Level of <i>HER2</i> Gene Amplification Predicts Response and Overall Survival in HER2-Positive Advanced Gastric Cancer Treated With Trastuzumab

Gómez‐Martín, Carlos; Plaza, Carlos; Pazo-Cid, Roberto; Salud, Antonieta; Pons, Francesc; Fonseca, Paula; León, Ana; Alsina, María; Visa, Laura; Rivera, Fernando; Galan, MaCarmen; Valle, Elena del; Vilardell, Felip; Iglesias, Mar; Fernández, Susana; Landolfi, Stefania; Cuatrecasas, Míriam; Mayorga, Marta; Paúles, María José; Sanz-Moncasi, Pilar; Montagut, Clara; Garralda, Elena; Rojo, Federico; Hidalgo, Manuel; López‐Ríos, Fernando

doi:10.1200/jco.2013.48.9070

Cited by 178 publications

(154 citation statements)

References 24 publications

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“…Interestingly, the characteristics of ERBB2 positivity in our colorectal cancer samples are more similar to those of breast cancer than to gastric cancer. 3,22,28 ERBB2 staining in gastric cancer is not directly correlated to ERBB2 amplification, with up to 30% of ERBB2 amplification-positive cases showing only focal staining or diffuse staining in o 30% of tumor cells. 24 On the contrary, ERBB2 protein expression and gene amplification in our colorectal cancer samples tallied quite accurately.…”

Section: Discussionmentioning

confidence: 99%

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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Section: Discussionmentioning

confidence: 99%

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

et al. 2015

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“…Polysomy of chromosome 17 indicates some degree of clinical benefit for the use of trastuzumab in gastric cancer as well [36]. Our data raise the possibility that chromosome 7 polysomy may represent a potential biomarker for EGFR therapy, although further studies are needed for corroboration.…”

Section: Discussionmentioning

confidence: 59%

Gene copy number gain of EGFR is a poor prognostic biomarker in gastric cancer: evaluation of 855 patients with bright-field dual in situ hybridization (DISH) method

et al. 2014

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Background EGFR overexpression is a prognostic biomarker and is expected to be a predictive biomarker for anti-EGFR therapies in gastric cancer. However, few studies have reported the clinical impact of EGFR gene copy number (GCN) and its correlation with EGFR overexpression. Methods We used dual in situ hybridization (DISH) to detect EGFR GCN and chromosome 7 centromere (CEN7) in a set of tissue microarrays representing 855 patients with gastric cancer. These data were compared with those of immunohistochemical (IHC) analysis of EGFR expression to evaluate prognostic value. Results EGFR GCN gain (C2.5 EGFR signals per cell) was detected in 194 patients (22.7 %) and indicated poor prognosis. Among 194 patients, EGFR amplification (EGFR/CEN7 C 2.0) was observed in 29 patients (14.9 %), which was almost identical to the IHC 3? subgroup and worst prognostic subgroup. Patients with EGFR GCN gain but not amplification, including those exhibiting polysomy, also exhibited poorer prognosis than GCN nongain patients and were distributed between IHC 0/1? and 2? subgroups. GCN gain was frequently observed in patients with more advanced disease, but served as an independent prognostic factor regardless of the pathological stage. Conclusions EGFR GCN gain is a more accurate prognostic biomarker than EGFR overexpression in patients with gastric cancer.

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“…This can result in inaccuracy/heterogeneity in HER2 positivity, and confirmation on multiple tumor specimens has been recommended to ensure accuracy (81). Newer technologies such as gene copy number have been used in breast cancer, and may be applied to GEJ cancers as well (82). It is this inaccuracy in molecular diagnosis that leads to at least some of the primary resistance of GEJ cancers to trastuzumab.…”

Section: Resistance To Her2: Primarymentioning

confidence: 99%

Primary and acquired resistance to biologic therapies in gastrointestinal cancers

Lubner

Uboha

Deming

2017

J. Gastrointest. Oncol.

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Improvements in the understanding of cancer biology have led to therapeutic advances in the treatment of gastrointestinal cancers. Drugs which target the vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) pathways have led the way in colon cancer. Monoclonal antibodies (mAbs) such as bevacizumab, ramucirumab, cetuximab, and panitumumab, have improved progression free survival and overall survival (OS) for colorectal cancers and were quickly adopted. Human epidermal growth factor receptor 2 (HER2) has demonstrated significant benefit for gastroesophageal cancers and in the setting of HER2 amplification, trastuzumab in combination with chemotherapy has become the standard of care. However, responses have not been as durable nor as robust as once hoped. Mechanisms of resistance for each of these biologic compounds have been hypothesized and are in the process of being better elucidated. This review will approach the innate and acquired mechanisms of resistance of the above compounds.Additionally, we will explore some ongoing clinical trials to capitalize on the mechanisms of resistance in the hopes of retaining the promise of targeting these pathways. Resistance to EGFR inhibitors: primaryAs many tumors of the gastrointestinal tract arise from epithelial origins, the attractiveness of treating with therapies blocking EGFR is readily evident. A series of colon cancer trials have shown, improvements in RRs and OS, particularly in populations without mutations in EGFR and/or downstream effectors, which are described in the next section. In most other GI cancers, however, blocking EGFR has not demonstrated clinically relevant improvements in outcome (2-4). New strategies to investigate anti-EGFR therapy in other tumor types are focusing on selecting for patients whose tumors overexpress EGFR, or do not harbor deleterious mutations (ENRICH study, NCT 01813253) (5). KRAS/NRASKRAS and NRAS belong to the family of RAS oncogenes.

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Level of HER2 Gene Amplification Predicts Response and Overall Survival in HER2-Positive Advanced Gastric Cancer Treated With Trastuzumab

Abstract: The level of HER2 gene amplification significantly predicts sensitivity to therapy and overall survival in advanced gastric cancer treated with trastuzumab-based chemotherapy.

Cited by 178 publications

References 24 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

Gene copy number gain of EGFR is a poor prognostic biomarker in gastric cancer: evaluation of 855 patients with bright-field dual in situ hybridization (DISH) method

Primary and acquired resistance to biologic therapies in gastrointestinal cancers

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