Testing Radiation and HER2-targeted Therapy Versus HER2-targeted Therapy Alone for Low-risk HER2-positive Breast Cancer

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.

Eligibility 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.