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Comparing radiation therapy with HER2-targeted therapy to HER2-targeted therapy alone for low-risk HER2-positive breast cancer

A Phase III Randomized Trial of Radiotherapy Optimization for Low-Risk HER2-Positive Breast Cancer (HERO)

Phase 3 Interventional NRG Oncology · NCT05705401

This study is testing whether women with early-stage, low-risk HER2-positive breast cancer can safely skip radiation therapy after surgery while still getting effective treatment with HER2-targeted therapy.

Quick facts

PhasePhase 3
Study typeInterventional
Enrollment1300 (estimated)
Ages40 Years and up
SexAll
SponsorNRG Oncology Academic / other
Drugs / interventionschemotherapy, radiation, trastuzumab
Locations409 sites (Phoenix, Arizona and 408 other locations)
Trial IDNCT05705401 on ClinicalTrials.gov

What this trial studies

This Phase III trial investigates the recurrence-free interval among patients with early-stage, low-risk HER2-positive breast cancer who have undergone breast-conserving surgery. Participants are randomized to receive either standard HER2-directed therapy alone or in combination with adjuvant breast radiotherapy. The study aims to determine if omitting radiation therapy can maintain effective cancer control while reducing treatment-related morbidity. The trial builds on previous findings that have shown improved outcomes with HER2-targeted therapies.

Who should consider this trial

Good fit: Ideal candidates include individuals aged 40 and older with histologically confirmed HER2-positive invasive breast cancer who have undergone breast-conserving surgery and completed at least 12 weeks of HER2-targeted therapy.

Not a fit: Patients with HER2-negative breast cancer or those who have not undergone the required surgical and treatment protocols may not benefit from this study.

Why it matters

Potential benefit: If successful, this study could lead to less invasive treatment options for patients with low-risk HER2-positive breast cancer, potentially reducing the need for radiation therapy.

How similar studies have performed: Previous studies have shown promising results with HER2-targeted therapies, but this specific comparison of radiation therapy versus no radiation in this patient population is novel.

Eligibility criteria

Show full inclusion / exclusion criteria 
Inclusion Criteria:

* The patient or a legally authorized representative must provide study-specific informed consent prior to study entry and, for patients treated in the U.S., authorization permitting release of personal health information.
* female and male patients who have undergone breast conserving surgery and completed a minimum of 4 cycles (12 weeks) of neoadjuvant or adjuvant chemotherapy in combination with HER2-targeted therapy.

  -≥ 40 years of age
* ECOG performance status of 0 ,1, or 2/Karnofsky performance status above 60
* Histologically or cytologically confirmed invasive breast carcinoma.
* tumor must have been determined to be HER2-positive by current ASCO/CAP guidelines based on local testing results.
* Patient must have undergone axillary staging, either sentinel node biopsy (SNB) or axillary lymph nodal dissection (ALND). In neoadjuvant patients, SNB following neoadjuvant therapy is strongly recommended. SNB prior to neoadjuvant therapy is discouraged, but patients are permitted if node negative (pN0).
* The following staging criteria must be met according to AJCC 8th edition criteria:

Adjuvant cohort : By pathologic evaluation, the patient's primary tumor must be \</= 2 cm and ipsilateral nodes must be pN0. Surgical lumpectomy margins must be negative for invasive cancer and ductal carcinoma in situ (no ink on tumor).

Neoadjuvant cohort: Prior to neoadjuvant therapy, the patient's primary tumor must be \< 3 cm by imaging studies, with negative axillary nodes (cN0) based on axillary U/S, CT, PET or MRI. Physical examination is not sufficient documentation of cN0 status; • Must be ypT0N0 at surgery (lumpectomy); patients with residual non-invasive disease (DCIS) in the surgical specimen (ypTis), are NOT eligible.

