Single nucleotide polymorphisms associated with risk for contralateral breast cancer in the Women's Environment, Cancer, and Radiation Epidemiology (WECARE) Study

Introduction

Genome-wide association studies, focusing primarily on unilateral breast cancer, have identified single nucleotide polymorphisms (SNPs) in a number of genomic regions that have alleles associated with a significantly increased risk of breast cancer. In the current study we evaluate the contributions of these previously identified regions to the risk of developing contralateral breast cancer. The most strongly disease-associated SNPs from prior studies were tested for association with contralateral breast cancer. A subset of these SNPs, selected upon their main effects on contralateral breast cancer risk was further evaluated for interaction with treatment modalities and estrogen receptor (ER) status.

Methods

We genotyped 21 SNPs in 708 women with contralateral breast cancer and 1394 women with unilateral breast cancer who serve as the cases and controls in the Women's Environment, Cancer and Radiation Epidemiology (WECARE) Study. Records of treatment and ER status were available for most of WECARE Study participants. Associations of SNP genotypes and risk for contralateral breast cancer were calculated with multivariable adjusted conditional logistic regression methods.

Results

Multiple SNPs in the FGFR2 locus were significantly associated with contralateral breast cancer, including rs1219648 (per allele rate ratio (RR) = 1.25, 95%CI = 1.08-1.45). Statistically significant associations with contralateral breast cancer were also observed at rs7313833, near the PTHLH gene (per allele RR = 1.26, 95%CI = 1.08-1.47), rs13387042 (2q35) (per allele RR = 1.19, 95%CI = 1.02-1.37), rs13281615 (8q24) (per allele RR = 1.21, 95%CI = 1.04-1.40), and rs11235127 near TMEM135 (per allele RR = 1.26, 95%CI = 1.04-1.53). The A allele of rs13387042 (2q35) was significantly associated with contralateral breast cancer in ER negative first tumors while the A allele of rs11235127 (near TMEM135) was significantly associated with contralateral breast cancer in ER positive first tumors. Although some SNP genotypes appeared to modify contralateral breast cancer risk with respect to tamoxifen treatment or particular radiation doses, trend tests for such effects were not significant.

Conclusions

Our results indicate that some common risk variants associated with primary breast cancer also increase risk for contralateral breast cancer, and that these risks vary with the ER status of the first tumor.     

Phase 2 trial of induction and concurrent chemoradiotherapy with weekly irinotecan and cisplatin followed by surgery for esophageal cancer

BACKGROUND:

Preoperative chemoradiation improves survival in esophageal and gastroesophageal junction (GEJ) cancer. We evaluated irinotecan and cisplatin as induction chemotherapy followed by concurrent chemoradiation in esophageal cancer.

METHODS:

Patients with uT1N1M0 or uT2‐4NanyM0 resectable squamous cancer or adenocarcinoma of the esophagus or GEJ received irinotecan 65 mg/m² and cisplatin 30 mg/m² for 4 treatments in weeks 1 through 5, followed by 4 treatments in weeks 7 through 11 with 50.4 Gy in daily fractions, followed by surgery. The primary endpoint was pathologic complete response (pCR). Positron emission tomography (PET) scan was performed prior to chemotherapy and as restaging prior to radiotherapy.

RESULTS:

Fifty‐five patients were evaluable, 75% of whom had adenocarcinoma and 65% of whom had uT3N1 disease. Thirty‐eight patients underwent R0 resection (69%). The incidence of pCR was 16% (95% confidence interval, 8%‐29%). Median overall survival was 31.7 months. An exploratory analysis of PET response to induction chemotherapy indicated a correlation with pCR (32% vs 4%), R0 resection (84% vs 57%), progression‐free survival (24.1 vs 7.7 months), and overall survival (40.2 vs 25.5 months).

CONCLUSIONS:

Weekly treatment with irinotecan, cisplatin, and radiation achieved results no better and potentially inferior to other phase 2 chemoradiotherapy trials with a low rate of pCR. The use of PET scan after induction chemotherapy to direct chemotherapy during subsequent radiotherapy merits further study. Cancer 2011. © 2011 American Cancer Society.     

Risk of contralateral breast cancer associated with common variants in BRCA1 and BRCA2: potential modifying effect of BRCA1/BRCA2 mutation carrier status

Rare deleterious mutations in BRCA1 and BRCA2 are associated with an elevated risk of breast and ovarian cancer. Whether or not common variants in these genes are independently associated with risk of breast cancer remains unclear. In this study, we included 632 Caucasian women with asynchronous contralateral breast cancer (CBC, cases) and 1,221 women with unilateral breast cancer (UBC, controls) from the WECARE (Women's Environment, Cancer and Radiation Epidemiology) Study. BRCA1 and BRCA2 deleterious mutation status was measured using denaturing high-performance liquid chromatography followed by direct sequencing, yielding including 88 BRCA1 and 60 BRCA2 deleterious mutation carriers. We also genotyped samples on the Illumina Omni1-Quad platform. We assessed the association between CBC risk and common (minor allele frequency (MAF)?>?0.05) single-nucleotide polymorphisms (SNPs) in BRCA1 (n SNPs?=?22) and BRCA2 (n SNPs?=?30) and haplotypes using conditional logistic regression accounting for BRCA1/BRCA2 mutation status. We found no significant associations between any single-SNPs or haplotypes of BRCA1 or BRCA2 and risk of CBC among all women. When we stratified by BRCA1 and BRCA2 mutation carrier status, we found suggestive evidence that risk estimates for selected SNPs in BRCA1 (rs8176318, rs1060915, and rs16940) and BRCA2 (rs11571686, rs206115, and rs206117) may differ in non-carriers and carriers of deleterious mutations in BRCA1 and BRCA2. One common haplotype on BRCA1 was inversely significantly associated with risk only among non-BRCA1 and BRCA2 carriers. The association between common variants in BRCA1 and BRCA2 and risk of CBC may differ depending on BRCA1 and BRCA2 mutation carrier status.     

Ferromagnetism and Superconductivity in CaRuO3/YBa2Cu3O7-δ Heterostructures

The deposition of a ferromagnetic layer can affect the properties of high-temperature superconductors underneath. We investigated the influence of ferromagnetic CaRuO₃ on the properties of YBa₂Cu₃O_7-x (YBCO) superconducting thin films when the layers are either in direct contact or separated by a barrier layer of 5 nm SrTiO₃. Detailed measurements of the magnetic moment of the superconductor and ferromagnet as a function of temperature and magnetic field have been performed using SQUID magnetometry. Magnetometry and relaxation measurements show that the modification of the superconducting properties of YBCO strongly depends on the interaction with the ferromagnetic layer on top. The barrier layer has a significant impact on both the supercon-ducting properties of the YBCO film and the ferromagnetic ordering of CaRuO₃. The physical properties mentioned above were discussed in correlation with the materials’ structure determined by XRD analysis.