Targeting HER2 in colorectal cancer: The landscape of amplification and short variant mutations in <i>ERBB2</i> and <i>ERBB3</i>

Ross, Jeffrey S.; Fakih, Marwan; Ali, Siraj M.; Elvin, Julia A.; Schrock, Alexa B.; Suh, James; Vergilio, Jo‐Anne; Ramkissoon, Shakti; Severson, Eric Allan; Daniel, Sugganth; Fabrizio, David; Frampton, Garrett M.; Sun, James; Miller, Vincent A.; Stephens, Philip J.

doi:10.1002/cncr.31125

Cited by 170 publications

(140 citation statements)

References 94 publications

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“…In the present analysis, we observed a 6.7% incidence of HER2 positivity, in line with studies highlighting a higher incidence of HER2 positivity among patients without KRAS mutations than in the unselected population [5]. We found that HER2 positivity was associated with the presence of lung metastases and a higher tumor burden.…”

Section: Discussionsupporting

confidence: 92%

“…In metastatic colorectal cancer (mCRC), the rate of HER2 amplification or overexpression ranges from 1.3% to 3.2% of cases in all stages, molecularly unselected , up to 5.2% in KRAS exon 2 wild‐type patients in the metastatic setting . In a recent study performed in a large cohort of colorectal cancer (CRC) samples from stage IV patients by next‐generation sequencing (NGS) of a panel of 315 cancer‐related genes, amplification of ERBB2 was found in 2.8%, and KRAS mutations were found to occur less frequently in ERBB2 ‐amplified samples .…”

Section: Introductionmentioning

confidence: 99%

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HER2 Positivity Predicts Unresponsiveness to EGFR-Targeted Treatment in Metastatic Colorectal Cancer

et al. 2019

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Background HER2 amplification is detected in 3% of patients with colorectal cancer (CRC), making tumors in the metastatic setting vulnerable to double pharmacological HER2 blockade. Preclinical findings show that it also might impair response to anti‐epidermal growth factor receptor (EGFR) treatment. Subjects and Methods Patients with KRAS exon 2 wild‐type metastatic CRC underwent molecular screening of HER2 positivity by HERACLES criteria (immunohistochemistry 3+ or 2+ in ≥50% of cells, confirmed by fluorescence in situ hybridization). A sample of consecutive HER2‐negative patients was selected as control. A regression modeling strategy was applied to identify predictors explaining the bulk of HER2 positivity and the association with response to previous anti‐EGFR treatment. Results From August 2012 to April 2018, a total of 100 HER2‐positive metastatic CRC tumors were detected out of 1,485 KRAS exon 2 wild‐type screened patients (6.7%). HER2‐positive patients show more frequently lung metastases (odds ratio [OR], 2.04; 95% confidence interval [CI], 1.15–3.61; p = .014) and higher tumor burden (OR, 1.48; 95% CI, 1.10–2.01; p = .011), and tumors were more likely to be left sided (OR, 0.50; 95% CI, 0.22–1.11; p = .088). HER2‐positive patients who received treatment with anti‐EGFR agents (n = 79) showed poorer outcome (objective response rate, 31.2% vs. 46.9%, p = .031; progression‐free survival, 5.7 months vs. 7 months, p = .087). Conclusion Testing for HER2 should be offered to all patients with metastatic CRC because the occurrence of this biomarker is unlikely to be predicted based on main clinicopathological features. Patients with HER2‐amplified metastatic CRC are less likely to respond to anti‐EGFR therapy. Implications for Practice Patients with HER2‐amplified/overexpressed metastatic colorectal cancer (mCRC) harbor a driver actionable molecular alteration that has been shown in preclinical models to hamper efficacy of the anti‐epidermal growth factor receptor (EGFR) targeted therapies. The present study confirmed that this molecular feature was associated with worse objective tumor response and shorter progression‐free survival in response to previous anti‐EGFR therapies. Moreover, it was found that the occurrence of this biomarker is unlikely to be predicted based on main clinicopathological features. Therefore, HER2 status assessment should be included in the molecular diagnostic workup of all mCRC for speedy referral to clinical trials encompassing HER2‐targeted double blockade independently of previous anti‐EGFR treatment.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

