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Fribbens C.,Institute of Cancer Research | Fribbens C.,Royal Marsden Hospital | O'Leary B.,Institute of Cancer Research | O'Leary B.,Royal Marsden Hospital | And 17 more authors.
Journal of Clinical Oncology | Year: 2016

Purpose ESR1 mutations are selected by prior aromatase inhibitor (AI) therapy in advanced breast cancer. We assessed the impact of ESR1 mutations on sensitivity to standard therapies in two phase III randomized trials that represent the development of the current standard therapy for estrogen receptor-positive advanced breast cancer. Materials and Methods In a prospective-retrospective analysis, we assessed ESR1 mutations in available archived baseline plasma from the SoFEA (Study of Faslodex Versus Exemestane With or Without Arimidex) trial, which compared exemestane with fulvestrant-containing regimens in patients with prior sensitivity to nonsteroidal AI andinbaselineplasmafromthePALOMA3(Palbociclib Combined With Fulvestrant in Hormone Receptor-Positive HER2-Negative Metastatic Breast Cancer After Endocrine Failure) trial, which compared fulvestrant plus placebo with fulvestrant plus palbociclib in patients with progression after receiving prior endocrine therapy. ESR1 mutations were analyzed by multiplex digital polymerase chain reaction. Results In SoFEA, ESR1 mutations were found in 39.1% of patients (63 of 161), of whom 49.1% (27 of 55) were polyclonal, with rates of mutation detection unaffected by delays in processing of archival plasma. Patients with ESR1 mutations had improved progression-free survival (PFS) after taking fulvestrant (n = 45) compared with exemestane (n = 18; hazard ratio [HR], 0.52; 95% CI, 0.30 to 0.92; P = .02), whereas patients with wildtype ESR1 had similar PFS after receiving either treatment (HR, 1.07; 95% CI, 0.68 to 1.67; P = .77). In PALOMA3, ESR1 mutations were found in the plasma of 25.3% of patients (91 of 360), of whom 28.6% (26 of 91) were polyclonal, with mutations associated with acquired resistance to prior AI. Fulvestrant plus palbociclib improved PFS compared with fulvestrant plus placebo in both ESR1 mutant (HR, 0.43; 95% CI, 0.25 to 0.74; P = .002) and ESR1 wild-type patients (HR, 0.49; 95% CI, 0.35 to 0.70; P , .001). Conclusion ESR1 mutation analysis in plasma after progression after prior AI therapy may help direct choice of further endocrine-based therapy. Additional confirmatory studies are required. © 2016 by American Society of Clinical Oncology.

Nariculam J.,Epsom and St Helier NHS Trust | Shabbir M.,Epsom and St Helier NHS Trust | Thomas K.,Royal Marsden Hospital | Le Roux P.J.,Epsom and St Helier NHS Trust | And 4 more authors.
British Journal of Medical and Surgical Urology | Year: 2012

Aim: The AUA Best Practice Statement on PSA advocates a risk-based approach to selecting men for biopsy, based not on a PSA threshold, but on the risk of finding cancer on biopsy. We have therefore studied the association between candidate risk factors and prostate biopsy results. Method: All patients who underwent a prostate biopsy within the Epsom and St Helier NHS Trust between July 2005 and July 2007 were identified. Those with a serum PSA value of <15.0. ng/ml were selected for inclusion. Univariate and multivariate logistic regression analysis was done to analyse risk factors for the presence of cancer, and of significant cancer, on biopsy. Significant prostate cancer on biopsy was arbitrarily defined as either a Gleason score of 7 or more, or the presence of cancer in 50% or more of the cores. Results: Of 400 cases, 153 (38%) were found to have prostate cancer on biopsy, of which 93 were classed as significant. On multivariate analysis, smaller prostate volume, abnormal DRE, PSA level and absence of previous negative biopsy were independent predictors of significant prostate cancer. The multivariate logistic regression results were used to create a predictive nomogram for significant cancer. Conclusion: The PSA level is merely one of several factors that predict biopsy results. A risk-based, rather than a PSA-based, approach to selecting men for prostate biopsy has the potential to both reduce the number of men undergoing biopsy, and increase the detection of significant cancers. © 2011 British Association of Urological Surgeons.

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