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Background: A genomic index for sensitivity to endocrine therapy (SET) was previously derived from genes strongly positively and negatively coexpressed with estrogen receptor (Symmans et al. 2010, JCO 28:4111). This SET index has been reported to predict survival benefit from adjuvant endocrine therapy independently of prognosis. Materials and Methods: Affymetrix gene expression profiling was performed on 307 ER positive primary breast cancers from a retrospective cohort treated solely with endocrine therapy. In a blinded study the SET index' ability to predict survival was analyzed in this previously unpublished dataset. Affymetrix profiles (CEL files) were anonymized and provided to the developers of SET index (Nuvera Biosciences) without any clinical information. The 261 profiles that passed QC were categorized into SET classes based on the published prespecified cutoffs. Samples categorized as ER negative based on gene expression were excluded. Subsequently classifications were unblinded and clinical associations analyzed according to a predefined protocol. Exploratory analyses were performed on the relationship of SET index to other genomic signatures. We also assessed a potential pure prognostic value of SET index in an additional dataset of 164 node negative ER positive patients that did not receive any adjuvant treatment. Results: A lower SET index significantly correlated with higher grade (p = 0.009) and negative PgR status (p = 0.016). We detected no significant differences for age, tumor size, lymph node status, and HER2 status between patients with high, intermediate, and low SET index. In the lymph node negative (LNN) cohort (n = 120) we observed a significant difference in DFS (5yr DFS 77.1±10.2% vs 94.4±2.2%; HR 4.20, 95% CI 1.72--10.2; p = 0.002) and DMFS (HR 3.18, 95% CI 1.20--8.47; p = 0.020) for patients with low SET index. In contrast, we found no prognostic value of SET index in lymph node positive patients (n = 95). In multivariate analyses of LNN patients including SET, age, tumor size, histological grade, and PgR status, only SET was significantly associated with DFS (HR 3.37, 95% CI 1.25--9.01; p = 0.016) and DMFS (HR 3.03, 95% CI 1.08--8.55; p = 0.036). In exploratory analyses SET index was not correlated to other genomic signatures related to proliferation (as Recurrence Score, GGI, and NKI70) or immune response (e.g. 7IGS, SDPP). When we included all these genomic signatures as continous scores in a multivariate stepwise Cox regression model in the LNN endocrine treated cohort, only SET remained as significant (p = 0.025) while Recurrence Score displayed a strong trend (p = 0.054). We also verified that SET had no pure prognostic value in an additional dataset of 164 ER positive patients that did not receive any adjuvant treatment. Conclusions: In a blinded analysis the predictive ability of SET index was prospectively validated in an independent cohort of node-negative patients. Our exploratory analysis demonstrates that SET index is unrelated to other genomic signatures and delivers independent information on the response of patients to endocrine therapy rather than prognosis. [ABSTRACT FROM AUTHOR]

Purpose: In breast cancer, bevacizumab increased pCR rate but not long-term survival and no predictive markers are available to identify patients with long-term benefit from the drug., Experimental Design: We profiled 289 pretherapeutic formalin-fixed, paraffin-embedded (FFPE) biopsies of HER2-negative patients from the GeparQuinto trial of neoadjuvant chemotherapy ± bevacizumab by exome-capture RNA-sequencing (RNA-seq). In a prospectively planned study, we tested molecular signatures for response prediction. IHC validation was performed using tissue microarrays., Results: We found strong agreement of molecular and pathologic parameters as hormone receptors, grading, and lymphocyte infiltration in 221 high-quality samples. Response rates (49.3% pCR overall) were higher in basal-like (68.9%) and HER2-enriched (45.5%) than in luminal B (35.7%), luminal A (17.9%), and normal-like (20.0%) subtypes. T-cell (OR = 1.60; 95% confidence interval, 1.21-2.12; P = 0.001), proliferation (OR = 2.88; 95% CI, 2.00-4.15; P < 0.001), and hypoxia signatures (OR = 1.92; 95% CI, 1.41-2.60; P < 0.001) significantly predicted pCR in univariate analysis. In a prespecified multivariate logistic regression, a small hypoxia signature predicted pCR (OR = 2.40; 95% CI, 1.28-4.51; P = 0.006) with a significant interaction with bevacizumab treatment ( P = 0.020). IHC validation using NDRG1 as marker revealed highly heterogenous expression within tissue leading to profound loss of sensitivity in TMA analysis, still a significant predictive value for pCR was detected ( P = 0.025)., Conclusions: Exome-capture RNA-seq characterizes small FFPE core biopsies by reliably detecting factors as for example ER status, grade, and tumor-infiltrating lymphocytes levels. Beside molecular subtypes and immune signatures, a small hypoxia signature predicted pCR to bevacizumab, which could be validated by IHC. The signature can have important applications for bevacizumab treatment in different cancer types and might also have a role for novel combination therapies of bevacizumab with immune checkpoint inhibition., (©2020 American Association for Cancer Research.)

