Frontline Treatment Approaches for HR+/HER2- MBC

Joyce O’Shaughnessy, MD: Sarah, in the big picture— we’re going to get into more detailed data that help inform first-line choice—how do you approach the first-line therapeutically?

Sarah Sammons, MD: For first-line hormone receptor–positive and HER2- [human epidermal growth factor receptor 2–negative] breast cancer, for the vast majority of patients we’re recommending endocrine therapy backbone with the CDK4/6 inhibitor. For very select patient populations, we may choose endocrine monotherapy. In my practice that’s a rarity. As Neil mentioned, if somebody is in impending visceral crisis, then we’ll reach for a chemotherapy regimen.

The choice of endocrine therapy with the CDK4/6 inhibitor is based on their previous history with endocrine therapy. For an endocrine therapy–naïve patient or someone who we’d deem endocrine sensitive—meaning that they’ve relapsed 12 months or after their adjuvant endocrine therapy—we’ll reach for a nonsteroidal aromatase inhibitor [AI]. Whereas for a patient who is relapsing with metastatic disease on adjuvant endocrine therapy, we’d move toward fulvestrant. We do have PARSIFAL, which was a head-to-head study that looked at palbociclib with fulvestrant vs palbociclib and letrozole in the endocrine-sensitive population. In the endocrine-sensitive and endocrine-naïve population, fulvestrant was no better than AI in the first line.

Joyce O’Shaughnessy, MD: Thanks very much. I just want to emphasize how I’ve changed my practice from being fond of chemotherapy for patients with liver metastases. For example, with endocrine therapy resistance, I was worried, and that’s changed. Unless they are, as Neil said, in absolute organ crisis, I now know that the CDK4/6 inhibitors worked just as quickly as chemotherapy, but they work at least 3 times as long and they’re much less toxic. I’ve gone over wholesale to giving a trial of CDK4/6 numbers, except for the most extremely symptomatic patients. Speaking of the CDK4/6 inhibitors, what are they, Neil, and why are they helpful?

Neil M. Iyengar, MD: It’s helpful to understand the mechanism of action. Most of us are aware that the growth of most breast tumors depends on the presence of cyclin D1 and CDK4. The cyclin D/CDK4/6 complexes are critical regulators of cellular transition through the G1 to the S phase of the cell cycle. That G1 to S-phase restriction point is tightly regulated by the retinoblastoma tumor suppressor gene. The cell cycle machinery is dysregulated often in cancer cells, and that could be through a variety of mechanisms. I won’t go through all of them, but the most important ones to highlight are the most commonly dysregulated in breast cancer. That’s activation of upstream mitogenic pathways, like the classical PI3K/AKT/mTOR pathways or the RAS/RAF/MEK/ERK pathways. These all lead to increased levels of particular cyclins. The D-type cyclins or their partner site kinases, which are CDK4 and CDK6, are particularly important in breast cancer. By inhibiting the formation of those complexes, you can inhibit progression through the cell cycle and ultimately cellular proliferation.

The final thing that I’ll note is that the potency of the various CDK4/6 inhibitors that are approved varies when it comes to targeting CDK4 vs CDK6. This is important because CDK4 plays an important role here. There are new-generation CDK4/6 inhibitors that have more specific CDK targeting. This may impact both efficacy and toxicity. It’s going to be very interesting to see that data. Ultimately, this crosstalk between progression through the cell cycle, specifically phosphorylated RB, activation of the mitogenic pathways, and crosstalk with estrogen receptor and HER2 pathways, further underscore the important mechanistic use of CDK4/6 inhibitors in breast cancer.

Joyce O’Shaughnessy, MD: Thanks so much. They’ve revolutionized. Talk about a way to stop proliferation no matter what is impinging upon the cyclin D and the CDK4/6. Many pathways impinge on that and you hit the nodal point. You can stop proliferation most of the time.

Transcript edited for clarity.