Conundrums in Treating HER2-Positive Early Breast Cancer

Today’s oncologists are blessed with an abundance of therapies for HER2-positive early breast cancer, but this comes with the challenge of selecting among them. At the 2025 Miami Breast Cancer Conference, Sara A. Hurvitz, MD, FACP, offered insight on common clinical scenarios. Dr. Hurvitz is Professor of Medicine and Head of the Division of Hematology/Oncology at the University of Washington School of Medicine and Senior Vice President of the Clinical Research Division at Fred Hutchinson Cancer Center, Seattle.

“Since the approval of trastuzumab, we have gained an enormous armamentarium of agents, including three monoclonal antibodies, three HER2-targeted tyrosine kinase inhibitors, and two antibody-drug conjugates, with many others hot on the trail toward approval,” Dr. Hurvitz stated. “Knowing when to use each of them is becoming more and more critical, especially in early-stage disease, where we don’t want to overtreat or undertreat patients but to find the just-right amount of therapy.”

Small Node-Negative Disease

Treatment of patients with small tumors and negative lymph nodes remains controversial. The 2024 National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines^®) for stage I disease state that for both hormone receptor–positive or hormone receptor–negative, HER2-positive disease, regardless of tumor size, adjuvant systemic therapy (endocrine or endocrine plus trastuzumab) should at least be considered. For hormone receptor–negative disease, chemotherapy plus trastuzumab has a category 2B recommendation for node-negative disease and tumors ≤ 0.5 cm (ie, based on lower-level evidence, there is NCCN consensus the intervention is appropriate). Outcomes have been shown to be “pretty good,” she noted, in stage Ia HER2-positive disease regardless of the receipt of chemotherapy, but as tumor size increases, so does the benefit of chemotherapy, especially in patients with hormone receptor–negative disease.

“For patients who are healthy enough, even with small tumors, we should consider therapy.”

— SARA A. HURVITZ, MD, FACP

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A recent multi-institutional retrospective analysis—an ASCO LinQ database of 1,184 patients with T1a-c node-negative disease—showed invasive disease–free survival at 5 years to be 76% for patients not receiving chemotherapy or trastuzumab and 83% for those who received trastuzumab with or without chemotherapy; the 5-year overall survival rates were 94% and 96%, respectively.¹ Patients receiving some type of treatment had far better outcomes than untreated patients. “For patients who are healthy enough, even with small tumors, we should consider therapy,” Dr. Hurvitz added.

The APT trial’s regimen of weekly paclitaxel for 12 cycles plus 1 year of trastuzumab has been established as beneficial in small, node-negative, HER2-positive disease, but the question has been how it compares with adjuvant ado-trastuzumab emtansine (T-DM1), she said. With paclitaxel plus trastuzumab, the disease-free survival rate at 10 years was 91% in APT,² and in the ATEMPT trial, the 5-year disease-free survival rate with T-DM1 was 97%.³ The ongoing ATEMPT 2.0 is evaluating T-DM1 for six cycles, followed by subcutaneous trastuzumab, vs the APT regimen (paclitaxel plus trastuzumab) in patients with stage 1 disease.

Some have also questioned whether the omission of carboplatin is detrimental. However, Dr. Hurvitz has been reassured by a propensity score–matching analysis by the U.S. Food and Drug Administration that found disease-free survival and overall survival to be similar, regardless of carboplatin’s inclusion.⁴

Neoadjuvant Therapy for High-Risk Patients

“For patients with T1c or clinically node-positive tumors, I would argue we should give neoadjuvant therapy,” Dr. Hurvitz continued. This recommendation is based on the results from the KATHERINE trial, which evaluated T-DM1 vs trastuzumab in patients with cT1cN0 tumors and residual disease in the breast or nodes after neoadjuvant therapy.⁵ At a median follow-up of 8.4 years, not only was invasive disease–free survival improved by 46% (P < .0001), but deaths were reduced by 44% (P = .0027; threshold for significance P < .0263) after treatment with adjuvant TDM-1.

“The question of node positivity comes up when we are grappling with whether to give patients neoadjuvant therapy or not.”

— SARA A. HURVITZ, MD, FACP

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“Now, a question comes up in tumor boards: If a patient with a T1 tumor goes straight to surgery, what is the chance she will prove to have node-positive disease, even though we could not see or feel nodal disease clinically prior to surgery? The question of node positivity comes up when we are grappling with whether to give patients neoadjuvant therapy or not,” Dr. Hurvitz explained.

