Multiple PIK3CA mutation clonality correlates with outcomes in taselisib + fulvestrant-treated ER+/HER2-, PIK3CA-mutated breast cancers.

Background: Mutations in the p110α catalytic subunit of phosphatidylinositol 3-kinase (PI3K), encoded by the PIK3CA gene, cause dysregulation of the PI3K pathway in 35-40% of patients with HR+/HER2- breast cancer. Preclinically, cancer cells harboring double or multiple PIK3CA mutations (mut) elicit hyperactivation of the PI3K pathway leading to enhanced sensitivity to p110α inhibitors.

Methods: To understand the role of multiple PIK3CAmut in predicting response to p110α inhibition, we estimated the clonality of multiple PIK3CAmut in circulating tumor DNA (ctDNA) from patients with HR+/HER2- metastatic breast cancer enrolled to a prospectively registered clinical trial of fulvestrant ± taselisib, and analyzed the subgroups against co-altered genes, pathways, and outcomes.

ER+, HER2- advanced breast cancer treated with taselisib and fulvestrant: genomic landscape and associated clinical outcomes.

Taselisib is a potent β-sparing phosphatidylinositol 3-kinase (PI3K) inhibitor that, with endocrine therapy, improves outcomes in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA)-mutated (PIK3CAmut) advanced breast cancer. To understand alterations associated with response to PI3K inhibition, we analysed circulating tumour DNA (ctDNA) from participants enrolled in the SANDPIPER trial. Participants were designated as either PIK3CAmut or PIK3CA no mutation was detected (NMD) per baseline ctDNA.

Comparison of Mutation Prevalence in Breast Cancer Across Predicted Ancestry Populations.

Purpose: Understanding the differences in biomarker prevalence that may exist among diverse populations is invaluable to accurately forecast biomarker-driven clinical trial enrollment metrics and to advance inclusive research and health equity. This study evaluated the frequency and types of mutations (mut) detected in predicted genetic ancestry subgroups across breast cancer (BC) subtypes.

Methods: Analyses were conducted using real-world genomic data from adult patients with BC treated in an academic or community setting in the United States and whose tumor tissue was submitted for comprehensive genomic profiling.

Phase I Basket Study of Taselisib, an Isoform-Selective PI3K Inhibitor, in Patients with -Mutant Cancers.

Purpose: Somatic mutations in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (), which encodes the p110α catalytic subunit of PI3K, are found in multiple human cancers. While recurrent mutations in helical, regulatory, and kinase domains lead to constitutive PI3K pathway activation, other mutations remain uncharacterized. To further evaluate their clinical actionability, we designed a basket study for patients with -mutant cancers with the isoform-specific PI3K inhibitor taselisib.

Predictive and Pharmacodynamic Biomarkers of Response to the Phosphatidylinositol 3-Kinase Inhibitor Taselisib in Breast Cancer Preclinical Models.

The PI3K signaling pathway serves as a central node in regulating cell survival, proliferation, and metabolism. , the gene encoding the PI3K catalytic subunit p110-alpha, is commonly altered in breast cancer resulting in the constitutive activation of the PI3K pathway. Using an unbiased cell line screening approach, we tested the sensitivity of breast cancer cell lines to taselisib, a potent PI3K inhibitor, and correlated sensitivity with key biomarkers (, HER2, PTEN, and ).

Tumor-Infiltrating Lymphocytes in Patients Receiving Trastuzumab/Pertuzumab-Based Chemotherapy: A TRYPHAENA Substudy.

Background: There is an urgent requirement to identify biomarkers to tailor treatment in human epidermal growth factor receptor 2 (HER2)-amplified early breast cancer treated with trastuzumab/pertuzumab-based chemotherapy.

Methods: Among the 225 patients randomly assigned to trastuzumab/pertuzumab concurrently or sequentially with an anthracycline-containing regimen or concurrently with an anthracycline-free regimen in the Tryphaena trial, we determined the percentage of tumor-infiltrating lymphocytes (TILs) at baseline in 213 patients, of which 126 demonstrated a pathological complete response (pCR; ypT0/is ypN0), with 28 demonstrating event-free survival (EFS) events. We investigated associations between baseline TIL percentage and either pCR or EFS after adjusting for clinicopathological characteristics using logistic and Cox regression models, respectively.

The molecular landscape of high-risk early breast cancer: comprehensive biomarker analysis of a phase III adjuvant population.

Breast cancer is a heterogeneous disease and patients are managed clinically based on ER, PR, HER2 expression, and key risk factors. We sought to characterize the molecular landscape of high-risk breast cancer patients enrolled onto an adjuvant chemotherapy study to understand how disease subsets and tumor immune status impact survival. DNA and RNA were extracted from 861 breast cancer samples from patients enrolled onto the United States Oncology trial 01062.

Phase I Dose-Escalation Study of Taselisib, an Oral PI3K Inhibitor, in Patients with Advanced Solid Tumors.

Taselisib is a potent and selective tumor growth inhibitor through PI3K pathway suppression. Thirty-four patients with locally advanced or metastatic solid tumors were treated (phase I study, modified 3+3 dose escalation; 5 cohorts; 3-16 mg taselisib once-daily capsule). Taselisib pharmacokinetics were dose-proportional; mean half-life was 40 hours.

