Constitutive phosphorylated STAT3-associated gene signature is predictive for trastuzumab resistance in primary HER2-positive breast cancer

Background: The likelihood of recurrence in patients with breast cancer who have HER2-positive tumors is relatively high, although trastuzumab is a remarkably effective drug in this setting. Signal transducer and activator of transcription 3 protein (STAT3), a transcription factor that is persistently tyrosine-705 phosphorylated (pSTAT3) in response to numerous oncogenic signaling pathways, activates downstream proliferative and anti-apoptotic pathways. We hypothesized that pSTAT3 expression in HER2-positive breast cancer will confer trastuzumab resistance. Methods: We integrated reverse phase protein array (RPPA) and gene expression data from patients with HER2-positive breast cancer treated with trastuzumab in the adjuvant setting. Results: We show that a pSTAT3-associated gene signature (pSTAT3-GS) is able to predict pSTAT3 status in an independent dataset (TCGA; AUC = 0.77, P = 0.02). This suggests that STAT3 induces a characteristic set of gene expression changes in HER2-positive cancers. Tumors characterized as high pSTAT3-GS were associated with trastuzumab resistance (log rank P = 0.049). These results were confirmed using data from the prospective, randomized controlled FinHer study, where the effect was especially prominent in HER2-positive estrogen receptor (ER)-negative tumors (interaction test P = 0.02). Of interest, constitutively activated pSTAT3 tumors were associated with loss of PTEN, elevated IL6, and stromal reactivation. Conclusions: This study provides compelling evidence for a link between pSTAT3 and trastuzumab resistance in HER2-positive primary breast cancers. Our results suggest that it may be valuable to add agents targeting the STAT3 pathway to trastuzumab for treatment of HER2-positive breast cancer.Peer reviewe

Network Analysis Tools: from biological networks to clusters and pathways (vol 3, pg 1616, 2008)

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Schlafen-11 expression is associated with immune signatures and basal-like phenotype in breast cancer

PURPOSE: Breast cancer (BC) is a heterogeneous disorder, with variable response to systemic chemotherapy. Likewise, BC shows highly complex immune activation patterns, only in part reflecting classical histopathological subtyping. Schlafen-11 (SLFN11) is a nuclear protein we independently described as causal factor of sensitivity to DNA damaging agents (DDA) in cancer cell line models. SLFN11 has been reported as a predictive biomarker for DDA and PARP inhibitors in human neoplasms. SLFN11 has been implicated in several immune processes such as thymocyte maturation and antiviral response through the activation of interferon signaling pathway, suggesting its potential relevance as a link between immunity and cancer. In the present work, we investigated the transcriptional landscape of SLFN11, its potential prognostic value, and the clinico-pathological associations with its variability in BC. METHODS: We assessed SLFN11 determinants in a gene expression meta-set of 5061 breast cancer patients annotated with clinical data and multigene signatures. RESULTS: We found that 537 transcripts are highly correlated with SLFN11, identifying "immune response", "lymphocyte activation", and "T cell activation" as top Gene Ontology processes. We established a strong association of SLFN11 with stromal signatures of basal-like phenotype and response to chemotherapy in estrogen receptor negative (ER-) BC. We identified a distinct subgroup of patients, characterized by high SLFN11 levels, ER- status, basal-like phenotype, immune activation, and younger age. Finally, we observed an independent positive predictive role for SLFN11 in BC. CONCLUSIONS: Our findings are suggestive of a relevant role for SLFN11 in BC and its immune and molecular variability.status: publishe

HER2-Overexpressing Breast Cancers Amplify FGFR Signaling upon Acquisition of Resistance to Dual Therapeutic Blockade of HER2

Purpose: Dual blockade of HER2 with trastuzumab and lapatinib or pertuzumab has been shown to be superior to single-agent trastuzumab. However, a significant fraction of HER2-overexpressing (HER2(+)) breast cancers escape from these drug combinations. In this study, we sought to discover the mechanisms of acquired resistance to the combination of lapatinib + trastuzumab. Experimental Design: HER2(+) BT474 xenografts were treated with lapatinib + trastuzumab long-term until resistance developed. Potential mechanisms of acquired resistance were evaluated in lapatinib + trastuzumab-resistant (LTR) tumors by targeted capture next-generation sequencing. In vitro experiments were performed to corroborate these findings, and a novel drug combination was tested against LTR xenografts. Gene expression and copy-number analyses were performed to corroborate our findings in clinical samples. Results: LTR tumors exhibited an increase in FGF3/4/19 copy number, together with an increase in FGFR phosphorylation, marked stromal changes in the tumor microenvironment, and reduced tumor uptake of lapatinib. Stimulation of BT474 cells with FGF4 promoted resistance to lapatinib + trastuzumab in vitro. Treatment with FGFR tyrosine kinase inhibitors reversed these changes and overcame resistance to lapatinib + trastuzumab. High expression of FGFR1 correlated with a statistically shorter progression-free survival in patients with HER2(+) early breast cancer treated with adjuvant trastuzumab. Finally, FGFR1 and/or FGF3 gene amplification correlated with a lower pathologic complete response in patients with HER2(+) early breast cancer treated with neoadjuvant anti-HER2 therapy. Conclusions: Amplification of FGFR signaling promotes resistance to HER2 inhibition, which can be diminished by the combination of HER2 and FGFR inhibitors. (C) 2017 AACR.Peer reviewe

Genomic Characterization of Primary Invasive Lobular Breast Cancer

PURPOSE: Invasive lobular breast cancer (ILBC) is the second most common histologic subtype after invasive ductal breast cancer (IDBC). Despite clinical and pathologic differences, ILBC is still treated as IDBC. We aimed to identify genomic alterations in ILBC with potential clinical implications. METHODS: From an initial 630 ILBC primary tumors, we interrogated oncogenic substitutions and insertions and deletions of 360 cancer genes and genome-wide copy number aberrations in 413 and 170 ILBC samples, respectively, and correlated those findings with clinicopathologic and outcome features. RESULTS: Besides the high mutation frequency of CDH1 in 65% of tumors, alterations in one of the three key genes of the phosphatidylinositol 3-kinase pathway, PIK3CA, PTEN, and AKT1, were present in more than one-half of the cases. HER2 and HER3 were mutated in 5.1% and 3.6% of the tumors, with most of these mutations having a proven role in activating the human epidermal growth factor receptor/ERBB pathway. Mutations in FOXA1 and ESR1 copy number gains were detected in 9% and 25% of the samples. All these alterations were more frequent in ILBC than in IDBC. The histologic diversity of ILBC was associated with specific alterations, such as enrichment for HER2 mutations in the mixed, nonclassic, and ESR1 gains in the solid subtype. Survival analyses revealed that chromosome 1q and 11p gains showed independent prognostic value in ILBC and that HER2 and AKT1 mutations were associated with increased risk of early relapse. CONCLUSION: This study demonstrates that we can now begin to individualize the treatment of ILBC, with HER2, HER3, and AKT1 mutations representing high-prevalence therapeutic targets and FOXA1 mutations and ESR1 gains deserving urgent dedicated clinical investigation, especially in the context of endocrine treatment.status: publishe