VIDEO: Combining biotherapies, endocrine therapies in breast cancer

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The combination of biotherapies with endocrine therapies, the first one was the inhibition of Emcor inhibitors in patients within first or second-line of therapy. That was really the first biological therapy that came out on the basis of understanding that growth factor pathway seemed to be up regulated resistance to endocrine therapy. More recently, the cyclin-dependent kinase 4/6 inhibitors have been approved, similarly because the cell cycle is a pivotal control for all normal and malignant cell growth. But in hormone receptor positive breast cancer, there's a particular vulnerability to these drugs because of the way the cell cycle operates. And the fact that some of the mutations that co-op the cell cycle are not present in hormone receptor positive breast cancer, which allows the CDK inhibitors to work. But these drugs are now generally used in first or second-line therapy where they doubled progression-free survival. And we're starting to see survival advantages now from two of these drugs from abemaciclib and ribociclib. And so the use of these drugs now is broad and certainly the toxicity profiles are generally favorable. I mean, certainly they do have side effects including rarely some important and severe ones that need to be monitored. But, you know, that's certainly been a welcome advance. And then PI 3-kinase inhibitors, one approved so far, alpelisib, is the most recent addition to this area. And this one is specifically genomically targeted. It's effective in patients whose tumors carry a mutation in PIK3CA, which is the gene that encodes the catalytic domain of the alpha isoform of PI 3-kinase. And because that aberration is pretty common in hormone receptor positive breast cancer, about 40% of cases, it is now being used in the second-line setting. This drug has more side effects because PI 3-kinase is such a critical signaling pathway in growth and metabolic pathways.

For example, the insulin receptor signals through this, so hyperglycemia is one of the side effects and other growth factors like EGFR signal through PI 3-kinase. So you get some of the EGFR toxicities like skin rash and GI toxicities, but you know, these can be manageable especially if you prepare for them and even use some of the drugs prophylactically like the ones that prevent rash, histamine blockers, for example, and monitoring glucose carefully. And these drugs are being now looked at in different settings as well, earlier settings. And a field of hormone receptor positive breast cancer is going to move forward because it's rich in genomic aberrations that serve as escape pathways too. Tumor cells become resistant to endocrine therapy, for example, mutations in the estrogen receptor itself or the ESR1 gene now being targeted with selective estrogen receptor down regulators that are, that can be given orally. And these are still in clinical trials, but we are now routinely checking gene sequencing in these patients, not only for PIK3CA, which of course is an approved drug, but because it opens the door for many clinical trials that are targeting other aberrations that lead to resistance, for example, mutations in the HER2 receptor itself, even in HER2 negative cases, amplifications, and other gene rearrangements of the fibroblast growth factor receptor family, and many others.