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Background It is not clear how the pathology, presentation and outcome for patients who present with de novo metastatic breast cancer (dnMBC) compare with those who later develop distant metastases. DnMBC is uncommon in younger patients. We describe these differences within a cohort of young patients in the United Kingdom. Methods Women aged 40 years or younger with a first invasive breast cancer were recruited to the prospective POSH national cohort study. Baseline clinicopathological data were collected, with annual follow-up. Overall survival (OS) and post-distant relapse-free survival (PDRS) were assessed using Kaplan–Meier curves. Results In total, 862 patients were diagnosed with metastatic disease. DnMBC prevalence was 2.6% (76/2977). Of those with initially localised disease, 27.1% (786/2901) subsequently developed a distant recurrence. Median follow-up was 11.00 years (95% CI 10.79–11.59). Patients who developed metastatic disease within 12 months had worse OS than dnMBC patients (HR 2.64; 1.84–3.77). For PDRS, dnMBC was better than all groups, including those who relapsed after 5 years. Of dnMBC patients, 1.3% had a gBRCA1, and 11.8% a gBRCA2 mutation. Conclusions Young women with dnMBC have better PDRS than those who develop relapsed metastatic breast cancer. A gBRCA2 mutation was overrepresented in dnMBC.

To identify genetic variants associated with breast cancer prognosis we conduct a meta-analysis of overall survival (OS) and disease-free survival (DFS) in 6042 patients from four cohorts. In young women, breast cancer is characterized by a higher incidence of adverse pathological features, unique gene expression profiles and worse survival, which may relate to germline variation. To explore this hypothesis, we also perform survival analysis in 2315 patients aged ≤ 40 years at diagnosis. Here, we identify two SNPs associated with early-onset DFS, rs715212 (P meta = 3.54 × 10−5) and rs10963755 (P meta = 3.91 × 10−4) in ADAMTSL1. The effect of these SNPs is independent of classical prognostic factors and there is no heterogeneity between cohorts. Most importantly, the association with rs715212 is noteworthy (FPRP, Genetic variance can influence breast cancer prognosis. Here, the authors conduct a meta-analysis to explore genetic variance linked to breast cancer in young women, identifying a prognostic association with germline variation of ADAMTSL1.

Aim In breast cancer patients, post chemotherapy weight gain is linked with increased risk of cancer recurrence. We prospectively studied a cohort of premenopausal women receiving contemporary chemotherapy following a diagnosis of breast cancer to examine factors predicting weight increase. Methods Between May 2005 and January 2008, 523 patients enrolled into the Prospective Outcomes in Sporadic versus Hereditary breast cancer study entered this sub-study comparing weight prior to chemotherapy and weight and waist/hip measurements 12-months following chemotherapy. Results Data from 380 patients were available. Mean (standard deviation [SD]) pre-treatment body mass index (BMI) was 26.3 [5.6] kg/m2; 30% women gained > 5% body weight during the study period. Lower BMI at diagnosis predicted greater subsequent post treatment weight gain (4.3% relative weight gain for those in the 1st quartile of BMI compared to 0.8% for those in the 4th quartile; r=-0.22; p88cm). Conclusions Almost a third of premenopausal patients receiving adjuvant chemotherapy for breast cancer will gain clinically significant weight and over 40% will have central obesity 12-months following diagnosis. A greater weight gain is predicted by lower pretreatment BMI.

Background: We examined the associations between germline variants and breast cancer mortality using a large meta-analysis of women of European ancestry. Methods: Meta-analyses included summary estimates based on Cox models of twelve datasets using ~10.4 million variants for 96,661 women with breast cancer and 7697 events (breast cancer-specific deaths). Oestrogen receptor (ER)-specific analyses were based on 64,171 ER-positive (4116) and 16,172 ER-negative (2125) patients. We evaluated the probability of a signal to be a true positive using the Bayesian false discovery probability (BFDP). Results: We did not find any variant associated with breast cancer-specific mortality at P < 5 × 10 −8 . For ER-positive disease, the most significantly associated variant was chr7:rs4717568 (BFDP = 7%, P = 1.28 × 10 −7 , hazard ratio [HR] = 0.88, 95% confidence interval [CI] = 0.84–0.92); the closest gene is AUTS2. For ER-negative disease, the most significant variant was chr7:rs67918676 (BFDP = 11%, P = 1.38 × 10 −7 , HR = 1.27, 95% CI = 1.16–1.39); located within a long intergenic non-coding RNA gene (AC004009.3), close to the HOXA gene cluster. Conclusions: We uncovered germline variants on chromosome 7 at BFDP < 15% close to genes for which there is biological evidence related to breast cancer outcome. However, the paucity of variants associated with mortality at genome-wide significance underpins the challenge in providing genetic-based individualised prognostic information for breast cancer patients.

