Phosphatidylinositol 3-kinase pathway genomic alterations in 60,991 diverse solid tumors informs targeted therapy opportunities

Abstract

Background: The phosphatidylinositol 3-kinase (PI3K) pathway is frequently altered in cancer. This report describes the landscape of PI3K alterations in solid tumors as well as co-alterations serving as potential resistance/attenuation mechanisms.

Methods: Consecutive samples were analyzed in a commercial Clinical Laboratory Improvement Amendment-certified laboratory using comprehensive genomic profiling performed by next-generation sequencing (315 genes). The co-alterations evaluated included the Erb-B2 receptor tyrosine kinase 2 (ERBB2), ERBB3, ERBB4, RAS, MET proto-oncogene tyrosine kinase (MET), and mitogen-activated protein kinase kinase (MAP2K) genes as well as tumor protein 53 (TP53), estrogen receptor 1 (ESR1), and androgen receptor (AR).

Results: Alterations in any of 18 PI3K-pathway associated genes were identified in 44% of 60,991 tumors. Although single base and insertions/deletions (indels) were the most frequent alterations, copy number changes and rearrangements were identified in 11% and 0.9% of patients, respectively. Overall, the most frequently altered genes were PIK3 catalytic subunit α (PIK3CA) (13%), phosphatase and tensin homolog (PTEN) (9%), and serine/threonine kinase 11 (STK11) (5%). Tumor types that frequently harbored at least 1 PI3K alteration were uterine (77%), cervical (62%), anal (59%), and breast (58%) cancers. Alterations also were discerned frequently in tumors with carcinosarcoma (89%) and squamous cell carcinoma (62%) histologies. Tumors with a greater likelihood of co-occurring PI3K pathway and MAPK pathway alterations included colorectal cancers (odds ratio [OR], 1.64; P < .001), mesotheliomas (OR, 2.67; P = .024), anal cancers (OR, 1.98; P = .03), and nonsquamous head and neck cancers (OR, 2.03; P = .019). The co-occurrence of ESR1 and/or AR alterations with PI3K alterations was statistically significant in bladder, colorectal, uterine, prostate, and unknown primary cancers.

Conclusions: Comprehensive genomic profiling reveals altered PI3K-related genes in 44% of solid malignancies, including rare disease and histology types. The frequency of alterations and the co-occurrence of resistance pathways vary by tumor type, directly affecting opportunities for targeted therapy.

Keywords: cancer genome; molecular profile; phosphoinositide 3-kinase catalytic subunit α (PIK3CA); precision oncology; targeted therapy.

Figure 1

Genetic alterations in the phosphoinositide 3‐kinase (PI3K) pathway are illustrated in patients with cancer. The percentages of patients who had alterations are indicated on the y‐axis. The analysis of alteration frequency (%) was calculated based on at least 1 alteration per patient. Numbers in parentheses indicate the numbers of patients. (A) Results from an analysis of overall alterations are illustrated according to histology. “All” represents all samples, regardless of histology. GIST indicates gastrointestinal stromal tumor. (B) Specific gene alteration frequencies are illustrated according to histology. (C) The percentages of gene alterations are illustrated according to histology corresponding to A and B. The far right column lists the number of genes that were altered for each associated histologic type, and the bottom row indicates the number of histologies (from a total of 16) that had alterations in the listed genes (columns). (D) Results from an analysis of the overall percentages of alterations are illustrated according to disease type. Carc. indicates carcinoma; GEJ, gastroesophageal junction; NSCLC, nonsmall cell lung cancer; SCLC, small cell lung cancer. (E) Percentages of specific gene alterations are illustrated according to disease type. Other types include parathyroid carcinoma, placenta choriocarcinoma, spine ependymoma, soft tissue paraganglioma, spine glioma, and eye lacrimal duct carcinoma. (F) The percentages of gene alterations are illustrated according to disease type corresponding to D and E. The far right column lists the number of genes that were altered in for each associated disease type, and the bottom row indicates the number of disease types (from a total of 34) that had alterations in the listed genes (columns). On charts C and F, pink shading denotes the percentage above the median, yellow shading denotes the percentage below the median; 0% without shading indicates values of 0%, and 0% with shading indicates values between 0.001% and 0.5%. AKT1 indicates AKT serine/threonine kinase 1; AKT2, AKT serine/threonine kinase 2; AKT3, AKT serine/threonine kinase 3; FBXW7, F‐box and WD repeat domain containing 7; INPP4B, inositol polyphosphatate‐4‐phosphatase type IIB; MTOR, mammalian target of rapamycin; PIK3C2B, PIK3 catalytic subunit 2β; PIK3CA, PIK3 catalytic subunit α; PIK3CB, PIK3 catalytic subunit β; PIK3CG, PIK3 catalytic subunit γ; PIK3R1, PIK3 regulatory subunit 1; PIK3R2, PIK3 regulatory subunit 2; PTEN, phosphatase and tensin homolog; RICTOR, regulatory‐associated protein of mTOR/independent companion of mTOR complex 2; RPTOR, regulatory‐associated protein of mTOR complex 1; STK11, serine/threonine kinase 11; TSC1, tuberous sclerosis complex subunit 1; TSC2, tuberous sclerosis complex subunit 2.

