ShortStop-HER2: 12 Months vs. 6 Months of HER2-targeted Medications for People With HER2+ Breast Cancer Who Had a Pathologic Complete Response After Chemotherapy Plus Trastuzumab

Phase 3

Not yet recruiting

• Conditions: Anatomic Stage I Breast Cancer AJCC v8; Anatomic Stage II Breast Cancer AJCC v8; Early Stage Breast Carcinoma
• Interventions: Biological: Trastuzumab (Herceptin); Biological: Pertuzumab; Procedure: Echocardiography; Procedure: Multigated Acquisition Scan; Procedure: Mammography; Procedure: Ultrasound; Procedure: Magnetic Resonance Imaging; Procedure: Biospecimen Collection; Other: Questionnaire Administration

• Registration Number: NCT06876714
• Lead Sponsor: Alliance for Clinical Trials in Oncology

Brief Summary

This phase III trial compares 6 months of human epidermal growth factor receptor 2 (HER2)-targeted therapy to 12 months of HER2-targeted therapy for the treatment of HER2-positive (+) breast cancer in patients that had a pathologic complete response (pCR) after preoperative (neoadjuvant) chemotherapy with trastuzumab. Trastuzumab and pertuzumab are monoclonal antibodies and forms of targeted therapy that attach to a receptor protein called HER2. HER2 is found on some cancer cells. When trastuzumab or pertuzumab attach to HER2, the signals that tell the cells to grow are blocked and the tumor cell may be marked for destruction by the body's immune system. Giving 6 months of HER2-targeted therapy may work better than giving 12 months for the treatment of HER2+ breast cancer in patients that had a pCR after neoadjuvant chemotherapy with trastuzumab.

Detailed Description

The primary and secondary objectives of the study:

PRIMARY OBJECTIVES:

I. To evaluate whether 6 months of combined neoadjuvant (neo)/adjuvant HER2 blockade results in a non-inferior recurrence-free survival (RFS) compared to 12 months of combined neo/adjuvant HER2 blockade, in patients with early stage HER2+ breast cancer who achieve pCR after neoadjuvant chemotherapy with HER2 blockade.

II. To compare the Functional Assessment of Cancer Therapy-Breast (FACT-B) total score at 12 months between patients randomized to receive 6 months versus 12 months of combined neo/adjuvant HER2 blockade. (Quality of life)

SECONDARY OBJECTIVES:

I. Secondary objectives are to evaluate whether 6 months compared to 12 months results in differences for the following:

Ia. Grade 3 or higher adverse event (AE) rates; Ib. Overall survival (OS); Ic. Locoregional recurrence (LRR, both isolated LRR as first events, and LRR events simultaneous with distant metastasis \[DM\]) incidence; Id. RFS for key subgroups: baseline stage, hormone receptor (HR) status, neoadjuvant chemotherapy backbone, and dual versus single HER2 blockade in the adjuvant setting; Ie. Time to central nervous system (CNS) recurrence (both isolated CNS recurrence as first events, and CNS recurrence events simultaneous with distant metastasis and/or LRR).

II. To compare the FACT-B total score at 18 months between patients randomized to receive 6 months versus 12 months of combined neo/adjuvant HER2 blockade. (Quality of life) III. To compare side effect bother as measured by the Functional Assessment of Cancer Therapy General Population 5 (FACT GP5) item at 12 months between patients randomized to receive 6 months versus 12 months of combined neo/adjuvant HER2 blockade. (Quality of life) IV. To compare specific patient-reported symptomatic adverse events (i.e. diarrhea, constipation, fatigue, and rash) as measured by the Patient Reported Outcomes-Common Terminology Criteria for Adverse Events (PRO-CTCAE) at 12 months between patients randomized to receive 6 months versus 12 months of combined neo/adjuvant HER2 blockade. (Quality of life)

QUALITY OF LIFE EXPLORATORY OBJECTIVES:

I. To examine the different FACT-B subscales at all other evaluable time points.

II. To examine heterogeneity of treatment effects within subgroups defined by subcutaneous versus intravenous treatment delivery.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM 1: Patients receive trastuzumab intravenously (IV) or subcutaneously (SC) on day 1 of each cycle. Patients may also receive pertuzumab IV or SC, at the discretion of the treating investigator, on day 1 of each cycle. Cycles repeat every 21 days for up to 17 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo echocardiography (ECHO) or multigated acquisition (MUGA) as well as mammography, ultrasound, or magnetic resonance imaging (MRI) throughout the trial. Patients may also optionally undergo blood and tissue sample collection throughout the trial.

