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.