Testing the Effect of Decreasing Chemotherapy in Patients with HER2-Positive Breast Cancer Without Evidence of Remaining Cancer after Receiving Pre-Surgery Chemotherapy and HER2-Targeted Therapy

Summary

Objectives

PRIMARY OBJECTIVES:
I. To determine if 3-year recurrence-free survival (RFS) is greater than 92% among clinical stages II or IIIa patients (by American Joint Committee on Cancer [AJCC] cancer staging manual anatomic staging table, 8th edition) with HER2-positive/estrogen receptor (ER)-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). Post-operatively, patients will receive standard of care adjuvant locoregional therapy, plus completion of 12 months of HER2-targeted therapy (and standard adjuvant endocrine therapy for patients with estrogen receptor-positive disease).
II. To determine if 3-year recurrence-free survival (RFS) is greater than 92% among clinical stages II or IIIa patients (by AJCC cancer staging manual anatomic staging table, 8th edition) with HER2-positive/ER-negative breast cancer who achieve pCR (ypT0/is ypN0) after preoperative therapy with 12 weeks of a taxane, trastuzumab (or FDA approved biosimilar) and pertuzumab (THP x 12). Post-operatively, patients will receive standard of care adjuvant locoregional therapy, plus completion of 12 months of HER2-targeted therapy (and no adjuvant endocrine therapy for patients with estrogen receptor-negative disease).

