Neoadjuvant Study of Two Platinum Regimens in Triple Negative Breast Cancer

Sporadic and germline BRCA mutation associated triple-negative breast cancer share several pathological and molecular similarities which have led to the exploration of DNA damaging agents like platinum compounds in patients with triple-negative breast cancer. Recent studies demonstrate that addition of neoadjuvant carboplatin to doxorubicin/cyclophosphamide/taxane-based chemotherapy improves pathological complete response in patients with stage I-III triple-negative breast cancer but also increase toxicity.

A recent study reported encouraging pathological complete response rates with a non-anthracycline carboplatin plus docetaxel neoadjuvant chemotherapy regimen in a cohort of 49 triple negative breast cancer patients. This chemotherapy regimen of carboplatin plus docetaxel yielded an overall pathological complete response rate of 65% in unselected triple-negative breast cancer with pathological complete response rates of 61% in sporadic and 77% in germline BRCA-associated triple-negative breast cancer. The chemotherapy regimen of carboplatin/docetaxel is well tolerated and should be studied further and compared with regimens that add carboplatin to the standard anthracycline/taxane containing regimens.

This is the basis for the proposed randomized neoadjuvant phase II study to further estimate and compare pathological complete response rates of carboplatin plus docetaxel x 6 cycles to carboplatin plus paclitaxel x 4 cycles followed by doxorubicin plus cyclophosphamide x 4 cycles in stage I-III triple negative-breast cancer.

Inclusion criteria

• Patients with newly diagnosed stage I (T>1cm), II or III triple negative breast cancer who have not had definitive breast surgery or received systemic chemotherapy
• The invasive tumor must be hormone receptor-poor, defined as both estrogen receptor and progesterone receptor staining present in ≤ 10% of invasive cancer cells by Immunohistochemistry.
• HER- 2 negativity will be based on the current ASCO-CAP guidelines for HER testing
• No prior chemotherapy, endocrine therapy or radiation therapy with therapeutic intent for this cancer
• Female subjects age 18 - 70 years
• ECOG Performance Status of 0-1
• Adequate organ and marrow function as defined below:

• Leukocytes ≥ 3,000/uL
• Absolute neutrophil count ≥ 1500/uL
• Platelets ≥ 100,000/uL
• Total bilirubin ≤ 1.5mg/dL
• AST(SGOT)/ALT(SPGT) ≤ 2 x institutional upper limit of normal
• Creatinine ≤ 1.5mg/dl and/or Creatinine Clearance ≥ 60mL/min
• Serum albumin ≥ 3.0 g/dL
• Women of child-bearing potential must agree to use adequate contraception
• Pretreatment lab values must be performed within 14 days of treatment initiation, and other baseline studies performed within 30 days prior to registration
• Subjects should have LVEF ≥ 50% by echocardiogram or MUGA scan performed within 4 weeks prior to treatment initiation
• Subjects should have breast and axillary imaging with breast MRI or breast and axillary ultrasound within 4 weeks prior to treatment initiation
• Subjects with clinically/radiologically abnormal axillary lymph nodes should have pathological confirmation of disease with image guided biopsy/fine needle aspiration.
• Subjects must be already enrolled in P.R.O.G.E.C.T observational registry
• Staging to rule out metastatic disease is recommended for subjects with clinical stage III disease
• Subjects with bilateral disease are eligible if they meet other eligibility criteria.
• Neuropathy: No baseline neuropathy grade > 2

Exclusion criteria

• Current or anticipated use of other investigational agents
• Subject has received chemotherapy, radiotherapy or surgery for the treatment of breast cancer
• Subject with metastatic disease
• History of allergic reactions to compounds of similar chemical or biologic composition to carboplatin, docetaxel, doxorubicin, cyclophosphamide, paclitaxel, or other agents used in the study
• Subjects with inflammatory breast cancer
• Uncontrolled intercurrent illness including, but not limited to ongoing or active infection or psychiatric illness/social situations that would limit compliance with study requirements
• Subject is pregnant or nursing
• Subjects with concomitant or previous malignancies within the last 5 years. Exceptions include: adequately treated basal or squamous cell carcinoma of the skin, carcinoma in situ of the cervix, and ductal carcinoma in situ (DCIS).
• Ejection Fraction <50% on ECHO or MUGA
• Cardiac function: Subjects with congestive heart failure, myocardial infarction, unstable angina pectoris, an arterial thrombotic event, stroke or transient ischemia attack within the past 12 months, uncontrolled hypertension (Systolic BP>160 or Diastolic BP>90), uncontrolled or symptomatic arrhythmia, or grade ≥ 2 peripheral vascular disease