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

NCT01560663 | Unknown

• 1 other identifier: GOMHGUGM022011
• Study Type: observational
• Target: 415
• Locations: 1 country
• Sites: 1

Brief Summary

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).

Conditions

Breast Cancer; Breast Cancer Stage II-III

Keywords

Breast Cancer; Neoadjuvant therapy; Triple negative; predictor of response; predictor of resistance; Continuous Renal Replacement Therapy

Outcome Measures

Primary Outcomes (1)

• predictors of response to docetaxel-carboplatin in patients with triple negative primary tumors

  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).

  6 months

Secondary Outcomes (1)

• predictors of good pathological response and chemoresistance

  3 months

Study Arms (1)

Docetaxel Carboplatino

Doses of AUC 5-6 of carboplatin in combination with 75 mg/m2 of docetaxel are easily combined, being myelosuppression the most important toxicity. This combination has been studied in metastatic breast cancer as well as in the neoadjuvant setting. The combination of taxanes and platinum salts is increasingly used as neoadjuvant chemotherapy for TNBC. The docetaxel-carboplatin (TCb) regimen is an active and tolerable regimen in metastatic and locally advanced breast cancer, and the efficacy and toxicity characterization in the clinical setting are regaining interest in the era where the role of anthracyclines is controversial in the adjuvant setting. The avoidance of potentially serious long-term toxicities in specific breast cancer subtypes is a real challenge in an attempt to individualize therapies.

Drug: Docetaxel- Carboplatin

Interventions

Docetaxel- Carboplatin DRUG

Docetaxel 75mg/m2 day 1 and Carboplatin(AUC6)day 1, each 21 days for 6 cycles.

Docetaxel Carboplatino

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Female patients with triple negative primary tumors

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Miguel Martín Jiménez: lead
• UNC Lineberger Comprehensive Cancer Center: collaborator
• Hospital Universitario Ramon y Cajal: collaborator
• Hospital San Carlos, Madrid: collaborator
• Centro Nacional de Investigaciones Oncologicas CARLOS III: collaborator

Study Sites (1)

Hospital Universitario Gregorio Marañon

Madrid, 28007, Spain

Location

Related Publications (4)

• Echavarria I, Lopez-Tarruella S, Picornell A, Garcia-Saenz JA, Jerez Y, Hoadley K, Gomez HL, Moreno F, Monte-Millan MD, Marquez-Rodas I, Alvarez E, Ramos-Medina R, Gayarre J, Massarrah T, Ocana I, Cebollero M, Fuentes H, Barnadas A, Ballesteros AI, Bohn U, Perou CM, Martin M. Pathological Response in a Triple-Negative Breast Cancer Cohort Treated with Neoadjuvant Carboplatin and Docetaxel According to Lehmann's Refined Classification. Clin Cancer Res. 2018 Apr 15;24(8):1845-1852. doi: 10.1158/1078-0432.CCR-17-1912. Epub 2018 Jan 29.

  PMID: 29378733 BACKGROUND

• Sharma P, Lopez-Tarruella S, Garcia-Saenz JA, Khan QJ, Gomez HL, Prat A, Moreno F, Jerez-Gilarranz Y, Barnadas A, Picornell AC, Monte-Millan MD, Gonzalez-Rivera M, Massarrah T, Pelaez-Lorenzo B, Palomero MI, Gonzalez Del Val R, Cortes J, Fuentes-Rivera H, Morales DB, Marquez-Rodas I, Perou CM, Lehn C, Wang YY, Klemp JR, Mammen JV, Wagner JL, Amin AL, O'Dea AP, Heldstab J, Jensen RA, Kimler BF, Godwin AK, Martin M. Pathological Response and Survival in Triple-Negative Breast Cancer Following Neoadjuvant Carboplatin plus Docetaxel. Clin Cancer Res. 2018 Dec 1;24(23):5820-5829. doi: 10.1158/1078-0432.CCR-18-0585. Epub 2018 Jul 30.

  PMID: 30061361 BACKGROUND

• Picornell AC, Echavarria I, Alvarez E, Lopez-Tarruella S, Jerez Y, Hoadley K, Parker JS, Del Monte-Millan M, Ramos-Medina R, Gayarre J, Ocana I, Cebollero M, Massarrah T, Moreno F, Garcia Saenz JA, Gomez Moreno H, Ballesteros A, Ruiz Borrego M, Perou CM, Martin M. Breast cancer PAM50 signature: correlation and concordance between RNA-Seq and digital multiplexed gene expression technologies in a triple negative breast cancer series. BMC Genomics. 2019 Jun 3;20(1):452. doi: 10.1186/s12864-019-5849-0.

  PMID: 31159741 BACKGROUND

• Yau C, Osdoit M, van der Noordaa M, Shad S, Wei J, de Croze D, Hamy AS, Lae M, Reyal F, Sonke GS, Steenbruggen TG, van Seijen M, Wesseling J, Martin M, Del Monte-Millan M, Lopez-Tarruella S; I-SPY 2 Trial Consortium; Boughey JC, Goetz MP, Hoskin T, Gould R, Valero V, Edge SB, Abraham JE, Bartlett JMS, Caldas C, Dunn J, Earl H, Hayward L, Hiller L, Provenzano E, Sammut SJ, Thomas JS, Cameron D, Graham A, Hall P, Mackintosh L, Fan F, Godwin AK, Schwensen K, Sharma P, DeMichele AM, Cole K, Pusztai L, Kim MO, van 't Veer LJ, Esserman LJ, Symmans WF. Residual cancer burden after neoadjuvant chemotherapy and long-term survival outcomes in breast cancer: a multicentre pooled analysis of 5161 patients. Lancet Oncol. 2022 Jan;23(1):149-160. doi: 10.1016/S1470-2045(21)00589-1. Epub 2021 Dec 11.

  PMID: 34902335 BACKGROUND

Related Links

• Related Info
• Related Info

Biospecimen

Retention: SAMPLES WITH DNA

DNA and RNA from triple negative breast cancer patients

MeSH Terms

Conditions

Breast Neoplasms

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor of Medicine, Medical Oncology Service

Study Record Dates

• First Submitted: March 20, 2012
• First Posted: March 22, 2012
• Study Start: January 1, 2012
• Primary Completion: December 1, 2023
• Study Completion: December 1, 2023
• Last Updated: September 29, 2023

Record last verified: 2023-09

Locations

ES (1)