* For the Adjuvant cohort, adjuvant therapy must have consisted of a minimum of 4 cycles (12 weeks) of chemotherapy in combination with HER2-targeted therapy.
* For the Neoadjuvant cohort, neoadjuvant therapy must have consisted of a minimum of 4 cycles (12 weeks) of chemotherapy in combination with HER2-targeted therapy.- ; Patients who did not receive chemotherapy in the neoadjuvant setting are not eligible, even if they achieved pCR with their preoperative treatment; nor would these patients become eligible by receiving chemotherapy after surgery.
* In patients assigned to radiation therapy, treatment should start ≤ 12 weeks from surgery on the Neoadjuvant cohort and ≤ 8 weeks from the completion of chemotherapy on the Adjuvant cohort. Patients should continue HER2-targeted therapy during assigned study treatment (radiation or observation).
* Bilateral mammogram or MRI within 52 weeks prior to randomization.
* HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months of randomization are eligible for this trial.

Exclusion Criteria:

* Definitive clinical or radiologic evidence of metastatic disease.
* On the Adjuvant cohort, patients with a primary tumor \>2 cm on pathologic examination of the surgical specimen. On the Neoadjuvant cohort, patients with a primary tumor \> 3 cm or with abnormal or suspicious ipsilateral axillary nodes by pretreatment imaging, unless demonstrated to be negative by cytologic or histologic examination.
* Pathologically positive axillary nodes at any time including of pN0(i+) or pN0(mol+) ypN0(i+) or ypN0(mol+) disease.
* Patient planning for or status-post mastectomy.
* Radiographically suspicious ipsilateral or contralateral axillary, supraclavicular, infraclavicular, or internal mammary lymph nodes, unless there is histological confirmation that these nodes are negative for metastatic disease.
* Suspicious microcalcifications, densities, or palpable abnormalities (in the ipsilateral or contralateral breast), or mass or non-mass enhancement on MRI (if performed) aside from the known cancer, unless biopsied and found to be benign.
* Non-epithelial breast malignancies such as sarcoma or lymphoma.
* Multicentric carcinoma (invasive cancer or DCIS) in more than one quadrant or separated by \> 4 centimeters. If multifocal, all foci should be confined to a maximum tumor bed of 3 cm determined by pathological assessment.
* Paget's disease of the nipple.
* Synchronous (unilateral or bilateral) invasive breast cancer or DCIS. (Patients with synchronous and/or previous contralateral LCIS are eligible.)
* On the Adjuvant cohort, surgical margins that cannot be microscopically assessed or are positive at pathologic evaluation. (If surgical margins are rendered free of disease by re-excision, the patient is eligible).
* Treatment plan that includes regional nodal irradiation.
* Patients treated for a prior invasive breast malignancy are excluded. Contralateral DCIS ≥ 10 years prior to enrollment is permissible.
* Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.
* Patients on oral, transdermal, or subdermal estrogen replacement (including all estrogen only and estrogen-progesterone formulas) are not eligible unless discontinued prior to randomization.
* Prior ipsilateral breast or thoracic RT for any condition (contralateral RT for DCIS ≥ 10 years prior to randomization is permitted).
* Active collagen vascular disease, specifically dermatomyositis with a CPK level above normal or with an active systemic lupus erythematosus, or scleroderma.
* Clinicians should consider whether any conditions would make this protocol unreasonably hazardous for the patient.
* Pregnancy or lactation at the time of randomization or intention to become pregnant during treatment. (Note: Pregnancy testing according to institutional standards for patients of childbearing potential must be performed within 14 days prior to randomization.)
* Use of any investigational product within 30 days prior to randomization.

Where this trial is running

Phoenix, Arizona and 408 other locations

+359 more sites — see ClinicalTrials.gov for the full list.

Study contacts

How to participate

  1. Review the eligibility criteria above with your treating physician.
  2. Visit the official trial page on ClinicalTrials.gov for the most current contact information and recruitment status.
  3. Contact the listed study coordinator or principal investigator to request pre-screening. Pre-screening is free and never obligates you to enroll.
View on ClinicalTrials.gov → Find more trials like this →
Conditions HER2-positive Breast Cancer
Last reviewed 2026-06-13 by the Find a Trial editorial team. Information on this page is for educational purposes and is not medical advice. Always consult qualified healthcare professionals about clinical trial participation.