CLINICAL TRIAL / NCT05705401
Testing Radiation and HER2-targeted Therapy Versus HER2-targeted Therapy Alone for Low-risk HER2-positive Breast Cancer
- Interventional
- Recruiting
- NCT05705401
Contact Information
A Phase III Randomized Trial of Radiotherapy Optimization for Low-Risk HER2-Positive Breast Cancer (HERO)
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.
The landmark trials that established breast conservation therapy (BCT) (breast-conserving
surgery followed by adjuvant breast irradiation) as a suitable alternative to mastectomy
were conducted in an era that predated biological subtyping of breast cancer and the use
of HER2-directed therapies in patients with HER2+ cancers. These trials established
adjuvant radiotherapy following breast-conserving surgery as necessary to maximize local
control, yet, in the intervening years, overall outcomes have improved significantly
owing to widespread adoption of screening mammography, resulting in a substantial
reduction in average tumor size at diagnosis, as well as improvements in surgical
techniques and, crucial for this proposal, the development of highly active systemic
therapies.
Before the development of HER2-targeted therapies, patients with HER2-driven localized
breast cancer had among the highest rates of local recurrence. However, with improved
identification of these patients and the advent of HER2-directed therapies, outcomes have
improved significantly, and trials have sought to optimize treatment to reduce the
morbidity of both local and systemic treatment. Among the most salient of these examples
is the APT trial, a single-arm adjuvant study that enrolled 410 breast cancer patients
with HER2+ tumors ≤ 3cm in size and negative axillary nodes, who received adjuvant
systemic therapy with weekly paclitaxel and trastuzumab for 12 weeks (TH) followed by 9
months of trastuzumab monotherapy. In addition to demonstrating a very low incidence of
distant recurrence, among those on the trial who underwent BCT (lumpectomy and radiation,
n = 244), only 2 local recurrence (LR) events have been reported after 7 years of
follow-up (7-year LR = 1.2%), representing among the most favorable local outcomes of any
breast cancer cohort studied to date. Confirmatory results are forthcoming from the
ATEMPT trial, which evaluated the antibody-drug conjugate T-DM1 (ado-trastuzumab
emtansine) (n=383) vs the TH regimen from the APT trial (n = 114), thus far showing only
3 LRs in each arm with a median 3-years of follow-up. Importantly, per the current
standard of care for HER2+ patients undergoing BCT, all patients presumably received
adjuvant breast radiotherapy.
The balance of the BCT literature, including a landmark meta-analysis by the Early Breast
Cancer Trialists' Collaborative Group, suggests that adjuvant radiotherapy approximately
halves the risk of local recurrence following lumpectomy across all analyzable subgroups.
While the relative benefit appears constant across subgroups, the absolute benefit of
adjuvant radiotherapy varies with the underlying risk. Taking the favorable results of
the APT trial (1.2% 7-year LR), if one presumes that omission of radiotherapy yields a
doubling or tripling of local recurrence (based on the observed RR of 0.5 - 0.66 for
those receiving radiotherapy across the preponderance of historical trials), this
population might have manifested a LR rate of 2.4 - 3.6% with the omission of
radiotherapy. That is to say, the hypothesis is that administration of RT to APT patients
undergoing BCT may have reduced the 7-year absolute risk of LR by only 1.2-2.4%. Through
the identification of patients who are at low risk of LR, it may be acceptable for such
patients to forego radiation. This hypothesis will be studied by evaluating omission of
radiotherapy among patients with pT1N0 disease at breast-conserving surgery who receive
adjuvant HER2-directed therapy (trastuzumab/paclitaxel preferred, other options per
protocol), or with clinical tumors ≤ 3 cm and clinically negative axillary nodes (cN0)
who achieve a pathologic complete response (pCR; ypT0N0) following preoperative
(neoadjuvant) administration of HER2-directed therapy (trastuzumab/paclitaxel preferred,
other options per protocol). It is expcted that the 5-year LR rate for this population
omitting radiotherapy will be 2% or less, and that omission of radiation will not have a
measurable impact on regional and distant recurrences or overall survival.
The practice of breast radiation oncology has benefited immensely from practice-changing
trials that have refined the application of adjuvant radiotherapy since the early
surgical studies determined whole breast radiotherapy to be necessary following
lumpectomy. There are now several favorable breast cancer subtypes in which patients
routinely forego radiotherapy after trials demonstrating modest benefits in terms of
local recurrence and no impact on distant recurrence or survival, such as among small,
low grade luminal cancers in older women and "good-risk" DCIS. Therefore, this will study
the omission of radiotherapy among a population of HER2+ breast cancer patients who are
now appreciated to also have favorable risk, so as to similarly weigh the attendant
inconveniences, cost and morbidity of radiotherapy in light of an established absolute
benefit, which may prove to be modest.
Gender
All
Age Group
40 Years and up
Accepting Healthy Volunteers
No
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.