Early Clinical Response Correlation to Pathologic Outcome for Treatment in Patients with Invasive Breast Cancer Undergoing Chemotherapy Before Surgery

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This phase II trial evaluates whether clinical tumor measurements (measurements of the breast tumor obtained by imaging or clinical exam) can be used to predict the amount of tumor remaining at the time of surgery for treating patients with invasive breast cancer undergoing chemotherapy before surgery (neoadjuvant). Neoadjuvant therapy, also called preoperative therapy, is treatment that is given prior to surgery and has become an important part of standard management of certain subtypes and clinical stages of breast cancer. It has been long established that patients who achieve pathologic complete response (pCR) after receiving neoadjuvant treatment have better outcomes than those who don’t, especially in triple-negative breast cancer (TNBC), HER2 positive (+), and aggressive estrogen receptors (ER)+ breast cancer. So far, the only way to discern whether a patient achieved pCR is to give them the full course of therapy and then proceed to surgery. One of the areas that has attracted significant research interest has been the effort to develop early predictors of pCR. This way, treatment can be tailored in the future to each patient and each tumor to spare patients from ineffective therapy. Some of these predictors are biomarkers, which are biological molecules found in blood, other body fluids, or tissues as well as imaging markers that can be a sign of a normal or abnormal process, or of a condition or disease to be used to see how well the body responds to a treatment for a disease or condition. This study may help researchers learn whether tumor specimens and imaging scans done prior to treatment can be used to predict the amount of tumor remaining at the time of surgery for patients with invasive breast cancer undergoing neoadjuvant chemotherapy.

Inclusion Criteria

At least 18 years of age, and legally able to provide informed consent. Both men and women are eligible
Histologically confirmed, invasive breast cancer. Tumor may be: * Triple-negative (as defined by American Society of Clinical Oncology [ASCO]-College of American Pathologists [CAP] guidelines), * HER2-positive (as defined by ASCO-CAP guidelines), * Or high-risk estrogen receptor-positive (as defined by ASCO-CAP guidelines). To be considered "high-risk," at least two of the following criteria must be met: 1) patient age < 50; 2) histologic grade 3; 3) ER Allred score < 6; 4) Ki-67 >= 30%
Tumors must be >= 2 cm by clinical exam or ultrasound
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
Left ventricular ejection fraction (LVEF) >= the institutional lower limit of normal, as assessed by echocardiogram or MUGA scan
Absolute neutrophil count (ANC) >= 1200/mm^3
Platelets >= 100,000/mm^3
Hemoglobin >= 9 g/dL
Total bilirubin =< institutional upper limit normal (ULN), unless patient has Gilbert's disease or similar syndrome
Alkaline phosphatase (ALP) =< 2.5 x institutional ULN
Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 1.5 x institutional ULN
Serum creatinine =< institutional ULN
The participant, if of childbearing potential, is willing to use effective, non-hormonal contraception while on treatment
Participation in a concurrent clinical trial is permitted, with principal investigator approval

Exclusion Criteria

Definitive clinical or radiologic evidence of stage IV disease
Bilateral invasive breast cancer
Inflammatory breast cancer
Participants who are pregnant or lactating
History of an excisional biopsy or lumpectomy performed prior to study entry
Prior treatment with anthracyclines for any malignancy
Prior treatment for currently diagnosed breast cancer (i.e., endocrine therapy, chemotherapy, targeted therapy, or radiation)
History of cardiac disease that would preclude the use of drugs included in these treatment regimens. This includes, but is not limited to: * Angina pectoris requiring 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 * Symptomatic pericarditis * Documented cardiomyopathy * History of documented congestive heart failure (CHF) * Myocardial infarction documented by elevated cardiac enzymes, or persistent regional wall abnormalities on assessment of left ventricular (LV) function
Current human immunodeficiency virus (HIV), hepatitis B, or hepatitis C infection
History of non-breast malignancies (with the exception of in situ cancers treated only by local excision, and basal cell or squamous cell carcinoma of the skin) within 5 years prior to enrollment
Any other non-malignant systemic disease that would preclude treatment with any of the treatment regimens or prevent required follow-up
Any psychiatric or addictive disorders, adverse social situations, or other medical conditions that, in the opinion of the investigator, would preclude the participant from meeting study requirements

PRIMARY OBJECTIVE:

I. To determine if absence of early clinical response correlates to absence of pathologic complete response in patients receiving neoadjuvant chemotherapy for breast cancer.

