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Response to Paclitaxel, Trastuzumab, and Pertuzumab before Surgery in Determining Treatment after Surgery in Patients with Stage II-III HER2-Positive Breast Cancer

Trial Status: Active

This phase I trial studies whether the response to paclitaxel, trastuzumab, and pertuzumab before surgery helps to determine treatment after surgery in patients with stage II-III HER2-positive breast cancer. Drugs used in chemotherapy, such as paclitaxel, 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. Evaluating the response to paclitaxel, trastuzumab, and pertuzumab before surgery may help patients and doctors determine treatment options after surgery.

Inclusion Criteria

  • Patients must have stage II or III (according to American Joint Committee on Cancer [AJCC] cancer staging manual anatomic staging table, 8th edition) histologically confirmed invasive carcinoma of the breast. A minimum tumor size of 1.5 cm determined by physical exam or imaging (whichever is larger) is required. Patients with inflammatory breast carcinoma (T4d) are NOT eligible
  • Tumors must be HER-2 positive by 2018 criteria, as assessed by standard local institutional protocol (central testing is not required): * Immunohistochemistry (IHC) 3+ AND/OR * Fluorescence in situ hybridization (FISH) positive based on the following criteria: ** Dual-probe HER2/CEP17 ratio >= 2.0 with an average HER2 copy number >= 6.0 signals/cell; AND/OR ** Based on 2018 American Society of Clinical Oncology/College of American Pathologists guidelines for HER2 testing
  • Estrogen receptor (ER)/progesterone receptor (PR) determination is required. ER- and PR-assays should be performed by immunohistochemical methods according to the local institution standard protocol
  • Bilateral breast cancers are allowed as long as both cancers are HER2-positive or the contralateral cancer is a =< 1 cm, ER+, and HER2- tumor
  • Patients with multifocal or multicentric disease are eligible if the treating physician has determined the patient should be treated as HER2-positive
  • Breast imaging should include dedicated ultrasound of the ipsilateral axilla. For subjects with a clinically positive axilla based on exam or imaging, a fine needle aspiration or core biopsy procedure will be performed to determine the presence of metastatic disease in the lymph nodes (though lymph node sampling procedure need not be resulted prior to patient’s registration on trial, as long as all other eligibility are met)
  • Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1
  • Absolute neutrophil count (ANC) >= 1000/mm^3
  • Hemoglobin >= 9 g/dl
  • Platelets >= 100,000/mm^3
  • Serum creatinine < 1.5 x upper limit of normal (ULN) (institutional) OR calculated glomerular filtration rate (GFR) >= 60 mL/min
  • Total bilirubin =< 1.5 x ULN (institutional). For patients with Gilbert syndrome, the direct bilirubin should be within the institutional normal range OR total bilirubin =< 2.0 mg/dL
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN (institutional)
  • Left ventricular ejection fraction (LVEF) >= 50%
  • Premenopausal women must have a negative serum pregnancy test within 14 days of registration, including women who have had a tubal ligation and for women less than 12 months after the onset of menopause
  • Women of childbearing potential and men with partners of childbearing potential must be willing to use one highly effective form of non-hormonal contraception or two effective forms of non-hormonal contraception by the patient and/or partner and continue its use for the duration of the study treatment and for 7 months after the last dose of study treatment
  • Patients with a history of ipsilateral ductal carcinoma in situ (DCIS) are eligible
  • Patients undergoing breast conservation therapy (i.e. lumpectomy) must not have any contraindications to radiation therapy
  • Non-English-speaking patients are eligible, but will be exempt from patient-completed questionnaires
  • Willing and able to sign informed consent
  • Willing to provide tissue for research purposes

Exclusion Criteria

  • Pregnant or nursing women due to the teratogenic potential of the study drugs
  • Active, unresolved infection
  • Receipt of intravenous antibiotics for infection within 7 days prior to registration
  • 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 first study medication, unstable angina, congestive heart failure (CHF) of New York Heart Association (NYHA) class II or higher, or serious cardiac arrhythmia requiring medication
  • Significant symptoms (grade >= 2) from peripheral neuropathy
  • Other concurrent serious diseases that may interfere with planned treatment, including severe pulmonary conditions/illness, uncontrolled infections, uncontrolled diabetes
  • Any prior treatment for the current breast cancer, including chemotherapy, hormonal therapy, radiation, or experimental therapy


Beth Israel Deaconess Medical Center
Status: ACTIVE
Contact: Neelam V. Desai
Phone: 617-667-7081
Brigham and Women's Hospital
Status: ACTIVE
Contact: Adrienne Gropper Waks
Phone: 617-632-3779
Dana-Farber Cancer Institute
Status: ACTIVE
Contact: Adrienne Gropper Waks
Phone: 617-632-3779
Massachusetts General Hospital Cancer Center
Status: ACTIVE
Contact: Laura M. Spring
Dana-Farber / Brigham and Women's Cancer Center at Milford Regional
Status: ACTIVE
Contact: Michael Constantine
South Weymouth
Dana-Farber / Brigham and Women's Cancer Center at South Shore
Status: ACTIVE
Contact: Meredith Faggen


I. To assess adherence to protocol-specified antibody doublet therapy (HP) in the adjuvant setting among patients with stage II-III HER2 positive (+) breast cancer who achieve pathologic complete response (pCR) following neoadjuvant paclitaxel/trastuzumab/pertuzumab (THP).


I. To assess pCR rate (defined as ypT0/is N0) in all patients, hormone receptor (HR)+ patients, and HR negative (-) patients.

II. To assess residual cancer burden (RCB) scores in all patients, HR+ patients, and HR- patients.

III. To assess reasons for off-protocol escalation (for patients with pCR) or de-escalation (for patients without pCR).

IV. To assess the percentage of patients completing one year of HP.

V. To measure event-free survival (EFS) and recurrence-free interval (RFI), and to compare EFS (or RFI) in the following subgroups: patients with pCR versus patients without pCR and patients with RCB 0 or 1, versus patients with RCB 2 or 3.

VI. To measure overall survival (OS) as an exploratory endpoint.

VII. To evaluate the correlation between post-THP imaging findings and pathology findings in the surgical specimen. (Exploratory)


I. To assess how specific tumor-infiltrating lymphocyte (TIL) phenotype and T cell repertoire impact response to chemotherapy plus HER2-directed therapy.

II. To assess how myeloid cells within the tumor microenvironment impact the response to standard THP administered neoadjuvantly to HER2+ breast cancer patients.

III. To explore how the presence and functional activity of natural killer (NK) cells impacts response to anti-HER2 antibody therapy.


Patients receive paclitaxel intravenously (IV) over 30-180 minutes on days 1, 8, and 15. Patients also receive trastuzumab IV over 30-90 minutes and pertuzumab IV over 30-60 minutes on day 1. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity. Within 14-42 days after completion of treatment, patients undergo definitive breast surgery. Patients then receive trastuzumab IV over 30-90 minutes and pertuzumab IV over 30-60 minutes on day 1. Treatment repeats every 21 days for at least 13 cycles in the absence of disease progression or unacceptable toxicity. Patients who do not achieve pCR at the time of surgery may also receive therapy with trastuzumab emtansine for 14 doses per treating physician.

After completion of study treatment, patients are followed up for at least every 6 months for 5 years, then at least yearly for 10 years.

Trial Phase Phase I

Trial Type Treatment

Lead Organization
Dana-Farber Harvard Cancer Center

Principal Investigator
Adrienne Gropper Waks

  • Primary ID 18-394
  • Secondary IDs NCI-2018-02827
  • ID NCT03716180