Treatment Options for Early-Stage HER2+ Breast Cancer - Episode 1

Goals of Care for Patients with Early-Stage versus Advanced or Metastatic HER2+ Breast Cancer

Sarah M. Tolaney, MD, MPH, provides an overview of how goals of care and prognosis differ between patients with early-stage HER2+ breast cancer and advanced or metastatic HER2+ breast cancer.

Sarah M. Tolaney, MD, MPH: I think in general outcomes for patients with HER2-positive disease actually are excellent, which is very different than what we would've said 20 years ago. What's really interesting is that originally, of all the subtypes of breast cancer, we actually thought HER2-positive cancers had the worst prognosis relative to ER [estrogen receptor] positive and even triple-negative disease early on. But now with the advent of HER2-directed therapies, outcomes are actually very similar to HER2-negative patients. And really again, this is attributed to the benefits of HER2-directed therapies. Our general approach for patients with early-stage disease is to determine if they need preoperative therapy or not. Generally speaking, for someone who has more than 2 centimeters of HER2-positive disease, or has clinical nodal involvement, those are patients who need to get systemic therapy prior to surgery. That's not just because we are able to shrink a tumor down and make surgery easier, but actually because it's really important to understand how well someone responds to treatment to be able to adapt adjuvant therapy; this adaptation of therapy based on the patient’s response actually can change outcomes. It is really important to understand how someone benefits from preoperative treatment, if they, for example, can achieve PCR [pathological complete response] or not in order to figure out what appropriate adjuvant systemic therapy should be given. For small cancers, or tumors less than 2 centimeters and node-negative, if they go to upfront surgery, then we're often giving adjuvant systemic therapy such as TH [docetaxel trastuzumab] or T-DM1 [trastuzumab emtansine] to those patients. I think the bottom line for early-stage cancers though, is for most patients, instances of recurrence are, generally speaking, low after HER2-directed therapy, because again, these agents work so well. Certainly, some patients are at a higher risk of recurrence, and those are generally patients who have significant nodal involvement or patients who have significant residual disease. Those are patients who unfortunately are still at a high risk of recurrent. For the metastatic patients though, patients who present with cancer that has spread outside the breast and lymph node area, we unfortunately have multiple HER2­-directed therapies that we can use sequentially over time in this patient population. We've seen approvals for agents like pertuzumab [Perjeta], trastuzumab deruxtecan [Enhertu], T-DM1, tucatinib [Tukysa], neratinib [Nerlynx], and margetuximab-cmkb [Margenza]. It's just incredible the number of HER2-directed therapy options we have for this group of patients. We are seeing median survival times for patients with metastatic HER2-positive disease exceed 5 years, which is really nice to see. And I think, again, these data aren't even based on all the recent approvals that we've had, so time will tell how survival will really pan out with all these agents being in our hands. I think overall, metastatic disease does so much better in the setting of newly approved HER2­-directed therapies.

When we think about the risk for someone with early-stage HER2-positive disease, generally I think one of the biggest risk factors is the degree of nodal involvement. We do know that in itself is an independent prognostic indicator so even in someone who achieves pathologic complete response to therapy if they had 4 or more positive nodes, they still have a significant risk of recurrence, even though they've achieved PCR, which is actually interesting, that baseline stage is still prognostic even in PCR patients. But I think outside of nodal involvement, certainly, response to therapy is a huge prognostic indicator. For patients with PCR, generally, we quote them around baseline risk, but somewhere around 10% to 12% risk of recurrence. Whereas someone who had significant nodal involvement and loss of residual disease that patient could have a 20% or more risk of recurrence. Risk, I think again, is hugely dependent on nodal status and response to therapy. ER status isn't quite as much of a prognostic indicator in general; we know that ER-positive for HER2-positive patients. When you look at long-term outcomes, generally they do a teeny bit better than ER-negative HER2-positive patients. We also know ER-negative patients that are HER2-positive tend to have earlier recurrences than ER-positive HER2-positive patients. And that ER-negative patients tend to have higher rates of PCR to HER2-directed therapy compared to ER-positive patients. But again, when just looking at overall prognostic indicators, it's not a strong one in the setting of HER2­-directed therapies and adequate therapies.

Transcript edited for clarity.