SECONDARY OBJECTIVES:

I. To estimate the pathologic complete response rate in three subtypes of breast cancer with specific chemotherapy regimens.

II. To estimate the sensitivity, specificity, negative predictive value and positive predictive value of early clinical response to predict pathologic complete response in three subtypes of breast cancer with specific chemotherapy regimen.

EXPLORATORY OBJECTIVES:

I. To correlate circulating tumor deoxyribonucleic acid (ctDNA) levels from serially collected blood samples to clinical response and pathologic complete response.

II. To correlate proteogenomic and magnetic resonance imaging (MRI) changes in tumor tissue with clinical response in triple-negative breast cancer.

OUTLINE: Patients are assigned to 1 of 3 cohorts.

COHORT I (TNBC): Patients receive standard of care paclitaxel intravenously (IV) over 60-90 minutes and carboplatin IV over 2 hours on days 1, 8, and 15 of each cycle and may also recieve pembrolizumab IV over 30 minutes on day 1 every 3-6 weeks. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then recieve doxorubicin IV with cyclophosphamide IV over 2-3 hours on day 1 of of each cycle. Patients may also continue pembrolizumab IV over 30 minutes on day 1 every 6 weeks. Treatment repeats every 14 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo MRI, mammogram, and/or ultrasound, along with an ecohocardiography (ECHO) or multigated acquisition scan (MUGA) during screening and on trial. Patients undergo a chest x-ray, computed tomography (CT), or positron emission tomography (PET)/CT and may undergo a bone scan during screening. Patients also undergo biopsy during screening and may undergo on trial. Patients undergo blood sample collection during screening and on trial.

COHORT II (HER2+ BC): Patients receive standard of care paclitaxel IV over 60-90 minutes, trastuzumab subcutaneously (SC) over 3-5 minutes or IV over 30-90 minutes on day 1, and pertuzumab SC over 3-5 minutes or IV over 30-60 minutes on day 1 of each cycle. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then recieve doxorubicin IV with cyclophosphamide IV over 2-3 hours on day 1 of of each cycle. Treatment repeats every 14 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo MRI, mammogram, and/or ultrasound, along with an ECHO or MUGA during screening and on trial. Patients undergo a chest x-ray, CT, or PET/CT and may undergo a bone scan during screening. Patients may also undergo biopsy during screening and on trial. Patients undergo blood sample collection during screening and on trial.

COHORT III (HIGH-RISK ER+ BC): Patients receive standard of care paclitaxel IV over 60-90 minutes of each cycle. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then recieve doxorubicin IV with cyclophosphamide IV over 2-3 hours on day 1 of each cycle. Treatment repeats every 14 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo MRI, mammogram, and/or ultrasound, along with an ECHO or MUGA during screening and on trial. Patients undergo a chest x-ray, CT, or PET/CT and may undergo a bone scan during screening. Patients may also undergo biopsy during screening and on trial. Patients undergo blood sample collection during screening and on trial.

After completion of study treatment, patients are followed up between 30-45 days, 4-6 weeks after surgery, and yearly up to 3 years.

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Early Clinical Response Correlation to Pathologic Outcome for Treatment in Patients with Invasive Breast Cancer Undergoing Chemotherapy Before Surgery

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Early Clinical Response Correlation to Pathologic Outcome for Treatment in Patients with Invasive Breast Cancer Undergoing Chemotherapy Before Surgery

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