Alpelisib in combination with fulvestrant in patients with advanced breast cancer carrying PIK3CA mutations [84].…”

“…Alpelisib is a p110α isoform specific oral PIK3CA inhibitor, and results from the SOLAR I trial showed a benefit from treatment with Alpelisib in combination with fulvestrant in patients with advanced breast cancer carrying PIK3CA mutations [84]. These PIK3CA mutations remain almost stable between the primary tumor and metastases, indicating that a biopsy of the primary tumor site is sufficient for therapy indication [83]. Therefore, routine molecular testing for PIK3CA mutations should be implemented for the treatment of ER+ metastatic disease.…”