CompassHER2-pCR: Decreasing Chemotherapy for Breast Cancer Patients After Pre-surgery Chemo and Targeted Therapy
CompassHER2-pCR: Decreasing Chemotherapy for Breast Cancer Patients After Pre-surgery Chemo and Targeted Therapy
This trial studies how well paclitaxel, trastuzumab, and pertuzumab work in eliminating
 further chemotherapy after surgery in patients with HER2-positive stage II-IIIa breast cancer
 who have no cancer remaining at surgery (either in the breast or underarm lymph nodes) after
 pre-operative chemotherapy and HER2-targeted therapy. Drugs used in chemotherapy, such as
 paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the
 cells, by stopping them from dividing, or by stopping them from spreading. Trastuzumab and
 pertuzumab are both a form of "targeted therapy" because they work by attaching themselves to
 specific molecules (receptors) on the surface of tumor cells, known as HER2 receptors. When
 these drugs attach to HER2 receptors, 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 paclitaxel,
 trastuzumab, and pertuzumab may enable fewer chemotherapy drugs to be given without
 compromising patient outcomes compared to the usual treatment.
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.
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 ASCO/CAP HER2 testing guideline focused update
 (Wolff et al, 2018) and determined by local testing.

 -  Patients hormone receptor (estrogen 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 AJCC 8th Edition stage II or IIIa according to anatomic staging
 table at diagnosis

 -  Patients without nodal involvement (cN0) are eligible if T size > 2.0 cm (T2-3)

 -  Patients with nodal involvement (cN1-2) are eligible if T1-3

 -  Patients with clinical T4 or N3 disease are not eligible

 -  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 bilateral invasive breast cancers are eligible if both cancers are
 HER2-positive (as defined in 3.1.3) at least one meets protocol eligibility and
 neither cancer renders the patient ineligible (i.e. per eligibility 3.1.5)

 -  Patients with multiple ipsilateral invasive tumors are eligible as long as all tumors
 are HER2-positive, and at least one tumor focus meets eligibility criteria (per
 eligibility 3.1.5). Multiple lesions that appear part of the same index tumor do not
 require additional biopsy/HER2 testing.

 -  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 not have > grade 1 peripheral neuropathy of any etiology.

 -  Patients must have a bilateral mammogram and a diagnostic breast ultrasound including
 imaging of the axilla [on the side of the cancer(s)] (with or without breast MRI)
 performed at screening. Either a mammogram or breast MRI must be performed 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. (If there are more than 1 suspicious axillary nodes, only one clipped node
 is required).

 -  Patient of childbearing potential and sexually active patients 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:

 -  Patients must not have impaired decision-making capacity

 -  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

 -  Patient 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 patients of childbearing potential must have a blood test
 or urine study within 14 days prior to registration to rule out pregnancy

 -  All patients 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)