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 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)
VII. To determine if breast magnetic resonance imaging (MRI) radiomics signatures reflecting intratumor heterogeneity and microenvironment at baseline are predictive of pCR. (Secondary Correlative Objective)
VIII. To evaluate the association between tumor infiltrating lymphocytes (TILs) in the baseline tumor and 3-yr RFS in all patients. (Secondary Correlative Objective)
IX. To evaluate the associations between TILs in the baseline tumor with pCR in all patients. (Secondary Correlative Objective)
X. To evaluate the association between HER2DX risk score in the baseline tumor and RFS in patients who achieved pCR after neoadjuvant THP therapy (i.e., arm A). (Secondary Correlative Objective)
XI. To evaluate the association between HER2DX risk score in the baseline tumor and RFS in patients who had residual disease after neoadjuvant THP therapy (i.e., arm B). (Secondary Correlative Objective)
XII. To evaluate the associations between HER2DX pCR likelihood score in the baseline tumor with pCR in patients with HER2-positive/ER-positive disease and in patients with HER2-positive/ER-negative disease, separately. (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) in the baseline tumor with pathologic response and long-term outcomes (including RFS, EFS, IDFS, DDFS, DRFS, RFI, OS and breast cancer-specific survival), and in the residual tumor with long-term outcomes. (Exploratory Correlative Objective)
VIII. To evaluate the associations between immune activation gene signatures in the baseline tumor and pathologic response as well as outcomes (including RFS, EFS, IDFS, DDFS, DRFS, RFI, OS and breast cancer-specific survival). (Exploratory Correlative Objective)
IX. To evaluate the association of intrinsic subtype at baseline with outcomes (pathologic response and survival). (Exploratory Correlative Objective)
X. To determine the frequency of change in intrinsic subtype between pretreatment tumor specimen and residual disease at the time of surgery and to evaluate any association with survival. (Exploratory Correlative Objective)
XI. 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)
XII. To determine if functional dynamic contrast-enhanced (DCE)-MRI markers (e.g., functional tumor volume, signal enhancement ratio) reflecting tumor vascularity at baseline are predictive of treatment outcome (pCR and EFS). (Exploratory Correlative Objective)
XIII. To determine if breast MRI radiomics signatures at post-treatment/presurgery are predictive of treatment outcome (pCR and EFS). (Exploratory Correlative Objective)
XIV. To investigate the performance of combined modeling incorporating radiomics and other prognostic markers (e.g., ER, progesterone receptor [PR], intrinsic subtype, tumor infiltrating lymphocytes [TILs] levels) to predict treatment response in women with HER2+ breast cancer. (Exploratory Correlative Objective)
XV. To evaluate the association between TILs in the baseline tumor with pCR and 3-yr RFS in patients with HER2-positive/ER-positive breast cancer and in patients with HER2-positive/ER-negative breast cancer, separately. (Exploratory Correlative Objective)
XVI. To evaluate the association between TILs in the baseline tumor with 3-yr RFS in patients in Arm A (i.e., patients who have pCR) and those in Arm B (i.e., no pCR), separately. (Exploratory Correlative Objective)
XVII. To evaluate the associations between TILs in the residual tumor with 3-yr RFS in patients in Arm B. (Exploratory Correlative Objective)
XVIII. To evaluate the association between TILs in the baseline tumor with other long-term outcomes (including EFS, IDFS, DDFS, DRFS, RFI, OS and Breast Cancer-Specific Survival) in all patients and separately in patients with HER2-positive/ER-positive disease and in patients with HER2-positive/ER-negative disease. This association will also be evaluated separately for patents in Arm A and Arm B. (Exploratory Correlative Objective)
XIX. To evaluate the associations between changes in TILs in the baseline tumor and residual cancer at surgery with long-term outcomes (including RFS, EFS, IDFS, DDFS, DRFS, RFI, OS and Breast Cancer-Specific Survival), for patients in Arm B. (Exploratory Correlative Objective)
XX. To evaluate the associations between TILs in the baseline tumor and RCB score in all patients, and separately in patients with HER2-positive/ER-positive disease and in patients with HER2-positive/ER-negative disease. (Exploratory Correlative Objective)
XXI. To evaluate the association between HER2DX risk score in the baseline tumor and RFS in patients who achieved pCR after neoadjuvant THP therapy (i.e., arm A) in HER2-positive/ER-positive breast cancer and HER2-positive/ER-negative breast cancer, separately. (Exploratory Correlative Objective)
XXII. To evaluate the association between HER2DX risk score in the baseline tumor and RFS in patients who had residual disease after neoadjuvant THP therapy (i.e., arm B) in HER2-positive/ER-positive breast cancer and HER2-positive/ER-negative breast cancer, separately. (Exploratory Correlative Objective)
XXIII. To evaluate the association between HER2DX risk score in the baseline tumor with other long-term outcomes (including EFS, IDFS, DDFS, DRFS, RFI, OS and breast cancer-specific survival) for patents in arm A and arm B, separately. (Exploratory Correlative Objective)
XXIV. To evaluate the associations between HER2DX pCR likelihood score in the baseline tumor and RCB score in all patients, and separately in patients with HER2-positive/ER-positive disease and in patients with HER2-positive/ER-negative disease. (Exploratory Correlative Objective)
XXV. To evaluate the discrimination and calibration performance of HER2DX pCR likelihood score in terms of pCR in all patients, and separately in patients with HER2-positive/ER-positive disease and in patients with HER2-positive/ER-negative disease. (Exploratory Correlative Objective)
XXVI. To evaluate the discrimination and calibration performance of HER2DX risk score in terms of RFS in arm A patients. (Exploratory Correlative Objective)
XXVII. To evaluate the discrimination and calibration performance of HER2DX risk score in terms of RFS in arm B patients. (Exploratory Correlative Objective)
XXVIII. To evaluate the association of CTCs and change at 3 weeks and 12 weeks with pCR. (Exploratory Correlative Objective)
XXIX. To evaluate the association of change in CTCs with RFS. (Exploratory Correlative Objective)
XXX. To evaluate the association of CTC phenotype and change with pCR and RFS. (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 and weekly thereafter, and pertuzumab IV on day 1. Patients may substitute trastuzumab-hyaluronidase subcutaneously (SC) over 2-5 minutes on day 1 in place of trastuzumab or pertuzumab-trastuzumab-hyaluronidase SC over 8 minutes on day 1 of cycle 1 and over 5 minutes on day 1 of cycles 2-4 in place of trastuzumab and pertuzumab. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. However, if surgery occurs later than 21 days after the 4th cycle of trastuzumab and pertuzumab, patients receive an additional cycle of trastuzumab and pertuzumab before surgery.

SURGERY: Within 126 days (18 weeks) after the first 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. Patients may substitute trastuzumab-hyaluronidase SC over 2-5 minutes on day 1 in place of trastuzumab or pertuzumab-trastuzumab-hyaluronidase SC over 5 minutes on day 1 in place of trastuzumab and pertuzumab. 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.

All patients undergo echocardiogram (ECHO) or multigated acquisition scan (MUGA) during screening and then every 3 months during pre-operative and post-operative therapy. Patients undergo mammogram and ultrasound with or without MRI during screening, and up to one week before cycle 4 day 1. Patients may undergo mammogram annually for 15 years. Patients undergo collection of blood cycle 1 day 1, cycle 2 day 1, pre-surgery, post-surgery, on the day of the first post-surgery systemic therapy, and after completion of all HER2-targeted therapy. Patients may undergo computed tomography (CT) and bone scan or positron emission tomography (PET)/CT during screening.

After completion of study treatment, patients are followed up every 3 months for 12 months, every 6 months for 1-5 years, then annually for 5-15 years from date of surgery.