An analysis of two international cohorts looked at nodal status in patients with HER2-positive, clinically node-negative diseases treated with upfront surgery.⁶ It revealed that 20% of patients with clinically node-negative disease, 26% of patients with cT1cN0 tumors, and even 10% of patients with T1mi/a/b tumors were found to have node-positive disease at surgery. For patients who instead underwent neoadjuvant therapy first, many fewer—including 11% with T1c tumors—had node-positive disease at surgery. “This may argue that for our T1c, and maybe some T1b patients, we should at least discuss neoadjuvant therapy,” she suggested.

What Systemic Therapy Is Recommended?

“I would strongly argue that we don’t need anthracyclines,” Dr. Hurvitz continued. She based this recommendation on numerous studies showing no meaningful benefit, including BCIRG 006 in the adjuvant setting for HER2-positive disease^7,8 and three neoadjuvant studies (including neoCARH,⁹ TRYPHAENA,¹⁰ and TRAIN-2¹¹). “Reassuringly, disease-free and event-free survival with anthracycline-containing vs nonanthracycline-containing regimens do not appear to be different,” she noted.

“But what we do know is different is a higher rate of cardiomyopathy. We are grossly underestimating the damage we’re doing to patients’ hearts long term,” she said. A disturbing extent of occult cardiac damage has been revealed from long-term pediatric studies, along with studies such as NSABP B-31¹² and NSABP 9831,¹³ which registered a high rate of treatment discontinuations because of cardiac-related issues.

Discussing the use of other drugs in the adjuvant setting, Dr. Hurvitz cited 8-year outcomes from APHINITY, showing improved outcomes with pertuzumab added to trastuzumab in patients with node-positive disease (a 5% absolute benefit)—but not in those with node-negative disease.¹⁴ She therefore does not use adjuvant pertuzumab in patients with HER2-positive, node-negative disease.

With neratinib, the 8-year follow-up of ExteNET showed an absolute 5% benefit in invasive disease–free survival (P = .002) with 1 year of neratinib after completion of trastuzumab, but this benefit was restricted to those with hormone receptor–positive disease, and an overall survival benefit was lacking.^15,16 With the caveat that neratinib was not tested in patients after T-DM1, Dr. Hurvitz approves of its use in very high–risk patients.

Response-Guided Approaches

Response-guided approaches using imaging, biological features, and pathologic response are being evaluated. PHERGain successfully used positive-emission tomography (PET) to adapt adjuvant treatment after neoadjuvant therapy in patients with HER2-positive disease¹⁷; PET-adapted response is now being incorporated into other clinical trials. TRAIN-3 found magnetic resonance imaging (MRI) response to neoadjuvant therapy to be useful in guiding treatment duration for HER2-positive tumors,¹⁸ although this benefit was heavily weighted toward hormone receptor–negative tumors, “so more work to be done here,” she commented.

Response to neoadjuvant therapy is known to be related to features of the tumor and its microenvironment. Thus, the ARIADNE study is exploring the use of an intrinsic subtype to guide treatment selection in HER2-positive disease. Additionally, the COMPASS trials are using pathologic response to neoadjuvant therapy (yes vs no) in patients with HER2-positive disease to select patients for enrollment into trials of various treatments. “These studies and a number of others in HER2-posive early breast cancer are going to make us smarter and better able to deliver personalized therapy to our patients,” she predicted.

Dr. Hurvitz’s Recommendations for Treating HER2-Positive, Stage I–III Breast Cancer

For cT1a/b cN0 Tumors:

• Surgery followed by trastuzumab-based therapy alone (especially T1a) or with chemotherapy or endocrine therapy
• For high-risk, multifocal disease or when size is poorly estimated, neoadjuvant THP (docetaxel, trastuzumab, pertuzumab) or TCHP (docetaxel, carboplatin, trastuzumab, pertuzumab) should be considered.