Figure 2

Phosphoinositide 3‐kinase (PI3K) pathway alterations are illustrated in rare or uncommon cancer types. The percentages of patients who had alterations are indicated. Numbers in parentheses represent the numbers of patients. The cancer types illustrated include: (A) unknown primaries, (B) thyroid, (C) adenoid cystic, (D) salivary gland, (E) skin (nonmelanoma), (F) vaginal and vulvar, (G) anus, (H) neuroendocrine tumors, and (I) small intestine. AKT1 indicates AKT serine/threonine kinase 1; AKT2, AKT serine/threonine kinase 2; AKT3, AKT serine/threonine kinase 3; FBXW7, F‐box and WD repeat domain containing 7; INPP4B, inositol polyphosphatate‐4‐phosphatase type IIB; MTOR, mammalian target of rapamycin; NOS, not otherwise specified; PIK3C2B, PIK3 catalytic subunit 2β; PIK3CA, PIK3 catalytic subunit α; PIK3CB, PIK3 catalytic subunit β; PIK3CG, PIK3 catalytic subunit γ; PIK3R1, PIK3 regulatory subunit 1; PIK3R2, PIK3 regulatory subunit 2; PTEN, phosphatase and tensin homolog; RICTOR, regulatory‐associated protein of mTOR/independent companion of mTOR complex 2; RPTOR, regulatory‐associated protein of mTOR complex 1; STK11, serine/threonine kinase 11; TSC1, tuberous sclerosis complex subunit 1; TSC2, tuberous sclerosis complex subunit 2.

Figure 3

Charts illustrate the co‐occurrence of pathway alterations in the phosphoinositide 3‐kinase (PI3K) pathway and the (A) mitogen‐activated kinase (MAPK) pathway, (B) tumor protein 53 (TP53), and (C) estrogen receptor 1 (ESR1) and/or androgen receptor (AR) (hormone receptor) pathways. (A) The co‐occurrence of alterations in the MAPK pathway and the PI3K pathway is illustrated. The ratio of alterations in the PI3K pathway only, in the MAPK pathway only, and in both pathways is depicted for all disease types, and a significant association is noted between the 2 pathways (P ≤ .05 for co‐occurrence; in total, 14 disease types had a significant association). (B) The co‐occurrence of pathway alterations in the TP53 pathway and the PI3K pathway is illustrated. The ratio of alterations in the PI3K pathway only, in the TP53 pathway only, and in both pathways is depicted for all disease types, and a significant association is noted between the 2 pathways (P ≤ .05 for co‐occurrence; in total, 21 disease types had a significant association). (C) The co‐occurrence of alterations in the hormone receptor pathways and the PI3K pathway is illustrated. The ratio of alterations in the PI3K pathway only, in the ESR1 and/or AR pathway only, or in both pathways is depicted for all disease types, and a significant association is noted between the 2 pathways (P ≤ .05 for co‐occurrence; in total, 33 disease types had a significant association). No alterations in either ESR1 or AR were observed in kidney clear cell carcinoma, cervix adenocarcinoma, bladder urothelial (transitional cell) carcinoma, small intestine adenocarcinoma, breast metaplastic carcinoma, kidney urothelial carcinoma, duodenum adenocarcinoma, cervix squamous cell carcinoma (SCC), lung large cell neuroendocrine carcinoma, salivary gland carcinoma (not otherwise specified [NOS]), head and neck adenoid cystic carcinoma, unknown primary undifferentiated small cell carcinoma, ovary carcinosarcoma, uterus endometrial adenocarcinoma (NOS), uterus endometrial adenocarcinoma endometrioid, thymus carcinoma (NOS), brain ependymoma, or diffuse type stomach adenocarcinoma. CNS indicates central nervous system; CRC, colorectal cancer; GIST, gastrointestinal stromal tumor; HCC, hepatocellular carcinoma; HNSCC, head and neck squamous cell carcinoma; NSCLC, nonsmall cell lung cancer; SCLC, small cell lung cancer.