Local recurrence and breast oncological surgery in young women with breast cancer: The POSH observational cohort study

Objective: To assess clinical and surgical factors affecting local recurrence and survival in young breast cancer patients in the Prospective study of Outcomes in Sporadic versus Hereditary breast cancer (POSH). Background: Emerging data suggest young age is a predictor of increased local recurrence. Methods: POSH is a prospective cohort of 3024 women of 18 to 40 years with breast cancer. Cohort characteristics were grouped by mastectomy or BCS. Endpoints were local-recurrence interval (LRI), distant disease-free interval (DDFI), and overall survival (OS); described using cumulative-hazard and Kaplan-Meier plots and multivariable analyses by Flexible Parametric and Cox regression models. Results: Mastectomy was performed in 1464 patients and breast-conserving surgery (BCS) in 1395. Patients undergoing mastectomy had larger tumors and higher proportions of positive family history, estrogen receptor+, progesterone receptor+, and/or human epidermal growth factor receptor 2+ tumors. Local events accounted for 15% of recurrences. LRI by surgical type varied over time with LRI similar at 18 months (1.0% vs 1.0%, P = 0.348) but higher for BCS at 5 and 10 years (5.3% vs 2.6%, P < 0.001; and 11.7% vs 4.9%, P < 0.001, respectively). Similar results were found in the adjusted model. Conversely, distant-metastases and deaths were lower for BCS but not after adjusting for prognostic factors. After mastectomy chest-wall radiotherapy was associated with improved LRI (hazard ratio, HR = 0.46, P = 0.015). Positive surgical margins, and development of local recurrence predicted for reduced DDFI (HR = 0.50, P < 0.001; and HR = 0.29, P = 0.001, respectively). Conclusions: Surgical extent appears less important for DDFI than completeness of excision or, where appropriate, chest-wall radiotherapy. Despite higher local-recurrence rates for BCS, surgical type does not influence DDFI or OS after adjusting for known prognostic factors in young breast cancer patients

A Genome Wide Meta-Analysis Study for Identification of Common Variation Associated with Breast Cancer Prognosis

Non peer reviewe

Validating “Image box”-a new approach to multicentre radiology reviews using a web-based image review system: study protocol

ObjectivesTo validate the use of “Imagebox”- a web-based image review system for large scale multicentre trials.Patients and MethodsAs part of the multicentre trial ‘Prospective study of Outcomes in Sporadic versus Hereditary breast cancer (POSH) study’ mammograms were collected and digitised. Software was created allowing digitised mammograms to be viewed from any location with internet access. Two validation studies were performed. Firstly phantom studies using line-pairs (1–20 lpmm-1) to assess spatial resolution and the CDMAM 3.4 phantom were used to assess the visibility of gold discs for contrast detail .Secondly a comparison was made between the scoring of 77 patients’ original diagnostic analogue mammograms from 29 hospitals and the corresponding web images. Films and web images were scored by one experienced breast radiologist according to the BIRADS classification. At least 8 weeks elapsed between scoring images from the same patient.ResultsThe original analogue spatial resolution was 20 lpmm-1 and web resolution of the same image reduced at 8.9 lpmm-1. Contrast detail assessment demonstrated analogue and web images with near concordance and the image quality factor, IQFinv for the web was reduced but within the 95% confidence interval of the original mammograms. BIRADS final assessment showed good agreement between the analogue and the identical web images (Kappa 0.82).ConclusionThe overall reduction in spatial resolution did not adversely affect the quality of the diagnostic image on “Imagebox”. This may be due to its functionality, specifically the high magnification zoom which enhances diagnostic interpretation. Imagebox is a promising solution to address the logistical challenges for large breast imaging reviews and has further potential for education and self assessment

A Genome Wide Meta-Analysis Study for Identification of Common Variation Associated with Breast Cancer Prognosis

Genome wide association studies (GWAs) of breast cancer mortality have identified few potential associations. The concordance between these studies is unclear. In this study, we used a meta-analysis of two prognostic GWAs and a replication cohort to identify the strongest associations and to evaluate the loci suggested in previous studies. We attempt to identify those SNPs which could impact overall survival irrespective of the age of onset. was used to determine significance. Replication was performed in 1523 additional patients from the POSH study..In a genome wide meta-analysis of two independent cohorts from UK and Finland, we identified potential associations at three distinct loci. Phenotypic heterogeneity and relatively small sample sizes may explain the lack of genome wide significant findings. However, the replication at three SNPs in the validation cohort shows promise for future studies in larger cohorts. We did not find strong evidence for concordance between the few associations highlighted by previous GWAs of breast cancer survival and this study

Replication of most significant associations from the discovery set meta-analysis in the replication samples.

<p>Results are presented for those SNPs which remained associated in the same direction in the validation set as in the discovery set (adjusted for ER-status).</p><p>Replication of most significant associations from the discovery set meta-analysis in the replication samples.</p

Associations of SNPs with nominal replication signals with clinical characteristics associated with breast cancer in a pooled set of discovery and replication cohorts.

<p>N-stage = metastasis to lymph node, M-stage = metastasis stage and T-stage = Tumour stage.</p><p>Associations of SNPs with nominal replication signals with clinical characteristics associated with breast cancer in a pooled set of discovery and replication cohorts.</p

Kaplan-Meier plots depicting breast cancer related survival in response to rs421379 genotypes in pooled POSH stage-1, HEBCS and POSH stage-2 samples.

<p>Kaplan-Meier plots depicting breast cancer related survival in response to rs421379 genotypes in pooled POSH stage-1, HEBCS and POSH stage-2 samples.</p

Manhattan plot of results from genome wide meta-analysis of POSH stage-1 and HEBCS hazard ratios and 95% confidence intervals.

<p>The 25 most associated SNPs are highlighted in green.</p

TRACEBACK: Testing of Historical Tubo-Ovarian Cancer Patients for Hereditary Risk Genes as a Cancer Prevention Strategy in Family Members

PURPOSE: Tubo-ovarian cancer (TOC) is a sentinel cancer for BRCA1 and BRCA2 pathogenic variants (PVs). Identification of a PV in the first member of a family at increased genetic risk (the proband) provides opportunities for cancer prevention in other at-risk family members. Although Australian testing rates are now high, PVs in patients with TOC whose diagnosis predated revised testing guidelines might have been missed. We assessed the feasibility of detecting PVs in this population to enable genetic risk reduction in relatives. PATIENTS AND METHODS: In this pilot study, deceased probands were ascertained from research cohort studies, identification by a relative, and gynecologic oncology clinics. DNA was extracted from archival tissue or stored blood for panel sequencing of 10 risk-associated genes. Testing of deceased probands ascertained through clinic records was performed with a consent waiver. RESULTS: We identified 85 PVs in 84 of 787 (11%) probands. Familial contacts of 39 of 60 (65%) deceased probands with an identified recipient (60 of 84; 71%) have received a written notification of results, with follow-up verbal contact made in 85% (33 of 39). A minority of families (n = 4) were already aware of the PV. For many (29 of 33; 88%), the genetic result provided new information and referral to a genetic service was accepted in most cases (66%; 19 of 29). Those who declined referral (4 of 29) were all male next of kin whose family member had died more than 10 years before. CONCLUSION: We overcame ethical and logistic challenges to demonstrate that retrospective genetic testing to identify PVs in previously untested deceased probands with TOC is feasible. Understanding reasons for a family member's decision to accept or decline a referral will be important for guiding future TRACEBACK projects.</p