The ‘Dynamic Space’ of HER2 Breast Cancer Treatment Strategies

In Clinical Studies News by Barbara Jacoby

By: Rosana Gnanajothy, MD


More evident than ever that one-size-fits-all approach is less likely to work

Since the discovery of targeted therapy for HER2-positive breast cancer, the treatment algorithm has been modified by the advent of trials optimizing disease outcomes in high-risk disease, as well as trials exploring de-escalation strategies in lower-risk disease. A review by Danielle File, MD, and colleagues in the ASCO Educational Book highlights the recent advances in treatment and discusses how the clinical landscape is shifting toward tailored therapies based on disease characteristics and biomarkers.

In early stage HER2 positive disease, we have the option of utilizing trastuzumab, pertuzumab, neratinib, TDM1, and a variety of combination chemotherapeutic regimens. With the current treatment options in early stage HER2 breast cancer, we are able to achieve 3-year invasive disease-free survival rates of close to 90%. However, the availability of these options introduces the potential for overtreatment.

This may cause unnecessary side effects and financial toxicity. Most de-escalation strategies have been explored in the anatomical low-risk population. One of the groundbreaking early stage HER2-positive disease de-escalation trials in recent years was the APT trial, which showed that T1, node-negative tumors can be treated with paclitaxel and trastuzumab alone.

The recent ATTEMPT trial introduced another option — TDM1, for the same group of low clinical risk patients (cT1N0). However, this regimen has a different side effect profile, which showed lower rates of neuropathy, cardiac failure, and thrombocytopenia, but more hepatic dysfunction and a higher discontinuation rate.

It remains to be seen if clinical practice patterns will shift towards TDM1 rather than the APT regimen. Nevertheless, this represents an alternative to patients with baseline neuropathy and cardiac risk factors.

Another strategy of de-escalation, studied extensively, is the shorter duration of HER2-targeted adjuvant therapy. This has been studied with mixed results in several trials. The current consensus would be to complete 1 year of adjuvant HER2 blockade unless patients have significant side effects or cardiac dysfunction, in which case a shorter duration of therapy may be chosen. This is reasonable as the clinical outcomes between shorter duration therapy (3-6 months) as opposed to a longer duration of therapy (12 months) is modest.

In the anatomically higher clinical risk group (T2 and above, or node-positive disease), therapy has shifted to utilizing more neoadjuvant therapy and subsequent surgical de-escalation by increasing rates of breast conservation and lower rates of axillary dissections. This shift in practice patterns is also driven by the recent KATHERINE trial results. The KATHERINE trial showed that the neoadjuvant approach could help tailor adjuvant therapy by identifying patients who would benefit from adjuvant TDM1 based on the presence of postoperative residual disease suggestive of a more resistant disease pathology.

The chemotherapy backbone that is used in HER2 disease has been studied extensively. The recent TRAIN-2 trial results presented at the 2020 ASCO virtual meeting showed that anthracycline-free regimens are just as efficacious and more tolerable than anthracycline-based regimens, even in a higher-risk population.

The role of chemotherapy, especially anthracyclines, is becoming less useful with the advent of more targeted therapies in HER2 disease. The question of avoiding chemotherapy altogether and just using anti-HER2 therapy is also being explored. While studies have shown that pathological complete response (PCR) rates may be higher in patients receiving chemotherapy plus anti-HER2 blockade than in patients receiving anti-HER2 therapy alone, those achieving PCR in both groups had similar disease-free survival rates.

This prompted research into this group of patients, who may be able to avoid chemotherapy or receive a less aggressive regimen as they are presumed to have higher disease sensitivity to HER2 blockade. The Compass HER2-PCR trial is hoping to shed light on this question by minimizing upfront neoadjuvant chemotherapy to taxane-based options alone and using dual HER2 blockade without chemotherapy if PCR is achieved for 1 year.

Also of research interest is whether intrinsic subtypes play a role in sensitivity to anti-HER2 blockade. Studies suggest that the HER2-enriched subtype might be more sensitive to anti-HER2 therapy than other luminal subtypes and hence able to avoid the need for cytotoxic chemotherapy. Therefore, further studies exploring intrinsic subtypes, tumor-infiltrating lymphocytes, biomarkers, and mutations to tailor therapy in early stage HER2-positive breast cancer are being explored. This further research will help personalize therapies in anatomically high risk disease.

Newer therapies in HER2 disease such as tucatinib and trastuzumab deruxtecan will likely broaden the adjuvant therapy algorithms in the future as they are studied in earlier lines of therapy.

Early stage HER2 breast cancer treatment strategies have proven to be a dynamic space and it’s more evident that a “one size fits all” approach is less likely to work and should be tailored to the patient by considering anatomic and biological risk.