In patients with early HER2+ breast cancer, giving neoadjuvant therapy and determining the pathological response at the time of surgery allows us to better understand the tumor’s sensitivity to systemic therapy and to guide adjuvant treatment recommendations. In those patients with a tumor that is more than 2 cm or with lymph node involvement, we do want to make sure that they receive preoperative therapy, and we will usually give the TCHP regimen, which is a combination of docetaxel, carboplatin, trastuzumab, and pertuzumab, for 6 cycles. 

Such patients with residual disease at the time of surgery have worse outcomes than those who have a pathological complete response (pCR), but we can essentially rescue them by giving trastuzumab emtansine (T-DM1) instead of trastuzumab in the setting of residual disease. The use of T-DM1 is based on the results of KATHERINE, a phase 3 trial that enrolled patients with early HER2+ breast cancer who had residual invasive disease at the time of surgery after receiving neoadjuvant therapy with a taxane and trastuzumab. In this study, the use of adjuvant T-DM1 was associated with a 50% reduction in the risk of recurrence of invasive breast cancer or death compared with adjuvant trastuzumab. In addition, the 3-year rate of invasive disease-free survival was estimated at approximately 88% in patients receiving T-DM1, which is a really big deal because it means that most individuals who received T-DM1 did not recur. There are a number of ongoing studies attempting to further improve outcomes for patients with residual disease by adding tucatinib or by replacing T-DM1 with trastuzumab deruxtecan.

If, after neoadjuvant therapy, such patients have a pCR, I think that the main controversy is whether they need to continue on both trastuzumab and pertuzumab, or if they can just receive trastuzumab alone. My argument would be that these patients should receive dual HER2-directed therapy in the adjuvant setting since our long-term outcomes data come from APHINITY, where patients received a full year of trastuzumab and pertuzumab. In Europe, for example, it is not always standard to give patients the pertuzumab; they often do not have approval to do that. When we use pertuzumab, we really need to remember that the data showing long-term benefit were in the setting of a full year of treatment, so I think that it is important to give patients the full year of pertuzumab.

Although these individuals have very good outcomes with the combination, some will argue that pertuzumab has not shown benefit in patients with node-negative disease (ie, in a subgroup analysis of the APHINITY trial, patients with node-negative disease did not seem to have a disease-free or overall survival benefit after 8 years of follow-up). However, my counterargument would be that we do not evaluate nodal status prior to the use of neoadjuvant therapy, so we do not really know the true nodal status of the patients in this trial.