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Colleran G.,National University of Ireland | Colleran G.,University of Oxford | McInerney N.,National University of Ireland | McInerney N.,University of Oxford | And 8 more authors.
Breast Cancer Research and Treatment | Year: 2010

A polymorphic 9-bp deletion in exon 1 of TGFBR1 (TGFBR1*6A) has been identified as a low-penetrance cancer susceptibility allele. The strongest association in the initial studies was with breast cancer; however, these studies included patients with different types of cancer, including colon, cervical and breast carcinomas, with only a small proportion being breast cancer patients. In subsequent case-control studies focussing on breast cancer alone, the results have been equivocal. In order to clarify whether TGFBR1*6A is associated with breast cancer risk, we have genotyped this polymorphism in 988 breast cancer cases and 1,016 controls from the West of Ireland and also performed a meta-analysis of previously published data (5,150 cases and 6,344 controls). In our series from the West of Ireland, we found no association (genotypic odds ratio (OR) under a dominant model = 0.93, 95% confidence interval (CI) 0.73-1.19, P = 0.57; allelic OR = 0.93, 95% CI 0.74-1.15, P = 0.49). Meta-analysis showed evidence of heterogeneity among studies. Using the random effects model, it was found that there was no evidence of an association of the*6A allele with breast cancer (genotypic OR under a dominant model = 1.10, 95% CI = 0.94-1.28, P = 0.24, allelic OR = 1.12, 95% CI 0.97-1.31, P = 0.13). In conclusion, our study shows that there is no association between TGFBR1*6A and breast cancer risk. © 2009 Springer Science+Business Media, LLC. Source

Whipp E.,University of Bristol | Beresford M.,University of Bristol | Sawyer E.,St Thomas Cancer Center | Halliwell M.,University of Bristol
International Journal of Radiation Oncology Biology Physics | Year: 2010

Purpose: Better accuracy of local radiotherapy may substantially improve local control and thus long-term breast cancer survival. Magnetic resonance imaging (MRI) has high resolution and sensitivity in breast tissue and may depict the tumor bed more accurately than conventional planning techniques. A postoperative complex (POCx) comprises all visible changes thought to be related to surgery within the breast and acts as a surrogate for the tumor bed. This study reports on local recurrence rates after MRI-assisted radiotherapy planning to ensure adequate coverage of the POCx. Methods and Materials: Simple opposed tangential fields were defined by surface anatomy in the conventional manner in 221 consecutive patients. After MRI, fields were modified by a single radiation oncologist to ensure encompassment of the POCx with a 10-mm margin. Genetic analysis was performed on all local relapses (LRs) to distinguish true recurrences (TRs) from new primaries (NPs). Results: This was a high risk cohort at 5 years: only 9.5% were classified as low risk (St Gallen): 43.4% were Grade 3 and 19.9% had surgical margins <1 mm; 62.4% of patients received boosts. Adjustments of standard field margins were required in 69%. After a median follow-up of 5 years, there were 3 LRs (1.3%) as the site of first relapse in 221 patients, comprising two TRs (0.9%) and one NP (0.4%). Conclusions: Accurate targeting of the true tumor bed is critical. MRI may better define the tumor bed. © 2010 Elsevier Inc. All rights reserved. Source

McInerney N.M.,National University of Ireland | McInerney N.M.,University of Oxford | Miller N.,National University of Ireland | Rowan A.,University of Oxford | And 8 more authors.
Breast Cancer Research and Treatment | Year: 2010

It has been proposed that rare variants within the double strand break repair genes CHEK2, BRIP1 and PALB2 predispose to breast cancer. The aim of this study was to evaluate the prevalence of these variants in an Irish breast cancer cohort and determine their contribution to the development of breast cancer in the west of Ireland. We evaluated the presence of CHEK2-1100delC variant in 903 breast cancer cases and 1,016 controls. Six previously described variants within BRIP1 and five within PALB2 were screened in 192 patients with early-onset or familial breast cancer. Where a variant was evident, it was then examined in the remainder of our 711 unselected breast cancer cases. CHEK2-1100delC was found in 5/903 (0.5%) breast cancer cases compared to 1/1016 (0.1%) controls. One mutation at BRIP1 (2392 C>T) was identified in the early-onset/familial cohort. Examination of this variant in the remainder of our cohort (711 cases) failed to identify any additional cases. None of the previously described PALB2 variants were demonstrated in the early-onset/familial cohort. We show evidence of CHEK2-1100delC and BRIP1 2392 C>T within the Irish population. CHEK2-1100delC and BRIP1 mutations incidence in Ireland is similar to that found in other unselected breast cancer cohorts from northern European countries. We found no evidence to suggest that PALB2 mutation is an important breast cancer predisposition gene in this population. © 2009 Springer Science+Business Media, LLC. Source

