PAM50 breast cancer intrinsic subtypes and effect of gemcitabine in advanced breast cancer patients

<div><p></p><p><b>Background.</b> In vitro studies suggest basal breast cancers are more sensitive to gemcitabine relative to other intrinsic subtypes. The main objective of this study was to use specimens from a randomized clinical trial to evaluate whether the basal-like subtype identifies patients with advanced breast cancer who benefit from gemcitabine plus docetaxel (GD) compared to single agent docetaxel (D).</p><p><b>Material and methods.</b> From patients randomly assigned to GD or D, RNA was isolated from archival formalin-fixed, paraffin-embedded primary breast tumor tissue and used for PAM50 intrinsic subtyping by NanoString nCounter. Statistical analyses were prespecified as a formal prospective-retrospective clinical trial correlative study. Using time to progression (TTP) as primary endpoint, overall survival (OS) and response rate as secondary endpoints, relationships between subtypes and outcome after chemotherapy were analyzed by the Kaplan-Meier method, and Cox proportional hazards regression models. Data analysis was performed independently by the Danish Breast Cancer Cooperative Group (DBCG) statistical core and all statistical tests were two-sided.</p><p><b>Results.</b> RNA from 270 patients was evaluable; 84 patients (31%) were classified as luminal A, 97 (36%) luminal B, 43 (16%) basal-like, and 46 (17%) as HER2-enriched. PAM50 intrinsic subtype was a significant independent prognostic factor for both TTP (p = 0.014) and OS (p = 0.0003). Response rate was not different by subtype, and PAM50 was not a predictor of TTP by treatment arm. PAM50 was however a highly significant predictor of OS following GD compared to D (p_interaction = 0.0016). Patients with a basal-like subtype had a significant reduction in OS events [hazard ratio (HR) = 0.29, 95% confidence interval (CI) = 0.15–0.57; p_interaction = 0.0006].</p><p><b>Conclusion.</b> A significantly improved and clinically important prolongation of survival was seen from the addition of gemcitabine to docetaxel in advanced basal-like breast cancer patients.</p></div

A New Type of Methacrylate-Substituted Oxozirconium Clusters: [Zr3O(OR)5(OMc)5]2 and [Zr3O(OR)3(OMc)7]2

 The new clusters Zr6O2(OBu)10(OMc)10 and Zr6O2(OMe)4(OBu)2(OMc)14 were prepared from Zr(OBu)4 and methacrylic acid. For the preparation of Zr6O2(OMe)4(OBu)2(OMc)14, partial exchange of the butoxy groups is necessary. The clusters consist of two Zr3 subunits that dimerize via alkoxide bridges. The structures are of the same type, except that four terminal butoxy ligands in Zr6O2(OBu)10(OMc)10 are exchanged for chelating methacrylate ligands in Zr6O2(OMe)4(OBu)2(OMc)14

List of prognostic miRNAs for overall survival. Hazard ratios with confidence intervals, Wald <i>P</i>-values and Bonferroni adjusted <i>P</i>-values are given.

<p>List of prognostic miRNAs for overall survival. Hazard ratios with confidence intervals, Wald <i>P</i>-values and Bonferroni adjusted <i>P</i>-values are given.</p

Baseline characteristics of the patients.

<p>(N = 138).</p

Concordance, Univariable and Multivariable Cox analyses of overall survival and progression-free survival in 138 patients, with metastatic colorectal cancer treated with 3^rd line cetuximab and irinotecan according to a miRNAs, gender, age, performance status and <i>KRAS</i> and, <i>PI3KCA</i> mutation status. miRNAs are tested as continuous variables in interquartile ranges units.

<p>Concordance, Univariable and Multivariable Cox analyses of overall survival and progression-free survival in 138 patients, with metastatic colorectal cancer treated with 3^rd line cetuximab and irinotecan according to a miRNAs, gender, age, performance status and <i>KRAS</i> and, <i>PI3KCA</i> mutation status. miRNAs are tested as continuous variables in interquartile ranges units.</p

Box plot showing the association between miR-345 expression and response to treatment (partial response, stable disease and progression). Mann-Whitney test; <i>KRAS</i> wt patients (green dots), <i>KRAS</i> mutated patients (red dots).

<p>If we restrict our set of patients to those with partial response (n = 24) and progressive disease (n = 37), a significant relationship between miR-345 expression and response to therapy was obtained with an odds ratio of 5.37, (<i>P</i>-value = 0.004 and 95% CI: 1.56–20.94).</p