IntroductionSelf-management and remaining physically active are first-line recommendations for the care of patients with low back pain (LBP). With a lifetime prevalence of up to 85%, novel approaches to support behavioural self-management are needed. Internet interventions may provide accessible support for self-management of LBP in primary care. The aim of this randomised controlled trial is to determine the clinical and cost-effectiveness of the ‘SupportBack’ internet intervention, with or without physiotherapist telephone support in reducing LBP-related disability in primary care patients.Methods and analysisA three-parallel arm, multicentre randomised controlled trial will compare three arms: (1) usual primary care for LBP; (2) usual primary care for LBP and an internet intervention; (3) usual primary care for LBP and an internet intervention with additional physiotherapist telephone support. Patients with current LBP and no indicators of serious spinal pathology are identified and invited via general practice list searches and mailouts or opportunistic recruitment following LBP consultations. Participants undergo a secondary screen for possible serious spinal pathology and are then asked to complete baseline measures online after which they are randomised to an intervention arm. Follow-ups occur at 6 weeks, 3, 6 and 12 months. The primary outcome is physical function (using the Roland and Morris Disability Questionnaire) over 12 months (repeated measures design). Secondary outcomes include pain intensity, troublesome days in pain over the last month, pain self-efficacy, catastrophising, kinesophobia, health-related quality of life and cost-related measures for a full health economic analysis. A full mixed-methods process evaluation will be conducted.Ethics and disseminationThis trial has been approved by a National Health Service Research Ethics Committee (REC Ref: 18/SC/0388). Results will be disseminated through peer-reviewed journals, conferences, communication with practices and patient groups. Patient representatives will support the implementation of our full dissemination strategy.Trial registration numberISRCTN14736486.

Purpose Recent advances in DNA sequencing have led to the development of breast cancer susceptibility gene panels for germline genetic testing of patients. We assessed the frequency of mutations in 17 predisposition genes, including BRCA1 and BRCA2, in a large cohort of patients with triple-negative breast cancer (TNBC) unselected for family history of breast or ovarian cancer to determine the utility of germline genetic testing for those with TNBC. Patients and Methods Patients with TNBC (N = 1,824) unselected for family history of breast or ovarian cancer were recruited through 12 studies, and germline DNA was sequenced to identify mutations. Results Deleterious mutations were identified in 14.6% of all patients. Of these, 11.2% had mutations in the BRCA1 (8.5%) and BRCA2 (2.7%) genes. Deleterious mutations in 15 other predisposition genes were detected in 3.7% of patients, with the majority observed in genes involved in homologous recombination, including PALB2 (1.2%) and BARD1, RAD51D, RAD51C, and BRIP1 (0.3% to 0.5%). Patients with TNBC with mutations were diagnosed at an earlier age (P < .001) and had higher-grade tumors (P = .01) than those without mutations. Conclusion Deleterious mutations in predisposition genes are present at high frequency in patients with TNBC unselected for family history of cancer. Mutation prevalence estimates suggest that patients with TNBC, regardless of age at diagnosis or family history of cancer, should be considered for germline genetic testing of BRCA1 and BRCA2. Although mutations in other predisposition genes are observed among patients with TNBC, better cancer risk estimates are needed before these mutations are used for clinical risk assessment in relatives.

BACKGROUND: Obese breast cancer patients have a poorer prognosis than non-obese patients. We examined data from a large prospective cohort study to explore the associations of obesity with tumour pathology, treatment and outcome in young British breast cancer patients receiving modern oncological treatments. PATIENTS AND METHODS: A total of 2956 patients aged ≤40 at breast cancer diagnosis were recruited from 126 UK hospitals from 2001 to 2007. Height and weight were measured at registration. Tumour pathology and treatment details were collected. Follow-up data were collected at 6, 12 months, and annually. RESULTS: A total of 2843 eligible patients (96.2%) had a body mass index (BMI) recorded: 1526 (53.7%) were under/healthy-weight (U/H, BMI

Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry. We identified 65 new loci that are associated with overall breast cancer risk at P

BACKGROUND: Breast cancer at a young age is associated with poor prognosis. The Prospective Study of Outcomes in Sporadic and Hereditary Breast Cancer (POSH) was designed to investigate factors affecting prognosis in this patient group. METHODS: Between 2000 and 2008, 2956 patients aged 40 years or younger were recruited to a UK multicenter prospective observational cohort study (POSH). Details of tumor pathology, disease stage, treatment received, and outcome were recorded. Overall survival (OS) and distant disease-free interval (DDFI) were assessed using Kaplan-Meier curves. All statistical tests were two-sided. RESULTS: Median age of patients was 36 years. Median tumor diameter was 22 mm, and 50% of patients had positive lymph nodes; 59% of tumors were grade 3, 33.7% were estrogen receptor (ER) negative, and 24% were human epidermal growth factor receptor 2 (HER2) positive. Five-year OS was higher for patients with ER-positive than ER-negative tumors (85.0%, 95% confidence interval [CI] = 83.2% to 86.7% vs 75.7%, 95% CI = 72.8% to 78.4%; P < .001), but by eight years, survival was almost equal. The eight-year OS of patients with ER-positive tumors was similar to that of patients with ER-negative tumors in both HER2-positive and HER2-negative subgroups. The flexible parametric survival model for OS shows that the risk of death increases steadily over time for patients with ER-positive tumors in contrast to patients with ER-negative tumors, where risk of death peaked at two years. CONCLUSIONS: These results confirm the increased frequency of ER-negative tumors and early relapse in young patients and also demonstrate the equally poor longer-term outlook of young patients who have ER-positive tumors with HER2-negative or -positive disease.

BACKGROUND: Black ethnic groups have a higher breast cancer mortality than Whites. American studies have identified variations in tumour biology and unequal health-care access as causative factors. We compared tumour pathology, treatment and outcomes in three ethnic groups in young breast cancer patients treated in the United Kingdom. METHODS: Women aged ≤ 40 years at breast cancer diagnosis were recruited to the POSH national cohort study (MREC: 00/06/69). Personal characteristics, tumour pathology and treatment data were collected at diagnosis. Follow-up data were collected annually. Overall survival (OS) and distant relapse-free survival (DRFS) were assessed using Kaplan-Meier curves, and multivariate analyses were performed using Cox regression. RESULTS: Ethnicity data were available for 2915 patients including 2690 (91.0%) Whites, 118 (4.0%) Blacks and 87 (2.9%) Asians. Median tumour diameter at presentation was greater in Blacks than Whites (26.0 mm vs 22.0 mm, P=0.0103), and multifocal tumours were more frequent in both Blacks (43.4%) and Asians (37.0%) than Whites (28.9%). ER/PR/HER2-negative tumours were significantly more frequent in Blacks (26.1%) than Whites (18.6%, P=0.043). Use of chemotherapy was similarly high in all ethnic groups (89% B vs 88.6% W vs 89.7% A). A 5-year DRFS was significantly lower in Blacks than Asians (62.8% B vs 77.0% A, P=0.0473) or Whites (62.8 B% vs 77.0% W, P=0.0053) and a 5-year OS for Black patients, 71.1% (95% CI: 61.0-79.1%), was significantly lower than that of Whites (82.4%, 95% CI: 80.8-83.9%, W vs B: P=0.0160). In multivariate analysis, Black ethnicity had an effect on DRFS in oestrogen receptor (ER)-positive patients that is independent of body mass index, tumour size, grade or nodal status, HR: 1.60 (95% CI: 1.03-2.47, P=0.035). CONCLUSION: Despite equal access to health care, young Black women in the United Kingdom have a significantly poorer outcome than White patients. Black ethnicity is an independent risk factor for reduced DRFS particularly in ER-positive patients.

