Joyce O’Shaughnessy, MD: Neil, we’ve got our molecular evaluation, and we want to start thinking about treatment. What are some of the key prognostic variables that would send you down different therapeutic strategies for patients?

Neil M. Iyengar, MD: Our thinking with regard to prognostication has changed a bit in terms of how the treatment landscape has changed. What I mean by that is, this approach of looking at risk factors such as presence of visceral disease—I have moved further away from that because we see the benefit of standard first-line therapy, CDK4/6 inhibitors with endocrine therapy, across the board for multiple subgroups of patients with ER+ [estrogen receptor–positive] metastatic breast cancer. I’m finding it exceedingly rare to not use that kind of an approach: CDK4/6 inhibitor plus hormone therapy in the up-front setting.

If somebody is truly in a visceral crisis and we have already occurring or impending organ dysfunction, then I might reach for something like chemotherapy in the up-front setting. We’re seeing that less and less as we become more comfortable using CDK4/6 inhibitors with endocrine therapy in the setting of visceral disease.

Perhaps a more important risk factor or prognostic factor rather is understanding the natural history of an individual’s breast cancer. Is their presence of endocrine therapy resistance, for example? This can be helpful for choosing the endocrine therapy partner. As we heard from Gabe, getting that mutational profile and the presence of an ESR1 mutation may push us to reach for fulvestrant in the up-front setting. We can look at the natural history without the molecular data to guide that decision-making. If someone progressed or relapsed while they were on their aromatase inhibitor, then we have that information and can go straight to fulvestrant. The presence of endocrine therapy resistance, especially if it’s acquired resistance, is a prognostic factor that does have implications for treatment selection.

Transcript edited for clarity.