Low Overexpression of HER-2/Neu in Advanced Colorectal Cancer Limits the Usefulness of Trastuzumab (Herceptin®) and Irinotecan as Therapy. A Phase II Trial

Ramanathan, Ramesh K.; Hwang, Jimmy J.; Zamboni, William C.; Sinicrope, Frank A.; Safran, Howard; Wong, Michael K.; Earle, Martin F.; Brufsky, Adam; Evans, Terry; Troetschel, Monica; Walko, Christine M.; Day, Roger; Chen, Alice; Finkelstein, Sydney

doi:10.1081/cnv-200039645

Cited by 132 publications

(82 citation statements)

References 22 publications

(1 reference statement)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…[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: 97%

“…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.…”

mentioning

confidence: 99%

See 1 more Smart Citation

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

et al. 2015

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 97%

mentioning

confidence: 99%

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

et al. 2015

View full text Add to dashboard Cite

show abstract

“…The HER2 protein, a product of HER2 oncogene, is found to be over expressed in some proportion of CRC cells, and seems to be a potentially valid target of interest in the management of colorectal tumors [1,8,19]. One of the main obstacles to conducting relevant studies on HER2 as a predictive and/or prognostic factor is the infrequency of its overexpression in the membrane of CRC cells, which is required for trastuzumab therapy [9,16,19,21].…”

Section: Discussionmentioning

confidence: 99%

Expression of HER2 in Colorectal Cancer Does Not Correlate with Prognosis

et al. 2010

View full text Add to dashboard Cite

Abstract. Estimation of HER2 membranous expression is routinely used in breast and gastric cancers, as both a prognostic and a predictive factor. To date there is no evidence for similar application of HER2 expression in colorectal cancer (CRC) cells. In CRC, HER2 is sometimes overexpressed in the cell membrane and very often in the cytoplasm. This study was conducted to determine possible correlations between both membranous and cytoplasmatic expression of HER2 in CRC cells and the outcome of the disease. The prognostic significance of combined staining intensity in the cell membrane and cytoplasm in the entire CRC cell was also investigated. HER2 expression in resectable colorectal adenocarcinoma cells was evaluated by immunohistochemistry in specimens taken from 202 patients. The percentage of cancer cells with membranous or cytoplasmatic reactions and the staining intensity of the reaction in the whole cell were recorded. A membranous reaction was present in 27% of cases, and cytoplasmatic reaction in 66% of cases. The total staining intensity in the entire cell was evaluated as moderate (2+) in 32% of cases and strong (3+) staining in 15%. There was no correlation found between either membranous or cytoplasmatic HER2 expression and survival. Furthermore combined staining intensity did not provide any prognostic information. We conclude that HER2 expression in CRC does not correlate with prognosis.

show abstract

“…In this context, evidence is emerging that comparative testing of multiple combination strategies in PDXs can be exploited to select for the most effective therapeutic strategy among different options based on a similar rationale (22). For example, the observation obtained in PDXs that a combination of trastuzumab and lapatinib, but not treatment with either drug alone, can induce effective tumor shrinkage of HER2-amplified colorectal cancer is being confirmed in the clinical setting (43); again in line with observations obtained in PDX, trials have failed to demonstrate clinical efficacy of trastuzumab-based regimens in colorectal cancer (55). Similarly, the efficacy of the afatinib/cetuximab combination was effectively predicted by genetically modified mouse models of NSCLC and then confirmed by clinical data (39,56).…”

Section: Discussionmentioning

confidence: 89%

Molecular Pathways: Sensitivity and Resistance to Anti-EGFR Antibodies

Bertotti

Sassi

2015

Clinical Cancer Research

View full text Add to dashboard Cite

Monoclonal antibodies targeting the EGF receptor (EGFR) tyrosine kinase, such as cetuximab and panitumumab, achieve clinically meaningful responses in patients affected by head and neck and colorectal cancers. Despite this evidence of efficacy, no genomic abnormalities that robustly predict sensitivity to EGFR blockade have been yet identified. This suggests that, in some tumor contexts, EGFR dependency is not acquired during neoplastic transformation and rather reflects an aberrant declination of physiologic traits typical of normal tissue counterparts. Indeed, EGFR signals are crucial for the reconstitution of damaged mucosa in the context of acute inflammation, and their sustained activation is likely to turn into a pro-oncogenic cue during chronic inflammation. Although positive predictors of response to anti-EGFR antibodies remain unknown, multiple determinants of resistance have been described, including alterations interfering with antibody-receptor interaction, deregulation of parallel signaling pathways, and mutations in downstream transducers. These findings provide new opportunities for the optimization of therapeutic strategies based on drug combinations. However, the emerging notion that genetic interactions and compensatory mechanisms may affect-both positively and negatively-the efficacy of targeted therapies complicates the rational design of combinatorial approaches and implies a rethinking of the criteria required to prioritize laboratory findings for clinical validation in investigational trials. Clin Cancer Res; 21(15); 3377-83. Ó2015 AACR.

show abstract

Low Overexpression of HER-2/Neu in Advanced Colorectal Cancer Limits the Usefulness of Trastuzumab (Herceptin®) and Irinotecan as Therapy. A Phase II Trial

Abstract: The low overexpression rate of HER-2/neu (8.0%) in advanced CRC limits the potential for further investigation of regimens involving trastuzumab, despite evidence suggestive of activity. Irinotecan did not alter the pharmacokinetic disposition of trastuzumab.

Cited by 132 publications

References 22 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

Expression of HER2 in Colorectal Cancer Does Not Correlate with Prognosis

Molecular Pathways: Sensitivity and Resistance to Anti-EGFR Antibodies

Contact Info

Product

Resources

About