Abstract P3-06-30: Predictors of Pathologic Complete Response to Chemotherapy and Antiangiotherapy in Breast Cancer.
Authors: Makhoul I , Griffin RJ , Dhakal I , Raj V , Hennings L , Kadlubar SA 
Published: August 2014

Vascular endothelial growth factor (VEGF) is a central mediator of angiogenesis in breast cancer. We have conducted a clinical trial using bevacizumab (B) in breast cancer in the neoadjuvant setting and showed improved pathologic complete response (pCR) when B was added to chemotherapy (CT). 41% of patients (Pts) who received B+CT achieved pCR. Blood and tumor samples were collected at baseline and serially on treatment from 39 patients who participated in the study. The correlative study was approved by the IRB and consent forms were obtained at the time of enrollment. Since patients do not equally benefit from B, it has become necessary to define the profile of patients who will benefit and those who are more likely to have major side effects from the drug. This study was conducted to evaluate for the presence of specific SNPs and CNV in the germ line and a serum protein profile that might be predictive of pCR in the neoadjuvant setting in breast cancer patients receiving B and CT.

Methods: To test for the presence of functional germ line SNPs and CNVs that may influence pCR, DNA was extracted from buffy coats of study participants and SNPs/CNVs were determined using Illumina technology. To test the hypothesis that individuals who achieved pCR were those with differential expression of selected proteins in their blood, custom multiplex was performed for the following serum proteins: ANG-1, ANG-2, bFGF, IL-1a, MMP-9, PDGF-BB, PECAM-1, Tie-2, VEGF, and VEGFR2.

Statistical test: The association between genotype and CNV of each SNP vs. pCR status were analyzed using Cochran-Armitage Trend Test. Differences in serum protein levels between pCR and non-pCR groups were examined by Wilcoxon rank sum test. Significance of association was evaluated in two settings of α (i) α=0.05 (ii) α=0.00001.

Results: Genotype and CNV vs. pCR (n = 38). In genotype vs. pCR status by SNPs tests, 131618 (∼13%) SNPs with allele frequency &lt;0.05 were excluded from the analysis. In CNV vs. pCR status by SNPs tests, only 46891 (4.6%) SNPs were analyzed. Many SNPs were excluded because there was no variability in their CNVs. Though no SNPs found significant at genome-wide level of significance (&lt;10−5), a number of SNPs were significant at the level of individual tests in these comparisons. Four SNPs at a p value &lt; 0.0001 were identified. A SNP in the promoter region of H(+)-myo-inositol co-transporter gene was most frequently associated with pCR.

Analysis of baseline serum protein data (n = 34). The results of pCR vs. serum protein data analysis suggest that there is a statistically significant difference between the concentration of bFGF and Tie-2 in the pCR group (higher baseline values) and those in the non-pCR group (p-values &lt;0.05). The difference of concentrations of VEGF trended toward significance between these two groups.

Conclusion: Elevated serum baseline Tie-2 and bFGF and special SNP in the promoter of H(+)-myo-inositol co-transporter gene are candidate predictors for pCR in response to B/CT and need to be validated in a larger clinical study.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-06-30.