Estrogen receptor (ER)-negative breast cancer shows a higher incidence in women of African ancestry compared to women of European ancestry. In search of common risk alleles for ER-negative breast cancer, we combined genome-wide association study (GWAS) data from women of African ancestry (1,004 ER-negative cases and 2,745 controls) and European ancestry (1,718 ER-negative cases and 3,670 controls), with replication testing conducted in an additional 2,292 ER-negative cases and 16,901 controls of European ancestry. We identified a common risk variant for ER-negative breast cancer at the TERT-CLPTM1L locus on chromosome 5p15 (rs10069690: per-allele odds ratio (OR) = 1.18 per allele, P = 1.0 × 10(-10)). The variant was also significantly associated with triple-negative (ER-negative, progesterone receptor (PR)-negative and human epidermal growth factor-2 (HER2)-negative) breast cancer (OR = 1.25, P = 1.1 × 10(-9)), particularly in younger women (

Genome-wide association studies (GWAS) of breast cancer defined by hormone receptor status have revealed loci contributing to susceptibility of estrogen receptor (ER)-negative subtypes. To identify additional genetic variants for ER-negative breast cancer, we conducted the largest meta-analysis of ER-negative disease to date, comprising 4754 ER-negative cases and 31 663 controls from three GWAS: NCI Breast and Prostate Cancer Cohort Consortium (BPC3) (2188 ER-negative cases; 25 519 controls of European ancestry), Triple Negative Breast Cancer Consortium (TNBCC) (1562 triple negative cases; 3399 controls of European ancestry) and African American Breast Cancer Consortium (AABC) (1004 ER-negative cases; 2745 controls). We performed in silico replication of 86 SNPs at P ≤ 1 × 10(-5) in an additional 11 209 breast cancer cases (946 with ER-negative disease) and 16 057 controls of Japanese, Latino and European ancestry. We identified two novel loci for breast cancer at 20q11 and 6q14. SNP rs2284378 at 20q11 was associated with ER-negative breast cancer (combined two-stage OR = 1.16; P = 1.1 × 10(-8)) but showed a weaker association with overall breast cancer (OR = 1.08, P = 1.3 × 10(-6)) based on 17 869 cases and 43 745 controls and no association with ER-positive disease (OR = 1.01, P = 0.67) based on 9965 cases and 22 902 controls. Similarly, rs17530068 at 6q14 was associated with breast cancer (OR = 1.12; P = 1.1 × 10(-9)), and with both ER-positive (OR = 1.09; P = 1.5 × 10(-5)) and ER-negative (OR = 1.16, P = 2.5 × 10(-7)) disease. We also confirmed three known loci associated with ER-negative (19p13) and both ER-negative and ER-positive breast cancer (6q25 and 12p11). Our results highlight the value of large-scale collaborative studies to identify novel breast cancer risk loci.

Background Germline mutations in BRCA1/2 account for ∼3% of breast cancer cases but >10% of young patients who present with triple negative (TN) breast cancer. Young age at diagnosis is also associated with an increased risk of recurrence and inferior survival compared to older patients. Numerous publications describe an increased incidence of adverse biological features in tumours from young breast cancer patients; however it is unclear whether these fully explain the poor outcome. The effect of carrying a BRCA1/2 mutation on the prognosis of breast cancer remains controversial with retrospective studies reporting better, similar and worse outcomes for mutation carriers compared to patients with sporadic tumours. BRCA carriers could feasibly have enhanced or reduced sensitivity to certain chemotherapeutics; however retrospective studies are problematic due to missing data and biased ascertainment. POSH is multicentre prospective observational cohort study designed to investigate factors which affect prognosis in young breast cancer patients (Copson et al, JNCI, 2013). Here we report the pathology, treatment and outcome of patients with TN tumours as a preliminary analysis to determine the impact of a germline BRCA1 mutation on survival. The whole cohort analysis including BRCA1 and BRCA2 is in progress. Methods 2956 patients aged ≤40 at breast cancer diagnosis were recruited from 127 UK oncology centres between 2000 and 2008. Patient characteristics, family history, risk factors, tumour pathology and treatment information, and blood DNA were collected at recruitment. Follow-up data were collected at 6 and 12 months, then annually. Summary statistics were used to describe patients by BRCA1 status. Kaplan-Meier estimates were used to describe univariate survival data. Results BRCA1 status is currently available for 542 patients with TN tumours. Pathogenic BRCA1 mutations were identified in 122 patients (BRCA1+); 420 had no BRCA1 mutation (BRCA1-). BRCA1+ were younger than BRCA1- (median age 34 vs 36 years, p Median follow-up was 7.3 years. Overall survival of patients with stage 1-3 disease treated with anthracycline +/- taxane neoadjuvant chemotherapy (n=538; 151 deaths) was better for BRCA1+ vs BRCA1- (79.1% vs 73.6% at 5-yrs; HR[95%CI]=0.84[0.57,1.25],p=0.388). Distant disease-free survival (DDFS) was also higher for BRCA1+ (5-yr DDFS 76.1% vs 71.5%; HR[CI]=0.92[0.63,1.35], p=0.682). Moreover, survival after first distant relapse was better for BRCA1+ patients (41.9% vs 36.8% at 1-yr; HR[CI]=0.78[0.51,1.18], p=0.233). Conclusions Our prospective data show better survival in young BRCA1+ patients with early TN breast cancer treated with anthracycline/-taxane chemotherapy than BRCA1- patients. However, the difference between the groups was not significant in this partial sample. Results for the whole cohort will be available by the time of the meeting. Citation Format: Eccles DM, Copson ER, Maishman T, Tapper W, Cutress R, Gerty S, Stanton L, Altman DG, Durcan L, Simmonds P, Decker B, Allen J, Luccarini C, Easton D, Dunning A, POSH Steering Group and Collaborators. Does BRCA status affect outcome in young breast cancer patients? Results from the prospective study of outcomes in sporadic and hereditary breast cancer (POSH) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr S2-03.

