HER2+ Early Breast Cancer: Tailoring Therapy in the Era of Expanding Options

Although early-stage HER2-positive breast cancer remains a highly heterogeneous disease, its evolving treatment paradigm of tailored approaches has led to a focus on both neoadjuvant and adjuvant strategies based on tumor biology, stage, and patient factors.

“We now have an enormous armamentarium of agents for HER2-positive disease: 3 monoclonal antibodies, 3 HER2-targeted TKIs, and 2 antibody-drug conjugates, with many more hot on the trail toward getting approved,” Sara A. Hurvitz, MD, FACP, professor of medicine and head, Division of Hematology/Oncology, University of Washington School of Medicine; and senior vice president, Clinical Research Division, Fred Hutchinson Cancer Center in Seattle, said.

At the 42nd Annual Miami Breast Cancer Conference, Hurvitz discussed improved outcomes associated with the expanding armamentarium of targeted agents in HER2-positive breast cancer and how medical oncologists can optimize treatment while minimizing toxicity.1

“Deciding among these agents and knowing when to use these therapies is becoming more and more critical, especially in early-stage disease, where we don’t want to overtreat or undertreat patients, but find the just right spot,” she added.

Small, Lymph Node–Negative Disease

To start, Hurvitz noted that small, lymph node–negative, HER2-positive breast cancer is one area that remains controversial. When evaluating stage I disease, according to the 2024 National Comprehensive Cancer Network Guidelines, regardless of hormone receptor status and size, adjuvant systemic therapy is considered. However, for those with hormone receptor–negative disease, the use of chemotherapy with trastuzumab (Herceptin) should be considered.

“[According to a Surveillance, Epidemiology, and End Results (SEER) Database Analysis],2 for hormone receptor–negative [disease], we’re using more chemotherapy, and over 30% of patients are receiving chemotherapy, even for small T1a tumors with better node-negative [status],” Hurvitz said.

The analysis also demonstrated that 7-year breast cancer–specific survival was high, regardless of whether patients had received chemotherapy. However, Hurvitz noted that patients who did receive chemotherapy tended to have better outcomes, and the differences appeared greater for those with hormone receptor–negative disease.

Further, additional data from a multi-institutional retrospective analysis from the ASCO LinQ Database showed that patient with T1a-c, node-negative tumors experienced superior 5-year invasive disease-free survival (iDFS; 82.9% vs 76.1%) and overall survival (OS; 95.6% vs 94.0%) with trastuzumab with or without chemotherapy, compared with observation, respectively.3 However, Hurvitz noted that receipt of chemotherapy was not randomized, therefore, confounding variables may bias results, affecting the observed differences.

From the same database, outcomes of patients with T1a-b status showed that patients in the T1a group had superior outcomes with treatment with trastuzumab, whereas those in the T1b/c group showed improvements with some form of systemic therapy.

“Hopefully, this convinces you that for patients who are healthy enough, even if the tumor is small, we should be considering therapy,” Hurvitz explained. “And now we have therapy that is easier for patients to take.”

Adjuvant Paclitaxel and Trastuzumab

In the phase 2 APT trial (NCT00542451)4 of the combination use of paclitaxel and trastuzumab the 10-year iDFS rate was 91.3% (95% CI, 88.3%-94.4%), while the phase 2 ATEMPT trial (NCT01853748)5 of ado-trastuzumab emtansine (T-DM1; Kadcyla) demonstrated a 5-year iDFS rate of 97.0% (95% CI, 95.2%-98.7%).

“I have always wondered, how does the APT regimen compare to [anthracycline/cyclophosphamide/taxane/trastuzumab (ACTH) or taxane/carboplatin/ trastuzumab (TCH)]?” Hurvitz said, adding that the FDA’s propensity score matching analysis6 supported the use of paclitaxel and trastuzumab in this setting.

“That gives us reassurance that omitting the carboplatin is probably not harming patients if you tend to use TCH in these patients,” she explained.

Higher Risk Node-Positive Tumors

For patients in this disease setting, Hurvitz recommends the use of adjuvant therapy in patients with HER2-positive early breast cancer with residual invasive disease after neoadjuvant therapy.

This can be supported by results from the phase 3 KATHERINE trial (NCT01772472), which was designed to evaluate T-DM1 vs trastuzumab.7 Eight-year follow-up data yielded sustained improvements in iDFS and OS in HER2-positive early breast cancer harboring residual invasive disease following neoadjuvant treatment.