Yates L.,St Thomas Cancer Center | Kirby A.,St Thomas Cancer Center | Crichton S.,Kings College London | Gillett C.,Kings College London | And 3 more authors.
International Journal of Radiation Oncology Biology Physics | Year: 2012

Purpose: In many centers, supraclavicular fossa radiotherapy (SCF RT) is not routinely offered to breast cancer patients with one to three positive lymph nodes. We aimed to identify a subgroup of these patients who are at high risk of supra or infraclavicular fossa relapse (SCFR) such that they can be offered SCFRT at the time of diagnosis to improve long term locoregional control. Methods and Materials: We performed a retrospective analysis of the pathological features of 1,065 cases of invasive breast cancer with one to three positive axillary lymph nodes. Patients underwent radical breast conserving surgery or mastectomy. A total of 45% of patients received adjuvant chest wall/breast RT. No patients received adjuvant SCFRT. The primary outcome was SCFR. Secondary outcomes were chest wall/breast recurrence, distant metastasis, all death, and breast-cancer specific death. Kaplan-Meier estimates were used to calculate actuarial event rates and survival functions compared using log-rank tests. Multivariate analyses (MVA) of factors associated with outcome were conducted using Cox proportional hazards models. Results: Median follow-up was 9.7 years. SCFR rate was 9.2%. Median time from primary diagnosis to SCFR was 3.4 years (range, 0.7-14.4 years). SCFR was associated with significantly lower 10-year survival (18% vs. 65%; p < 0.001). Higher grade and number of positive lymph nodes were the most significant predictors of SCFR on MVA (p < 0.001). 10 year SCFR rates were less than 1% in all patients with Grade 1 cancers compared with 30% in those having Grade 3 cancers with three positive lymph nodes. Additional factors associated with SCFR on univariate analysis but not on MVA included larger nodal deposits (p = 0.002) and proportion of positive nodes (p = 0.003). Conclusions: Breast cancer patients with one to three positive lymph nodes have a heterogenous risk of SCFR. Patients with two to three positive axillary nodes and/or high-grade disease may warrant consideration of SCFRT. © 2012 Elsevier Inc. Source

Yang X.R.,U.S. National Institutes of Health | Chang-Claude J.,Institute of Cancer Research | Goode E.L.,German Cancer Research Center | Nevanlinna H.,Mayo Medical School | And 129 more authors.
Journal of the National Cancer Institute | Year: 2011

Background Previous studies have suggested that breast cancer risk factors are associated with estrogen receptor (ER) and progesterone receptor (PR) expression status of the tumors. Methods We pooled tumor marker and epidemiological risk factor data from 35568 invasive breast cancer case patients from 34 studies participating in the Breast Cancer Association Consortium. Logistic regression models were used in case-case analyses to estimate associations between epidemiological risk factors and tumor subtypes, and case-control analyses to estimate associations between epidemiological risk factors and the risk of developing specific tumor subtypes in 12 population-based studies. All statistical tests were two-sided. Results In case-case analyses, of the epidemiological risk factors examined, early age at menarche (≤12 years) was less frequent in case patients with PR- than PR+ tumors (P =. 001). Nulliparity (P = 3 × 10 -6) and increasing age at first birth (P = 2 × 10-9) were less frequent in ER- than in ER+ tumors. Obesity (body mass index [BMI] ≥ 30 kg/m2) in younger women (≤50 years) was more frequent in ER-/PR- than in ER +/PR+ tumors (P = 1 × 10-7), whereas obesity in older women (>50 years) was less frequent in PR- than in PR+ tumors (P = 6 × 10-4). The triple-negative (ER-/PR-/HER2-) or core basal phenotype (CBP; triple-negative and cytokeratins [CK]5/6+ and/or epidermal growth factor receptor [EGFR]+) accounted for much of the heterogeneity in parity-related variables and BMI in younger women. Case-control analyses showed that nulliparity, increasing age at first birth, and obesity in younger women showed the expected associations with the risk of ER+ or PR + tumors but not triple-negative (nulliparity vs parity, odds ratio [OR] = 0.94, 95% confidence interval [CI] = 0.75 to 1.19, P =. 61; 5-year increase in age at first full-term birth, OR = 0.95, 95% CI = 0.86 to 1.05, P =. 34; obesity in younger women, OR = 1.36, 95% CI = 0.95 to 1.94, P =. 09) or CBP tumors. Conclusion sThis study shows that reproductive factors and BMI are most clearly associated with hormone receptor-positive tumors and suggest that triple-negative or CBP tumors may have distinct etiology. © 2011 The Author. Source

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