Background BRCA1 gene carriers frequently develop triple negative breast cancer (TNBC) at young ages. Retrospective studies have reached conflicting conclusions about the prognostic implications of breast cancer diagnosed on a background of a constitutional BRCA1 gene mutation. Many studies have the disadvantages of retrospective design and small numbers or both. The Prospective study of Outcomes in Sporadic versus Hereditary breast cancer (POSH) recruited 3024 patients diagnosed before 41 years of age and treated for breast cancer in the UK between 2000 and 2007 (protocol published: Eccles et al BMC Cancer 2008). Aim: To investigate the effect of family history and BRCA1 gene mutation status on breast cancer survival in women aged younger than 41 years at diagnosis. Methods: Cases in which the primary tumour pathology report was not available (2.8% of total) were excluded from this analysis. A completed family history questionnaire was available for 2907 cases (99% of total). The primary end point for this analysis was the development of distant metastases from breast cancer. All patients were younger than the starting age for screening in the UK except for known gene carriers of which there were only 8 in total, the remainder of identified gene carriers were tested after cancer diagnosis or as part of this study. Over 90% of patients received adjuvant or neoadjuvant chemotherapy with over 90% of these receiving an anthracycline based regimen. Kaplan Meier survival analysis and log rank test were used to assess survival differences. Results: 2937 patients were included in the analysis. Mean and median age at diagnosis was 36 years and the cohort was followed prospectively for a mean and median follow up time of 50 months. Overall distant disease free survival in the whole cohort was only 75% at 5 years. The effect of family history on presentation was explored. Patients who reported a first or second degree relative with breast cancer presented with smaller tumours (20mm compared to 22.5mm, p= 0.006) but no difference in axillary nodal status (p=0.2605). Survival was however significantly better comparing the 499 patients who reported a family history of breast cancer compared with the rest of the cohort (p=0.0164). 539 patients had been tested for mutations in the BRCA1/2 genes and 176 high risk gene BRCA1/BRCA2 carriers were identified. We compared 118 patients with a known BRCA1 gene mutation (almost all diagnosed after the cancer) to the 465 patients with confirmed TNBC (p=0.0118). Survival was significantly better in the BRCA1 carriers (p=0.0118). After excluding 29 gene carriers whose primary tumour showed any of ER, HER2 or PR as positive, the same improved survival trend was seen although significant at the 10% level (p=0.07). Conclusion: This prospective study indicates that BRCA1 gene carriers clearly do not have a worse prognosis when compared to triple negative breast cancers or young onset breast cancer overall and these early follow up data indicate an improved outlook in gene carriers. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-12-03.

Breast cancer is the most common cancer women in the UK, with approximately 50,000 new cases each year. PREDICT (http://www.predict.nhs.uk) is an online prognostic tool developed to help determine the best available treatment and long-term outcome for early breast cancer. This study was conducted to establish how well PREDICT performs in estimating survival in a large cohort of younger women (aged ≤40 years) recruited to the POSH study.

