Cisplatin or Doxorubicin Hydrochloride and Cyclophosphamide before Surgery in Treating Patients with Newly Diagnosed Breast Cancer and BRCA Mutations
This randomized phase II trial studies how well cisplatin or doxorubicin hydrochloride and cyclophosphamide before surgery work in treating patients with newly diagnosed breast cancer with an inherited mutation (a change in the deoxyribonucleic acid [DNA] sequence of a cell) in the breast cancer early onset 1 (BRCA1) or BRCA2 gene. Drugs used in chemotherapy, such as cisplatin, doxorubicin hydrochloride, and cyclophosphamide work in different way to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving chemotherapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. It is not yet known whether cisplatin is more effective than doxorubicin hydrochloride and cyclophosphamide when given before surgery in treating patients with breast cancer.
Inclusion Criteria
- Participant must have a confirmed germline deleterious BRCA mutation; participants with a BRCA1 or BRCA2 classified as “variant, suspected deleterious” by Myriad Genetics are also eligible for the trial; participants with only a BRCA1 or BRCA2 VUS (variant of uncertain significance) are not eligible for this study; if a potential subject is considered high risk for carrying a BRCA1/BRCA2 mutation by National Comprehensive Cancer Network (NCCN) criteria but does not have insurance coverage for testing or if results from available testing options will not be ready in time for enrollment in the study Myriad Genetic Laboratories may cover the cost of the test; genetic testing does not have to be performed by Myriad Genetic Laboratories but a study-specific test request form is available for tests submitted to Myriad; this form may also be used for genetic testing which will be covered by the participant’s insurance and may lead to more expedited testing
- Histologic documentation: pathologic confirmation of invasive breast cancer by core or surgical biopsy (fine-needle aspiration [FNA] alone is not adequate)
- Stage: clinical T1 >= 1.0 cm, T2 or T3, N0-3, M0; participants with multicentric or bilateral disease are eligible if at least one lesion meets stage eligibility criteria for the study (i.e., >= 1.0 cm operable breast cancer) and no tumor is human epidermal growth factor receptor 2 (HER2)-positive (3+ by immunohistochemistry [IHC] or in situ hybridization [ISH] amplified >= 2.0); in this circumstance, the investigator must determine which will represent the target lesion to be assessed for response; this should remain consistent throughout the study; the target lesion should be selected on the basis of its size (lesion with the longest diameter) and suitability for accurate repetitive measurements
- HER 2 status: tumors must be HER2 negative defined as HER2 0 or 1+ by immunohistochemical (IHC) assays and/or lack of gene amplification by fluorescence in situ hybridization (FISH) defined as a ratio < 2 on invasive tumor; a tumor is considered HER2+ if 3+ by IHC or ISH amplified >= 2.0
- Estrogen receptor (ER) and progesterone receptor (PgR) status by immunohistochemistry must be known; ER positive tumors are allowed in patients for whom the treating investigator has determined neoadjuvant chemotherapy is appropriate
- Breast imaging should include imaging of the ipsilateral axilla; for subjects with a clinically negative axilla, a sentinel lymph node biopsy will be performed either up front or after preoperative therapy at the discretion of the subject’s physicians; for subjects with a clinically positive axilla, a needle aspiration, core biopsy or sentinel lymph node (SLN) procedure will be performed prior to registration to confirm the presence of metastatic disease in the lymph nodes; while not mandated by the protocol, it is strongly recommended that participants with positive lymph nodes undergo a level I and II lymph node dissection at the time of definitive surgery; participants with axillary adenopathy only are not eligible for this study
- Cardiac ejection fraction (left ventricular ejection fraction [LVEF]) >= institutional lower limit of normal by multi gated acquisition scan (MUGA)/radionuclide ventriculogram (RVG) or echocardiogram (ECHO)
- Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
- Absolute neutrophil count (ANC) >= 1,500/mm^3
- Platelet count >= 100,000/mm^3
- Bilirubin =< 1.5 x institutional upper limits of normal (ULN); if patient has documented Gilbert’s syndrome bilirubin must be < 3 x institutional ULN
- Alanine aminotransferase (ALT), aspartate aminotransferase (AST) =< 2.5 x institutional ULN
- Alkaline phosphatase (ALK Phos) =< 2.5 x institutional ULN
- Glucose < 200 mg/dl
- Hemoglobin >= 9 g/dl
- Creatinine =< 1.5 mg/dl OR creatinine clearance >= 60 cc/min (can be calculated by 24 hour urine or by the Cockcroft-Gault formula)
- Life expectancy of greater than six months
- Use of an effective means of contraception is required in subjects of childbearing potential; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately; women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation
- Ability to understand and the willingness to sign a written informed consent document
- Individuals with a history of other malignancies are eligible if they have been disease-free for at least 5 years and are deemed by the investigator to be at low risk for recurrence of that malignancy and did not receive prior chemotherapy; individuals with the following cancers are eligible if diagnosed and treated within the past 5 years: cervical cancer in situ, and basal cell or squamous cell carcinoma of the skin
