clinical topic updates
Clinical Roundup: HER2+ Disease at Recent Breast Cancer Conference
There was much activity in the human epidermal growth factor receptor 2 (HER2) space at the recent 45th Annual San Antonio Breast Cancer Symposium (SABCS), for both HER2-positive (HER2+) and HER2-low breast cancers. Overall results in patients with high-risk HER2+ breast cancer are good, and recent data on patients with low-risk HER2+ disease are also promising.
Ian Krop, MD, PhD
Professor of Internal Medicine, Section of Medical Oncology
“The final 10-year survival outcomes data from the APT trial were recently presented at the SABCS. . . . 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.”
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.
Krop IE, Im S-A, Barrios C, et al. Trastuzumab emtansine plus pertuzumab versus taxane plus trastuzumab plus pertuzumab after anthracycline for high-risk human epidermal growth factor receptor 2-positive early breast cancer: the phase III KAITLIN study. J Clin Oncol. 2022;40(5):438-448. doi:10.1200/JCO.21.00896
Ma Y, Zhu M, Zhang J, Lv M, Chen X, Liu Z. Prognostic value of the evolution of HER2-low expression after neoadjuvant chemotherapy. Cancer Res Treat. 2023 Apr 4. doi:10.4143/crt.2022.1633
Modi S, Jacot W, Yamashita T, et al; DESTINY-Breast04 Trial Investigators. Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. N Engl J Med. 2022;387(1):9-20. doi:10.1056/NEJMoa2203690
Piccart M, Procter M, Fumagalli D, et al; APHINITY Steering Committee and Investigators. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer in the APHINITY trial: 6 years' follow-up. J Clin Oncol. 2021;39(13):1448-1457. doi:10.1200/JCO.20.01204
Prat A, Guarneri V, Pascual T, et al. Development and validation of the new HER2DX assay for predicting pathological response and survival outcome in early-stage HER2-positive breast cancer. EBioMedicine. 2022;75:103801. doi:10.1016/j.ebiom.2021.103801
Tarantino P, Tayob N, Dang CT, et al. Adjuvant trastuzumab emtansine versus paclitaxel plus trastuzumab for stage I HER2+ breast cancer: 5-year results and correlative analyses from ATEMPT (TBCRC033) [abstract PD-18-01]. Abstract presented at: San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, TX.
Tolaney SM, Tarantino P, Graham N, et al. Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer: final 10-year analysis of the open-label, single-arm, phase 2 APT trial. Lancet Oncol. 2023;24(3):273-285. doi:10.1016/S1470-2045(23)00051-7
Tolaney SM, Tarantino P, Graham N, et al. Adjuvant Paclitaxel and Trastuzumab trial (APT) for node-negative, human epidermal growth factor receptor 2–positive (HER2+) breast cancer: final 10-year analysis [abstract PD-18-02]. Abstract presented at: San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, TX.
Tolaney SM, Tayob N, Dang C, et al. Adjuvant trastuzumab emtansine versus paclitaxel in combination with trastuzumab for stage I HER2-positive breast cancer (ATEMPT): a randomized clinical trial. J Clin Oncol. 2021;39(21):2375-2385. doi:10.1200/JCO.20.03398