Introduction The distribution of histopathological features of invasive breast tumors in BRCA1 or BRCA2 germline mutation carriers differs from that of individuals with no known mutation. Histopathological features thus have utility for mutation prediction, including statistical modeling to assess pathogenicity of BRCA1 or BRCA2 variants of uncertain clinical significance. We analyzed large pathology datasets accrued by the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and the Breast Cancer Association Consortium (BCAC) to reassess histopathological predictors of BRCA1 and BRCA2 mutation status, and provide robust likelihood ratio (LR) estimates for statistical modeling. Methods Selection criteria for study/center inclusion were estrogen receptor (ER) status or grade data available for invasive breast cancer diagnosed younger than 70 years. The dataset included 4,477 BRCA1 mutation carriers, 2,565 BRCA2 mutation carriers, and 47,565 BCAC breast cancer cases. Country-stratified estimates of the likelihood of mutation status by histopathological markers were derived using a Mantel-Haenszel approach. Results ER-positive phenotype negatively predicted BRCA1 mutation status, irrespective of grade (LRs from 0.08 to 0.90). ER-negative grade 3 histopathology was more predictive of positive BRCA1 mutation status in women 50 years or older (LR = 4.13 (3.70 to 4.62)) versus younger than 50 years (LR = 3.16 (2.96 to 3.37)). For BRCA2, ER-positive grade 3 phenotype modestly predicted positive mutation status irrespective of age (LR = 1.7-fold), whereas ER-negative grade 3 features modestly predicted positive mutation status at 50 years or older (LR = 1.54 (1.27 to 1.88)). Triple-negative tumor status was highly predictive of BRCA1 mutation status for women younger than 50 years (LR = 3.73 (3.43 to 4.05)) and 50 years or older (LR = 4.41 (3.86 to 5.04)), and modestly predictive of positive BRCA2 mutation status in women 50 years or older (LR = 1.79 (1.42 to 2.24)). Conclusions These results refine likelihood-ratio estimates for predicting BRCA1 and BRCA2 mutation status by using commonly measured histopathological features. Age at diagnosis is an important variable for most analyses, and grade is more informative than ER status for BRCA2 mutation carrier prediction. The estimates will improve BRCA1 and BRCA2 variant classification and inform patient mutation testing and clinical management. Electronic supplementary material The online version of this article (doi:10.1186/s13058-014-0474-y) contains supplementary material, which is available to authorized users.

Familial studies were among the first to indicate that breast cancer prognosis has a heritable component. Subsequently many variants associated with prognosis have been identified using a range of techniques including genome-wide association studies (GWAs). Despite these advances, much of the heritability remains unexplained. In young women, breast cancer is characterised by a higher incidence of adverse pathological features, unique tumour gene expression profiles and worse survival. In addition, the association of risk with conventional epidemiological exposures is less clear in women with early onset. We hypothesise that some of these difference between early and late onset could be influenced by germline variation. To identify additional variants that influence breast cancer prognosis we conducted a two stage meta-analysis of four GWAs consisting of 6,042 patients from the UK (POSH), Finland (HEBCS), Germany (SUCCESS-A) and Australia (ABCFS). Cox-regression analyses were used to investigate overall survival (OS, n=1,101 events) and disease-free survival (DFS, n=1,316 events) with correction for oestrogen status (ER). These survival analyses were repeated in a subset of patients with early onset (aged ≤40 at diagnosis, n=2,315 patients, OS n=604 events, DFS n=716 events). Meta-analysis identified two intronic SNPs in ADAMTSL1 that were associated exclusively with early onset DFS, rs715212 (Pmeta=3.54x10-5) and rs10963755 (Pmeta=3.91x10-4) without heterogeneity between cohorts. Multivariable Cox-regression demonstrated that the effect of these SNPs were independent of the classical prognostic factors. Most importantly, rs715212 reached genome-wide significance (Pmultivariate=5.37x10-8) in the multivariate model. ADAMTSL1 encodes a glycoprotein that forms part of the extracellular matrix (ECM) and may function in cell-cell or cell-matrix interactions or may regulate other ADAMTS proteases. Previous studies have shown that ADAMTSL1 is hypermethylated in ER positive breast cancer tumours. Using GTEx to perform eQTL analysis, we found that rs715212 is associated with the expression of several biologically relevant genes AREG (P=0.035), TNF (P=0.015), FASLG (P=0.0031) and EGF (P=0.0018) in breast mammary tissue. Interestingly, separate studies have shown that AREG is overexpressed in ER-positive breast tumours from pre-menopausal women versus post-menopausal women. Furthermore, AREG is differentially expressed between parous and non-parous mammary glands and is persistently downregulated by parity, which suggests it may contribute to the susceptibility of the nulliparous gland to breast cancer. We conclude that rs715212 is associated with an increased risk of disease progression in patients with early onset and speculate that this could be due to an interaction with the expression of AREG. Note: This abstract was not presented at the meeting. Citation Format: Latha Kadalayil, Sofia Khan, Heli Nevanlinna, Peter A. Fasching, Fergus J. Couch, John Hopper, Jianjun Liu, Tom Maishman, Lorraine Durcan, Carl Bloomqvist, Andy Collins, Dianna Eccles, William Tapper. A meta-analysis of genome-wide association studies identifies novel loci that influence breast cancer prognosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1322. doi:10.1158/1538-7445.AM2017-1322

