Germline variation in ADAMTSL1 is associated with prognosis following breast cancer treatment in young women

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 agedPeer reviewe

Germline BRCA mutation and outcome in young-onset breast cancer (POSH): a prospective cohort study.

BACKGROUND: Retrospective studies provide conflicting interpretations of the effect of inherited genetic factors on the prognosis of patients with breast cancer. The primary aim of this study was to determine the effect of a germline BRCA1 or BRCA2 mutation on breast cancer outcomes in patients with young-onset breast cancer. METHODS: We did a prospective cohort study of female patients recruited from 127 hospitals in the UK aged 40 years or younger at first diagnosis (by histological confirmation) of invasive breast cancer. Patients with a previous invasive malignancy (except non-melanomatous skin cancer) were excluded. Patients were identified within 12 months of initial diagnosis. BRCA1 and BRCA2 mutations were identified using blood DNA collected at recruitment. Clinicopathological data, and data regarding treatment and long-term outcomes, including date and site of disease recurrence, were collected from routine medical records at 6 months, 12 months, and then annually until death or loss to follow-up. The primary outcome was overall survival for all BRCA1 or BRCA2 mutation carriers (BRCA-positive) versus all non-carriers (BRCA-negative) at 2 years, 5 years, and 10 years after diagnosis. A prespecified subgroup analysis of overall survival was done in patients with triple-negative breast cancer. Recruitment was completed in 2008, and long-term follow-up is continuing. FINDINGS: Between Jan 24, 2000, and Jan 24, 2008, we recruited 2733 women. Genotyping detected a pathogenic BRCA mutation in 338 (12%) patients (201 with BRCA1, 137 with BRCA2). After a median follow-up of 8·2 years (IQR 6·0-9·9), 651 (96%) of 678 deaths were due to breast cancer. There was no significant difference in overall survival between BRCA-positive and BRCA-negative patients in multivariable analyses at any timepoint (at 2 years: 97·0% [95% CI 94·5-98·4] vs 96·6% [95·8-97·3]; at 5 years: 83·8% [79·3-87·5] vs 85·0% [83·5-86·4]; at 10 years: 73·4% [67·4-78·5] vs 70·1% [67·7-72·3]; hazard ratio [HR] 0·96 [95% CI 0·76-1·22]; p=0·76). Of 558 patients with triple-negative breast cancer, BRCA mutation carriers had better overall survival than non-carriers at 2 years (95% [95% CI 89-97] vs 91% [88-94]; HR 0·59 [95% CI 0·35-0·99]; p=0·047) but not 5 years (81% [73-87] vs 74% [70-78]; HR 1·13 [0·70-1·84]; p=0·62) or 10 years (72% [62-80] vs 69% [63-74]; HR 2·12 [0·82-5·49]; p= 0·12). INTERPRETATION: Patients with young-onset breast cancer who carry a BRCA mutation have similar survival as non-carriers. However, BRCA mutation carriers with triple-negative breast cancer might have a survival advantage during the first few years after diagnosis compared with non-carriers. Decisions about timing of additional surgery aimed at reducing future second primary-cancer risks should take into account patient prognosis associated with the first malignancy and patient preferences. FUNDING: Cancer Research UK, the UK National Cancer Research Network, the Wessex Cancer Trust, Breast Cancer Now, and the PPP Healthcare Medical Trust Grant

Prospective study of outcomes in Sporadic versus hereditary breast cancer (POSH): study protocol