Exclusion Criteria
- Any prior anthracycline or platinum based therapy at any time
- Any prior treatment for the current breast cancer, including chemotherapy, hormonal therapy, radiation or experimental therapy
- Ipsilateral breast recurrence, unless prior treatment consisted of excision alone for ductal carcinoma in situ (DCIS) or breast-conserving treatment and hormonal therapy for DCIS or invasive cancer
- Peripheral neuropathy of any etiology that exceeds grade 1
- Significant hearing loss that would prevent cisplatin administration
- Renal dysfunction for which exposure to cisplatin would be unsafe or require cisplatin dose modification (i.e., creatinine [Cre] > 1.5 mg/dl or glomerular filtration rate [GFR] < 60 cc/min)
- Use of any other investigational or study agents
- History of allergic reactions attributed to compounds of similar chemical or biologic composition to study drugs (e.g. cisplatin)
- Uncontrolled intercurrent illness including, but not limited to ongoing or active systemic infect ion, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, steroid dependent asthma, or psychiatric illness/social situations that would limit compliance with study requirements
- Any condition that would prohibit administration of corticosteroids
- Pregnancy or breast-feeding because the chemotherapy agents in this study have the potential for teratogenic or abortifacient effects as well as unknown but potential risks in nursing infants
- Uncontrolled diabetes (if non-fasting blood sugar > 200 mg/dl, perform a fasting blood sugar which must be =< 200 mg/dl)
- Any pre-existing medical condition that would represent toxicity in excess of grade 1 as measured by CTCAE (National Cancer Institute [NCI] Common Toxicity Criteria for Adverse Events version 4.03) unless the symptom is not considered medically significant by the treating investigator (e.g., alopecia)
- Known human immunodeficiency virus (HIV)-positive individuals on combination antiretroviral therapy are ineligible because these individuals are at increased risk of lethal infections when treated with marrow-suppressive therapy
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT01670500.
PRIMARY OBJECTIVES:
I. To determine if the pathologic complete response (pCR) rate (determined by the Miller-Payne method) (pCR in breast and nodes [i.e. residual cancer burden (RCB) 0] or pCR in breast [i.e. Miller Payne 5] if nodes are not evaluable [i.e. positive nodes were removed surgically before chemo]) to neoadjuvant cisplatin is at least 20% greater than the pCR to doxorubicin (doxorubicin hydrochloride)/cyclophosphamide (AC) in women with newly diagnosed breast cancer and a germline BRCA mutation.
SECONDARY OBJECTIVES:
I. To determine the residual cancer burden (RCB) and compare the rates of RCB 0 as well as RCB 0 and RCB 1 (combined, with the inclusion of pCR in the breast when nodes are not evaluable, i.e. Miller-Payne 5 when positive nodes were removed prior to chemo) after neoadjuvant cisplatin or doxorubicin/cyclophosphamide (AC) in women with newly diagnosed breast cancer and a germline BRCA mutation.
II. To compare the rates of Miller Payne 4 (near pCR) and 5 (pCR) combined between those subjects who received neoadjuvant cisplatin and those who received neoadjuvant AC.
III. To determine the clinical response rate, defined as the number of partial and complete responses, after preoperative therapy with either cisplatin or AC in participants with a germline BRCA mutation and breast cancer.
IV. To compare the toxicities of cisplatin and AC preoperative chemotherapy in BRCA mutation carriers with newly diagnosed breast cancer.
V. To collect pre-chemotherapy biopsies for future analyses of biomarkers that predict for response to cisplatin or AC chemotherapy in BRCA mutation carriers, including homologous recombination deficiency (HRD) using an assay developed by Myriad Genetic Laboratories.
VI. To determine if 3-year recurrence-free survival (RFS) is significantly better for germline BRCA mutation (gBRCAm) carriers with newly diagnosed HER2-negative breast cancer allocated to cisplatin versus (vs.) AC chemotherapy.
VII. To determine if 3-year RFS is significantly improved for gBRCAm carriers who achieved pCR compared with those who did not.
OUTLINE: Patients are randomized to 1 of 2 treatment arms.
ARM A: Patients receive doxorubicin hydrochloride intravenously (IV) and cyclophosphamide IV over 30-60 minutes once every 2-3 weeks. Treatment repeats every 2-3 weeks for up to 4 courses in the absence of disease progression or unacceptable toxicity.
ARM B: Patients receive cisplatin IV over 60 minutes once every 3 weeks. Treatment repeats every 3 weeks days for up to 4 courses in the absence of disease progression or unacceptable toxicity.
All patients undergo definitive breast surgery (excision and/or mastectomy) within 42 days of completing chemotherapy. Patients with significant residual disease after completion of protocol therapy may receive additional preoperative chemotherapy at the discretion of the treating oncologist.
After completion of study treatment, patients are followed up for 30 days and then annually for 3 years.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationDana-Farber Harvard Cancer Center
Principal InvestigatorNadine Muskatel Tung
- Primary ID12-258
- Secondary IDsNCI-2012-02217, TBCRC031
- ClinicalTrials.gov IDNCT01670500