Aim To evaluate the surgical and clinical factors affecting local recurrence and other outcomes in young breast cancer patients using the POSH study. Background POSH (MREC:00/06/69) is a prospective cohort study of 3024 women aged 18-40 with breast cancer. Randomized controlled trials suggest equivalent survival between mastectomy and breast conserving surgery (BCS); however, very few young patients were included in these analyses. Emerging data also suggests a possible survival advantage for mastectomy in gene mutation carriers, and young age may be a predictor of higher rates of local recurrence. Methods Summary statistics were used to describe the cohort by surgical type (mastectomy or BCS). Study endpoints were in-breast ipsilateral local-recurrence interval, distant disease-free interval and overall survival. Cumulative hazard and Kaplan-Meier plots were used to describe survival data. Univariable and multivariable analyses were carried out using Cox proportional hazards models and flexible parametric survival (FPS) models (for any models with time-varying covariates). Results Of 2882 patients analysed, 1464 underwent mastectomy, 1395 BCS; and 23 had lymph node surgery only. Patients undergoing mastectomy had significantly larger tumours and higher proportions of positive Family History, positive estrogen receptor (ER+), progesterone receptor (PR+) and/or human epidermal growth factor 2 (HER2+) tumours. Local events only accounted for 15% of recurrences. Local recurrence varied over time by surgical type; local recurrence rate was similar at 18 months but higher for BCS compared to mastectomy at 5- and 10-years (18-months: 1.0% vs 1.0%, FPS-HR[95%CI]=1.43[0.89,2.32], p=0.348; 5-years: 5.3% vs 2.6%, FPS-HR[CI]=3.39[2.03,5.66], p Conclusions In the short term, there is no difference in local recurrence between BCS and mastectomy in young women. Longer term, local recurrence is higher in BCS, but there is no difference in survival between surgical groups after adjusting for known prognostic factors. Surgical extent appears to be less important for distant relapse or death from breast cancer than completeness of excision or, where appropriate, chest-wall radiotherapy. Acknowledgements Data collection/analysis funded by CRUK (grants:A7572,A11699,C1275/A15956). Sponsored by UHS NHS Foundation Trust. Citation Format: Maishman T, Cutress RI, Hernandez A, Gerty S, Copson ER, Durcan L, Eccles DM. Local recurrence in young women with invasive breast cancer; the prospective study of outcomes in sporadic and hereditary breast cancer (POSH) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr PD6-02.

Triple-negative (TN) breast cancer is an aggressive subtype of breast cancer associated with a unique set of epidemiologic and genetic risk factors. We conducted a two-stage genome-wide association study of TN breast cancer (stage 1: 1529 TN cases, 3399 controls; stage 2: 2148 cases, 1309 controls) to identify loci that influence TN breast cancer risk. Variants in the 19p13.1 and PTHLH loci showed genome-wide significant associations (P < 5 × 10(-) (8)) in stage 1 and 2 combined. Results also suggested a substantial enrichment of significantly associated variants among the single nucleotide polymorphisms (SNPs) analyzed in stage 2. Variants from 25 of 74 known breast cancer susceptibility loci were also associated with risk of TN breast cancer (P < 0.05). Associations with TN breast cancer were confirmed for 10 loci (LGR6, MDM4, CASP8, 2q35, 2p24.1, TERT-rs10069690, ESR1, TOX3, 19p13.1, RALY), and we identified associations with TN breast cancer for 15 additional breast cancer loci (P < 0.05: PEX14, 2q24.1, 2q31.1, ADAM29, EBF1, TCF7L2, 11q13.1, 11q24.3, 12p13.1, PTHLH, NTN4, 12q24, BRCA2, RAD51L1-rs2588809, MKL1). Further, two SNPs independent of previously reported signals in ESR1 [rs12525163 odds ratio (OR) = 1.15, P = 4.9 × 10(-) (4)] and 19p13.1 (rs1864112 OR = 0.84, P = 1.8 × 10(-) (9)) were associated with TN breast cancer. A polygenic risk score (PRS) for TN breast cancer based on known breast cancer risk variants showed a 4-fold difference in risk between the highest and lowest PRS quintiles (OR = 4.03, 95% confidence interval 3.46-4.70, P = 4.8 × 10(-) (69)). This translates to an absolute risk for TN breast cancer ranging from 0.8% to 3.4%, suggesting that genetic variation may be used for TN breast cancer risk prediction.

