In the late 1980s, it became clear that HER2 overexpression was associated with the worst outcomes in breast cancer, and, within 15 years, we saw the development and US Food and Drug Administration approval of the first anti-HER2 antibody therapy. Going back to the introduction of trastuzumab, this was an advance because it improved outcomes in patients with advanced HER2-overexpressing breast cancer, but it was also an advance in the ability to individualize therapy for specific subsets of patients. It is very possible that trastuzumab might not have shown clinical benefit if it had been tested in an unselected group of patients with breast cancer. 

It was later shown in the mid-2000s that the addition of trastuzumab to chemotherapy in the adjuvant setting could reduce the risk of recurrence by approximately one-half. Further gains were produced with the availability of dual anti–HER2-directed therapy that targets different domains of the HER2 molecule (eg, the phase 3 CLEOPATRA trial, with the addition of pertuzumab to trastuzumab with docetaxel for the first-line treatment of metastatic disease).

Tyrosine kinase inhibitors and antibody-drug conjugates that can overcome mechanisms of resistance are 2 other very important advances. I would say that, even if all development of new therapies for HER2+ breast cancer somehow stopped tomorrow, we would still likely gain ground in the next decade by learning how best to use the drugs that we already have in terms of sequencing them appropriately and preventing resistance. 

There is still a lot of work to be done. One thing that we need to determine is whether or not we should use dual anti-HER2 and cytotoxic therapies or an antibody-drug conjugate as the first-line treatment for metastatic or localized disease. Additionally, a vexing problem that persists is the optimal treatment of central nervous system (CNS) disease, which continues to be a problem for 25% to 50% of patients with HER2+ breast cancer. The longer patients survive with metastatic disease, the greater the likelihood of developing CNS metastases, and they are generally more difficult to treat.

Patients with HER2+ breast cancer are living longer and longer and are getting through more and more lines of therapy, which is amazing. I think that this is because we have developed so many HER2-directed therapies. I would not attribute the survival gain to 1 particular drug; it is more a summation of having so many very potent HER2-directed therapies that can be used sequentially over a lifetime. 

The CLEOPATRA trial showed that adding pertuzumab to trastuzumab plus a taxane led to a 16-month improvement in overall survival, and we now know that the use of other agents leads to improvements in survival. For instance, trastuzumab deruxtecan improved survival over trastuzumab emtansine in the phase 3 DESTINY-Breast03 trial. Further, the addition of tucatinib to trastuzumab and capecitabine improved overall survival in patients with HER2+ metastatic breast cancer compared with placebo alone in the phase 2 HER2CLIMB trial. 

As Dr Sparano noted, the problem that we are facing as patients live longer is CNS metastases and recurrence in the brain. When that happens, life expectancy can be limited, and, therefore, developing better strategies to treat CNS metastases will be critical. As we continue to develop new HER2-directed therapies, we need to make sure that we are developing drugs that also effectively treat the brain. 

There are some bold new approaches that are being considered to explore whether we could use drugs sequentially in a rapid-fire manner for patients with metastatic disease the way that we do in the adjuvant setting to cure patients, so that is something to look for in the future as well.

With the optimization of adjuvant and neoadjuvant therapies for patients with early-stage HER2+ breast cancer, we are seeing fewer and fewer recurrences of disease. Preventing recurrence, in the first place, continues to be a very important way to improve survival. The progress in that area will likely continue as we explore the possibility of using potent anti-HER2 therapies such as trastuzumab deruxtecan and tucatinib in the early-stage setting in clinical trials.

In addition to having these effective therapies that continue to improve long-term survival in the early-stage setting with sequential drugs, I think that we are getting to a point where we can try to improve the cure rate, or at least the long-term disease control rate, in patients with metastatic disease. In the CLEOPATRA study, which evaluated the combination of docetaxel with trastuzumab and pertuzumab as frontline therapy for HER2+ metastatic breast cancer, 16% of patients had disease control at 8 years. Arguably, those patients could be considered cured or, at least, very long-term responders.

The question is: How can you build on that and increase that rate of long-term disease control? As Dr Tolaney noted, some interesting new approaches are being considered by the Translational Breast Cancer Research Consortium to try to improve outcomes in patients with metastatic disease. We have multiple drugs with what we hope are non–cross-resistant mechanisms, and there is interest in strategies that might allow us to take advantage of all of these different agents. The thought is that, rather than allowing the cancer a chance to develop resistance to 1 drug, giving 1 drug after another in a more rapid succession might eradicate all of the potentially resistant subclones. It is certainly an ambitious idea, but it does seem to be a ripe time to take advantage of all of these different drugs that are available and to try to look at metastatic disease a little differently.