Docetaxel, Carboplatin, Trastuzumab, and Pertuzumab With or Without Estrogen Deprivation in Treating Patients With Hormone Receptor-Positive, HER2-Positive Operable or Locally Advanced Breast Cancer
Docetaxel, Carboplatin, Trastuzumab, and Pertuzumab With or Without Estrogen Deprivation in Treating Patients With Hormone Receptor-Positive, HER2-Positive Operable or Locally Advanced Breast Cancer
This randomized phase III trial studies docetaxel, carboplatin, trastuzumab, and pertuzumab
 with estrogen deprivation to see how they work compared to docetaxel, carboplatin,
 trastuzumab, and pertuzumab without estrogen deprivation in treating patients with hormone
 receptor-positive, human epidermal growth factor receptor 2 (HER2)-positive breast cancer
 that is operable or has spread from where it started to nearby tissue or lymph nodes (locally
 advanced). Drugs used in chemotherapy, such as docetaxel, carboplatin, trastuzumab, and
 pertuzumab, 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. Giving more than
 one drug (combination chemotherapy) may kill more tumor cells. Estrogen can cause the growth
 of breast cancer cells. Hormone therapy using goserelin acetate and aromatase inhibition
 therapy may fight breast cancer by blocking the use of estrogen by the tumor cells. Radiation
 therapy uses high energy x rays to kill tumor cells. Giving combination chemotherapy and
 radiation therapy with or without hormone therapy may be an effective treatment for hormone
 receptor-positive, HER2-positive, operable or locally advanced breast cancer.
PRIMARY OBJECTIVES:

 I. To determine whether the addition of estrogen deprivation to neoadjuvant therapy
 consisting of therapy of docetaxel, carboplatin, trastuzumab, and pertuzumab (TCHP) yields a
 greater rate of pathologic complete response (pCR) (breast and nodes) than TCHP alone when
 administered to women with operable, hormone receptor-positive, HER2-positive breast cancer.

 SECONDARY OBJECTIVES:

 I. To determine whether the addition of estrogen deprivation to neoadjuvant therapy
 consisting of TCHP will increase the pCR rate in the breast compared to TCHP alone when
 administered to women with operable, hormone receptor-positive, HER2-positive breast cancer.

 II. To determine whether the addition of estrogen deprivation to neoadjuvant therapy
 consisting of TCHP improves recurrence-free interval (RFI) in women with operable, hormone
 receptor-positive, HER2-positive breast cancer.

 III. To determine whether the addition of estrogen deprivation to neoadjuvant therapy
 consisting of TCHP improves overall survival (OS) in women with operable, hormone
 receptor-positive, HER2-positive breast cancer.

 IV. To compare the rates of second primary invasive cancer by treatment arm. V. Assessment of
 patterns of pCR, RFI, and OS by menopausal status. VI. To evaluate the cardiac toxicity
 associated with each of the regimens. VII. To compare the effect of adding estrogen
 deprivation to neoadjuvant therapy on endocrine-related symptoms in all patients by treatment
 arm.

 VIII. To compare the effect of adding estrogen deprivation to neoadjuvant therapy on
 vasomotor symptoms, musculoskeletal, and vaginal complaints as well as quality of life.

 IX. To determine a relationship between pCR and a potential mechanism of
 resistance/sensitivity in hormone receptor-positive, HER2-positive tumors.

 X. To evaluate tumor infiltrating lymphocytes (TILs) and immune biomarkers as predictors of
 pCR.

 XI. To study early changes in TILs and other immune biomarkers in response to TCHP.

 OUTLINE: Patients are randomized to 1 of 2 treatments arms.

 NEOADJUVANT:

 ARM I: Patients receive docetaxel intravenously (IV) over 60 minutes, carboplatin IV over
 30-60 minutes, trastuzumab IV over 30-90 minutes, and pertuzumab IV over 30-60 on day 1.
 Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or
 unacceptable toxicity. Patients enrolled after Amendment #4 undergo 2 core biopsies prior to
 course 3 of treatment.

 ARM II: All patients receive docetaxel, carboplatin, trastuzumab, and pertuzumab as in arm I.
 Premenopausal patients also receive goserelin acetate subcutaneously (SC) every 28 days until
 surgery and aromatase inhibition therapy at the investigator's discretion daily until 1 day
 before surgery. Postmenopausal patients receive aromatase inhibition therapy at the
 investigator's discretion daily until 1 day before surgery. Patients enrolled after Amendment
 #4 undergo 2 core biopsies prior to course 3 of treatment.

 SURGERY: Patients undergo lumpectomy or mastectomy.

 RADIATION: Patients undergo whole breast irradiation within 8 weeks following surgery.

 ADJUVANT: Patients receive trastuzumab IV over 30-60 minutes every 21 days for up to 1 year.