Background: young women presenting with breast cancer are more likely to have a genetic predisposition to the disease than breast cancer patients in general. A genetic predisposition is known to increase the risk of new primary breast (and other) cancers. It is unclear from the literature whether genetic status should be taken into consideration when planning adjuvant treatment in a young woman presenting with a first primary breast cancer. The primary aim of the POSH study is to establish whether genetic status influences the prognosis of primary breast cancer independently of known prognostic factors. Methods/design: the study is a prospective cohort study recruiting 3,000 women aged 40 years or younger at breast cancer diagnosis; the recruiting period covers 1st June 2001 to 31st December 2007. Written informed consent is obtained at study entry. Family history and known epidemiological risk data are collected by questionnaire. Clinical information about diagnosis, treatment and clinical course is collected and blood is stored. Follow up data are collected annually after the first year. An additional recruitment category includes women aged 41 to 50 years who are found to be BRCA1 or BRCA2 gene carriers and were diagnosed with their first breast cancer during the study recruiting period. Discussion: power estimates were based on 10% of the cohort carrying a BRCA1 gene mutation. Preliminary BRCA1 and BRCA2 mutation analysis in a pilot set of study participants confirms we should have 97% power to detect a difference of 10% in event rates between gene carriers and sporadic young onset cases. Most of the recruited patients (>80%) receive an anthracycline containing adjuvant chemotherapy regimen making planned analyses more straightforwar

Information requirements of young women with breast cancer treated with mastectomy or breast conserving surgery: a systematic review

OBJECTIVES:Young women with breast cancer have poorer prognosis, greater lifetime risk of local recurrence, contralateral recurrence, and distant disease, regardless of surgery received. Here we systematically review published evidence relating to the information requirements and preferences of young women diagnosed with early-stage breast cancer offered a choice between mastectomy and Breast Conservation Surgery (BCS). Findings will inform the development of a surgical decision aid for young women.METHODS:Eight databases were searched to identify research examining information requirements of young women facing breast oncological surgery treatment decisions (MESH headings). Twelve studies met the inclusion criteria. Data were extracted and summarised in a narrative synthesis.RESULTS:Findings indicate that young women prefer greater and more detailed information regarding treatment side effects, sexuality, and body image. Younger age of diagnosis leads to an increased risk perception of developing a second breast cancer. Young women's choices are influenced by factors associated with family and career. Information is required in a continuum throughout the treatment experience and not only at diagnosis when treatment decisions are made. Young women show differing levels of participation preferences.CONCLUSION:Young women find decision-making challenging when the characteristics of diagnosis provide a surgical choice between mastectomy and breast conservation surgery. Efforts should be made to provide information regarding sexuality, body image, reconstruction, fertility and likelihood of familial predisposition. Further research is needed to identify the specific level and information requirements of this young-onset group. The low number of studies indicate a need to design studies targeting specifically this age group of breast cancer patients

Resource Guide for Commingling ADA and Non-ADA Paratransit Riders

Resource Guide for Commingling ADA and Non-ADA Paratransit Riders is designed to help public transit agencies explore whether and how to commingle Americans with Disabilities Act of 1990 (ADA) paratransit and non-ADA paratransit riders. The guide is designed to help practitioners define the purposes and objectives for commingling riders, identify potential capacity and funding, evaluate service compatibility, and consider primary service parameters

"It's like we don't exist": Tailoring education for young women undergoing surgery for early-stage breast cancer

PURPOSE: The implications of a diagnosis and consequent surgical treatment for breast cancer may be different for young women compared to older women. This study investigated the information requirements of young women to support their treatment decision making at diagnosis. PARTICIPANTS &amp; SETTING: A purposeful sample of 20 women diagnosed with breast cancer aged 40 years or younger who had undergone surgery and had participated in a large cohort study in the United Kingdom. METHODOLOGIC APPROACH: Audio recordings of semistructured interviews were used to reveal information received at the time of surgical treatment. FINDINGS: Themes identified were types of breast cancer, surgical treatments, nonsurgical treatments, fertility, and surgery and after surgery. Participants felt that information required throughout treatment was influenced by individual life circumstances, such as children or plans for children, relationships, and career intentions. Participants felt information was lacking on the effects of treatment on body image, reconstructive surgery, and genetic predisposition to breast cancer. IMPLICATIONS FOR NURSING: Knowledge of the information requirements of young women diagnosed with breast cancer allows nursing staff to provide tailored support at times identified as most useful.</p

