Testing the Ability to Decrease Chemotherapy in Patients with HER2-Positive Breast Cancer Who Have No Remaining Cancer at Surgery after Limited Pre-operative Chemotherapy and HER2-Targeted Therapy

Inclusion Criteria

• Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Patient must have histologically confirmed HER2-positive primary invasive breast carcinoma, as defined by the 2018 American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) HER2 testing guideline focused update (Wolff et al, 2018) and determined by local testing
• Patients hormone receptor (ER and progesterone receptor [PR]) status must be known and will be determined by local testing. Patients with either hormone receptor –positive or hormone receptor- negative HER2-positive breast cancer are eligible
• Patients must have clinical stage II and IIIa (T2-3/N0-2/M0) at diagnosis * Patients without nodal involvement (cN0) are eligible if T size >= 2.0 cm * Patients with nodal involvement (cN1-2) are eligible if T size >= 1.5 cm
• Patient must be willing and able (i.e., have no contraindication) to receive standard adjuvant therapy, consisting of HER2-directed therapy, radiation (if indicated) and endocrine therapy (if ER+) if achieving pCR at surgery
• Patient with two separate invasive breast cancers (ipsilateral or bilateral) are eligible if both cancers are HER2-positive and at least one meets protocol eligibility (i.e., >= 1.5 cm if cN1-2; >= 2 cm if cN0) (neither tumor can be T4 or N3)
• Patients with multifocal or multicentric disease are eligible as long as all tumor foci that were tested for HER2 status at the local institution are HER2-positive, and at least one tumor focus meets eligibility criteria
• Patients must not have impaired decision-making capacity
• Patients with a history of other non-breast malignancies are eligible if they have been disease-free for at least 5 years, and are deemed by the investigator to be at low risk for recurrence of that malignancy * Patients with the following cancers are eligible if diagnosed and treated within the past 5 years: cervical cancer in situ, basal cell or squamous cell carcinoma of the skin, and localized papillary or follicular thyroid cancer who have completed recommended treatment including surgery. Patients with any other cancers within the last 5 years are ineligible
• Patents must have a left ventricular ejection fraction (LVEF) within normal institutional parameters (or > 50%)
• Patients must have a bilateral mammogram and diagnostic breast ultrasound (with or without breast magnetic resonance imaging [MRI]) performed at screening (within 42 days of registration)
• Baseline imaging of the ipsilateral axilla by ultrasound is mandatory. For subjects with axillary lymph node(s) suspicious on clinical exam or imaging, patient must be willing to have a needle aspiration or core biopsy to determine the presence of metastatic disease in the lymph nodes. A clip must be placed in the involved axillary lymph node
• Women of childbearing potential and sexually active males must use accepted and effective method(s) of contraception or to abstain from sexual intercourse for the duration of their participation in the study and for 7 months after the last dose of study treatment
• Patient must be willing and able to sign informed consent
• Leukocytes >= 3,000/mcL (obtained =< 28 days prior to protocol registration)
• Absolute neutrophil count >= 1,500/mcL (obtained =< 28 days prior to protocol registration)
• Platelets >= 100,000/mcL (obtained =< 28 days prior to protocol registration)
• Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (obtained =< 28 days prior to protocol registration)
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional ULN (obtained =< 28 days prior to protocol registration)
• Creatinine =< 1.5 x institutional ULN (obtained =< 28 days prior to protocol registration)
• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
• Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load

Exclusion Criteria

• Patient must not have a history of any prior (ipsilateral or contralateral) invasive breast cancer * One exception: a patient with a history of T1N0 triple negative breast cancer diagnosed more than 10 years earlier, who remains disease free is eligible
• Patient must not have prior ipsilateral ductal breast carcinoma in situ (DCIS). Patients with prior lobular breast carcinoma in situ (LCIS), atypical hyperplasia, other high risk benign lesions or contralateral DCIS (without evidence of microinvasion) are eligible * NOTE: Patients currently receiving endocrine therapy for prior contralateral DCIS are eligible
• Patient must not have stage IV (metastatic) breast cancer * Staging studies (computed tomography [CT] chest/abdomen/pelvis and a bone scan or positron emission tomography [PET]-CT scan) are required for stage III disease or those with abnormal baseline liver function tests (LFTs), symptoms (e.g. new bone pain) or abnormal physical exam findings (National Comprehensive Cancer Network [NCCN] guidelines version [V]1.2019)
• Patient must not have T4 and/or N3 disease, including inflammatory breast cancer
• Patient must not have any prior treatment for the current breast cancer, including surgery, chemotherapy, hormonal therapy, radiation or experimental therapy
• Patients must not have > grade 1 peripheral neuropathy of any etiology
• Patient must not have a concurrent serious medical condition that would preclude completion of study therapy. For example, uncontrolled hypertension (systolic > 180 mm Hg and/or diastolic > 100 mm Hg) or clinically significant (i.e. active) cardiovascular disease: cerebrovascular accident/stroke or myocardial infarction within 6 months prior to registration, unstable angina, congestive heart failure (CHF) or serious cardiac arrhythmia requiring medication and other concurrent serious diseases that may interfere with planned treatment
• Women must not be pregnant or breast-feeding due to the potential harm to an unborn fetus and possible risk for adverse events in nursing infants with the treatment regimens being used. Patients must also not expect to conceive from the time of registration, while on study treatment, and until at least 7 months after the last dose of study treatment. All females of childbearing potential must have a blood test or urine study within 14 days prior to registration to rule out pregnancy * A female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy; or 3) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)

PRIMARY OBJECTIVES:

I. To determine if 3-year recurrence-free survival (RFS) is greater than 92% among clinical stages II or IIIa patients with HER2-positive breast cancer who achieve pathologic complete response (pCR) (ypT0/is ypN0) after preoperative therapy with 12 weeks of a taxane, trastuzumab (or Food and Drug Administration [FDA] approved biosimilar) and pertuzumab (THP x 12).

