A well-known means to differentiate between normal and malignant tumors is tissue hypoxia, and a recent study confirmed “extensive intertumor- and intratumor-type heterogeneity in tumor hypoxia” in 8006 tumors across 19 tumor types.The study authors noted “subsets of patients with a range of solid tumors with genetic instability may benefit from hypoxia-targeting therapy.”For community oncologists, study results should help increase awareness on the role hypoxia plays in cancer evolution, “and there is very active work to understand the clinical relevance,” said Paul C. Boutros, PhD, University of California Los Angeles, and one of the study authors.

Fellow corresponding author Robert G. Bristow, MD, PhD, FRCPC, University of Manchester UK, said that while community oncologists “will not have to change practice,” they will now be aware “hypoxia is genetically driven and genetically unstable tumors usually will be hypoxic.”

Study Specifics

Hypoxia is both an adverse and targetable prognostic feature across numerous tumor types but genomic correlates in large cohorts had not been previously described. This study identified somatic mutational hallmarks of hypoxia across multiple tumor types, in addition to some associations between hypoxia and ancestry.

Overall, squamous cell tumors of the head and neck, cervix, and lung were the most hypoxic, whereas adenocarcinomas of the thyroid and prostate were found to be the least. Intertumoral variability in hypoxia was “particularly pronounced” in lung, pancreatic, and breast cancers.

In breast tumors, where the sample size was twice that of other cancer types, the study found a “strong association with subject-reported ancestry: tumors arising in subjects of Caucasian ancestry had less hypoxia than tumors in subjects with either Asian or African ancestry.” The authors noted the findings might explain why evofosfamide (a hypoxia-activated investigational prodrug) showed higher efficacy in subjects of Asian descent in the phase 3 MAESTRO study.

“It’s a curious finding,” Dr Bristow said. “We will need much more data on tumors that exist in patients between different cultural ancestry before we could address differences.”

Hypoxic breast cancer tumors were more likely to harbor loss of APC (Bonferroni-adjusted P = 1.25 x 10−42, Mann–Whitney U test) and gain of MYCN (Bonferroni-adjusted P = 2.75 x 10−32, Mann–Whitney U test), and show an elevated rate of TP53 point mutations (Bonferroni-adjusted P =4.38 x 10−61, Mann–Whitney U test).

For more details on the data, the authors said the raw sequencing data have been deposited in the European Genome-Phenome Archive under accession code EGAS00001000900. Processed variant calls are available through the ICGC Data Portal under the project PRAD-CA. TCGA data are available as well. Previously published CPC-GENE data are available at the European Genome-Phenome Archive under accession code EGAS00001000900. Previously published CPC-GENE mRNA abundance data are available at the Gene Expression Omnibus under accession code GSE84043.