Predictors of Response to Neoadjuvant Docetaxel-Carboplatin Chemotherapy for Patients With Stage II and III Triple Negative Breast Cancer


Condition: Breast Cancer, Breast Cancer Stage II-III

Intervention:

  • Drug: Docetaxel- Carboplatin

Purpose: Neoadjuvant (preoperative) chemotherapy is an interesting research tool which allows investigators to test new drugs and/or new schedules with a validated surrogate endpoint, pCR. It also represents an ideal model to evaluate the relationships between treatments and tumor biomarkers. Recent publications have shown that new molecular classifications of breast cancer (intrinsic subtypes) have an important prognostic and predictive value. Using microarrays for gene expression profiling seems to be the best way to perform this classification; nevertheless such assays are not optimally available for common clinical practice. The IHC-based classification systems are still useful, as fresh tissue is not normally available in clinical practice, and has been shown to correlate well with intrinsic classification using gene expression microarrays. Recently the PAM50 gene set provided a risk of relapse score not only in ER-positive, node negative patients (similarly to the Oncotype Dx Recurrence Score) but also in the ER negative disease. Additionally, the PAM 50 assay was highly predictive of neoadjuvant response when considering all patients. This assay added significant prognostic and predictive value to pathologic staging, histologic grade, and standard clinical molecular markers while using an easy technique that can be performed in clinical practice because the qRT-PCR assay can be performed using FFEP tissue. Triple Negative Breast Cancer (TNBC) is defined by a lack of expression of ER, PgR and HER-2. DNA microarray profiling studies have led to the classification of invasive breast carcinoma into five subtypes: luminal A and B, normal breast-like, HER2/neu overexpressing and basal-like subtypes, with clinical implications. Later on, a new subtype, the claudin-low, has been described. Although not synonymous, the majority of TNBCs carry the basal-like breast cancer (BLBC) molecular profile. The triple negative subtype accounts for 11-20% of breast cancer in different studies, whereas in selected cohorts of patients with advanced breast cancer or African-American ethnicity, TNBC may be diagnosed among as many as 23-28%. Patients with TN breast tumors treated with standard chemotherapy have a shorter DFS and OS than non-TNBC, this difference have been shown to be independent from tumor grade, nodal status and treatment in some studies. The peak risk of recurrence occurs within the first 3 years after initial treatment, with the majority of deaths occurring in the first five years. Chemotherapy remains the only systemic treatment option available for TNBC patients. Several studies have shown that TNBC/BLBC is associated with an increased response rate to neoadjuvant chemotherapy when compared with luminal tumors. However, TNBC patients have a significantly decreased DFS and OS in comparison with luminal patients. The largest study exploring response and survival in early stage breast cancer treated with neoadjuvant chemotherapy was reported by Liedtke et al. Although an increase pCR rate was observed among the TNBC patients, they had a shorter lifespan than the non-TN ones. Patients experiencing pCR had an excellent OS regardless of hormone receptor expression, but patients with residual disease had a significantly shorter survival associated with TNBC compared with non-TN ones. This demonstrates that poor OS is derived from chemo-resistant patients (what unfortunately represent > 50% of them). A relevant problem is the differential response to drugs of TN tumors. These tumors are usually treated with multidrug combinations including anthracyclines and taxanes, with pCR´s of 28-32%. Only recently, the results of a few small trials combining platinum salts and taxanes have been reported, with encouraging results (pCR of 44-77%). The taxane-platinum salt combinations have a biological background, since TN not associated BRCA1 mutations are sensitive to taxanes and resistant to anthracyclines and platinum salts are effective in TN tumors probably because a significant proportion of them have functional DNA repair deficiencies. The primary objective of the study is to identify predictors of response to docetaxel-carboplatin in patients with triple negative primary tumors. Response is defined as lack of invasive tumor in breast plus axilla after neoadjuvant chemotherapy (PCR, pathological complete response).

Study Type: Observational

Clinical Trials Identifier NCT 8-digits: NCT01560663

Sponsor: Hospital General Universitario Gregorio Marañon

Primary Outcome Measures:

  • Measure: predictors of response to docetaxel-carboplatin in patients with triple negative primary tumors
  • Time Frame: 6 months
  • Safety Issue:

Secondary Outcome Measures:

  • Measure: predictors of good pathological response and chemoresistance
  • Time Frame: 3 months
  • Safety Issue:

Estimated Enrollment: 185

Study Start Date: January 2012

Eligibility:

  • Age: minimum 18 Years maximum 75 Years
  • Gender: Female

Inclusion Criteria:

  • Informed consent form signed by the patient to accept study enrollment.
  • Female with pathologically confirmed diagnosis of primary invasive operable breast cancer, stage IIa-IIIc (6th edition of the AJCC Cancer Staging Manual), with tumors ≥ 2cm. Triple negative phenotype patients (RE and PR of less than 1% of stained cells by IHQ, IHC for HER2 of 0-1+ or ISH negative if 2/3+), according to local laboratory.
  • Age 18-75 years.
  • Adequate performance status (ECOG <2).
  • Adequate renal and liver function and bone marrow reserve.

Exclusion Criteria:

  • Clinical or radiologic evidence of Metastatic disease.
  • Prior or concurrent anti-cancer therapy for current disease (hormone therapy, chemotherapy, radiotherapy, immunotherapy).
  • Prior therapy with taxanes, anthracyclines or carboplatin for any malignancy.
  • Contraindication for study drugs (docetaxel or carboplatin).
  • Serious concomitant systemic disorder that in the opinion of the investigator would compromise the patient's ability to complete the study, or have any other disease that could be worsened by chemotherapy or other potential support therapies.

Contact:

  • Miguel Martin, Medical Oncology
  • 91 5869070

Location:

  • Hospital Universitario Gregorio Marañon
  • Madrid 28007 Spain

View trial on ClinicalTrials.gov


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