HER-2/neu overexpression is an independent prognostic factor in colorectal cancer

Park, Dong Il; Kang, Mun Su; Oh, Suk Joong; Kim, Hong Joo; Cho, Yong Kyun; Sohn, Chong Il; Jeon, Woo Kyu; Kim, Byung Ik; Han, Won Kon; Kim, Hungdai; Ryu, Seungho; Sepulveda, Antonia R.

doi:10.1007/s00384-006-0192-8

Cited by 94 publications

(90 citation statements)

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“…[6][7][8][9][12][13][14][15][16][17][18][19][20] The present study is unique because the only study with an equally large sample size, albeit without clinical validation, reported much lower rates of both ERBB2 expression (2.7%) and positive amplification (1.6%). 8 This difference very likely resides in the fact that while our findings have been obtained on a primarily metastatic population, Heppner et al 8 tested only primary tumors using a different staining antibody (SP3) and a different in situ hybridization method (CISH), and employed gastric cancer criteria to test and score the samples.…”

Section: Discussionmentioning

confidence: 96%

“…1,2 Overexpression of ERBB2 is an established therapeutic target in breast and gastric cancers and is successfully exploited in the clinic using a variety of anti-ERBB2 agents, leading to remarkable outcome improvements. 3,4 Although the comprehensive molecular characterization of human colorectal cancer has identified ERBB2 amplification as a potential therapeutic target 5 and ERBB2 overexpression has been controversially linked to prognosis, [6][7][8][9] the clinical significance of ERBB2 alterations remains elusive. Recently, we and others have found that activation of ERBB2 signaling causes resistance to anti-EGFR therapy in a fraction of metastatic colorectal patients, wild type for RAS codons 12-13.…”

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confidence: 99%

“…These are routinely used to establish ERBB2 status in breast and gastric cancer but have not been customized for colorectal cancer for which the reported rate for ERBB2 positivity ranges enormously from o1% to 450%. [6][7][8][9][12][13][14][15][16][17][18][19][20] The aim of the present study was to develop a validated ERBB2 scoring system for colorectal cancer with the goal of identifying ERBB2-positive patients suitable for enrollment in the HERACLES trial.…”

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confidence: 99%

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Assessment of a HER2 scoring system for colorectal cancer: results from a validation study

et al. 2015

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We sought to develop criteria for ERBB2-positivity (HER2) in colorectal cancer to ensure accurate identification of ERBB2-amplified metastatic colorectal cancer patients suitable for enrolment in a phase II trial of ERBB2-targeted therapy (HERACLES trial). A two-step approach was used. In step 1, a consensus panel of pathologists adapted existing protocols for use in colorectal cancer to test ERBB2 expression and amplification. Collegial revision of an archival test cohort of colorectal cancer samples led to specific recommendations for adapting current breast and gastric cancer criteria for scoring ERBB2 in colorectal cancer. In step 2, from September 2012 to January 2015, colorectal-specific ERBB2 testing protocols and ERBB2 scoring criteria were used to centrally screen for ERBB2-positive KRAS wild-type colorectal cancer patients to be enrolled in the HERACLES trial (clinical validation cohort). In both archival test (N = 256) and clinical validation (N = 830) cohorts, a clinically sizeable 5% fraction of KRAS wild-type colorectal cancer patients was found to be ERBB2-positive according to the colorectal cancer-specific ERBB2 scoring criteria. ERBB2-positive tumors showed ERBB2 immunostaining consisting of intense membranous ERBB2 protein expression, corresponding to homogenous ERBB2 amplification, in 450% of cells. None of the immunohistochemistry 0 or 1+ cases was amplified. Concordance between SISH and FISH was 100%. In conclusion, we propose specific criteria for defining ERBB2-positivity in colorectal cancer (HERACLES Diagnostic Criteria). In a phase II trial of trastuzumab and lapatinib in a cetuximabresistant population, HERACLES Diagnostic Criteria shaped the selection of patients and defined ERBB2 as a predictive marker for response to ERBB2-targeted therapy in metastatic colorectal cancer.

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Assessment of a HER2 scoring system for colorectal cancer: results from a validation study

et al. 2015

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“…33,34 In particular, overexpression of EGFR and HER-2 in colorectal cancers correlates with an extremely poor clinical prognosis. 35,36 A majority of solid tumors, including those of the colon, overexpress one or more members of the EGFR and coexpression of EGFR with HER-2 or HER-3 results in the development of enhanced drug resistance. 37,38 These tumors would thus escape treatment with drugs that target only one member of the EGFR family.…”

Section: Discussionmentioning

confidence: 99%

Curcumin enhances the effects of 5‐fluorouracil and oxaliplatin in mediating growth inhibition of colon cancer cells by modulating EGFR and IGF‐1R