ARM 2: Patients receive trastuzumab IV or SC on day 1 of each cycle. Patients may also receive pertuzumab IV or SC, at the discretion of the treating investigator, on day 1 of each cycle. Cycles repeat every 21 days for up to 9 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo ECHO or MUGA as well as mammography, ultrasound, or MRI throughout the trial. Patients may also optionally undergo blood and tissue sample collection throughout the trial.

After completion of study treatment, patients are followed up every 6 months for 5 years after registration or until recurrence and then annually for a total of 10 years after registration.

Study Timeline

• Status Verified: 2025-03
• Study First Submitted: 2025-03-10
• Study First Submitted QC: 2025-03-10
• Last Update Submitted: 2025-03-10
• Study First Posted: 2025-03-14
• Last Update Posted: 2025-03-14
• Study Start: 2025-03-25
• Primary Completion: 2028-03-13
• Study Completion: 2037-03-13

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 1524

Inclusion Criteria

• Patients (females and males) with clinical stage T1c-T3 (or Tx) and nodal stage N0-N1 (except T3N1 tumors, which are not eligible)

• Patients must have no residual invasive disease in the breast or lymph nodes after the completion of neoadjuvant therapy. Residual ductal carcinoma in situ (DCIS) is allowed. Patients with residual isolated tumor cells at surgery are considered node-positive and are not eligible

• HER2+ by American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines. Central pathology review is not required. In cases where there were multiple tumor sites in breast/nodes that had HER2 testing at diagnosis, at least one site must have been HER2+ AND the treating investigator must feel it is in the patient's best interest to be treated as having HER2+ breast cancer

• Known hormone receptor status as defined by ASCO/CAP guidelines. Estrogen receptor (ER) and progesterone receptor (PR) of any values are allowed. Hormone receptor positive status can be determined by either known positive ER or known positive PR status; hormone receptor negative status must be determined by both known negative ER and known negative PR

• If invasive disease was present in both breasts, participation in the study is permitted as long as the eligibility criteria are met for both tumors/breasts (including the requirement that at least one biopsied site on each side must have been HER2+)

• Age ≥ 18 years

• Eastern Cooperative Oncology Group (ECOG) performance status 0-2

• Patients must have received neoadjuvant chemotherapy in combination with trastuzumab with or without pertuzumab for a minimum of 12 weeks. All chemotherapy must have been completed preoperatively

  • Patient must complete a minimum of 12 weeks of coverage with trastuzumab and a maximum of 24 weeks in the combined neoadjuvant and adjuvant setting prior to trial registration. Trastuzumab may have been administered either weekly or once every 3 weeks (q3weeks). (For purposes of this eligibility criterion, a single dose of q3week trastuzumab would provide 3 weeks of coverage; a single dose of once a week (q1week) trastuzumab would provide 1 week of coverage. If a q3week dose of trastuzumab were administered and then the subsequent dose was delayed for any period of time, that would still count as 3 weeks of coverage.)
  • Administration of endocrine therapy for treatment of this breast cancer is allowed prior to trial registration. If a patient received prior breast cancer endocrine therapy (eg tamoxifen or aromatase inhibitor) for DCIS or preventive indication, and endocrine therapy is indicated for treatment of their current breast cancer, then prior endocrine therapy must have been stopped > 12 months prior to registration on this protocol
  • No use of investigational anti-cancer agents at time of registration