For ≥ T1c or ≥ cN1 Tumors:

• Neoadjuvant TCHP: The need for anthracycline should be considered carefully, as data for benefit are not strong. In the future, less toxic therapy may become standard, and PET or MRI may be used to determine a need to switch therapy.
  • Residual invasive disease: T-DM1 × 14, with a move to neratinib if hormone receptor–positive and node-positive disease. (Note: Neratinib has not been tested after T-DM1 or pertuzumab.)
  • tpCR (ypT0/Tis ypN0): Trastuzumab for 1 year, or trastuzumab/pertuzumab for 1 year if starts as node-positive disease. (Note: Adjuvant pertuzumab has not been tested after neoadjuvant pertuzumab.) Neratinib should be considered for those at very high risk, even with pathologic complete response, for protection of the central nervous system.

DISCLOSURE: Dr. Hurvitz has received grants and research support from numerous companies but reported no personal conflicts of interest.

REFERENCES

1. 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 10:49, 2024.
2. 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 24:273-285, 2023.
3. 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 42:3652-3665, 2024.
4. 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 31:1704-1708, 2020.
5. 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. 2023 San Antonio Breast Cancer Symposium. Abstract GS03-12.
6. Weiss A, Martínez-Sáez O, Waks AG, et al: Nodal positivity and systemic therapy among patients with clinical T1-T2N0 human epidermal growth factor receptor-positive breast cancer: Results from two international cohorts. Cancer 129:1836-1845, 2023.
7. Slamon D, Eiermann W, Robert N, et al: Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med 365:1273-1283, 2011.
8. Slamon D, Eiermann W, Robert N, et al: Phase III randomized trial comparing doxorubicin and cyclophosphamide followed by docetaxel (AC→T) with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab (AC→TH) with docetaxel, carboplatin and trastuzumab (TCH) in Her2neu positive early breast cancer patients: BCIRG 006 Study. Cancer Res 69(24_suppl):abstract 62, 2009.
9. Gao HF, Wu Z, Lin Y, et al: Anthracycline-containing versus carboplatin-containing neoadjuvant chemotherapy in combination with trastuzumab for HER2-positive breast cancer: The neoCARH phase II randomized clinical trial. Ther Adv Med Oncol 13:17588359211009003, 2021.
10. Schneeweiss A, Chia S, Hickish T, et al: Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: A randomized phase II cardiac safety study (TRYPHAENA). Ann Oncol 24:2278-2284, 2013.
11. van Ramshorst MS, van der Voort A, van Werkhoven ED, et al: Neoadjuvant chemotherapy with or without anthracyclines in the presence of dual HER2 blockade for HER2-positive breast cancer (TRAIN-2): A multicentre, open-label, randomised, phase 3 trial. Lancet Oncol 19:1630-1640, 2018.
12. Romond EH, Jeong JH, Rastogi P, et al: Seven-year follow-up assessment of cardiac function in NSABP B-31, a randomized trial comparing doxorubicin and cyclophosphamide followed by paclitaxel (ACP) with ACP plus trastuzumab as adjuvant therapy for patients with node-positive, human epidermal growth factor receptor 2-positive breast cancer. J Clin Oncol 30:3792-3799, 2012.
13. Advani PP, Ballman KV, Dockter TJ, et al: Long-term cardiac safety analysis of NCCTG N9831 (Alliance) adjuvant trastuzumab trial. J Clin Oncol 34:581-587, 2016.
14. Loibl S, Jassem J, Sonnenblick A, et al: Adjuvant pertuzumab and trastuzumab in early human epidermal growth factor receptor 2-positive breast cancer in the APHINITY trial: Third interim overall survival analysis with efficacy update. J Clin Oncol 42:3643-3651, 2024.
15. Holmes FA, Moy B, Delaloge S, et al: Overall survival with neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): A randomised, double-blind, placebo-controlled, phase 3 trial. Eur J Cancer 184:48-59, 2023.
16. Chan A, Moy B, Mansi J, et al: Final efficacy results of neratinib in HER2-positive hormone receptor-positive early-stage breast cancer from the phase III ExteNET trial. Clin Breast Cancer 21:80-91.e7, 2021.
17. 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 403:1649-1659, 2024.
18. van der Voort A, Louis FM, van Ramshorst MS, et al: MRI-guided optimisation of neoadjuvant chemotherapy duration in stage II-III HER2-positive breast cancer (TRAIN-3): A multicentre, single-arm, phase 2 study. Lancet Oncol 25:603-613, 2024.

MORE INFORMATION

For more on therapeutic strategies for HER2-positive breast cancer, see a video with Sara A. Hurvitz, MD, FACP, on The ASCO Post Newsreels at ascopost.com/videos.