Oncology

HER2+ Breast Cancer

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Clinical Roundup: HER2+ Disease at Recent Breast Cancer Conference

clinical topic updates by Ian Krop, MD, PhD

Overview

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.

Expert Commentary

Ian Krop, MD, PhD

Professor of Internal Medicine, Section of Medical Oncology
Associate Cancer Center Director, Clinical Research
Chief Clinical Research Officer
Yale Cancer Center
Yale School of Medicine
New Haven, CT

“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.”

Ian Krop, MD, PhD

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. 

References

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

Ian Krop, MD, PhD

Professor of Internal Medicine, Section of Medical Oncology
Associate Cancer Center Director, Clinical Research
Chief Clinical Research Officer
Yale Cancer Center
Yale School of Medicine
New Haven, CT

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