Le fonctionnement de la mémoire

Introduction: common variants that alter breast cancer risk are being discovered. Here, we determine how these variants influence breast cancer prognosis, risk and tumour characteristics.Methods: we selected 1,001 women with early onset nonfamilial invasive breast cancer from the Prospective study of Outcomes in Sporadic versus Hereditary breast cancer (POSH) cohort and genotyped 206 single nucleotide polymorphisms (SNPs) across 30 candidate genes. After quality control, 899 cases and 133 SNPs remained. Survival analyses were used to identify SNPs associated with prognosis and determine their interdependency with recognized prognostic factors. To identify SNPs that alter breast cancer risk, association tests were used to compare cases with controls from the Wellcome Trust Case Control Consortium. To search for SNPs affecting tumour biology, cases were stratified into subgroups according to oestrogen receptor (ER) status and grade and tested for association.Results: we confirmed previous associations between increased breast cancer risk and SNPs in CASP8, TOX3 (previously known as TNRC9) and ESR1. Analysis of prognosis identified eight SNPs in six genes (MAP3K1, DAPK1, LSP1, MMP7, TOX3 and ESR1) and one region without genes on 8q24 that are associated with survival. For MMP7, TOX3 and MAP3K1 the effects on survival are independent of the main recognized clinical prognostic factors. The SNP in 8q24 is more weakly associated with independent effects on survival. Once grade and pathological nodal status (pN stage) were taken into account, SNPs in ESR1 and LSP1 showed no independent survival difference, whereas the effects of the DAPK1 SNP were removed when correcting for ER status. Interestingly, effects on survival for SNPs in ESR1 were most significant when only ER-positive tumours were examined. Stratifying POSH cases by tumour characteristics identified SNPs in FGFR2 and TOX3 associated with ER-positive disease and SNPs in ATM associated with ER-negative disease.Conclusions: we have demonstrated that several SNPs are associated with survival. In some cases this appears to be due to an effect on tumour characteristics known to have a bearing on prognosis; in other cases the effect appears to be independent of these prognostic factors. These findings require validatation by further studies in similar patient group

Identification of inherited genetic variations influencing prognosis in early-onset breast cancer

Genome-Wide Association Studies (GWAS) have begun to investigate associations between inherited genetic variations and breast cancer prognosis. Here, we report our findings from a GWAS conducted in 536 patients with early-onset breast cancer aged 40 or less at diagnosis and with a mean follow-up period of 4.1 years (SD = 1.96). Patients were selected from the Prospective Study of Outcomes in Sporadic versus Hereditary breast cancer. A Bonferroni correction for multiple testing determined that a P value of 1.0 × 10(-7) was a statistically significant association signal. Following quality control, we identified 487,496 single nucleotide polymorphisms (SNP) for association tests in stage 1. In stage 2, 35 SNPs with the most significant associations were genotyped in 1,516 independent cases from the same early-onset cohort. In stage 2, 11 SNPs remained associated in the same direction (P ? 0.05). Fixed effects meta-analysis models identified one SNP associated at close to genome wide level of significance 556 kb upstream of the ARRDC3 locus [HR = 1.61; 95% confidence interval (CI), 1.33-1.96; P = 9.5 × 10(-7)]. Four further associations at or close to the PBX1, ROR?, NTN1, and SYT6 loci also came close to genome-wide significance levels (P = 10(-6)). In the first ever GWAS for the identification of SNPs associated with prognosis in patients with early-onset breast cancer, we report a SNP upstream of the ARRDC3 locus as potentially associated with prognosis (median follow-up time for genotypes: CC = 4 years, CT = 3 years, and TT = 2.7 years; Wilcoxon rank-sum test CC vs. CT, P = 4 × 10(-4) and CT vs. TT, P = 0.76). Four further loci may also be associated with prognosis.<br/