Everolimus in hormone receptor-positive metastatic breast cancer: PIK3CA mutation H1047R was a potential efficacy biomarker in a retrospective study

Abstract

Background Everolimus, an inhibitor of mammalian target of rapamycin ( mTOR ), has been shown to increase the efficacy of endocrine therapies in hormone receptor (HR)-positive metastatic breast cancer. However, because breast cancer is a highly heterogeneous disease, the responses of different patients to everolimus may vary. Therefore, we performed this study to better select patients who will benefit most from or be resistant to everolimus. Methods Patients with HR-positive breast cancer who were treated with everolimus at the Cancer Hospital, Chinese Academy of Medical Sciences from February 2014 to March 2017 were enrolled in the present study. Mutations in ctDNA were assayed in 1021 tumor-related genes via gene panel target capture-based next-generation sequencing. Results In total, 120 patients with metastatic breast cancer who were treated with everolimus were enrolled in the present study. The median progression-free survival (PFS) of all patients was 5.1 months (95% confidence interval [CI] 3.9–6.3 months). No difference in survival was observed between patients who received endocrine drugs used in previous treatment regimens and patients who did not receive these drugs (median PFS 5.2 and 5.1 months, respectively, p > 0.05). Additionally, we did not find any difference in outcomes between patients who had primary resistance to previously used endocrine drugs and patients who had nonprimary resistance to previous treatments ( p > 0.05). Multivariate analysis showed that < 3 metastatic sites, < 2 lines of previous endocrine therapy, < 2 lines of previous chemotherapy, and treatment with everolimus combined with fulvestrant were associated with improved survival ( p < 0.05). Sixteen patients underwent ctDNA analysis before everolimus treatment. The frequency of PIK3CA gene mutations was 62.5%, and H1047R was the most frequently detected mutation. Patients with the PIK3CA/ H1047R mutation had longer PFS than patients with wild-type or other mutant forms of PIK3CA , and the median PFS in these two groups of patients was 8.8 and 4.1 months, respectively ( p < 0.05). Conclusions Our data suggest that patients who receive more lines of chemotherapy or endocrine therapy are less likely to benefit from everolimus. For everolimus combination therapy, we can even select endocrine drugs that gave rise to primary resistance in previous treatments. Additionally, the PIK3CA/ H1047R mutation may be a potential biomarker of sensitivity to everolimus. Electronic supplementary material The online version of this article (10.1186/s12885-019-5668-3) contains supplementary material, which is available to authorized users.

PI3K/AKT/mTOR Signaling Pathway in Breast Cancer: From Molecular Landscape to Clinical Aspects

“…Moreover, studies have shown that everolimus enhances letrozole effects, blocking the breast cell cycle and stimulating apoptosis [ 185 ]. On the other hand, another study that included 120 women with hormone receptor-positive metastatic breast cancer treated with endocrine therapy and more chemotherapy agents revealed that no significant benefits were obtained by adding everolimus to the therapeutic strategy [ 186 ].…”

PI3K pathway protein analyses in metastatic breast cancer patients receiving standard everolimus and exemestane

“…In the placebo arm, however, patients with an E545K/E542K mutation had a shorter PFS than those with wild-type PIK3CA . Yi et al (Yi et al 2019 ) have reported in a small study on pre-treatment ctDNA from 16 MBC patients receiving everolimus plus endocrine therapy that patients with the PIK3CA /H1047R mutation had a longer PFS than those with wild-type or other mutant forms of PIK3CA. Our ctDNA analyses including 10 relevant breast cancer genes recently performed in the current study cohort has revealed that patients with low/no ctDNA load or < 3 hotspot mutations experienced a longer PFS while treated with EVE/EXE (Kruger et al 2020 ).…”

Applied precision cancer medicine in metastatic biliary tract cancer

“…One of the patients harbored a PIK3CA and a KRAS mutation and had an expression of progesterone receptor. A study by Yi et al [22] suggests that PIK3CA mutation may be a potential biomarker of sensitivity to everolimus. Thus, everolimus was recommended in combination with an aromatase inhibitor.…”