Faculty Collaboration Database

Landscape of Phosphatidylinositol-3-Kinase Pathway Alterations Across 19 784 Diverse Solid Tumors. JAMA Oncol 2016 Dec 01;2(12):1565-1573

Date

07/09/2016

Pubmed ID

27388585

DOI

10.1001/jamaoncol.2016.0891

Scopus ID

2-s2.0-85013149379 (requires institutional sign-in at Scopus site)   187 Citations

Abstract

IMPORTANCE: Molecular aberrations in the phosphatidylinositol-3-kinase (PI3K) pathway drive tumorigenesis. Frequently co-occurring alterations in hormone receptors and/or human epidermal growth factor receptor 2 (HER2) may be relevant to mechanisms of response and resistance.

OBJECTIVE: To identify patterns of aberration in the PI3K and interactive pathways that might lead to targeted therapy opportunities in clinical practice.

DESIGN, SETTING, AND PARTICIPANTS: From January 2013 through December 2014, 19 784 consecutive tumor samples (>40 cancer types) were sent from thousands of clinicians in 60 countries to a single commercial laboratory for molecular profiling, including next generation sequencing, protein expression (immunohistochemical analysis [IHC]), and gene amplification (fluorescent in situ hybridization or chromogenic in situ hybridization).

MAIN OUTCOMES AND MEASURES: Patterns in targetable genomic and proteomic alterations in the PI3K pathway and coincidence with hormone receptor and HER2 alterations.

EXPOSURES: Molecular profiling across solid tumors.

RESULTS: Overall, 38% of patients had an alteration in 1 or more PI3K pathway components, most commonly phosphatase and tensin homologue (PTEN) loss (by IHC) (30% of all patients), followed by mutations in PIK3CA (13%), PTEN (6%), or AKT1 (1%). Seventy percent of patients with endometrial cancer and more than 50% of patients with breast, prostate, anal, hepatocellular, colorectal, and cervical cancer exhibited alterations in at least 1 PI3K pathway gene and/or gene product. Examples of frequent aberrations included PTEN loss in hepatocellular (57% of patients), colorectal (48%), gastric (36%), prostate (52%), and endometrial cancer (49%); PIK3CA mutations in endometrial (37%), breast (31%), cervical (29%), and anal cancer (27%). PIK3CA, PTEN, and AKT1 mutations occurred more frequently in the presence of hormone receptor overexpression (androgen, progesterone, or estrogen receptor). PIK3CA mutations were also more common in the HER2-positive than in the HER2-negative group; the opposite pattern was seen for PTEN mutation or PTEN loss.

CONCLUSIONS AND RELEVANCE: PI3K pathway aberrations are among the most common in cancer. They do not segregate by classic cancer histologic characteristics. Patterns of biomarker coalterations involving HER2 and hormone receptors may be important for optimizing combination treatments across cancer types.

Author List

Millis SZ, Ikeda S, Reddy S, Gatalica Z, Kurzrock R

Author

Razelle Kurzrock MD Center Associate Director, Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Carcinogenesis
Class I Phosphatidylinositol 3-Kinases
Estrogen Receptor alpha
Female
Gene Expression Regulation, Neoplastic
Genome, Human
High-Throughput Nucleotide Sequencing
Humans
In Situ Hybridization, Fluorescence
Male
Membrane Proteins
Mutation
Neoplasms
PTEN Phosphohydrolase
Phosphatidylinositol 3-Kinases
Proto-Oncogene Proteins c-akt
Receptor, ErbB-2
Receptors, Androgen
Receptors, Progesterone
Signal Transduction