Triple-negative breast cancer (TNBC) is a highly aggressive, heterogeneous disease with poor prognosis and no effective targeted therapies. EGFR is highly expressed in basal-like TNBC and is considered as a potential therapeutic target. However, EGFR targeting exerts only marginal clinical benefits, possibly due to activation of compensatory signaling pathways, which are frequently associated with HER3 upregulation. Here we show that concomitant targeting of EGFR and the nonreceptor tyrosine kinases PYK2/FAK synergistically inhibits the proliferation of basal-like TNBC cells in vitro and attenuates tumor growth in a mouse xenograft model. Dual targeting of EGFR and PYK2/FAK inhibited complementary key growth and survival pathways mediated by AKT, S6K, STAT3, and ERK1/2 activation. PYK2 inhibition also abrogated HER3 upregulation in response to EGFR antagonists, thereby circumventing HER3-associated drug resistance. Mechanistically, PYK2 inhibition facilitated the proteasomal degradation of HER3 while inducing upregulation of NDRG1 (N-myc downstream regulated 1 gene). NDRG1 enhanced the interaction of HER3 with the ubiquitin ligase NEDD4, while PYK2, which interacts with NEDD4 and HER3, interfered with NEDD4-HER3 binding, suggesting that the PYK2-NDRG1-NEDD4 circuit has a critical role in receptor degradation, drug response, and resistance mechanism. Our studies offer a preclinical proof of concept for a strategy of cotargeting the EGFR and PYK2/FAK kinases to improve TNBC therapy. Cancer Res; 77(1); 86-99. ©2016 AACR., (©2016 American Association for Cancer Research.)

Purpose: A common characteristic of mammary carcinomas is an inverse relationship between the estrogen receptor (ER) status and the proliferative activity of the tumor. Yet, a subset of ER-positive breast cancers is characterized by a high proliferation, suggesting malfunctions in ER responsiveness that influence the biological and therapeutic behavior of tumor cells. The expression of several ER-dependent genes seems to be dysregulated among those "uncoupled" tumors. One of those genes is plexin B1, a cell-surface receptor for the semaphorin Sema4D (CD 100). However, the biological role of plexin B1 in breast cancer is largely unknown., Experimental Design: Expression data of plexin B1 were obtained from Affymetrix microarray analysis of n = 119 breast cancer specimens. Validation was done by quantitative real-time PCR and protein expression was evaluated by immunohistochemistry. Expression data were compared with clinical characteristics as well as follow-up data of the disease., Results: Low plexin B1 expression levels characterize a more aggressive tumor phenotype. The expression of plexin B1 is strongly correlated with the ER status. However, even among ER-positive tumors, loss of plexin B1 is associated with an impaired prognosis of breast cancer patients in both univariate (all patients, P = 0.0062; ER positive, P = 0.0107) and multivariate analyses (all patients, P = 0.032; ER positive, P = 0.022). Immunohistochemistry reveals that the tumor cells themselves and not the endothelial cells are the major source of plexin B1 expression in the tumor., Conclusion: Plexin B1 acts not only as a new important prognostic but should also represent a predictive marker indicating an endocrine resistance. These data give a new insight in markers that could be involved in endocrine dysregulation of breast cancer.