The TLR4 polymorphism predicts the response of breast cancer patients to anthracyclins

10612 Background: Conventional anticancer therapy mainly relies upon chemotherapy which supposedly directly eliminates tumor cells. However, we showed in mice that chemotherapy-induced tumor cell death markedly enhanced T-cell mediated tumor rejection, suggesting a role of innate immune receptors in the response to anthracyclins. Moreover, anthracyclins are less effective in athymic nude or Toll like receptor-4 (TLR4) deficient mice (Obeid et al. Nat. Med. 2006). A single nucleotide polymorphism (SNP) in TLR4 (896A/G, Asp299Gly) affecting the extracellular domain of TLR4 is associated with reduced endotoxin responses in humans. We addressed whether the TLR4 SNP could affect the response to anthracyclins in breast cancer patients. Methods: We included 280 patients from three cancer centers bearing non-metastatic breast cancer presenting with lymph node involvement and treated with anthracyclin-based regimen after local surgery. TLR4 genotyping performed on leukocytes (PCR based on exonuclease degradation of dual labelled allele-specific oligos) and statistical analyses were performed in a blinded fashion. Results: The frequency of Asp299Gly (heterozygote) and Gly299Gly (homozygote) TLR4 germline polymorphisms was 17.1 and 0.7 % respectively. Patients that exhibited a mutated TLR4 allele did not differ from patients displaying the normal TLR4 allele for all classical prognostic factors (age, pathological tumor size, lymph node involvement, tumor grade, hormone receptors, and median follow up, p>0.05). However, the frequency of metastases was statistically higher in the mutated TLR4 group five years after surgery (40% versus 26.5% in non mutated patients, p <0.05, RR: 1.7, 95% CI [1.2–3.6]). Moreover, the Kaplan Meier estimate of metastasis-free survival indicated an overall significantly lower percentage of metastases-free patients in the mutated TLR4 group (Log rank test, p = 0.03). Conclusions: It is the first demonstration of the role of innate immunity and TLR4 in the response to anthracyclins in localized breast cancer. No significant financial relationships to disclose.