• Patient must register within 14 weeks of final surgery

• Adequate excision: Surgical removal of all clinically evident disease in the breast and lymph nodes as follows:

  • Breast surgery: Total mastectomy with grossly negative margins (in the opinion of the surgeon there is no disease grossly at the margins) or breast-conserving surgery with histologically negative margins (no ink on tumor, including DCIS) unless those margins are anterior at the skin or posterior at the chest wall and no additional margin re-excision can be performed
  • Lymph node surgery: Lymph node surgery must have been performed and can include sentinel lymph node biopsy, targeted axillary dissection, or axillary dissection, at the discretion of the breast surgeon

• Adequate radiation: Patients who completed breast-conserving surgery (i.e. lumpectomy) must have received or plan to receive adjuvant radiation. If breast-conserving surgery was performed but patient will not be receiving breast radiation, the patient is not eligible. Patients for whom radiotherapy would be recommended for breast cancer treatment but for whom it is contraindicated because of medical reasons (e.g., connective tissue disorder or prior ipsilateral breast radiation) are not eligible

  • Adjuvant radiation can be given on study, and in this case is encouraged to be given concurrently with adjuvant HER2-directed therapy, per investigator discretion
  • Targeting of the regional nodal basins will be at treating investigator discretion

• Not pregnant and not nursing, because this study involves agents with known teratogenic potential. Therefore, for women of childbearing potential only, a negative serum or urine pregnancy test should be performed prior to receiving HER2-directed therapy according to local standard practice

• Adequate hepatic, renal and bone marrow function to receive adjuvant HER2-directed therapy in the opinion of the treating investigator. There are no specific required laboratory values for eligibility

• No stage IV (metastatic) breast cancer

• 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

• No history of any prior (ipsilateral [ipsi-] or contralateral) invasive breast cancer. Prior DCIS is allowed

• No evidence of recurrent disease following preoperative therapy and surgery

• Patients living with HIV who are healthy and deemed by their medical team to have a low risk of AIDS-related illnesses are included in this trial. Patients with Hepatitis B or Hepatitis C virus who are healthy and deemed by their medical team to meet all other enrollment criteria are included in this trial.

• Patients with inadequate cardiac function on most recent assessment of left ventricular ejection fraction (LVEF) are not eligible for this trial. Inadequate cardiac function is defined as LVEF < 50% on echocardiogram (echo) or multiple-gated acquisition (MUGA)

• No history of grade 3 or 4 toxicity related to trastuzumab. If pertuzumab is planned to be given on trial, patient must also have no history of grade 3-4 toxicity related to pertuzumab

• No contraindication to receipt of further HER2-directed therapy

• No patients with severe, uncontrolled systemic disease that may interfere with planned trial therapy.

