IntroductionBRCA-mutated breast cancer cells lack the DNA-repair mechanism homologous recombination that is required for error-free DNA double-strand-break (DSB) repair. Homologous recombination deficiency (HRD) may cause hypersensitivity to DNA DSB-inducing agents, such as bifunctional alkylating agents and platinum salts.
HRD can be caused by BRCA-mutations, and by other mechanisms. To identify HRD, studies have focused on triple-negative (TN) breast cancers as these resemble BRCA1-mutated breast cancer closely and might also share this hypersensitivity.
However, ways to identify HRD in non-BRCA-mutated, estrogen-receptor (ER)-positive breast cancers have remained elusive. The current study provides evidence that genomic patterns resembling BRCA1- or BRCA2-mutated breast cancers can identify breast cancer patients with TN as well as ER-positive, HER2-negative tumors that are sensitive to intensified, DSB-inducing chemotherapy.
Methods:
Array comparative genomic hybridization (aCGH) was used to classify breast cancers.
Patients with tumors with similar aCGH patterns as BRCA1- and/or BRCA2-mutated breast cancers were defined as having a BRCA-likeCGH status, others as Non-BCRA-likeCGH. Stage-III patients (n = 249) had participated in a randomized-controlled trial of adjuvant high-dose (HD) cyclophosphamide-thiotepa-carboplatin (CTC) versus 5-fluorouracil-epirubicin-cyclophosphamide (FE90C) chemotherapy.
Results:
Among patients with BRCA-likeCGH tumors (81/249, 32%), a significant benefit of HD-CTC compared to FE90C was observed regarding overall-survival (adjusted hazard ratio 0.19, 95%CI: 0.08 to 0.48) that was not seen for patients with Non-BRCA-likeCGH tumors (adjusted hazard ratio 0.90, 95%CI: 0.53 to 1.54) (P = 0.004).
Half of all BRCA-likeCGH tumors were ER-positive.
Conclusions:
Distinct aCGH patterns differentiated between HER2-negative patients with a markedly improved outcome after adjuvant treatment with an intensified DNA-DSB-inducing regimen (BRCA-likeCGH patients) and those without benefit (non-BRCA-likeCGH patients).
Author: Marieke A VolleberghEsther H LipsPetra M NederlofLodewyk FA WesselsJelle WesselingMarc J vd VijverElisabeth GE de VriesHarm van TinterenJos JonkersMichael HauptmannSjoerd RodenhuisSabine C Linn
Credits/Source: Breast Cancer Research 2014, 16:R4
Published on: 2014-05-15
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