Phase I/II clinical trial of everolimus combined with gemcitabine/cisplatin for metastatic triple-negative breast cancer

Abstract

Background: The PI3K/AKT/mTOR pathway is an important oncogenic driver in triple-negative breast cancer (TNBC). This study investigated the clinical efficacy and safety of the combination of gemcitabine and cisplatin with everolimus (GPE) in patients with metastatic TNBC.Methods: In phase I, we assessed the maximum tolerated dose (MTD) of GPE in metastatic TNBC patients. Then, using a seamless design, we conducted a randomized phase II trial to compare GPE to GP in terms of progression-free survival (PFS) and toxicity. In addition, we investigated the mutational status of PIK3CA (E542K, E545K, H1047R) in tumor tissues (n=14) and cell-free DNA (cfDNA) from blood samples (n=23) using droplet digital PCR.Results: In phase I (n=9), we found that the MTD of GPE was gemcitabine 800 mg/m2 and cisplatin 30 mg/m2 on days 1 and 8 every 3 weeks along with everolimus 5 mg daily. Phase II was terminated early after 14 patients had been enrolled because of slow recruitment and concerns about efficacy. Results of the combined analysis of phases I and II showed the objective response rate (ORR) of GPE (n=16) was 31.3% and the median PFS was 5.5 months (95% CI, 3.5-7.5). Stomatitis and hematologic toxicities were observed most frequently in the GPE arm. PIK3CA mutations were identified in 8 (57.1%) tumor samples and 17 (73.9%) cfDNA samples; there was no significant association between PIK3CA mutation status and response to GPE treatment.Conclusions: Although the majority of patients with metastatic TNBC demonstrated PIK3CA mutations in cfDNA, the addition of everolimus to gemcitabine/cisplatin did not have a synergistic effect in these patients. Further studies are needed to determine the most effective way to target the PI3K/AKT/mTOR pathway in TNBC patients.

Elevated estrogen receptor β expression in triple negative breast cancer cells is associated with sensitivity to doxorubicin by inhibiting the PI3K/AKT/mTOR signaling pathway

“…However, Park et al (31) previously found that the addition of the mTOR inhibitor everolimus to the gemcitabine/cisplatin treatment strategy did not result in a synergistic effect in patients with metastatic TNBC. In addition, the toxicities of everolimus, including stomatitis and hematologic toxicities, should be considered (31,34). The identification of other inhibitors of the PI3K/AKT/mTOR signaling pathway, which display increased tolerance and decreased toxicity, is essential for the effective treatment of TNBC.…”

“…In TNBC, the PI3K/AKT/mTOR signaling pathway serves as an oncogenic driver (30). PI3K mutations were reported in 73.9% cfDNA samples and 57.1% tumor samples obtained from patients with metastatic TNBC (31). In addition, overexpression of PI3K and overactivation of the PI3K/AKT/mTOR signaling pathway are associated with chemical drug resistance in breast cancer cells (32,33).…”

“…In addition, overexpression of PI3K and overactivation of the PI3K/AKT/mTOR signaling pathway are associated with chemical drug resistance in breast cancer cells ( 32 , 33 ). Therefore, some have hypothesized that combined treatment, including standard chemotherapy and specifically target components of the PI3K/AKT/mTOR signaling pathway could be used to effectively treat TNBC ( 31 ). However, Park et al ( 31 ) previously found that the addition of the mTOR inhibitor everolimus to the gemcitabine/cisplatin treatment strategy did not result in a synergistic effect in patients with metastatic TNBC.…”

Targeting mTOR and Metabolism in Cancer: Lessons and Innovations

“…In a randomized phase II study in patients with triple negative breast cancer, addition of everolimus to the paclitaxel/cisplatin combination was associated with more adverse events without improvement in clinical response compared to paclitaxel/cisplatin treatment [268]. In a phase I/II clinical trial of everolimus combined with gemcitabine/cisplatin for metastatic triple negative breast cancer, the combination treatment did not have synergistic effects despite the majority of patients harboring PIK3CA mutations [269]. The combination of ridaforolimus with paclitaxel and carboplatin in a phase I study in patients with solid tumor cancers showed antineoplastic activity with no unanticipated toxicities [266].…”

<p>Advances in the Detection Technologies and Clinical Applications of Circulating Tumor DNA in Metastatic Breast Cancer</p>

“…26 Park et al reported that more than 70% of the cfDNA samples of patients with MTNBC had PIK3CA hotspot mutations and the mutation frequency increased after the treatment. 81 In recent years, a number of studies supporting the prognostic role of PIK3CA in ABC have been carried out. [36][37][38]45,65,[82][83][84] O'Leary et al found that PIK3CA ctDNA level after 15 days' treatment strongly predicted the PFS of ABC patients on palbociclib and fulvestrant (hazard ratio 3.94, log-rank P = 0.0013).…”