 After completion of study treatment, patients are followed up every 6, 9, 12, and 18 months
 for 5 years.
Inclusion Criteria:

 -  Patients should have a life expectancy of at least 10 years, excluding their diagnosis
 of breast cancer; (comorbid conditions should be taken into consideration, but not the
 diagnosis of breast cancer)

 -  Women of reproductive potential must agree to use an effective non-hormonal method of
 contraception during study therapy (chemotherapy, trastuzumab, pertuzumab, and
 estrogen deprivation therapy) and for at least 7 months after the last dose of study
 therapy

 -  Submission of tumor samples is required for all patients; the local pathology
 department policy regarding release of tumor samples must be considered in the
 screening process; patients whose tumor samples are located in a pathology department
 that by policy will not submit any samples for research purposes should not be
 approached for participation in the B-52 trial

 -  The patient must have signed and dated an Institutional Review Board (IRB)-approved
 consent form that conforms to federal and institutional guidelines

 -  The patient must have an Eastern Cooperative Oncology Group (ECOG) performance status
 of 0 or 1

 -  Clinical staging for the primary tumor can be cT1c (must be 2.0 cm) or T2-T4 if
 clinically node negative; if the regional lymph nodes are cN1 and cytologically or
 histologically positive or if cN2-N3 with or without a biopsy, the primary breast
 tumor can be cT0-T4

 -  The diagnosis of invasive adenocarcinoma of the breast must have been made by core
 needle biopsy

 -  Ipsilateral axillary lymph nodes must be evaluated by imaging (mammogram, ultrasound,
 and/or magnetic resonance imaging [MRI]) within 6 weeks prior to randomization; if
 suspicious or abnormal, fine needle aspirate (FNA) or core biopsy is recommended, also
 within 6 weeks prior to randomization; findings of these evaluations will be used to
 determine the nodal status prior to randomization:

 -  Nodal status - negative

 -  Imaging of the axilla is negative

 -  Imaging is suspicious or abnormal but the FNA or core biopsy of the
 questionable node(s) on imaging is negative

 -  Nodal status - positive

 -  FNA or core biopsy of the node(s) is cytologically or histologically
 suspicious or positive

 -  Imaging is suspicious or abnormal but FNA or core biopsy was not performed

 -  Patients may be premenopausal or postmenopausal at the time of randomization; for
 study purposes, postmenopausal is defined as:

 -  Age 56 or older with no spontaneous menses for at least 12 months prior to study
 entry; or

 -  Age 55 or younger with no spontaneous menses for at least 12 months prior to
 study entry (e.g., spontaneous or secondary to hysterectomy) and with a
 documented estradiol level in the postmenopausal range according to local
 institutional/laboratory standard; or

 -  Documented bilateral oophorectomy

 -  The tumor must have been determined to be HER2-postive as follows:

 -  Immunohistochemistry (IHC) 3+ or

 -  In situ hybridization (ISH)-positive (defined by ratio of HER2 to circulating
 endothelial progenitors [CEP]17 >= 2.0 or HER2 gene copy number >= 6 per nucleus)

 -  The tumor must have been determined to be estrogen receptor (ER) and/or progesterone
 (PgR) positive assessed by current American Society of Clinical Oncology
 (ASCO)/College of American Pathologist (CAP) guideline recommendations for hormone
 receptor testing; patients with >= 1% ER or PgR staining by IHC are considered
 positive

 -  Absolute neutrophil count (ANC) must be >= 1200/mm^3

 -  Platelet count must be >= 100,000/mm^3

 -  Hemoglobin must be >= 10 g/dL

 -  Total bilirubin must be =< upper limit of normal (ULN) for the lab unless the patient
 has a bilirubin elevation > ULN to 1.5 x ULN due to Gilbert's disease or similar
 syndrome involving slow conjugation of bilirubin

 -  Alkaline phosphatase must be =< 2.5 x ULN for the lab

 -  Aspartate aminotransferase (AST) must be =< 1.5 x ULN for the lab

 -  Alkaline phosphatase and AST may not both be > the ULN; for example, if the alkaline
 phosphatase is > the ULN but =< 2.5 x ULN, the AST must be =< the ULN; if the AST is >
 the ULN but =< 1.5 x ULN, the alkaline phosphatase must be =< ULN; Note: If alanine
 aminotransferase (ALT) is performed instead of AST (per institution's standard
 practice), the ALT value must be =< 1.5 x ULN; if both were performed, the AST must be
 =< 1.5 x ULN

 -  Patients with AST or alkaline phosphatase > ULN are eligible for inclusion in the
 study if liver imaging (computed tomography [CT], MRI, positron emission tomography
 [PET]-CT, or PET scan) performed within 6 weeks prior to randomization does not
 demonstrate metastatic disease and the requirements are met

 -  Patients with alkaline phosphatase that is > ULN but =< 2.5 x ULN or unexplained bone
 pain are eligible for inclusion in the study if a bone scan, PET-CT scan, or PET scan
 performed within 6 weeks prior to randomization does not demonstrate metastatic
 disease

 -  Within 6 weeks prior to randomization, the most recent serum creatinine must be =< ULN
 or measured or calculated creatinine clearance must be > 60 mL/min

