Predictive specificity of TUBB3 mRNA expression for survival in treatment Groups A (40 mg/m², 3-weekly) and B (20 mg/m², weekly).

<p>TUBB3 RQ value cut-off was set at 75%. Among patients in Group B, those with tumors expressing high TUBB3 transcript levels had significantly shorter survival.</p

In Situ Quantitative Measurement of HER2mRNA Predicts Benefit from Trastuzumab-Containing Chemotherapy in a Cohort of Metastatic Breast Cancer Patients

<div><p>Background</p><p>We sought to determine the predictive value of in situ mRNA measurement compared to traditional methods on a cohort of trastuzumab-treated metastatic breast cancer patients.</p><p>Methods</p><p>A tissue microarray composed of 149, classified as HER2-positive, metastatic breast cancers treated with various trastuzumab-containing chemotherapy regimens was constructed. HER2 intracellular domain(ICD), HER2 extracellular domain(ECD) and HER2 mRNA were assessed using AQUA. For HER2 protein evaluation, CB11 was used to measure ICD and SP3 to measure ECD of the HER2 receptor. In addition, HER2 mRNA status was assessed using RNAscope assay ERRB2 probe. Kaplan – Meier estimates were used for depicting time-to-event endpoints. Multivariate Cox regression models with backward elimination were used to assess the performance of markers as predictors of TTP and OS, after adjusting for important covariates.</p><p>Results</p><p>HER2 mRNA was correlated with ICD HER2, as measured by CB11 HER2, with ECD HER2 as measured by SP3 (Pearson’s Correlation Coefficient, r = 0.66 and 0.51 respectively) and with FISH HER2 (Spearman’s Correlation Coefficient, r = 0.75). All markers, HER2 mRNA, ICD HER2 and ECD HER2, along with FISH HER2, were found prognostic for OS (Log-rank p = 0.007, 0.005, 0.009 and 0.043 respectively), and except for FISH HER2, they were also prognostic for TTP Log-rank p = 0.036, 0.068 and 0.066 respectively) in this trastuzumab- treated cohort. Multivariate analysis showed that in the presence of pre-specified set of prognostic factors, among all biomarkers only ECD HER2, as measured by SP3, is strong prognostic factor for both TTP (HR = 0.54, 95% CI: 0.31–0.93, p = 0.027) and OS (HR = 0.39, 95%CI: 0.22–0.70, p = 0.002).</p><p>Conclusions</p><p>The expression of HER2 ICD and ECD as well as HER2 mRNA levels was significantly associated with TTP and OS in this trastuzumab-treated metastatic cohort. In situ assessment of HER2 mRNA has the potential to identify breast cancer patients who derive benefit from Trastuzumab treatment.</p></div

PFS and survival for Groups A and B (red lines: PFS; blue lines: survival).

<p>PFS and survival for Groups A and B (red lines: PFS; blue lines: survival).</p

Associations between SNP and IHC markers.

<p>Associations between SNP and IHC markers.</p

Overall Survival (OS) by HER2 patient populations, as defined by each biomarker and HER2 gene status (Kaplan-Meier plots).

<p>(A) ICD HER2 as measured by CB11 (high vs. low); (B) ECD HER2 as measured by SP3 (high vs. low); (C) HER2 mRNA (high vs. low); (D) FISH HER2 (amplified vs. non-amplified).</p

Differential Expression of the Insulin-Like Growth Factor Receptor among Early Breast Cancer Subtypes

<div><p>Introduction</p><p>We sought to determine the level of protein expression of the critical components of the insulin-like growth factor receptor (IGFR) pathway and to evaluate their prognostic significance across the different early breast cancer subtypes.</p><p>Patients and Methods</p><p>Archival tumor tissue from 1,021 women with early, node positive breast cancer, who were prospectively evaluated within two randomized clinical trials, was used to construct tissue microarrays that were stained for hormone receptors (HR), Ki67, HER2, epidermal growth factor receptor (EGFR) and cytokeratins 5/6, to classify tumors into five immunophenotypical subgroups. Immunohistochemical (IHC) expression of IGF1R-alpha and beta subunits, IGF2R and IGF-binding protein 2 (IGFBP2) was assessed using the immunoreactive score (IRS). Repeated internal cross-validation was performed to examine the statistical validity of the cut off points for all biomarkers.</p><p>Results</p><p>After a median follow-up time of 105.4 months, overall 370 women (36.2%) had relapsed and 270 (26.4%) had died. Tumors expressing IGF1R-alpha above the median IRS were significantly more frequently HR positive (luminal A+B+HER2), as compared to HER2-enriched and triple negative ones (p<0.001 for both comparisons). IGF2R was overexpressed significantly more frequently in HR negative tumors (p = 0.001) and had an inverse correlation with all other biomarkers. Patients with luminal A and B tumors with high IGF1R-alpha and negative EGFR expression (N = 190) had significantly higher 4-year survival rates, as compared to the rest (log-rank p = 0.046), as did patients with luminal A and B tumors with high IGF1R-alpha and low IGF2R expression, as compared to the rest (N = 91), (log-rank p = 0.035). After adjustment for significant variables, patients in the latter group had a relative 45% reduction in the risk of death, as compared to the rest (p = 0.035).</p><p>Conclusion</p><p>Aberrant expression of components of the IGF1R pathway is associated with better clinical outcomes in women with luminal A and B, node positive, early breast cancer.</p></div

Waterfall plot of best change in target-lesion size from baseline, assessed by central review.

<p>In four patients (marked with a star), the best change in total lesion size from baseline showed an overall decrease but they were characterized as having progressive disease (PD) due to the development of new lesions. In four other patients (marked with a star as well), the best change in total lesion size from baseline was 100% but they were identified as partial response (PR) since in non-target lesions the response was stable disease (SD). CR: complete response.</p

Best response as given by local investigators (n = 59).

<p>CR = complete response; PR = partial response; ORR = overall response rate; SD = stable disease; PD = progressive disease; NE = non-evaluable.</p><p>% values were rounded up.</p>a<p>For details see text.</p>b<p>CR+PR+SD for at least 24 weeks.</p>c<p>Four patients were not centrally assessed.</p><p>(Numbers in parentheses indicate best response by central review [N = 55^c]).</p

OS analysis: Predictive evaluation of HER2 biomarkers and FISH for given prognostic factors (Cox Proportional Hazards Model).

<p>OS analysis: Predictive evaluation of HER2 biomarkers and FISH for given prognostic factors (Cox Proportional Hazards Model).</p