Breast Cancer De-Escalation Now Rests on Molecular Profiling: Denise Yardley, MD

Breast cancer is moving out of the 3 categories that long organized treatment decisions (ER-positive, HER2-positive, and triple-negative) toward pathways defined by individual tumor biology, according to Denise Yardley, MD, of Sarah Cannon Research Institute, at a recent Institute for Value-Based Medicine® event in Nashville, Tennessee, who described those historical boundaries as somewhat artificial.

How Molecular Profiling Reframes De-escalation

Modern precision medicine testing lets clinicians examine biology directly and match it to treatment strategy, Yardley said, adding precision for that patient.

Decisions were often made on tumor quantity, meaning nodal involvement or tumor size. However, the field has since recognized that a large tumor can carry inert biology while a small tumor can pack a big punch. Rather than applying arbitrary boundaries around lymph node involvement, clinicians can now identify favorable biology present in a lymph node that does not, on its own, trigger chemotherapy.

She cited the OPTIMA trial, where Prosigna assesses proliferation. Establishing that a tumor is not proliferative supports telling a patient that they are unlikely to benefit from chemotherapy, which, Yardley emphasized, is not the same as no treatment. An endocrine strategy reflects how that tumor walks and talks, and endocrine options for these patients are strong.

Why ADC Sequencing Has Become the Harder Problem

Antibody-drug conjugates (ADCs) entered breast cancer following hematology's lead, beginning with ado-trastuzumab emtansine. Yardley likened the expansion since then to a Pandora's box, with agents still evolving in adverse effects and delivery profiles. The challenge is determining who is best suited to which ADC, weighing schedule and toxicity, and choosing between 2 agents occupying the same space.

That choice involves shared decision-making, particularly around adverse events, including interstitial lung disease (ILD). For a patient with pulmonary risk factors, having an option without ILD risk matters. As ADCs move earlier and supplant chemotherapy, deciding what to use in the metastatic setting becomes harder if the patient has already been exposed, which is a great problem to have, she said.

What Closes the Community-Academic Gap

Those walls are coming down, Yardley said. She described her own large community-based research center as having strong drug development, partnering with outlying clinics and placing physicians there.

The persistent challenge is that a generalist medical oncologist must track every drug, schedule, and toxicity, which takes education through continuing medical education and other programs. Community research centers also partner with rural practices, so patients can travel in or stay local with a resource to consult.