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Testing Radiation and HER2-targeted Therapy Versus HER2-targeted Therapy Alone for Low-risk HER2-positive Breast Cancer
Trial ID: NCT05705401
This Phase III trial compares the recurrence-free interval (RFI) among patients with early-stage, low risk HER2+ breast cancer who undergo breast conserving surgery and receive HER2-directed therapy, and are randomized to not receive adjuvant breast radiotherapy versus those who are randomized to receive adjuvant radiotherapy per the standard of care.
A Phase III Randomized Trial of Radiotherapy Optimization for Low-Risk HER2-Positive Breast Cancer (HERO)
- 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 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.
- 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
- Use of any investigational product within 30 days prior to randomization.
radiation: Standard of Care Adjuvant Breast Radiation
drug: Standard of Care HER2-targeted Therapy Without Adjuvant Breast Radiation