Different associations of tumor PIK3CA mutations and clinical outcomes according to aspirin use among women with metastatic hormone receptor positive breast cancer

Abstract

Introduction: The relationships among PIK3CA mutations, medication use and tumor progression remains poorly understood. Aspirin use post-diagnosis may modify components of the PI3K pathway, including AKT and mTOR, and has been associated with lower risk of breast cancer recurrence and mortality. We assessed time to metastasis (TTM) and survival with respect to aspirin use and tumor PIK3CA mutations among women with metastatic breast cancer.Methods: Patients with hormone receptor positive, HER2 negative (HR+/HER2-) metastatic breast cancer treated in 2009-2016 who received tumor genotyping were included. Aspirin use between primary and metastatic diagnosis was extracted from electronic medical records. TTM and survival were estimated using Cox proportional hazards regression. Results: Among 267 women with metastatic breast cancer, women with PIK3CA mutated tumors had longer TTM than women with PIK3CA wildtype tumors (7.1 vs. 4.7 years, p = 0.008). There was a significant interaction between PIK3CA mutations and aspirin use on TTM (p = 0.006) and survival (p = 0.026). PIK3CA mutations were associated with longer TTM among aspirin non-users (HR = 0.60 95% CI:0.44-0.82 p = 0.001) but not among aspirin users (HR = 1.57 0.86-2.84 p = 0.139). Similarly, PIK3CA mutations were associated with reduced mortality among aspirin non-users (HR = 0.70 95% CI:0.48-1.02 p = 0.066) but not among aspirin users (HR = 1.75 95% CI:0.88-3.49 p = 0.110).

The Metabolic Mechanisms of Breast Cancer Metastasis

“…PIK3CA mutation, which leads to increased PI3K activity, is the most common somatic mutation in breast cancer, and 36% of patients with HR+/HER2- breast cancer are PIK3CA mutated ( 196 ). It was suggested that crosstalk between the ER and PI3K/AKT/mTOR signaling pathway exists during breast cancer development ( 197 ).…”

“…Activation of mTORC1 is adequate to provoke the expression of genes encoding the enzymes of both the oxidative and non-oxidative branches of the PPP, thus activating specific bioenergetic and anabolic cellular processes (194). The PI3K/AKT/mTOR pathway was recently showed to reduce oxidative stress and promote cell survival of breast epithelial cells segregated from the ECM by strengthening flux through the oxidative PPP (195) PIK3CA mutation, which leads to increased PI3K activity, is the most common somatic mutation in breast cancer, and 36% of patients with HR+/HER2-breast cancer are PIK3CA mutated (196). It was suggested that crosstalk between the ER and PI3K/ AKT/mTOR signaling pathway exists during breast cancer development (197).…”

The effects of PIK3CA and TP53 on prognosis in patients with Triple-negative breast cancer (TNBC): a single institution’s long-term follow-up (6 years)

“…Besides, promising data have been observed in randomized phase II trials of AKT inhibitors combined with fulvestrant or paclitaxel in metastatic HR-positive, HER2-negative disease, and Triple-negative breast cancer (TNBC) [27]. A further study has suggested that aspirin can prolong the metastasis time of breast cancer patients with PIK3CA mutation [28].…”

“…Many studies have shown that the mutation of TP53 predicts the poor prognosis for breast cancer [30,31]. The mutation of TP53 leads to the loss of the function of its tumor suppressor gene and leads to malignant expression [28]. Nevertheless, TP53 has not been considered a target for drug therapy.…”

Pathophysiological Integration of Metabolic Reprogramming in Breast Cancer

“…PI3KCA mutations in breast cancer occur in 36% of ERα+ HER2- tumors [ 146 ]. Indeed, there is crosstalk between the two pathways, whereby ERα stimulates the PI3K/AKT/mTOR pathway, favoring migration and tumor invasion [ 147 ], and the PI3K/AKT/mTOR pathway activates the expression of ERα [ 148 , 149 ].…”