Exclusion Criteria

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm 1 (12-month adjuvant therapy)	Trastuzumab (Herceptin)	Patients receive trastuzumab IV or SC on day 1 of each cycle. Patients may also receive pertuzumab IV or SC, at the discretion of the treating investigator, on day 1 of each cycle. Cycles repeat every 21 days for up to 17 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo ECHO or MUGA as well as mammography, ultrasound, or MRI throughout the trial. Patients may also optionally undergo blood and tissue sample collection throughout the trial.
Arm 1 (12-month adjuvant therapy)	Pertuzumab	Patients receive trastuzumab IV or SC on day 1 of each cycle. Patients may also receive pertuzumab IV or SC, at the discretion of the treating investigator, on day 1 of each cycle. Cycles repeat every 21 days for up to 17 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo ECHO or MUGA as well as mammography, ultrasound, or MRI throughout the trial. Patients may also optionally undergo blood and tissue sample collection throughout the trial.
Arm 1 (12-month adjuvant therapy)	Echocardiography	Patients receive trastuzumab IV or SC on day 1 of each cycle. Patients may also receive pertuzumab IV or SC, at the discretion of the treating investigator, on day 1 of each cycle. Cycles repeat every 21 days for up to 17 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo ECHO or MUGA as well as mammography, ultrasound, or MRI throughout the trial. Patients may also optionally undergo blood and tissue sample collection throughout the trial.
Arm 1 (12-month adjuvant therapy)	Multigated Acquisition Scan	Patients receive trastuzumab IV or SC on day 1 of each cycle. Patients may also receive pertuzumab IV or SC, at the discretion of the treating investigator, on day 1 of each cycle. Cycles repeat every 21 days for up to 17 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo ECHO or MUGA as well as mammography, ultrasound, or MRI throughout the trial. Patients may also optionally undergo blood and tissue sample collection throughout the trial.
Arm 1 (12-month adjuvant therapy)	Mammography	Patients receive trastuzumab IV or SC on day 1 of each cycle. Patients may also receive pertuzumab IV or SC, at the discretion of the treating investigator, on day 1 of each cycle. Cycles repeat every 21 days for up to 17 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo ECHO or MUGA as well as mammography, ultrasound, or MRI throughout the trial. Patients may also optionally undergo blood and tissue sample collection throughout the trial.
Arm 1 (12-month adjuvant therapy)	Ultrasound	Patients receive trastuzumab IV or SC on day 1 of each cycle. Patients may also receive pertuzumab IV or SC, at the discretion of the treating investigator, on day 1 of each cycle. Cycles repeat every 21 days for up to 17 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo ECHO or MUGA as well as mammography, ultrasound, or MRI throughout the trial. Patients may also optionally undergo blood and tissue sample collection throughout the trial.
Arm 1 (12-month adjuvant therapy)	Magnetic Resonance Imaging	Patients receive trastuzumab IV or SC on day 1 of each cycle. Patients may also receive pertuzumab IV or SC, at the discretion of the treating investigator, on day 1 of each cycle. Cycles repeat every 21 days for up to 17 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo ECHO or MUGA as well as mammography, ultrasound, or MRI throughout the trial. Patients may also optionally undergo blood and tissue sample collection throughout the trial.
Arm 1 (12-month adjuvant therapy)	Biospecimen Collection	Patients receive trastuzumab IV or SC on day 1 of each cycle. Patients may also receive pertuzumab IV or SC, at the discretion of the treating investigator, on day 1 of each cycle. Cycles repeat every 21 days for up to 17 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo ECHO or MUGA as well as mammography, ultrasound, or MRI throughout the trial. Patients may also optionally undergo blood and tissue sample collection throughout the trial.
Arm 1 (12-month adjuvant therapy)	Questionnaire Administration	Patients receive trastuzumab IV or SC on day 1 of each cycle. Patients may also receive pertuzumab IV or SC, at the discretion of the treating investigator, on day 1 of each cycle. Cycles repeat every 21 days for up to 17 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo ECHO or MUGA as well as mammography, ultrasound, or MRI throughout the trial. Patients may also optionally undergo blood and tissue sample collection throughout the trial.