Triple-negative breast cancers are an aggressive subtype of breast cancer with poor survival, but there remains little known about the etiologic factors that promote its initiation and development. Commonly inherited breast cancer risk factors identified through genome-wide association studies display heterogeneity of effect among breast cancer subtypes as defined by the status of estrogen and progesterone receptors. In the Triple Negative Breast Cancer Consortium (TNBCC), 22 common breast cancer susceptibility variants were investigated in 2,980 Caucasian women with triple-negative breast cancer and 4,978 healthy controls. We identified six single-nucleotide polymorphisms, including rs2046210 (ESR1), rs12662670 (ESR1), rs3803662 (TOX3), rs999737 (RAD51L1), rs8170 (19p13.1), and rs8100241 (19p13.1), significantly associated with the risk of triple-negative breast cancer. Together, our results provide convincing evidence of genetic susceptibility for triple-negative breast cancer. Cancer Res; 71(19); 6240–9. ©2011 AACR.

Background: Family history and young onset are the usual indicators of an underlying genetic predisposition to breast cancer development. BRCA1 associated breast tumours are more likely to be ER negative and express “basal” markers, however most patients with ER negative/ basal marker positive breast cancers (especially young onset) do not have inherited BRCA1 mutations. BRCA1 and BRCA2 gene carriers may have novel treatment options available and may need to consider future cancer prevention strategies. Genetic counselling and germline mutation analysis remains a relatively expensive option that is not appropriate for most breast cancer patients.Aim: To design a sensitive and specific pathology based predictor that would improve identification of BRCA1 and 2 gene carriers.Method: We assembled a training panel of breast cancer tumour blocks from 67 BRCA1, 71 BRCA2 associated and 105 sporadic young onset cases (≤ 40 years at diagnosis). All gene carriers were diagnosed before 50 years and were matched to sporadic cases for ER status. Tissue micro arrays (TMAs) were assembled and subjected to immunohistochemical analysis with a panel of 18 antibodies. DNA was extracted from micro dissected tumour tissue and matched patient lymphocytes and subjected to high resolution tiling path microarray-based Comparative Genomic Hybridisation (aCGH). Using robust statistical approaches, regions significantly differentially lost, gained or amplified in BRCA1, BRCA2 and controls were identified. Probes for chromogenic in situ hybridisation (CISH) for amplified regions were generated.Results: Two differentially amplified clones in BRCA1 cases designated P1 at 3q25.31 and P2 at 3q25.2 and one in BRCA2 cases, P3 at 20q13.13, were identified and amplifications validated in the training set using CISH. Logistic regression analysis of the panel comprising CISH and IHC markers was used to develop the best predictor. The best predictor for BRCA1 gene carriers was a combination of P1, ER and HER2. This combination outperformed all combinations of immunohistochemical markers, including ER and basal markers; the Positive Predictive Value (PPV) was 87.5% and NPV 92% giving a Receiver Operator Characteristic (ROC) curve with an AUC of 0.92 (CI 0.88-0.97). The BRCA2 signature panel is currently being evaluated. These BRCA1 and BRCA2 predictor panels are being validated in a new set of TMAs comprising 223 tumours from the POSH study1.Conclusion: This tumour based predictor for BRCA1 and BRCA2 carriers may prove useful to identify gene carriers at low a priori chance of having a mutation, to direct BRCA1/2 targeted treatment approaches and to identify familial non BRCA1/2 cases that may be suitable for new gene discovery studies.1. Eccles D et al. BMC Cancer 2007; 7(1):160. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5032.