Urothelial bladder cancer (UBC) is a common malignancy with significant mortality. However, treatment options of UBC were mainly chemotherapy and immunotherapy since few targeted agents had shown efficacy in UBC [1]. Everolimus, as an inhibitor of mammalian target of rapamycin (mTOR), showed antitumor activity in patients harboring aberrations in phosphatidylinositol 3-kinase (PI3K)/ protein kinase B (Akt)/mTOR pathway in multiple tumor types such as renal cell and breast cancer (Janku et al. 2013). In this case, we report a patient with metastatic UBC harboring a rare M1043I mutation of PIK3CA, who responded well to everolimus.
In June 2020, an 81-year-old male was admitted to the hospital for 1-month-history of weakness and low back pain. Pelvic computed tomography (CT) revealed a space-occupying lesion in the left anterior wall of bladder (Fig. 1a); meanwhile, multiple lymph node metastases were confirmed. Besides, osseous metastasis was considered due to ostealgia although nothing was verified by CT. Palliative transurethral resection was performed and post-operational immunohistochemical (IHC) staining showed: CK20 (-), CK7 (+), Ki-67 (+30%), p53 (+), p63 (+), GATA-3 (+), Syn (-), CgA (-), CD3 (-), CD20 (-). These results suggested a diagnosis of stage IV UBC (T3bN1M1).
The patient refused chemotherapy because of poor physical condition. To seek for precision therapy, formalin-fixed and paraffin-embedded specimens were subjected to next-generation sequencing (NGS) analysis. The M1043I mutation of PIK3CA was detected (Fig. 2), the concurrent alterations were listed in Table 1. The patient received everolimus (10 mg orally daily) as first-line treatment and obtained complete remission of lymph node metastases and felt no ostealgia within 1 month. The disease was evaluated as complete response (CR) (Fig. 1b) and no progression was observed before submission.
To our knowledge, this case is the first report of a BC patient with M1043I mutation of PIK3CA who responded well to everolimus. Alteration of PIK3CA occurred in approximately 20% of UBC [1]. In our case, the patient harbored a rare M1042I mutation. This mutation located in the kinase domain of PIK3CA and could enhance the activation level and lipid binding capacity of the coded protein p110α, which will constitutively activate Akt/mTOR pathway and contribute to tumorigenesis and cancer progression [2].
Previous studies indicated that PIK3CA mutation was associated with better response to PI3K/Akt/mTOR inhibitors [3, 4]. Analysis in breast cancer also presented better response of H1047R mutation variant to everolimus than non-H1047R mutation/wild-type (progression-free survival of 8.8 months versus 4.1 months) [5]. As for UBC, Everolimus showed growth inhibitory effect of on the tumor cells with of PI3K/Akt/mTOR aberrations in preclinical studies [6], while the clinical evidence of everolimus in PIK3CA mutant BC is lacking. So far, only an early phase II study in BC observed 1 partial response/stable disease with E542K mutation and 2 progressed disease with E545K mutation of PIK3CA [3]. Therefore, the efficacy of everolimus in PIK3CA mutant BC remained unclear. Our patient reached CR within 1 month of everolimus treatment, this implies that everolimus might be a promising treatment option for UBC patients with PIK3CA mutation.
Meanwhile, as the first report of significant benefit from everolimus, we infer that the rare M1043I mutation variant may be a potential biomarker of sensitivity to everolimus. Although a concurrent PIK3CA amplification (Table 1) was discovered, it may not be the sensitive alteration responded to everolimus since a recent trial of everolimus in PIK3CA amplification/mutation patients with advanced solid tumors failed to observe any response [7]. Further study is needed to investigate the molecular and responding mechanism of PIK3CA M1043I mutation in UBC.