Other Promising Targets in TNBC


Joyce A. O’Shaughnessy, MD: So, Aditya, finish us up. What’s next? What other targets are important to us in triple-negative breast cancer that are perhaps a little more near-term?

Aditya Bardia, MD, MPH: I think I’ll come back to what was said earlier in terms of genotyping. I think if we do genotyping of triple-negative breast cancers, a subset of them have activation of the PI3-kinase pathway. And that would either be based on PI3-kinase mutations or they could have B10 loss, which is a negative regulator of PI3-kinase. So, when this pathway is activated, potentially downstream inhibitors like Akt inhibitors could work in this setting. And that was the rationale for a trial presented at ASCO last year called the LOTUS trial, which looked at patients with metastatic triple-negative breast cancer but required that, as a subset analysis, we look at the PI3-kinase pathway alteration. And it was based on IHC, and they found that in tumors that had a PI3-kinase pathway that was altered, the addition of an Akt inhibitor, ipatasertib, to a taxane-based regimen improved progression-free survival. And it was a randomized phase II trial, so it was not a very big trial, but despite the smaller sample size, it was statusly significant, which talks about the higher effect side that was observed.

Interestingly, in that trial, they looked at different methods of looking at PI3-kinase pathway alteration, IHC-based and NGS-based. It was the NGS-based assay that was really predictive of benefit. The IHC was not that predictive. It could be an issue of the specimen or the way it was done, but the NGS-based assay was the clear winner.

And so, now this is being moved into a randomized phase III trial, which is a registration trial with this agent called ipatasertib. That’s an interesting name. And it’s a trial for metastatic triple-negative breast cancer, but also metastatic ER-positive breast cancers. So, this trial has both triple-negative and ER-positive subsets, and patients would be randomized to receive a taxane versus taxane plus an Akt inhibitor. And, if that’s positive, that would be another option for our patients with metastatic disease.

Joyce A. O’Shaughnessy, MD: And at least about 40% by NGS is either lost PTEN or amplified Akt, or has a PIK3 mutation or amplification. I think those are the main alterations that were there in the triple-negative. That’s pretty good. Maybe it will be even a little more when we screen widely. But it’s maybe closer to half of our patients who might be eligible. But, yes, super important. Because we know when you lose PTEN, the Akt is really an active signaling moiety in triple-negative breast cancer. So, great trial for patients who are for phase III now.

Well, thank you guys for a great discussion. And just giving last opportunities, if there’s any final thoughts that we have, I guess I’ll start and just say I’m looking forward mainly in this year ahead to figuring out how to incorporate the PARP inhibitors, and to my metastatic population, this is brand new upon us, so I have to figure that out and find those patients. And then where exactly do I use them? Probably early for the triple-negatives and after utilization for hormonal therapy in the ER-positive. And, for me, the other thing I’m just looking forward to is more checkpoint inhibitor data. Hopefully, a positive registration trial with atezolizumab soon, and then utilizing that first-line. How about you, Claudine, any final thoughts?

Claudine Isaacs, MD: I think the ADCs are all so fascinating. I really feel we’re at the cusp of being able to do something different for this incredibly high-risk population and that we’re starting to tease something apart. And, I think, in the next couple of years, we’re going to start to have many more options available to us. We’re going to have to, for those of us who are sort of older, relearn our molecular biology and immunology, which is great, it’ll keep us younger. And I think we’ll have many more options to offer our patients, sure.

Tiffany Traina, MD: I think we’re going to end up having to change the name of triple-negative breast cancer. You’re going to have to re-change the program title. Because as we started this whole conversation, it really is not about what is lacking, but now as we identify these biomarkers, you’re immediately going to meet a woman with advanced disease and really define it by what’s driving the cancer. And, serially, that may change. So, what we didn’t even begin to touch on is, hopefully, moving to the point of having cell-free DNA and assays where we can monitor the changes in a tumor without having to require such invasive procedures and biopsies.

Joyce A. O’Shaughnessy, MD: A good point. You’ve done a lot of that work already. Any final thoughts?

Aditya Bardia, MD, MPH: I would agree. I think we’ve called this triple-negative, but over time, we’ll find various positives in this triple-negative with these targets and targeted therapy. And if you think about it, in lung cancer, we don’t call tumors that are ALK-negative or EGFR-negative as triple-negative lung cancer. I think we just have to identify the targets, use therapies based on that, and the future is going to change. So, I’m very excited. I think it might be stories similar to HER2, where if you find something and you have an agent, do you actually want to have that subtype of breast cancer? And maybe with these ADCs and with PARP inhibitors, it’ll just change.

Joyce A. O’Shaughnessy, MD: We are a group of optimists. Well, thank you very much for joining us, and hopefully you found this Peer Exchange® very useful and informative. I certainly have. Thank you all very much.

Transcript Edited for Clarity

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