ABSTRACT
The results of the SOLAR-1 and CAPItello-291, highlight the benefit of the É-selective phosphoinositide 3-Kinase Pathway inhibitor (PI3Ki) alpelisib and the AKT inhibitor (AKTi) capivasertib in patients with hormone receptor-positive (HR+)/Human Epidermal Growth Factor Receptor 2 (HER2)- negative metastatic breast cancer (mBC) that have PIK3CA/AKT1/PTEN tumour alterations. Although effective, these drugs are associated with significant toxicities, which often limit their use, particularly in frail patients. Following the recent incorporation of these agents into clinical practice, and with many others currently in development, significant challenges have emerged, particularly those regarding biomarkers for patient selection. This review will discuss biomarkers of response and their resistance to PI3K/AKT inhibitors (PI3K/AKTis) in HR+/HER- BC in early and advanced settings to ascertain which populations will most benefit from these drugs. Of the biomarkers that were analysed, such as PIK3CA, AKT, PTEN mutations, insulin levels, 18â¯F-FDG-PET/TC, only the PIK3CA-mutations (PIK3CA-mut) and the AKT pathway alterations seem to have a predictive value for treatments with alpelisib and capivasertib. However, due to the retrospective and exploratory nature of the study, the data did not provide conclusive results. In addition, the different methods used to detect PIK3CA/AKT1/PTEN alterations underline the fact that the optimal diagnostic companion has yet to be established. We have summarised the clinical data on the approved and discontinued agents targeting this pathway and have assessed the drugs development, successes, and failures. Finally, because of tumour heterogeneity, we emphasise the importance of reassessing the mutational status of PI3KCA in both metastatic tissue and blood at the time of disease progression to better tailor treatment for patients.
Subject(s)
Biomarkers, Tumor , Breast Neoplasms , Proto-Oncogene Proteins c-akt , Receptor, ErbB-2 , Humans , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Breast Neoplasms/drug therapy , Breast Neoplasms/diagnosis , Breast Neoplasms/genetics , Female , Receptor, ErbB-2/metabolism , Receptor, ErbB-2/genetics , Proto-Oncogene Proteins c-akt/metabolism , Biomarkers, Tumor/metabolism , Biomarkers, Tumor/genetics , Signal Transduction/drug effects , Phosphatidylinositol 3-Kinases/metabolism , Protein Kinase Inhibitors/therapeutic use , Protein Kinase Inhibitors/pharmacology , Phosphoinositide-3 Kinase Inhibitors/therapeutic use , Phosphoinositide-3 Kinase Inhibitors/pharmacology , Class I Phosphatidylinositol 3-Kinases/genetics , Class I Phosphatidylinositol 3-Kinases/antagonists & inhibitors , Class I Phosphatidylinositol 3-Kinases/metabolism , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/pharmacologyABSTRACT
BACKGROUND: Immune checkpoint blockade (ICB) in combination with chemotherapy improves outcome of patients with triple-negative breast cancer (TNBC) in metastatic and early settings. The identification of predictive biomarkers able to guide treatment decisions is challenging and currently limited to programmed death-ligand 1 (PD-L1) expression and high tumor mutational burden (TMB) in the advanced setting, with several limitations. MATERIALS AND METHODS: We carried out a retrospective analysis of clinical-pathological and molecular characteristics of tumor samples from 11 patients with advanced TNBC treated with single-agent pembrolizumab participating in two early-phase clinical trials: KEYNOTE-012 and KEYNOTE-086. Clinical, imaging, pathological [i.e. tumor-infiltrating lymphocytes (TILs), PD-L1 status], RNA sequencing, and whole-exome sequencing data were analyzed. We compared our results with publicly available transcriptomic data from TNBC cohorts from TCGA and METABRIC. RESULTS: Response to pembrolizumab was heterogeneous: two patients experienced exceptional long-lasting responses, six rapid progressions, and three relatively slower disease progression. Neither PD-L1 nor stromal TILs were significantly associated with response to treatment. Increased TMB values were observed in tumor samples from exceptional responders compared to the rest of the cohort (P = 3.4 × 10-4). Tumors from exceptional responders were enriched in adaptive and innate immune cell signatures. Expression of regulatory T-cell markers (FOXP3, CCR4, CCR8, TIGIT) was mainly observed in tumors from responders except for glycoprotein-A repetitions predominant (GARP), which was overexpressed in tumors from rapid progressors. GARP RNA expression in primary breast tumors from the public dataset was significantly associated with a worse prognosis. CONCLUSIONS: The wide spectrum of clinical responses to ICB supports that TNBC is a heterogeneous disease. Tumors with high TMB respond better to ICB. However, the optimal cut-off of 10 mutations (mut)/megabase (Mb) may not reflect the complexity of all tumor subtypes, despite its approval as a tumor-agnostic biomarker. Further studies are required to better elucidate the relevance of the tumor microenvironment and its components as potential predictive biomarkers in the context of ICB.
