The Importance of HRD Testing

Key opinion leaders discuss the importance of HRD testing, with special consideration of tissue testing versus somatic testing.

Maurie Markman, MD: We talked about BRCA mutations, which it is increasingly understood that getting testing for BRCA1, BRCA2 is highly relevant. But then there’s this conversation about HRD [homologous recombination deficiency] and then HRD testing. Mike, you want to talk about that a little bit?

Michael Birrer, MD, PhD: This is an important topic, particularly after the ESMO [European Society for Medical Oncology] clinical trial presentations. Full disclosure, I’m still a sequencing kind of guy. I use panels. I want to look for Fanconi genes and their mutations. But you should be aware that there are at least 2 HRD assays, 1 by Foundation Medicine, 1 by Myriad Genetics. And they’re based upon looking for loss of heterozygosity [LOH] within the tumor. And the basis of that is that presumably if you have a tumor that has homologous recombination problems, you’re going to lose a lot of pieces of DNA. And so you see high LOH scores. The Myriad assay adds something called telomeric imbalance to it and also large-scale transitions, which are just other measures of damaged DNA.

I don’t use them that much, but my colleagues do and they certainly correlate with an increased benefit from PARP [poly ADP ribose polymerase] inhibitors. And I think the ESMO presentations really reinforced it. So we’re going to be seeing physicians using these assays more and more. The final point I would make is because you’re looking at what’s called a genomic scar, the loss of heterozygosity, that’s permanent. So if you’ve got a patient on a PARP inhibitor, they grow through the PARP inhibitor, they’re now resistant, the HRD assay is of no use because the scar remains. It doesn’t really predict in recurrent disease, after exposure to PARP sensitivity.

R. Wendel Naumann, MD: Two things. I think it’s important to understand that you cannot always rely on the sequencing to look for germline tumors. You will miss some germline tumors if you rely on Foundation Medicine or Caris Life Sciences. So they do need germline testing based on a high quality panel.

Michael Birrer, MD, PhD: In addition to somatic.

R. Wendel Naumann, MD: In addition to somatic, right. The germline is probably 10% to 15%, somatic is about half of that. SOLO-1 included somatic mutations, but there were only a couple in the entire trial, so we don’t have high quality data on that. But we don’t know of any data that suggest they don’t respond just as well as PARP inhibition. I guess these tests are how you sequence them, and how you pay for them is the other issue.

Maurie Markman, MD: We’re going to talk a little bit about the recurrent setting later, but as of today, FDA approval does not require this testing. It’s approved in the PARP setting. PARPs have been approved broadly in the recurrent setting. That may or may not continue in the frontline setting, so it may actually be, this type of testing may be required as per the FDA. It’s not been decided yet, but certainly some of the data suggest potential relevance, so I think we all need to stay tuned.

R. Wendel Naumann, MD: Was it this week that we got an indication for HRD-positive patients?

Maurie Markman, MD: In the recurrent setting.

R. Wendel Naumann, MD: In the recurrent setting based on the QUADRA data. Again, this changes so fast, it’s hard to keep up with.

Maurie Markman, MD: Again, this is a role for the pharmacists here. This is just so complicated right now, and an individual doctor wants to use a particular drug and to say these are the FDA indications, and another drug may have a different indication, even though you’re sort of in the same clinical setting, and this all becomes very important. Unfortunately, it doesn’t become less complicated.