 -  Left ventricular ejection fraction (LVEF) assessment must be performed within 90 days
 prior to randomization; (LVEF assessment performed by 2-dimensional [2-D]
 echocardiogram is preferred; however, multi gated acquisition scan [MUGA] scan may be
 substituted based on institutional preferences); the LVEF must be >= 50% regardless of
 the cardiac imaging facility's lower limit of normal; note: since the pre-entry LVEF
 serves as the baseline for comparing subsequent LVEF assessments, it is critical that
 this baseline study be an accurate assessment; if the baseline LVEF is > 65%, the
 investigator is encouraged to have the accuracy of the initial LVEF result confirmed
 and repeat the test if the accuracy is uncertain

 Exclusion Criteria:

 -  FNA alone to diagnose the breast cancer

 -  Excisional biopsy or lumpectomy performed prior to randomization

 -  Surgical axillary staging procedure prior to randomization; pre-neoadjuvant therapy
 sentinel node biopsy is not permitted

 -  Definitive clinical or radiologic evidence of metastatic disease; (chest imaging
 [mandatory for all patients] and other imaging [if required] must have been performed
 within 90 days prior to randomization)

 -  Synchronous bilateral invasive breast cancer

 -  Synchronous or previous contralateral invasive breast cancer; (patients with
 synchronous and/or previous contralateral ductal carcinoma in situ [DCIS] or lobular
 carcinoma in situ [LCIS] are eligible)

 -  Any previous history of ipsilateral invasive breast cancer or ipsilateral DCIS;
 (patients with synchronous or previous ipsilateral LCIS are eligible)

 -  Treatment including radiation therapy (RT), chemotherapy, targeted therapy, or
 endocrine therapy for the currently diagnosed breast cancer prior to randomization

 -  Previous endocrine therapy such as raloxifene or tamoxifen (or other selective
 estrogen receptor modulator [SERM]) or an aromatase inhibitor for any malignancy

 -  Previous therapy with anthracycline, taxanes, carboplatin, trastuzumab, or other HER2
 targeted therapies for any malignancy

 -  Any sex hormonal therapy, e.g., birth control pills, ovarian hormone replacement
 therapy, etc. (these patients are eligible if this therapy is discontinued prior to
 randomization)

 -  History of non-breast malignancies (except for in situ cancers treated only by local
 excision and basal cell and squamous cell carcinomas of the skin) within 5 years prior
 to randomization

 -  Cardiac disease (history of and/or active disease) that would preclude the use of the
 drugs included in the treatment regimens; this includes but is not confined to:

 -  Active cardiac disease:

 -  Angina pectoris that requires the use of anti-anginal medication;

 -  Ventricular arrhythmias except for benign premature ventricular
 contractions;

 -  Supraventricular and nodal arrhythmias requiring a pacemaker or not
 controlled with medication;

 -  Conduction abnormality requiring a pacemaker;

 -  Valvular disease with documented compromise in cardiac function; and

 -  Symptomatic pericarditis

 -  History of cardiac disease:

 -  Myocardial infarction documented by elevated cardiac enzymes or persistent
 regional wall abnormalities on assessment of left ventricular (LV) function;

 -  History of documented congestive heart failure (CHF); and

 -  Documented cardiomyopathy

 -  Uncontrolled hypertension defined as sustained systolic blood pressure (BP) > 150 mmHg
 or diastolic BP > 90 mmHg; (patients with initial BP elevations are eligible if
 initiation or adjustment of BP medication lowers pressure to meet entry criteria)

 -  Active hepatitis B or hepatitis C with abnormal liver function tests

 -  Intrinsic lung disease resulting in dyspnea

 -  Poorly controlled diabetes mellitus

 -  Active infection or chronic infection requiring chronic suppressive antibiotics

 -  Patients known to be human immunodeficiency virus (HIV) positive with a baseline
 cluster of differentiation (CD)4 count of < 250 cells/mm^3 or have a history of
 acquired immune deficiency syndrome (AIDS) indicator conditions; patients taking
 anti-retroviral therapy that may have a potential overlapping toxicity with the study
 therapy are not eligible

 -  Nervous system disorder (paresthesia, peripheral motor neuropathy, or peripheral
 sensory neuropathy) >= grade 2, per the Common Terminology Criteria for Adverse Events
 version 4.0 (CTCAE v4.0)

 -  Malabsorption syndrome, ulcerative colitis, resection of the stomach or small bowel,
 or other disease significantly affecting gastrointestinal function

 -  Other non-malignant systemic disease that would preclude treatment with any of the
 treatment regimens or would prevent required follow-up

 -  Conditions that would prohibit administration of corticosteroids

 -  Chronic daily treatment with corticosteroids with a dose of >= 10 mg/day
 methylprednisolone equivalent (excluding inhaled steroids)

 -  Known hypersensitivity to any of the study drugs or any of the ingredients or
 excipients of these drugs (e.g., polysorbate 80), including sensitivity to benzyl
 alcohol

 -  Pregnancy or lactation at the time of study entry; (note: pregnancy testing must be
 performed within 2 weeks prior to randomization according to institutional standards
 for women of childbearing potential)

 -  Psychiatric or addictive disorders or other conditions that, in the opinion of the
 investigator, would preclude the patient from meeting the study requirements

 -  Use of any investigational product within 30 days prior to randomization