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HER2 Positive EBC

CE / CME

Evolving Treatment Landscape for HER2-Positive/HER2-Low Early Breast Cancer

Physician Assistants/Physician Associates: 0.50 AAPA Category 1 CME credit

Pharmacists: 0.50 contact hour (0.05 CEUs)

ABIM MOC: maximum of 0.50 Medical Knowledge MOC point

Physicians: maximum of 0.50 AMA PRA Category 1 Credit™

Nurse Practitioners/Nurses: 0.50 Nursing contact hour

Released: May 01, 2026

Expiration: October 31, 2026

Laura Spring
Laura Spring, MD
CME/CE Information

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Proposed Strategy for Managing Patients With Stage I-III HER2-Positive EBC

With the continued expansion of available treatment options, management of HER2‑positive EBC is best approached using a risk‑adapted framework that incorporates tumor size, nodal status, and response to therapy.7 This approach allows treatment intensity to be aligned with recurrence risk while maintaining a focus on tolerability and patient preferences.

For patients with small tumors (≤1 cm) and node‑negative disease, the standard approach typically involves upfront surgery followed by adjuvant systemic therapy. Accurate assessment of nodal status is essential and often includes dedicated axillary imaging with ultrasound and biopsy when indicated. Adjuvant treatment most commonly consists of paclitaxel plus trastuzumab administered for 12 weeks, followed by continuation of trastuzumab to complete a total of 1 year of HER2‑directed therapy.7 In select cases, particularly for very small tumors, treatment decisions may involve shared decision‑making, weighing tumor biology, patient comorbidities, and individual risk tolerance.

Management of clinical T1c node‑negative disease is more variable and often individualized. Decisions regarding upfront surgery vs neoadjuvant therapy are guided by patient‑ and tumor‑specific factors, balancing the benefits of neoadjuvant therapy for risk stratification and potential treatment escalation against the likelihood of achieving a pCR. When neoadjuvant therapy is selected, commonly used regimens in clinical practice include THP or TCHP, although approaches may vary. If not pursuing neoadjuvant therapy, surgery with or without radiotherapy followed by adjuvant dual HER2 targeting is selected.21,23

For patients with stage II or III disease, neoadjuvant therapy remains the standard of care.7 Historically, commonly used regimens have included TCHP, or anthracycline‑based chemotherapy followed by THP. Emerging data are showing promise for T-DXd in the neoadjuvant setting. However, T-DXd use in this context remains investigational, and regulatory approval is pending as of May 2026.12,21

Postoperative treatment decisions are often guided by response to neoadjuvant therapy. For patients who achieve a pCR, therapy typically consists of continuation of trastuzumab, with or without pertuzumab, to complete 1 year of HER2‑directed therapy.7 For patients with residual invasive disease, treatment escalation is recommended, often based on the KATHERINE study of T‑DM1, now considered the standard of care in this setting, demonstrating a significant reduction in the risk of recurrence or death (hazard ratio: 0.50).19   Recent, emerging clinical trial data from DESTINY-Breast05 support the use of T-DXd over T-DM1 in patients with putative high-risk features following neoadjuvant therapy.20 T-DXd is now included in NCCN guideline recommendations in this setting. However, it is not currently FDA approved for use in early-stage disease but is under FDA priority review with a decision pending by late 2026.7,12

Extended adjuvant therapy with neratinib may also be considered following completion of trastuzumab‑based treatment, particularly in patients with HR-positive disease, where the greatest benefit has been observed.18

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Sequencing of HER2-Directed Therapy in EBC

As newer therapies are incorporated into earlier lines of treatment, sequencing decisions are becoming increasingly complex.

For T-DXd, evolving evidence in the (neo)adjuvant treatment setting for HER2‑positive EBC is raising important questions regarding its optimal sequencing, particularly in the investigational neoadjuvant setting as well as patient selection. At present, clinical guidance is evolving, and treatment decisions require careful consideration of FDA approvals, guideline recommendations, disease risk, therapeutic goals, and safety.

In clinical practice, sequencing decisions often involve balancing the potential benefit of early treatment intensification with T-DXd against the option to reserve this therapy for patients with residual disease following standard neoadjuvant treatment. Toxicity considerations, including the risk of ILD or pneumonitis, also play a critical role. For patients with the highest‑risk features, such as extensive nodal involvement, inflammatory breast cancer, or a significant residual disease burden, there may be a rationale for incorporating T-DXd earlier in the treatment course. In contrast, for patients with intermediate‑risk disease, many healthcare professionals (HCPs) may prefer a more stepwise approach, reserving T-DXd for the postneoadjuvant setting if residual disease is identified at surgery. At present, there are no data to guide the use of T-DXd in both the neoadjuvant and adjuvant settings within the same patient. As a result, uncertainty exists in situations where T-DXd is administered preoperatively and residual invasive disease persists at the time of surgery. In these scenarios, treatment decisions must be highly individualized, considering prior therapies received, treatment tolerability, response to neoadjuvant therapy, and overall recurrence risk.

Tumor biology may also influence sequencing considerations. HER2 expression exists along a spectrum, and tumors with more heterogeneous or lower levels of HER2 expression may derive particular benefit from T-DXd due to its bystander effect. As biomarker‑driven risk stratification continues to evolve, these biologic factors may further inform how and when T-DXd is optimally incorporated into EBC treatment algorithms.

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Ms Roberts is a 49‑year‑old Black woman with stage IIIB, ER‑negative/HER2‑positive EBC​. She received neoadjuvant THP​ and preoperative therapy. Postsurgery pathology shows residual invasive disease in the breast and axillary nodes​. Your team recommends adjuvant HER2‑directed therapy​. Ms Roberts voices strong concerns regarding lung side effects she read about online and is concerned about missing work​ to receive infusion-based treatments. She is the primary caregiver for her mother with liver cirrhosis. She says to you, “I don’t want to stop early like my cousin did when the side effects got bad.” You are about to start adjuvant HER2 directed therapy for Ms Roberts. Which coordinated action now best operationalizes shared decision making and communication to improve her adherence and persistence to adjuvant care?

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