PI3K inhibition enhances the anti-tumor effect of eribulin in triple negative breast cancer

Loss of the tumor suppressor phosphatase and tensin homolog (PTEN) is commonly observed in triple negative breast cancer (TNBC), leading to activation of the phosphoinositide 3-kinase (PI3K) signaling to promote tumor cell growth and chemotherapy resistance. In this study, we investigated whether adding a pan-PI3K inhibitor could improve the cytotoxic effect of eribulin, a non-taxane microtubule inhibitor, in TNBC patient-derived xenograft models (PDX) with loss of PTEN, and the underlying molecular mechanisms. Three TNBC-PDX models (WHIM6, WHIM12 and WHIM21), all with loss of PTEN expression, were tested for their response to BKM120 and eribulin, alone or in combinatio

Clinical challenges in the management of hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer: A literature review

Endocrine therapy (ET) is integral to the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC). Aromatase inhibitors (AIs; e.g., anastrozole, letrozole, exemestane), selective estrogen receptor modulators (e.g., tamoxifen), and the selective estrogen receptor degrader, fulvestrant, inhibit tumor cell proliferation by targeting ER signaling. However, the efficacy of ET could be limited by intrinsic and acquired resistance mechanisms, which has prompted the development of targeted agents and combination strategies. In recent years, the treatment landscape for HR+, HER2- MBC has evolved rapidly. AIs, historically the first-line treatment for postmenopausal patients with HR+, HER2- MBC, have been challenged by more effective ET, such as fulvestrant alone or in combination with an AI, and the cyclin-dependent kinase (CDK)4/6 inhibitors, which have increasingly become the new standard of care. For endocrine-resistant disease (≥ second-line), clinical trials demonstrated that the mammalian target of rapamycin inhibitor, everolimus, enhanced the efficacy of exemestane or fulvestrant after progression on an AI. CDK4/6 inhibitors in combination with fulvestrant have demonstrated superior progression-free survival and overall survival versus fulvestrant alone. Recently, the combination of fulvestrant with alpelisib in phosphatidylinositol-4,5-bisphosphate 3-kinase (PIK3CA) mutated HR+, HER2- MBC following progression on or after ET was approved, based on the SOLAR-1 study. However, the optimal sequencing of treatments is unknown, especially following disease progression on a CDK4/6 inhibitor. This review aims to provide practical guidance for the management of HR+, HER2- MBC based on available data and the utility of genomic biomarkers, including germline breast cancer genes 1 and 2 (BRCA1/2) mutations, and somatic estrogen receptor alpha gene (ESR1), HER2, and PIK3CA mutations

KSTAR: An algorithm to predict patient-specific kinase activities from phosphoproteomic data

Kinase inhibitors as targeted therapies have played an important role in improving cancer outcomes. However, there are still considerable challenges, such as resistance, non-response, patient stratification, polypharmacology, and identifying combination therapy where understanding a tumor kinase activity profile could be transformative. Here, we develop a graph- and statistics-based algorithm, called KSTAR, to convert phosphoproteomic measurements of cells and tissues into a kinase activity score that is generalizable and useful for clinical pipelines, requiring no quantification of the phosphorylation sites. In this work, we demonstrate that KSTAR reliably captures expected kinase activity differences across different tissues and stimulation contexts, allows for the direct comparison of samples from independent experiments, and is robust across a wide range of dataset sizes. Finally, we apply KSTAR to clinical breast cancer phosphoproteomic data and find that there is potential for kinase activity inference from KSTAR to complement the current clinical diagnosis of HER2 status in breast cancer patients

Interplay between ESR1/PIK3CA codon variants, oncogenic pathway alterations and clinical phenotype in patients with metastatic breast cancer (MBC): Comprehensive circulating tumor DNA (ctDNA) analysis

BACKGROUND: although being central for the biology and druggability of hormone-receptor positive, HER2 negative metastatic breast cancer (MBC), ESR1 and PIK3CA mutations are simplistically dichotomized as mutated or wild type in current clinical practice. METHODS: The study analyzed a multi-institutional cohort comprising 703 patients with luminal-like MBC characterized for circulating tumor DNA through next generation sequencing (NGS). Pathway classification was defined based on previous work (i.e., RTK, RAS, RAF, MEK, NRF2, ER, WNT, MYC, P53, cell cycle, notch, PI3K). Single nucleotide variations (SNVs) were annotated for their oncogenicity through OncoKB. Only pathogenic variants were included in the models. Associations among clinical characteristics, pathway classification, and ESR1/PIK3CA codon variants were explored. RESULTS: The results showed a differential pattern of associations for ESR1 and PIK3CA codon variants in terms of co-occurring pathway alterations patterns of metastatic dissemination, and prognosis. ESR1 537 was associated with SNVs in the ER and RAF pathways, CNVs in the MYC pathway and bone metastases, while ESR1 538 with SNVs in the cell cycle pathway and liver metastases. PIK3CA 1047 and 542 were associated with CNVs in the PI3K pathway and with bone metastases. CONCLUSIONS: The study demonstrated how ESR1 and PIK3CA codon variants, together with alterations in specific oncogenic pathways, can differentially impact the biology and clinical phenotype of luminal-like MBC. As novel endocrine therapy agents such as selective estrogen receptor degraders (SERDS) and PI3K inhibitors are being developed, these results highlight the pivotal role of ctDNA NGS to describe tumor evolution and optimize clinical decision making

Association of PET-based estradiol-challenge test for breast cancer progesterone receptors with response to endocrine therapy

Clinical estrogen receptor (ER) testing for breast cancer is limited in predicting response to endocrine therapy (ET). In this phase 2 clinical trial, authors demonstrate that the responsiveness to ET can be predicted by use of PET/CT with 21-[18F]fluorofuranylnorprogesterone (FFNP) to detect the change in tumor progesterone receptor (PgR) levels after a one-day estradiol challenge