Sara A. Hurvitz, MD: The discovery of the HER2 alteration in the 1980s and its implications on the biology of this subtype of breast cancer is nothing short of phenomenal. In the 1980s, it was demonstrated by Dr Dennis Slamon of UCLA Jonsson Comprehensive Cancer Center that in those patients who have HER amplification of the gene in their tumor cells, which at the time was reported around 25% to 30%, that leads to overexpression of the HER2 receptor, which was also shown to lead to more aggressive disease biology. This aggressive disease biology led to a worse outcome for patients diagnosed with all stages of disease, even early-stage disease. That association led to the development of an agent, a monoclonal antibody, trastuzumab, which aimed to target the HER2 receptor and improve outcomes for patients diagnosed with this disease.

Fast-forward to 2019, we think the incidence of HER2-positive breast cancer is a little lower, probably on the order of 20%. And the prognosis shift that we have noted since the development of HER2-targeted therapies is really quite extraordinary. We know from a number of clinical trials that have followed 10-year outcomes for patients diagnosed with early-stage or late-stage HER2-positive breast cancer that the addition of the HER2-targeted antibody trastuzumab to chemotherapy substantially improves not only the disease-free survival and progression-free survival of patients but also overall survival. Long term, this has turned it from 1 of the worst subtypes of breast cancer from a prognosis perspective into 1 of the best. In fact, the outcomes look neck and neck now with hormone receptor—positive HER2-negative breast cancer. It shows that the discovery of this alteration and the successful targeting of the alteration, because these tumors are addicted to HER2, have changed the outcome, the natural history of a very aggressive disease.

In spite of the phenomenal success and improvement in outcomes associated with trastuzumab, there is a not-insignificant proportion of women with early-stage disease who develop progression or recurrence of their breast cancer that’s metastatic. So we do have to do better. If you look at the 10-year outcomes from the large phase III adjuvant trials of trastuzumab, somewhere around a quarter of women who receive trastuzumab will have their disease come back. For this reason, other targeted therapies have been developed that have aimed to improve on that relapse rate and improve on the survival rate for patients who do have a relapse.

One of those agents is pertuzumab, which also targets the HER2 receptor in the extracellular domain, but it targets a different epitope and blocks the binding of HER2 with HER3, which in a downstream signaling pathway perspective, really blocks activation of that PI3 kinase pathway. Pertuzumab, when added to trastuzumab in the neoadjuvant setting, was shown in multiple trials to improve on pathologic complete response rates. That has truly become a standard of care in the neoadjuvant setting. We add to chemotherapy the trastuzumab and pertuzumab to give patients a good chance of having their disease disappear by the time of surgery.

Transcript Edited for Clarity