Arm 2 (6-month adjuvant therapy)	Trastuzumab (Herceptin)	Patients receive trastuzumab IV or SC on day 1 of each cycle. Patients may also receive pertuzumab IV or SC, at the discretion of the treating investigator, on day 1 of each cycle. Cycles repeat every 21 days for up to 9 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo ECHO or MUGA as well as mammography, ultrasound, or MRI throughout the trial. Patients may also optionally undergo blood and tissue sample collection throughout the trial.
Arm 2 (6-month adjuvant therapy)	Pertuzumab	Patients receive trastuzumab IV or SC on day 1 of each cycle. Patients may also receive pertuzumab IV or SC, at the discretion of the treating investigator, on day 1 of each cycle. Cycles repeat every 21 days for up to 9 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo ECHO or MUGA as well as mammography, ultrasound, or MRI throughout the trial. Patients may also optionally undergo blood and tissue sample collection throughout the trial.
Arm 2 (6-month adjuvant therapy)	Echocardiography	Patients receive trastuzumab IV or SC on day 1 of each cycle. Patients may also receive pertuzumab IV or SC, at the discretion of the treating investigator, on day 1 of each cycle. Cycles repeat every 21 days for up to 9 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo ECHO or MUGA as well as mammography, ultrasound, or MRI throughout the trial. Patients may also optionally undergo blood and tissue sample collection throughout the trial.
Arm 2 (6-month adjuvant therapy)	Multigated Acquisition Scan	Patients receive trastuzumab IV or SC on day 1 of each cycle. Patients may also receive pertuzumab IV or SC, at the discretion of the treating investigator, on day 1 of each cycle. Cycles repeat every 21 days for up to 9 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo ECHO or MUGA as well as mammography, ultrasound, or MRI throughout the trial. Patients may also optionally undergo blood and tissue sample collection throughout the trial.
Arm 2 (6-month adjuvant therapy)	Mammography	Patients receive trastuzumab IV or SC on day 1 of each cycle. Patients may also receive pertuzumab IV or SC, at the discretion of the treating investigator, on day 1 of each cycle. Cycles repeat every 21 days for up to 9 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo ECHO or MUGA as well as mammography, ultrasound, or MRI throughout the trial. Patients may also optionally undergo blood and tissue sample collection throughout the trial.
Arm 2 (6-month adjuvant therapy)	Ultrasound	Patients receive trastuzumab IV or SC on day 1 of each cycle. Patients may also receive pertuzumab IV or SC, at the discretion of the treating investigator, on day 1 of each cycle. Cycles repeat every 21 days for up to 9 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo ECHO or MUGA as well as mammography, ultrasound, or MRI throughout the trial. Patients may also optionally undergo blood and tissue sample collection throughout the trial.
Arm 2 (6-month adjuvant therapy)	Magnetic Resonance Imaging	Patients receive trastuzumab IV or SC on day 1 of each cycle. Patients may also receive pertuzumab IV or SC, at the discretion of the treating investigator, on day 1 of each cycle. Cycles repeat every 21 days for up to 9 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo ECHO or MUGA as well as mammography, ultrasound, or MRI throughout the trial. Patients may also optionally undergo blood and tissue sample collection throughout the trial.
Arm 2 (6-month adjuvant therapy)	Biospecimen Collection	Patients receive trastuzumab IV or SC on day 1 of each cycle. Patients may also receive pertuzumab IV or SC, at the discretion of the treating investigator, on day 1 of each cycle. Cycles repeat every 21 days for up to 9 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo ECHO or MUGA as well as mammography, ultrasound, or MRI throughout the trial. Patients may also optionally undergo blood and tissue sample collection throughout the trial.
Arm 2 (6-month adjuvant therapy)	Questionnaire Administration	Patients receive trastuzumab IV or SC on day 1 of each cycle. Patients may also receive pertuzumab IV or SC, at the discretion of the treating investigator, on day 1 of each cycle. Cycles repeat every 21 days for up to 9 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo ECHO or MUGA as well as mammography, ultrasound, or MRI throughout the trial. Patients may also optionally undergo blood and tissue sample collection throughout the trial.

