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Obesity is associated with an increased risk of developing breast cancer (BC) and worse prognosis in BC patients, yet its impact on BC biology remains understudied in humans. This study investigates how the biology of untreated primary BC differs according to patients' body mass index (BMI) using data from >2,000 patients. We identify several genomic alterations that are differentially prevalent in overweight or obese patients compared to lean patients. We report evidence supporting an ageing accelerating effect of obesity at the genetic level. We show that BMI-associated differences in bulk transcriptomic profile are subtle, while single cell profiling allows detection of more pronounced changes in different cell compartments. These analyses further reveal an elevated and unresolved inflammation of the BC tumor microenvironment associated with obesity, with distinct characteristics contingent on the estrogen receptor status. Collectively, our analyses imply that obesity is associated with an inflammaging-like phenotype. We conclude that patient adiposity may play a significant role in the heterogeneity of BC and should be considered for BC treatment tailoring., SCOPUS: ar.j, info:eu-repo/semantics/published

PURPOSE: Patients with 70-gene signature ultralow-risk breast cancers have shown excellent survival in historic cohorts, including randomized trials. The ultralow-risk subgroup was characterized to help avoid overtreatment. We evaluated outcomes of ultralow-risk patients in the largest cohort to date. METHODS: Of the 6,693 patients enrolled in the EORTC-10041/BIG-3-04 randomized phase III MINDACT trial, profiling revealed an ultralow-risk 70-gene signature in 1,000 patients (15%). Distant metastasis-free interval (DMFI) and breast cancer-specific survival (BCSS) were assessed in patients stratified by 70-gene signature result (high, low, and ultralow) by Kaplan-Meier analysis and hazard ratios with 95% CI from Cox regression. RESULTS: Median follow-up was 8.7 years. Of the ultralow-risk patients (n = 1,000), 67% were > 50 years, 81% had tumors ≤ 2 cm, 80% were lymph node-negative, 96% had grade 1 or 2 tumors, and 99% were estrogen receptor (ER)-positive. Systemic therapy was received by 84% of patients (69% endocrine therapy, 14% endocrine therapy plus chemotherapy, 1% other) and 16% received no adjuvant systemic treatment. The 8-year DMFI for ultralow-risk patients was 97.0% (95% CI, 95.8 to 98.1), which was 2.5% higher than for patients with low-risk tumors (n = 3,295, 94.5% [95% CI, 93.6 to 95.3]). The hazard ratio for DMFI was 0.65 (95% CI, 0.45 to 0.94) for ultralow versus low risk, after adjusting for clinical-pathologic and treatment characteristics. The 8-year BCSS for ultralow-risk patients was 99.6% (95% CI, 99.1 to 100). CONCLUSION: Patients with an ultralow-risk 70-gene signature have the best prognosis, distinctive from low risk, with 8-year BCSS above 99%, and very few patients developed distant metastases with an 8-year DMFI rate of 97%. These patients could be candidates for further de-escalation of treatment, to avoid overtreatment and the risk of side effects., SCOPUS: ar.j, DecretOANoAutActif, info:eu-repo/semantics/published

Gene expression data obtained in large studies hold great promises for discovering disease signatures or subtypes through data analysis. It is also prone to technical variation, whose removal is essential to avoid spurious discoveries. Because this variation is not always known and can be confounded with biological signals, its removal is a challenging task. Here we provide a step-wise procedure and comprehensive analysis of the MINDACT microarray dataset. The MINDACT trial enrolled 6693 breast cancer patients and prospectively validated the gene expression signature MammaPrint for outcome prediction. The study also yielded a full-transcriptome microarray for each tumor. We show for the first time in such a large dataset how technical variation can be removed while retaining expected biological signals. Because of its unprecedented size, we hope the resulting adjusted dataset will be an invaluable tool to discover or test gene expression signatures and to advance our understanding of breast cancer., SCOPUS: ar.j, info:eu-repo/semantics/published

Purpose: This study compares immunohistochemical (IHC) versus molecular subtyping (BluePrint and MammaPrint) in the population of patients enrolled in MINDACT and outcome based on molecular subtyping (MS) versus surrogate pathological subtyping (PS) as defined by the 2013 St. Gallen guidelines. Methods: MS classified patients in the following subtypes: Luminal A, Luminal B, HER-2-, and Basal-type. IHC/FISH for pathological subtyping (ER, PgR, HER-2, and Ki67) was centrally assessed in the European Institute of Oncology (n = 5806). Hazard ratios for distant-metastasis-free survival (DMFS) by subtype were adjusted for chemotherapy and endocrine therapy administration and thus independent of adjuvant treatment allocation. Results: PS Luminal cancers classified as HER-2+ or Basal-type by MS did not have a significantly lower DMFS than the Luminal-type cancers by MS (95.9%): HR = 1.40, 95% CI 0.75–2.60 (p = 0.294). More patients were identified with Luminal A disease by MS (63%) as compared with PS (47%) with comparable 5-year DMFS (≥96.0%). Among the 500 patients with PS TN cancers, MS identified 24 (5%) patients as Luminal-type with 5-year DMFS estimated at 100% versus 71.4% for MS HER-2+ or 90.1% for MS Basal-type. Conclusions: MS was able to re-stratify 54% of patients with a Luminal-B PS subtype to a low-risk Luminal A-type group with comparable outcome. Among TN EBC, 5% were classified as Luminal by MS with Luminal-like outcome. Molecular classification can help to identify a larger group of patients with low risk of recurrence compared with the more contemporarily used classification methodology including high-quality assessed Ki67., SCOPUS: ar.j, info:eu-repo/semantics/published

