Predicting response to alkylating chemotherapy in breast cancer patients using array comparative genomic hybridization.

Abstract

#6050 Background: Breast cancer cells lacking the DNA repair mechanism Homologous Recombination (HR) have recently been shown to be hypersensitive to bifunctional alkylating agents such as carboplatin and poly(ADP-ribose)polymerase(PARP)-inhibitors, a novel class of targeted agents. We have previously reported the construction of an array Comparative Genomic Hybridization (aCGH) classifier that detects the characteristic copy number aberrations of BRCA1-mutated tumors which are thought to be caused by HR deficiency. We hypothesized that metastatic breast cancer patients with tumors harboring such a BRCA1-profile may specifically benefit (longer progression-free survival (PFS)) from intensive treatment with bifunctional alkylating agents compared to patients without this tumor-profile.
 Methods: We isolated DNA from formalin-fixed paraffin-embedded primary tumor tissue collected from 3 prior studies carried out in our institute, in which metastatic breast cancer patients received intensive alkylating chemotherapy with carboplatin, thiotepa and cyclophosphamide (CTC). DNA from 40 tumors was tested for the presence of the BRCA1-profile by aCGH. Furthermore, we screened for the majority of BRCA1 and BRCA2 mutations that frequently occur in Dutch BRCA1 and BRCA2 families.
 Results: Sixteen patients had a tumor with a BRCA1-profile and had a better response to CTC-treatment, defined by achievement of a complete remission (p=0.01) and longer PFS (p=0.001, figure 1), with a hazard ratio for progression of 0.30 (p=0.002).
 
 All 6 patients who remain in continuous complete remission (56+ to 150+ months) had a tumor with a BRCA1 profile. Two BRCA1 and 2 BRCA2 mutations were found in 4 patients of whom 3 had a BRCA1-profile and a long PFS (> 30months), linking HR deficiency (BRCA1 and BRCA2 mutations) in breast cancer patients to good outcome on platinum-based chemotherapy.
 Discussion: Using an aCGH classifier initially constructed to identify BRCA1-mutated tumors we were able to identify a group of metastatic breast cancer patients treated with platinum-based chemotherapy with a high complete remission-rate and long progression free survival. Moreover, this group contained all patients who were apparently cured by intensive alkylating chemotherapy. Our aCGH assay may represent an effective test for BRCA-ness and could be important to select patients with sporadic tumors for therapy targeted at cells deficient in Homologous Recombination. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6050.

Cytotoxic and targeted therapy for hereditary cancers

“…It was a popular experimental approach for the treatment of breast cancer in mid 1990s, but failed to demonstrate improved long-term outcomes in unselected BC patients [ 116 – 118 ]. However, retrospective analysis of women with metastatic BC revealed several instances of unexpectedly long remission of the disease; importantly, these survivors are enriched by BRCA1/2 germ-line mutation carriers, which is in good agreement with the data on increased chemosensitivity of BRCA-driven BC [ 119 ]. Furthermore, patients with BRCA1-like stage III BC show substantial benefit from adjuvant high-dose therapy [ 91 , 120 ], and this effect correlates with the molecular status of BRCA1-related pathways [ 115 ].…”

Systemic therapy options in BRCA mutation-associated breast cancer

“…Huang et al [50] described a patient with BRCA2-mutation associated metastatic breast cancer, who was treated by high dose chemotherapy and remains disease free for more than 11 years. Vollebergh et al [51] detected that 6 of 40 patients with metastatic breast cancer who remained on complete remission for 56? to 150?…”

Poly (ADP-Ribose) Polymerase as a Novel Therapeutic Target in Cancer

“…Patients with BRCA1-like sporadic TNBC had a higher pathologic complete response rate with alkylator/anthracycline-based preoperative chemotherapy than did patients with non-BRCA1-like TNBC. In a similar study, patients with metastatic breast cancer (MBC) whose sporadic cancers expressed a BRCA1-like array CGH profile had a greater likelihood of achieving prolonged PFS with intensive high dose CTC (cyclophosphamide, thiotepa, carboplatin) chemotherapy than did patients with sporadic, non-BRCA1-like profiles (52). …”