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BackgroundMedian survival is 10 months and 2-year survival is 20% in metastatic non-small-cell lung cancer (NSCLC) treated with platinum-based chemotherapy. A small fraction of non-squamous cell lung cancers harbor EGFR mutations, with improved outcome to gefitinib and erlotinib. Experimental evidence suggests that BRCA1 overexpression enhances sensitivity to docetaxel and resistance to cisplatin. RAP80 and Abraxas are interacting proteins that form complexes with BRCA1 and could modulate the effect of BRCA1. In order to further examine the effect of EGFR mutations and BRCA1 mRNA levels on outcome in advanced NSCLC, we performed a prospective non-randomized phase II clinical trial, testing the hypothesis that customized therapy would confer improved outcome over non-customized therapy. In an exploratory analysis, we also examined the effect of RAP80 and Abraxas mRNA levels.Methodology/Principal FindingsWe treated 123 metastatic non-squamous cell lung carcinoma patients using a customized approach. RNA and DNA were isolated from microdissected specimens from paraffin-embedded tumor tissue. Patients with EGFR mutations received erlotinib, and those without EGFR mutations received chemotherapy with or without cisplatin based on their BRCA1 mRNA levels: low, cisplatin plus gemcitabine; intermediate, cisplatin plus docetaxel; high, docetaxel alone. An exploratory analysis examined RAP80 and Abraxas expression. Median survival exceeded 28 months for 12 patients with EGFR mutations, and was 11 months for 38 patients with low BRCA1, 9 months for 40 patients with intermediate BRCA1, and 11 months for 33 patients with high BRCA1. Two-year survival was 73.3%, 41.2%, 15.6% and 0%, respectively. Median survival was influenced by RAP80 expression in the three BRCA1 groups. For example, for patients with both low BRCA1 and low RAP80, median survival exceeded 26 months. RAP80 was a significant factor for survival in patients treated according to BRCA1 levels (hazard ratio, 1.3 [95% CI, 1–1.7]; P = 0.05).Conclusions/SignificanceChemotherapy customized according to BRCA1 expression levels is associated with excellent median and 2-year survival for some subsets of NSCLC patients , and RAP80 could play a crucial modulating effect on this model of customized chemotherapy.Trial RegistrationClinicalTrials.gov NCT00883480

BackgroundIndividualised breast cancer risk prediction models may be key for planning risk-based screening approaches. Our aim was to conduct a systematic review and quality assessment of these models addressed to women in the general population.MethodsWe followed the Cochrane Collaboration methods searching in Medline, EMBASE and The Cochrane Library databases up to February 2018. We included studies reporting a model to estimate the individualised risk of breast cancer in women in the general population. Study quality was assessed by two independent reviewers. Results are narratively summarised.ResultsWe included 24 studies out of the 2976 citations initially retrieved. Twenty studies were based on four models, the Breast Cancer Risk Assessment Tool (BCRAT), the Breast Cancer Surveillance Consortium (BCSC), the Rosner & Colditz model, and the International Breast Cancer Intervention Study (IBIS), whereas four studies addressed other original models. Four of the studies included genetic information. The quality of the studies was moderate with some limitations in the discriminative power and data inputs. A maximum AUROC value of 0.71 was reported in the study conducted in a screening context.ConclusionIndividualised risk prediction models are promising tools for implementing risk-based screening policies. However, it is a challenge to recommend any of them since they need further improvement in their quality and discriminatory capacity.