Background: Patients with BRCA1-like tumors correlate with improved response to DNA double-strand break-inducing therapy. A gene expression-based classifier was developed to distinguish between BRCA1-like and non-BRCA1-like tumors. We hypothesized that these tumors may also be more sensitive to PARP inhibitors than standard treatments. Methods: A diagnostic gene expression signature (BRCA1ness) was developed using a centroid model with 128 triple-negative breast cancer samples from the EU FP7 RATHER project. This BRCA1 ness signature was then tested in HER2-negative patients (n= 116) from the I-SPY 2 TRIAL who received an oral PARP inhibitor veliparib in combination with carboplatin (V-C), or standard chemotherapy alone. We assessed the association between BRCA1 ness and pathologic complete response in the V-C and control arms alone using Fisher ’s exact test, and the relative performance between arms (biomarker × treatment interaction, likelihood ratio p< 0.05) using a logistic model and adjusting for hormone receptor status (HR). Results: We developed a gene expression signature to identify BRCA1-like status. In the I-SPY 2 neoadjuvant setting the BRCA1ness signature associated signif icantly with response to V-C (p= 0.03), but not in the control arm (p = 0.45). We identified a significant interaction between BRCA1ness and V-C (p= 0.023) after correcting for HR. Conclusions: A genomic-based BRCA1-like signature was successfully translated to an expression-based signature (BRC1Aness). In the I-SPY 2 neoadjuvant setting, we determined that the BRCA1ness signature is capable of predicting benefit of V-C added to standard chemotherapy compared to standard chemotherapy alone. Trial registration: I-SPY 2 TRIAL beginning December 31, 2009: Neoadjuvant and Personalized Adaptive Novel Agents to Treat Breast Cancer (I-SPY 2), NCT01042379., Pattern Recognition and Bioinformatics

Background: A 70-gene signature was previously shown to have prognostic value in patients with node-negative breast cancer. Our goal was to validate the signature in an independent group of patients. Methods: Patients (n = 307, with 137 events after a median follow-up of 13.6 years) from five European centers were divided into high- and low-risk groups based on the gene signature classification and on clinical risk classifications. Patients were assigned to the gene signature low-risk group if their 5-year distant metastasis-free survival probability as estimated by the gene signature was greater than 90%. Patients were assigned to the clinicopathologic low-risk group if their 10-year survival probability, as estimated by Adjuvant! software, was greater than 88% (for estrogen receptor [ER]-positive patients) or 92% (for ER-negative patients). Hazard ratios (HRs) were estimated to compare time to distant metastases, disease-free survival, and overall survival in high- versus low-risk groups. Results: The 70-gene signature outperformed the clinicopathologic risk assessment in predicting all endpoints. For time to distant metastases, the gene signature yielded HR = 2.32 (95% confidence interval [CI] = 1.35 to 4.00) without adjustment for clinical risk and hazard ratios ranging from 2.13 to 2.15 after adjustment for various estimates of clinical risk; clinicopathologic risk using Adjuvant! software yielded an unadjusted HR = 1.68 (95% CI = 0.92 to 3.07). For overall survival, the gene signature yielded an unadjusted HR = 2.79 (95% CI = 1.60 to 4.87) and adjusted hazard ratios ranging from 2.63 to 2.89; clinicopathologic risk yielded an unadjusted HR = 1.67 (95% CI = 0.93 to 2.98). For patients in the gene signature high-risk group, 10-year overall survival was 0.69 for patients in both the low- and high-clinical risk groups; for patients in the gene signature low-risk group, the 10-year survival rates were 0.88 and 0.89, respectively. Conclusions: The 70-gene signature

Background In multifocal breast cancer, guidelines recommend basing adjuvant systemic treatment decisions on characteristics of the largest lesion, disregarding multifocality as an independent prognosticator. We assessed the association between multifocal disease and both the 70-gene signature (70-GS), and distant metastasis-free survival (DMFS) in clinical low-risk breast cancer patients enrolled in the European Organisation for Research and Treatment of Cancer 10041/BIG 03-04 Microarray In Node-negative and 1 to 3 positive lymph node Disease may Avoid ChemoTherapy (MINDACT) trial. Patients and methods The analysed population consisted of enrolled patients in the MINDACT trial with clinical low-risk disease, defined by a modified Adjuvant! Online cut-off for the 10-year risk of recurrent disease or death. Eligibility criteria of MINDACT dictate that patients with multifocal disease could be included if the different lesions had similar pathological characteristics. The presence of multifocal disease was deducted from the case report form (CRF)-question for sum of diameter for all invasive tumour foci. Clinicopathological characteristics and gene expression of patients with unifocal and multifocal (largest lesion) disease were compared. Subsequently, the association between multifocal disease and the 70-GS was evaluated as well as the association between multifocality and 5-year DMFS. Results The study included 3090 clinical low-risk patients with unifocal and 238 patients with multifocal disease. Apart from a higher prevalence of lobular tumours (21.8% versus 10.8%, by local pathology), we did not observe differences in baseline characteristics between multifocal and unifocal tumours. Patients with multifocal tumours were more likely to be at high genomic risk as compared to patients with unifocal tumours (22.7% versus 17.3%, odds ratio [OR] 1.45, 95% confidence interval [CI] 1.02–2.07, P = 0.038). We did not find a significant association between tumour focality a, SCOPUS: ar.j, info:eu-repo/semantics/published