We currently have this paradigm that if a patient has stage II or III HER2+ breast cancer, we give them preoperative therapy. Usually, the standard of care is the TCHP regimen, which is a combination of docetaxel, carboplatin, trastuzumab, and pertuzumab, for 6 cycles, and then, if the patient has a pathologic complete response, we give them trastuzumab plus pertuzumab for up to 1 year. If there is residual disease, we give the patient T-DM1. If a patient has stage I HER2+ breast cancer, we usually consider treatment with adjuvant paclitaxel plus trastuzumab based on the results of the phase 2 APT trial, or we consider T-DM1 based on the results of the phase 2 ATEMPT trial.

I think that this is the direction that we are moving toward because patients with early-stage breast cancer who have a pathologic complete response do so well that there is some thought that maybe we could give them an abbreviated chemotherapy regimen preoperatively, such as paclitaxel, trastuzumab, and pertuzumab. If they then have a pathologic complete response, we would just give them HER2-directed therapy after surgery, meaning that they would get less chemotherapy. This concept is currently being studied in the phase 2 CompassHER2-pCR trial and is not currently the standard of care.

I really hope that, in the future, we will have a greater understanding of who needs what therapy with the use of biomarkers, even before seeing how a patient responds to treatment. While there are a number of biomarkers that are being studied, I think that HER2DX is promising, as it is able to provide a predictive score for pathologic complete response and a prognostic score. This may allow us to tailor therapy to the individual patient in the future rather than having to wait to determine if the patient achieves a pathologic complete response to a particular regimen. And maybe it will tell us if a patient can get away with less treatment up front or if they require more treatment up front based on their cancer's biology.

With the introduction of multiple effective HER2-directed agents in the early-stage setting, most patients are now cured of their disease. We can now focus on tailoring therapy to the individual patient, with a goal of minimizing both overtreatment and undertreatment. To do this, we need to effectively risk stratify patients. We currently do this using both the initial clinical stage and response to neoadjuvant HER2 therapy. For patients with stage I cancer, we know from the APT and the ATEMPT trials that adjuvant treatment with either 12 weeks of paclitaxel and 1 year of trastuzumab, or, in select patients, 1 year of T-DM1 alone, results in distant recurrence rates of 1% to 2%. So, in these patients, upfront surgery followed by one of these generally well-tolerated adjuvant regimens is an optimal approach, and there is typically no benefit for neoadjuvant therapy. For patients with stage II to III disease, the cancer’s response to neoadjuvant therapy, typically with TCHP, is a very useful risk-stratification tool. Patients who achieve a pathologic complete response do very well with just the completion of 1 year of trastuzumab with or without pertuzumab. In my practice, if the patient initially had node-positive disease, I continue both antibodies. If the patient had clinically node-negative disease, the continuation of trastuzumab alone is reasonable, as the APHINITY trial found that adjuvant pertuzumab does not have proven benefit in the node-negative population. For those with residual disease after neoadjuvant therapy, it is more effective to switch to T-DM1 for 14 cycles.  

There are ongoing studies seeking to further optimize therapy for HER2+ early-stage disease. The CompassHER2-pCR trial is examining a de-escalation strategy, giving single-agent taxane therapy with trastuzumab and pertuzumab in the neoadjuvant setting for patients with stage II to III disease and, if those patients have a pathologic complete response, not adding any additional chemotherapy. Conversely, in higher-risk patients with residual disease after neoadjuvant therapy, the phase 3 CompassHER2 RD study is evaluating the addition of tucatinib to standard adjuvant T-DM1, while the phase 3 DESTINY-Breast05 study is designed to determine if trastuzumab deruxtecan is superior to T-DM1 in this population. Promising biomarkers, such as the HER2DX pathologic complete response score, which initial studies indicate can predict which patients are likely to achieve a pathologic complete response, if validated, could also potentially be used to optimally guide therapy. 

Together, these types of trials represent another step toward personalization, not only escalating high-risk patients but also de-escalating low-risk patients. I am highly optimistic that these types of approaches are going to further improve both outcomes and quality of life for these patients with early-stage HER2+ disease.

There has been an increasing use of neoadjuvant therapy, including anti–HER2-directed therapy, in the presurgical setting. Neoadjuvant therapy induces a high likelihood of a pathologic complete response, which has become a short-term pharmacodynamic biomarker that is prognostic for excellent long-term outcomes. In the past, we would have only used neoadjuvant systemic therapy in patients with local regionally advanced disease. Now, we have expanded it to patients who have negative nodes and tumors as small as 1.5 cm because of the effectiveness of therapy, which has been a major change in our approach.

The initial studies showed a benefit for adjuvant anti–HER2-directed therapy only in patients who were at higher risk, such as those who were node positive or high-risk node negative. However, it has been shown, largely through nonrandomized trials, that a milder adjuvant regimen of weekly paclitaxel and a single anti-HER2 agent such as trastuzumab alone, without additional anti–HER2-directed therapy, is highly effective in treating lower-risk patients who go directly to surgery and have negative nodes and a tumor size of up to 2 to 3 cm.

I think that, in the future, we will use biomarkers to identify the patients who may only require anti–HER2-directed therapy and can actually be spared the use of chemotherapy. This could be accomplished through the use of static biomarkers such as the HER2DX genomic test or dynamic biomarkers such as functional imaging (eg, positron emission tomography/computed tomography scanning), as a pharmacodynamic biomarker of response to dual anti–HER2-directed therapy. In the higher-risk population with residual disease after neoadjuvant anti–HER2-containing regimens who require additional systemic therapy in the adjuvant setting, integrating some of the therapies that have been really effective in metastatic disease, such as antibody-drug conjugates (ie, trastuzumab deruxtecan or T-DM1) alone or in combination with tyrosine kinase inhibitors, is a potentially promising direction that is currently being evaluated.