Growth factor receptor-bound protein-7 (Grb7) as a prognostic marker and therapeutic target in breast cancer

Nadler, Yasmine; González, Antonio; Camp, Robert L.; Rimm, David L.; Kluger, Harriet M.; Kluger, Yuval

doi:10.1093/annonc/mdp346

Cited by 69 publications

(84 citation statements)

References 46 publications

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“…This observation is in line with this study, where low expression of INSIG 2 is correlated with prolonged survival and improved disease control, thus reinforcing the caveat of whether our findings are truly predictive or prognostic. In previous reports from other solid tumors, high GRB 7 expression was independently associated with reduced OS in primary breast cancer, particularly in the subset with node-positive disease (51). Although high GRB 7 and HER2 expression were strongly correlated, coexpression of HER2 together with GRB 7 was associated with a significantly poorer prognosis than expression of HER2 alone.…”

Section: Discussionmentioning

confidence: 59%

Correlation between Gene Expression of IGF-1R Pathway Markers and Cetuximab Benefit in Metastatic Colorectal Cancer

Huang

Khambata‐Ford

2012

Clinical Cancer Research

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Purpose: This study examined potential correlations between markers related to the insulin-like growth factor-1 receptor (IGF-1R) pathway and clinical benefit from the anti-epidermal growth factor receptor (EGFR) monoclonal antibody cetuximab in metastatic colorectal cancer (mCRC).Experimental Design: Gene expression profiles for 70 pretreatment specimens from metastatic lesions of patients with chemorefractory mCRC receiving cetuximab monotherapy were analyzed using 74 predefined Gene-Chip probesets representing 33 unique IGF-1R pathway markers to determine correlations with progression-free survival (PFS) and disease control rate.Results: Higher IGF-1R, higher GRB 7 , and lower INSIG 2 expression were associated with longer PFS with cetuximab in univariate analyses, particularly in patients with wild-type K-Ras tumors: median, 122 versus 60 days (P ¼ 0.01), 122 versus 57 days (P ¼ 0.011), and 57 versus 156 days (P < 0.0001), favoring higher IGF-1R, higher GRB 7 , and lower INSIG 2 expression, respectively. Lower IGF-1 expression was associated with a PFS benefit with cetuximab, whereas lower IGFBP 3 and INSR expression levels showed trends for a PFS benefit. Lower INSIG 2 expression (vs. higher expression) was associated with greater PFS in the high epiregulin-expressing group (P ¼ 0.001), but not in the low-expressing cohort suggesting an effect independent from the previously reported effect of epiregulin expression. Lower INSIG 2 expression was also associated with higher disease control rate in the overall population (51.4% vs. 11.4%; P ¼ 0.001) and wild-type K-Ras subset (76.2% vs. 18.2%; P < 0.0001).Conclusions: These results suggest that markers of the IGF-1R pathway may play a role in predicting benefit from cetuximab therapy in mCRC. Additional clinical studies are warranted to validate these findings.

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Section: Discussionmentioning

confidence: 59%

Correlation between Gene Expression of IGF-1R Pathway Markers and Cetuximab Benefit in Metastatic Colorectal Cancer

Huang

Khambata‐Ford

2012

Clinical Cancer Research

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“…We also observed significant upregulation of other genes in CSFTCs, such as AGR2 (log 10 RQ ¼ 3.53; adj P ¼ 0.0007), TFF3 (log 10 RQ ¼ 3.21; adj P ¼ 0.0007), and GRB7 (log 10 RQ ¼ 2.86; adj P ¼ 0.01; Supplementary Table S3). Overexpression of these genes has been correlated with aggressive cancer biology (20)(21)(22)(23). Although statistical significance was not achieved, MYC (log 10 RQ ¼ 0.85) was upregulated in CSFTCs as compared with leukocytes (Supplementary Table S3).…”

