A lot of compelling information about HER2+ and HER2-low breast cancers was presented at SABCS 2022. We have been doing well with regard to treating high-risk HER2+ breast cancer. In fact, the overall results from the more recent, large, randomized trials of high-risk patients, such as the phase 3 APHINITY and KAITLIN trials, are showing disease-free survival that is generally higher than 90%. 

With respect to adjuvant therapy, there had been a lack of data that specifically spoke to patients with low-risk HER2+ disease, and clinicians were drawing on that limited data when considering options and recommending treatment. For example, owing to concerns of undertreatment, patients with low-risk disease were offered multiple chemotherapy agents plus trastuzumab. Of course, overtreatment is also a concern, and we now have additional guidance in that regard based on the results of 2 fairly large trials of patients with low-risk HER2+ breast cancer (ie, the criteria vary by trial, but mostly stage I cancers, ≤2 cm, and node negative). 

The first of these trials was the phase 2 APT trial, led by the Dana-Farber group, which enrolled approximately 400 patients with ≤3 cm, node-negative, HER2+ breast cancer who received just 12 weeks of paclitaxel and 1 year of trastuzumab (ie, significantly reducing the amount of chemotherapy, relying more on the efficacy of trastuzumab). The final 10-year survival outcomes data from the APT trial were recently presented at the SABCS. The 10-year recurrence-free interval, which is probably the most relevant patient-specific end point, was approximately 96%, and the 10-year invasive disease-free survival was approximately 91%. There were only 6 distant recurrences reported in more than 400 patients, which translates to less than 2% of patients. Although not every patient with stage I HER2+ breast cancer needs adjuvant paclitaxel-plus-trastuzumab therapy, the reduced chemotherapy approach used in the APT trial really should be considered the standard of care for patients for whom chemotherapy-based treatment is needed or warranted.

The 5-year survival outcomes data from the phase 2 ATEMPT study, which is the successor trial to the APT trial, were also presented at SABCS 2022. ATEMPT looked at eliminating conventional chemotherapy altogether for stage I HER+ breast cancer by using the HER2-directed antibody-drug conjugate trastuzumab emtansine (T-DM1). The invasive disease-free survival at 5 years was 97% among the nearly 400 patients in the T-DM1 cohort, and there were only 3 distant recurrences reported in this group (ie, <1% distant recurrences in these stage I patients treated with just 1 year of T-DM1 alone). Although these results are very good, T-DM1 should probably not be considered the standard of care, as these results are reported from a single study that was not designed to be a registrational trial. However, it does provide support for an alternative to paclitaxel and trastuzumab for those select patients in whom toxicity is a concern.

The recent reports from both the APT and the ATEMPT trials included prognostic information using the HER2DX assay. This is an interesting new prognostic model for HER2+ breast cancer that combines molecular and clinical features. These studies found it to be prognostic, even within this low-risk group; however, because there are very few events to evaluate within the low-risk group, the assay still needs to be validated in other trials.

In addition to these compelling data for low-risk patients, there was a lot of discussion at the SABCS about HER2-low breast cancer, which has an HER2 immunohistochemistry score of 1+ or 2+ with negative in situ hybridization. The DESTINY-Breast04 trial, which revealed the benefits of trastuzumab deruxtecan in HER2-low breast cancer, sparked a huge amount of interest in understanding what HER2-low cancer really is. I think that what came out of all of these different abstracts and discussions was that HER2-low is really a treatment target and does not designate a new biologic subtype of breast cancer. From a clinical standpoint, an important point is that, other than the use of HER2-directed therapy, patients with HER2-low disease have a similar prognosis and similar clinical behavior as HER2-zero patients. Another point is that HER2-low status can be dynamic. An HER2-zero cancer in the primary presentation could very well be HER2-low in the metastatic setting and could potentially benefit from an HER2-targeted therapy.