SECONDARY OBJECTIVES:

I. To determine 3-year IDFS (invasive disease-free survival), DDFS (distant disease-free survival), DRFS (distant relapse-free survival), RFI (recurrence-free interval), OS (overall survival) and breast cancer-specific survival in patients who achieve pCR (and by pretreatment clinical stage). (Secondary Clinical Objective)

II. To determine 3-year EFS (event-free survival) in all patients from time of study registration. (Secondary Clinical Objective)

III. To evaluate safety and tolerability for all patients during the pre-operative phase and for patients who attain pCR and de-escalate therapy (Arm A) until the completion of post-surgery protocol assigned therapy (i.e. until the end of trastuzumab and pertuzumab [HP] therapy). (Secondary Clinical Objective)

IV. To evaluate the association of estrogen receptor (ER) status in the untreated primary tumor with pathologic response and with long-term survival outcomes (including RFS, EFS, IDFS, DDFS, DRFS, RFI, OS, and breast cancer-specific survival). (Secondary Correlative Objective)

V. To evaluate the associations of detection of circulating tumor cells (CTCs) in the blood at baseline with pCR. (Secondary Correlative Objective)

VI. To evaluate the association of detection of CTCs in the blood at baseline, after 3 weeks of THP, after 12 weeks of THP (before surgery), after surgery before any additional therapy, and after completion of HER2-targeted therapy with RFS in patients who achieve pCR or not. (Secondary Correlative Objective)

EXPLORATORY OBJECTIVES:

I. To determine 3-year RFS, IDFS (invasive disease-free survival), DDFS (distant disease-free survival), DRFS (distant relapse-free survival), RFI (recurrence-free interval), OS (overall survival) and breast cancer-specific survival in patients who do not achieve pCR (and by pretreatment clinical stage). (Exploratory Clinical Objective)

II. To determine the pathologic response to THP neoadjuvant therapy, as assessed by residual cancer burden (RCB). (Exploratory Clinical Objective)

III. To determine the association between residual cancer burden (RCB) and all described standardized definitions for efficacy end points (STEEP) criteria outcomes. (Exploratory Clinical Objective)

IV. To determine the false negative rate (FNR) of limited staging procedures (defined as sentinel lymph node biopsy [SLNB] plus removal of clipped node) in patients who undergo such procedures with a planned axillary lymph node dissection (ALND). (Exploratory Clinical Objective)

V. To determine axillary pCR rates as a function of the burden of disease at presentation as determined on pre-treatment ultrasound (US) and the axillary staging technique (SLNB plus ensuring removal of clipped node versus ALND). (Exploratory Clinical Objective)

VI. To evaluate the associations between plasma tumor cell-free deoxyribonucleic acid (DNA) (cfDNA) tumor-specific mutations (baseline and after therapy) with pathologic response and long-term outcomes (including RFS, EFS, IDFS, DDFS, DRFS, RFI, OS, and breast cancer-specific survival). (Exploratory Correlative Objective)

VII. To evaluate the associations between tumor infiltrating lymphocytes (TILs) and immune activation gene signatures in the baseline tumor with pathologic response and long-term outcomes (including RFS, EFS, IDFS, DDFS, DRFS, RFI, OS and breast cancer-specific survival). (Exploratory Correlative Objective)

VIII. To determine the frequency of change in intrinsic subtype between pretreatment tumor specimen and residual disease at the time of surgery. (Exploratory Correlative Objective)

IX. To evaluate the associations between DNA copy number, DNA mutations, ribonucleic acid (RNA) expression and protein expression in the baseline tumor and changes from baseline to post-THP therapy with pathologic response and long-term outcomes (including RFS, EFS, IDFS, DDFS, DRFS, RFI, OS, and breast cancer-specific survival). (Exploratory Correlative Objective)

OUTLINE:

PRE-OPERATIVE/NEOADJUVANT THERAPY: Patients receive either paclitaxel or nab-paclitaxel intravenously (IV) on days 1, 8 and 15, or docetaxel IV on day 1 at the discretion of the treating oncologist. Patients also receive trastuzumab IV on day 1 or days 1, 8, and 15, and pertuzumab IV on day 1. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity.

SURGERY: Within 42 days after last dose of neoadjuvant therapy, patients undergo standard of care lumpectomy and/or mastectomy.

POST-OPERATIVE/ADJUVANT THERAPY: Patients are assigned to 1 of 2 arms.

ARM A: Patients with pCR after surgery receive trastuzumab and pertuzumab IV on day 1. Treatment repeats every 21 days for up to 13 cycles in the absence of disease progression or unacceptable toxicity. Patients may also undergo standard of care radiation therapy and receive hormone therapy if appropriate.

ARM B: Patients with remaining tumor after surgery receive standard of care trastuzumab emtansine for 14 doses in the absence of disease progression or unacceptable toxicity. Patients may also receive additional standard of care chemotherapy, as well as hormone therapy if appropriate.

After completion of study treatment, patients are followed up every 3 months for 2 years, every 6 months for 2-5 years, then annually for 5-15 years from date of surgery.

Trial Phase Phase II

Trial Type Treatment

Lead Organization
ECOG-ACRIN Cancer Research Group

Principal Investigator
Nadine Muskatel Tung

• Primary ID EA1181
• Secondary IDs NCI-2019-07439
• Clinicaltrials.gov ID NCT04266249