Section: Gene Expression Profilingmentioning

confidence: 99%

Molecular Profiling of Tumor Cells in Cerebrospinal Fluid and Matched Primary Tumors from Metastatic Breast Cancer Patients with Leptomeningeal Carcinomatosis

et al. 2013

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Although leptomeningeal carcinomatosis is a well-established clinical syndrome, virtually nothing is known about the tumor cells responsible for this particularly aggressive metastatic process. To isolate cerebrospinal fluid-derived tumor cells (CSFTC) from 15 patients with metastatic breast cancer diagnosed with leptomeningeal carcinomatosis, CSF samples were subjected to a two-step method involving immunomagnetic enrichment and fluorescence-activated cell sorting (IE/FACS), a technique previously used for isolating circulating tumor cells (CTC) from blood. CSFTCs were subjected to genome-wide copy number analysis by array comparative genomic hybridization. Genomic profiling was successfully performed for 13 of 15 patients (87%). Copy number analysis in CSFTCs revealed genomic alterations commonly observed in primary breast cancer and CTCs, indicating their malignant origin. Interestingly, 12 (92%) harbored high-level gains on the 8q24 locus, which includes the MYC oncogene. Comparison of CSFTCs against corresponding archival primary tumors in six patients revealed clonal relationships with some divergence. Good concordance among serial samples attested to the reproducibility of the assay. Our approach for isolation and molecular analysis of CSFTCs yielded new insights into the molecular nature of these cells. Further genomic and functional analyses may help elucidate mechanisms by which tumor cells metastasize to the central nervous system. Cancer Res; 73(23); 7134-43. Ó2013 AACR.

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“…In addition, Vinatazer et al (25) demonstrated a correlation between higher levels of GRB7 protein expression and lower disease-free and overall survival, a finding also reported by Cobleigh et al (26) and, more recently, by Nadler et al (27). These findings correlate well with the results of the present work which has demonstrated a significant relationship between higher levels of GRB7 and poorer disease-free survival up to 5 years, and taken together suggest that GRB7 holds greater clinical significance than acting simply as a surrogate marker for expression or amplification of HER2/neu.…”

Section: Discussionmentioning

confidence: 65%

Expression levels of HER2/neu and those of collocated genes at 17q12-21, in breast cancer

et al. 2012

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Abstract. HER2/neu is associated with poorer clinical outcome in breast cancer. Expression patterns of co-localised cancerassociated genes at 17q12-21 were examined using RT-PCR. The study group consisted of a 96-patient cohort. Relative quantity of mRNA expression was calculated using the comparative cycle threshold method and Qbase software. Results were analysed to detect expression patterns among the genes, and to identify associations between expression levels and clinical data. Levels of HER2/neu correlated with those of GRB7 (r=0.551, p<0.001), RARA (r=0.391, p<0.001), RPL19 (r=0.549, p<0.001) and LASP1 (r=0.399, p<0.001). GRB7 was significantly inversely associated with improved DFS at 60 months (p=0.036). RARA levels were greater in HER2/neu-positive as opposed to HER2/ neu-negative patients (p= 0.021); levels were significantly higher in ER-positive patients, relative to those who were ER-negative (p=0.003). Levels of RPL19 were significantly higher in the HER2/neu-overexpressing (p=0.010) and luminal B subtypes (p=0.007). LASP1 levels were higher in those patients who had been classified clinically as HER2/neu-positive (p=0.004). This study reaffirms the correlation between HER2/neu and the co-localised LASP1 and GRB7; the latter target may hold additional significance in addition to being a surrogate marker for HER2/neu expression. The relationship identified between RARA and ER-positivity may herald an avenue for targeted therapy of these tumours.

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Growth factor receptor-bound protein-7 (Grb7) as a prognostic marker and therapeutic target in breast cancer

Cited by 69 publications

References 46 publications

Correlation between Gene Expression of IGF-1R Pathway Markers and Cetuximab Benefit in Metastatic Colorectal Cancer

Correlation between Gene Expression of IGF-1R Pathway Markers and Cetuximab Benefit in Metastatic Colorectal Cancer

Molecular Profiling of Tumor Cells in Cerebrospinal Fluid and Matched Primary Tumors from Metastatic Breast Cancer Patients with Leptomeningeal Carcinomatosis

Expression levels of HER2/neu and those of collocated genes at 17q12-21, in breast cancer

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