The PI3K inhibitor taselisib overcomes letrozole resistance in a breast cancer model expressing aromatase.

Letrozole is a commonly used treatment option for metastatic hormone receptor-positive (HR+) breast cancer, but many patients ultimately relapse. Due to the importance of phosphoinositide-3 kinase (PI3K) in breast cancer, PI3K inhibitors such as taselisib are attractive for combination with endocrine therapies such as letrozole. Taselisib was evaluated as a single agent and in combination with letrozole in a breast cancer cell line engineered to express aromatase.

Heterogeneity and clinical significance of ESR1 mutations in ER-positive metastatic breast cancer patients receiving fulvestrant.

Mutations in ESR1 have been associated with resistance to aromatase inhibitor (AI) therapy in patients with ER+ metastatic breast cancer. Little is known of the impact of these mutations in patients receiving selective oestrogen receptor degrader (SERD) therapy. In this study, hotspot mutations in ESR1 and PIK3CA from ctDNA were assayed in clinical trial samples from ER+ metastatic breast cancer patients randomized either to the SERD fulvestrant or fulvestrant plus a pan-PI3K inhibitor.

Targeting activated Akt with GDC-0068, a novel selective Akt inhibitor that is efficacious in multiple tumor models.

Purpose: We describe the preclinical pharmacology and antitumor activity of GDC-0068, a novel highly selective ATP-competitive pan-Akt inhibitor currently in clinical trials for the treatment of human cancers.

Experimental Design: The effect of GDC-0068 on Akt signaling was characterized using specific biomarkers of the Akt pathway, and response to GDC-0068 was evaluated in human cancer cell lines and xenograft models with various genetic backgrounds, either as a single agent or in combination with chemotherapeutic agents.

Results: GDC-0068 blocked Akt signaling both in cultured human cancer cell lines and in tumor xenograft models as evidenced by dose-dependent decrease in phosphorylation of downstream targets.

Molecular biomarker analyses using circulating tumor cells.

Background: Evaluation of cancer biomarkers from blood could significantly enable biomarker assessment by providing a relatively non-invasive source of representative tumor material. Circulating Tumor Cells (CTCs) isolated from blood of metastatic cancer patients hold significant promise in this regard.

Methodology/principal Findings: Using spiked tumor-cells we evaluated CTC capture on different CTC technology platforms, including CellSearch and two biochip platforms, and used the isolated CTCs to develop and optimize assays for molecular characterization of CTCs.

Predictive biomarkers of sensitivity to the phosphatidylinositol 3' kinase inhibitor GDC-0941 in breast cancer preclinical models.

Purpose: The class I phosphatidylinositol 3' kinase (PI3K) plays a major role in proliferation and survival in a wide variety of human cancers. A key factor in successful development of drugs targeting this pathway is likely to be the identification of responsive patient populations with predictive diagnostic biomarkers. This study sought to identify candidate biomarkers of response to the selective PI3K inhibitor GDC-0941.

Molecular predictors of response to a humanized anti-insulin-like growth factor-I receptor monoclonal antibody in breast and colorectal cancer.

The insulin-like growth factor-I receptor (IGF-IR) pathway is required for the maintenance of the transformed phenotype in neoplastic cells and hence has been the subject of intensive drug discovery efforts. A key aspect of successful clinical development of targeted therapies directed against IGF-IR will be identification of responsive patient populations. Toward that end, we have endeavored to identify predictive biomarkers of response to an anti-IGF-IR-targeting monoclonal antibody in preclinical models of breast and colorectal cancer.

In vivo antitumor activity of MEK and phosphatidylinositol 3-kinase inhibitors in basal-like breast cancer models.

Purpose: The pathways underlying basal-like breast cancer are poorly understood, and as yet, there is no approved targeted therapy for this disease. We investigated the role of mitogen-activated protein kinase kinase (MEK) and phosphatidylinositol 3-kinase (PI3K) inhibitors as targeted therapies for basal-like breast cancer.

Experimental Design: We used pharmacogenomic analysis of a large panel of breast cancer cell lines with detailed accompanying molecular information to identify molecular predictors of response to a potent and selective inhibitor of MEK and also to define molecular mechanisms underlying combined MEK and PI3K targeting in basal-like breast cancer.

Proteomic analysis of breast cancer molecular subtypes and biomarkers of response to targeted kinase inhibitors using reverse-phase protein microarrays.

Although breast cancer molecular subtypes have been extensively defined by means of gene expression profiling over the past decade, little is known, at the proteomic level, as to how signaling pathways are differentially activated and serve to control proliferation in different breast cancer subtypes. We used reverse-phase protein arrays to examine phosphorylation status of 100 proteins in a panel of 30 breast cancer cell lines and showed distinct pathway activation differences between different subtypes that are not obvious from previous gene expression studies. We also show that basal levels of phosphorylation of key signaling nodes may have diagnostic utility in predicting response to selective inhibitors of phosphatidylinositol 3-kinase and mitogen-activated protein kinase/extracellular signal-regulated kinase kinase.