Clinical Implications

The metabolic reprogramming of cells via hypoxia “can now be associated with a series of distinct genomic alterations,” the authors noted, saying TP53 mutations are enriched in hypoxic tumors within each breast cancer subtype, thus supporting the idea that they are a genomic consequence or cause of tumor hypoxia. 

Intertumoral variability was particularly pronounced in breast tumors; Dr Boutros said the “striking” variability “is a bit of a mystery.” Several hypotheses could help explain the differences, including that some “’subtypes’ are more molecularly distinct and better defined in breast cancer than other tumors, or it may suggest something about the cell of origin,” he said.

Dr Bristow agreed, and both noted the findings supplement the understanding that breast cancers “really need to be treated as a set of fairly distinct diseases rather than a single one,” Dr Boutros said.

“We need more data to sort out differential treatments between these breast cancers,” Dr Bristow added.

There are “no real data” explaining why Caucasians had tumors that were less hypoxic, but 2 potential natural possibilities could be environmental or genetics, Dr Boutros said.

However, with the exception of the PTEN and TP53 findings (which were somewhat expected), “almost all those [mutations] correlated with hypoxia were surprising,” Dr Boutros said. “There’s been so little understanding of what would characterize hypoxic tumors that ultimately we’ve mostly been speculating previously, without the hard data from studies like this one. These data suggest that there is a need to start incorporating hypoxia measurements into the interpretations of trial data for many targeted agents to help understand their efficacy.”

Dr Bristow said the findings suggest that hypoxic tumors “can select for metastatic disease through association with aggressive genetic changes. We knew that hypoxia was associated with metastases, and this work starts to address which metastatic pathways can be targeted.”

This marks the first paper to describe genomic correlates of hypoxia, but Dr Boutros acknowledged it only looked at a couple of features of tumor evolution (point mutations and copy number changes).

“There is a next real need to expand such studies to look at others, like mutational processes, translocations, and fusion genes and timing; or when individual mutations happen relative to hypoxia,” Dr Boutros. Researchers “used to scratch our heads as there was heterogeneity in clinical trial responses that targeted hypoxia in patients with hypoxic tumors,” Dr Bristow said. This study data “suggest that it’s the patient that has hypoxia,” and these aggressive genetic changes need to be considered across any “new trials of antihypoxia drugs in combination with radiotherapy, chemotherapy, or surgery.”

Reference

  1. Bhandari V, Hoey C, Liu LY, et al. Molecular landmarks of tumor hypoxia across cancer typesNat Genetics.2019;51(2):308-318.