Primary Outcome Measures

Name	Time	Method
Recurrence-free survival (RFS)	From randomization to invasive local, regional or distant breast cancer recurrence, or death from any cause prior to a documented disease recurrence, assessed up to 10 years	The Kaplan-Meier method will be used to estimate the distribution of RFS times and a stratified log-rank test for non-inferiority will be used to assess whether RFS with 6 total months of human epidermal growth factor receptor 2 (HER2)-blockade is non-inferior to standard-of-care 12 total months of HER2-blockade in this patient population. Stratified Cox modeling will be used to estimate the hazard ratio and corresponding one-sided 95% confidence interval (CI).
Functional Assessment of Cancer Therapy-Breast (FACT-B) total score (Quality of life)	At 12 months	Will compare the FACT-B total score between patients randomized to receive 6 months versus 12 months of combined neoadjuvant/adjuvant HER2 blockade. All questionnaires will be scored according to published scoring algorithms, including recommendations for addressing missing items within a scale. An intention-to-treat (ITT) approach will be used for all analyses. All statistical tests will be 2-sided, and p-values \< 0.05 will be considered statistically significant. To evaluate the between-arm mean difference in scores, a repeated measures mixed model will be estimated based on FACT-B total scores at all time points.

Secondary Outcome Measures

Name	Time	Method
Incidence of grade 3 or higher adverse events (AE)	Baseline to 30 days after last dose of study treatment	Will be according to the Common Terminology Criteria for Adverse Events version 5.0. The maximum grade of a specific AE experienced by a patient will be used. The proportion of patients who report a grade 3 or higher AE will be compared between the two treatment arms with a chi-square test. AEs (type and grade) for both arms will be summarized with the frequency and relative frequency
Locoregional recurrence (LRR)	From randomization until invasive tumor recurs in the ipsilateral breast or chest wall, axillary, supraclavicular, or internal mammary nodes (if before or synchronous with a systemic recurrence), whichever comes first, assessed up to 10 years	The cumulative incidence of LRR will be analyzed with Kaplan-Meier estimates (curve starting at 0 rather than 1) and compared with a stratified log rank test.
Overall survival	From randomization until death due to any cause, assessed up to 10 years	Will be compared between the treatment arms with a stratified log rank test and a stratified Cox model will be used to generate the hazard ratio estimate (both a point estimate and 95% CI). The analyses will be done as ITT groups as well as per-protocol groups.
RFS for key subgroups	From randomization to invasive local, regional or distant breast cancer recurrence, or death from any cause prior to a documented disease recurrence, assessed up to 10 years	Forest plots will be generated for key prognostic variables (including the stratification variables) and subgroups of interest to determine whether the treatment effect appears homogeneous across the subgroups for the ITT population. Additional key subgroups of interest are neoadjuvant chemotherapy backbone and the type of adjuvant HER2-blockade the patient actually received (dual versus single). With respect to the latter analysis, the interest will be in whether there is an apparent difference in treatment effect among patients who received adjuvant pertuzumab versus those who did not.
Time to central nervous system (CNS) recurrence	up to 10 years	Will assess both isolated CNS recurrence as first events, and CNS recurrence events simultaneous with distant metastasis and/or LRR.
FACT-B total score (Quality of life)	At 18 months	Will compare the FACT-B total score between patients randomized to receive 6 months versus 12 months of combined neo/adjuvant HER2 blockade. All questionnaires will be scored according to published scoring algorithms, including recommendations for addressing missing items within a scale. An ITT approach will be used for all analyses. All statistical tests will be 2-sided, and p-values \<0.05 will be considered statistically significant. To evaluate the between-arm mean difference in scores, a repeated measures mixed model will be estimated based on FACT-B total scores at all time points.
Side effect bother (Quality of life)	At 6 or 12 months	Will be assessed by Functional Assessment of Cancer Therapy General Population 5 between patients randomized to receive 6 months versus 12 months of combined neo/adjuvant HER2 blockade. All questionnaires will be scored according to published scoring algorithms, including recommendations for addressing missing items within a scale. An ITT approach will be used for all analyses. All statistical tests will be 2-sided, and p-values \<0.05 will be considered statistically significant. To evaluate the between-arm mean difference in scores, a repeated measures mixed model will be estimated based on scores. Mean trajectories over time will be plotted by arm.
Patient reported symptomatic AE (Quality of life)	At 6 or 12 months	Will be measured by Patient Reported Outcomes-Common Terminology Criteria for Adverse Events (PRO-CTCAE). Will assess symptomatic AE using PRO-CTCAE measures for symptoms of interest, specifically diarrhea, constipation, fatigue, and rash. The proportion of patients with a maximum post-baseline score greater than 0 will be compared between arms using Fisher's exact test. For diarrhea, constipation, and fatigue, the proportion of patients with a maximum post-baseline score greater than or equal to 3 will be compared between arms using Fisher's exact test.