At a median follow-up of 8.4 years, the T-DM1 arm demonstrated a 7-year iDFS rate of 80.8% vs 67.1% in the trastuzumab arm (HR, 0.54; 95% CI, 0.44-0.66; P < .0001), while 7-year OS rates also favored T-DM1 (89.1% vs 84.4%, respectively; HR, 0.66; 95% CI, 0.51-0.87; P = .0027).

Systemic Therapy Options

Hurvitz explained that there may not be a need for anthracyclines, as various studies have demonstrated no statistically significant difference in DFS, pathologic complete response (pCR), and event-free survival. However, one major difference that she highlighted was a higher rate of cardiomyopathy when patients received anthracyclines.

“We are grossly underestimating the damage we’re doing to patients’ hearts long term with anthracyclines. Occult cardiac damage is occurring,” she added.

Response-Guided Approach

Hurvitz highlighted that many studies are also now looking at response-guided approaches using imaging of biological features or pathologic response in patients with HER2-positive breast cancer.

The phase 2 PHERGain trial (NCT03161353) used an18fluorine-fluorodeoxyglucose-PET-based, pCR-adapted strategy. Patients were randomized to receive either docetaxel plus carboplatin, trastuzumab, and pertuzumab (TCHP; group A) or trastuzumab and pertuzumab with or without endocrine therapy (group B).8

After a median follow-up of 43.3 months, the 3-year iDFS rate was 94.8% (95% CI, 91.4%-97.1%; P = .001) in group B. Further, the rate was 96.4% (95% CI, 92.4%-100.0%) among patients who did not receive chemotherapy and were PET responders with a pCR.

“This type of use of PET imaging is currently being incorporated into other studies,” Hurvitz added.

“The ARIADNE study [NCT05900206] is being conducted to do this response-guided approach, using luminal subtyping to stratify patients into different subgroups and try and ‘right size’ treatment. The PHERGain-2 phase 2 study [NCT04733118] is using imaging to further stratify therapy. We have the COMPASS studies that are using [pCR] to designate whether patients will get tucatinib [Tukysa]-based therapy. And then we have a number of other studies ongoing in HER2-positive early breast cancer that are going to make us smarter and better able to deliver personalized therapy to our patients.”

References

1. Hurvitz SA. Tailored strategies for HER2+ breast cancer: neoadjuvant and adjuvant approaches. Presented at: 42nd Annual Miami Breast Cancer Conference. March 6-9, 2025; Miami, Florida.
2. Waks AG, Tarantino P, Chen EL, et al. Outcomes and treatment patterns for stage I human epidermal growth factor receptor 2-positive breast cancer in the Surveillance, Epidemiology, and End Results database, 2010–2019. Cancer. 2025;131(3):e35729. doi:10.1002/cncr.35729
3. Johnson KCC, Ni A, Quiroga D, et al. The survival benefit of adjuvant trastuzumab with or without chemotherapy in the management of small (T1mic, T1a, T1b, T1c), node negative HER2+ breast cancer. NPJ Breast Cancer. 2024;10(1):49. doi:10.1038/s41523-024-00652-4
4. 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
5. Tarantino P, Tayob N, Villacampa G, et al. Adjuvant trastuzumab emtansine versus paclitaxel plus trastuzumab for stage I human epidermal growth factor receptor 2–positive breast cancer: 5-year results and correlative analyses from ATEMPT. J Clin Oncol. 2024;42(31):3652-3665. doi:10.1200/JCO.23.02170
6. Amiri-Kordestani L, Xie D, Tolaney SM, et al. A Food and Drug Administration analysis of survival outcomes comparing the Adjuvant Paclitaxel and Trastuzumab trial with an external control from historical clinical trials. Ann Oncol. 2020;31(12):1704-1708. doi:10.1016/j.annonc.2020.08.2106
7. Loibl S, Mano M, Untch M, et al. Phase III study of adjuvant ado-trastuzumab emtansine vs trastuzumab for residual invasive HER2-positive early breast cancer after neoadjuvant chemotherapy and HER2-targeted therapy: KATHERINE final IDFS and updated OS analysis. Cancer Res. 2024;84(suppl 9):GS03-12. doi:10.1158/1538-7445.SABCS23-GS03-12
8. Pérez-García JM, Cortés J, Ruiz-Borrego M, et al. 3-year invasive disease-free survival with chemotherapy de-escalation using an 18F-FDG-PET-based, pathological complete response-adapted strategy in HER2-positive early breast cancer (PHERGain): a randomised, open-label, phase 2 trial. Lancet. 2024;403(10437):1649-1659. doi:10.1016/S0140-6736(24)00054-0