Patel

Sengupta

Qazi

et al. 2007

Intl Journal of Cancer

193

133

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Curcumin (diferuloylmethane), which has been shown to inhibit growth of transformed cells, has no discernible toxicity and achieves high levels in colonic mucosa. 5-fluorouracil (5-FU) or 5-FU plus oxaliplatin (FOLFOX) remains the backbone of colorectal cancer chemotherapeutics, but with limited success. The present investigation was, therefore, undertaken to examine whether curcumin in combination with conventional chemotherapeutic agent(s)/regimen will be a superior therapeutic strategy for colorectal cancer. Indeed, results of our in vitro studies demonstrated that curcumin together with FOLFOX produced a significantly greater inhibition (p < 0.01) of growth and stimulated apoptosis (p < 0.001) of colon cancer HCT-116 and HT-29 cells than that caused by curcumin, 5-FU, curcumin 1 5-FU or FOLFOX. These changes were associated with decreased expression and activation (tyrosine phosphorylation) of EGFR, HER-2, HER-3 (72-100%) and IGF-1R (67%) as well as their downstream effectors such as Akt and cycloxygenase-2 (51-97%). Furthermore, while these agents produced a 2-3-fold increase in the expression of IGF-binding protein-3 (IGFBP-3), curcumin together with FOLFOX caused a 5-fold increase in the same, when compared to controls. This in turn led to increased sequestration of IGF by IGFBP-3 rendering IGF-1 unavailable for binding to and activation of IGF-1R. We conclude that the superior effects of the combination therapy of curcumin and FOLFOX are due to attenuation of EGFRs and IGF-1R signaling pathways. We also suggest that inclusion of curcumin to the conventional chemotherapeutic agent(s)/regimen could be an effective therapeutic strategy for colorectal cancer. ' 2007 Wiley-Liss, Inc.Key words: colorectal cancer; EGFR; IGF-1R; curcumin; chemotherapy; IGFBP3There will be an estimated 148,610 new cases and 55,170 deaths due to colorectal caner (CRC) in 2006 in the USA. 1 CRC is estimated to be the second and third leading cause of cancerrelated deaths in men and women, respectively, in 2006. 1 Surgery and subsequent chemotherapy can cure over 75% colon cancer patients, but more than 30% of these patients develop new neoplastic polyps, and 10% progress to frank second malignancy. [2][3][4] The risk of second malignancy is higher for microsatellite instable tumor (MSI). 5 Metastatic colorectal cancer has poor a prognosis with 5-year survival of less than 10%. 6 As a result of great efforts are being spent on improving chemotherapeutic interventions for metastatic colon cancer, and the median survival has improved to over 20 months of this group of patients. 7 However, this comes at a cost of additional toxicities, some of which are even fatal. 7 The validation of a nontoxic agent that could improve upon the current chemotherapeutic regimen would therefore be highly desirable.Accumulating evidence suggests that the development and progression of many malignancies, including colorectal cancer, are associated with constitutive activation of multiple signaling pathways that promote proliferation, inhibit apoptosis an...

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“…Thus, similar to CREB, HER-2/neu can affect a large number of cellular processes, including cell differentiation, proliferation, apoptosis, and cell cycle. Under physiologic conditions, HER-2/neu is expressed at low levels in many epithelial cells (15), whereas it is overexpressed and/or amplified in human tumor cells of distinct origin, including those of mammary carcinoma and colorectal cancer (16)(17)(18). HER-2/neu-mediated transformation is associated with initiation and maintenance of the transformed phenotype, aggressiveness of tumors, progression of disease, and poor prognosis and outcome for patients (19).…”

Section: Introductionmentioning

confidence: 99%

HER-2/neu Mediates Oncogenic Transformation via Altered CREB Expression and Function

Steven

Leisz

Massa

et al. 2013

Molecular Cancer Research

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The cyclic (c)AMP responsive element binding protein (CREB) plays a key role in many cellular processes, including differentiation, proliferation, and signal transduction. Furthermore, CREB overexpression was found in tumors of distinct origin and evidence suggests an association with tumorigenicity. To establish a mechanistic link between HER-2/neu-mediated transformation and CREB protein expression and function, in vitro models of HER-2/neu-overexpressing and HER-2/neu-negative/silenced counterparts as well as human mammary carcinoma lesions with defined HER-2/neu status were used. HER-2/neu overexpression resulted in the induction and activation of CREB protein in vitro and in vivo, whereas short hairpin RNA (shRNA)-mediated inhibition of HER-2/neu correlated with downregulated CREB activity. CREB activation in HER-2/neu-transformed cells enhanced distinct signal transduction pathways, whereas their inhibition negatively interfered with CREB expression and/or activation. CREB downregulation in HER-2/neu-transformed cells by shRNA and by the inhibitors KG-501 and lapatinib caused morphologic changes, reduced cell proliferation with G 0 -G 1 cell-cycle arrest, which was rescued by CREB expression. This was accompanied by reduced cell migration, wound healing, an increased fibronectin adherence, invasion, and matrix metalloproteinase expression. In vivo shCREB-HER-2/neu þ cells, but not control cells, exerted a significantly decreased tumorgenicity that was associated with decreased proliferative capacity, enhanced apoptosis, and increased frequency of T lymphocytes in peripheral blood mononuclear cells. Thus, CREB plays an important role in the HER-2/neu-mediated transformation by altering in vitro and in vivo growth characteristics.

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HER-2/neu overexpression is an independent prognostic factor in colorectal cancer

Abstract: HER-2/neu overexpression may constitute an independent prognostic factor in colorectal cancer patients, and patients exhibiting HER-2/neu overexpression might constitute potential candidates for a new adjuvant therapy which involves the use of humanized monoclonal antibodies.

Cited by 94 publications

References 30 publications

Assessment of a HER2 scoring system for colorectal cancer: results from a validation study

Assessment of a HER2 scoring system for colorectal cancer: results from a validation study

Curcumin enhances the effects of 5‐fluorouracil and oxaliplatin in mediating growth inhibition of colon cancer cells by modulating EGFR and IGF‐1R

HER-2/neu Mediates Oncogenic Transformation via Altered CREB Expression and Function

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