HER2 Positivity Predicts Unresponsiveness to EGFR-Targeted Treatment in Metastatic Colorectal Cancer

et al. 2019

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“…ERBB2/HER2 expression in the WT tumor was also significantly higher than in any of our 19 reference proteomes. The opportunity to target ERBB2/HER2 in colorectal cancer has recently emerged [43] as it is amplified and/or mutated in 5% of CRC tumors, most often in KRAS WT tumors [43], which agrees with our data.…”

Section: Quantitative Comparison Of Kras G12v and Kras Wt Tumorssupporting

confidence: 91%

Proteogenomics of Colorectal Cancer Liver Metastases: Complementing Precision Oncology with Phenotypic Data

Blank-Landeshammer

Richard

Mitsa

et al. 2019

Cancers

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Hotspot testing for activating KRAS mutations is used in precision oncology to select colorectal cancer (CRC) patients who are eligible for anti-EGFR treatment. However, even for KRAS wildtype tumors anti-EGFR response rates are <30%, while mutated-KRAS does not entirely rule out response, indicating the need for improved patient stratification. We performed proteogenomic phenotyping of KRAS wildtype and KRAS G12V CRC liver metastases (mCRC). Among >9000 proteins we detected considerable expression changes including numerous proteins involved in progression and resistance in CRC. We identified peptides representing a number of predicted somatic mutations, including KRAS G12V . For eight of these, we developed a multiplexed parallel reaction monitoring (PRM) mass spectrometry assay to precisely quantify the mutated and canonical protein variants. This allowed phenotyping of eight mCRC tumors and six paired healthy tissues, by determining mutation rates on the protein level. Total KRAS expression varied between tumors (0.47-1.01 fmol/µg total protein) and healthy tissues (0.13-0.64 fmol/µg). In KRAS G12V -mCRC, G12V-mutation levels were 42-100%, while one patient had only 10% KRAS G12V but 90% KRAS wildtype . This might represent a missed therapeutic opportunity: based on hotspot sequencing, the patient was excluded from anti-EGFR treatment and instead received chemotherapy, while PRM-based tumor-phenotyping indicates the patient might have benefitted from anti-EGFR therapy.

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“…59 Alterations in Her-2 signaling, either through genomic amplification or mutations is tumor promoting, and anti-HER2 therapies for preventing CRC recurrence and are a focus of on-going work. 60 We finally note that MAPK and PI3K-AKT signaling cascades are implicated in many of the above discussed pathways.…”

Section: Spatial Domain Network Reveal Domain-specific Network Biolomentioning

confidence: 88%

Spatial domain analysis predicts risk of colorectal cancer recurrence and infers associated tumor microenvironment networks

Uttam

Stern

Furman

et al. 2019

Preprint

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An unmet clinical need in solid tumor cancers is the ability to harness the intrinsic spatial information in primary tumors that can be exploited to optimize prognostics, diagnostics and therapeutic strategies for precision medicine. We have developed a transformational spatial analytics (SpAn) computational and systems biology platform that predicts clinical outcomes and captures emergent spatial biology that can potentially inform therapeutic strategies. Here we apply SpAn to primary tumor tissue samples from a cohort of 432 chemo-naïve colorectal cancer (CRC) patients iteratively labeled with a highly multiplexed (hyperplexed) panel of fifty-five fluorescently tagged antibodies. SpAn predicted the 5-year risk of CRC recurrence with a mean area under the ROC curve of 88.5% (SE of 0.1%), significantly better than current state-of-the-art methods. SpAn also inferred the emergent network biology of the tumor spatial domains revealing a synergistic role of known features from CRC consensus molecular subtypes that will enhance precision medicine. MainColorectal Cancer (CRC) is the second most common type of cancer and the third leading cause of cancer-related deaths worldwide. 1 This multi-factorial disease like other carcinomas, develops and progresses through the selection of epithelial clones with the potential to confer malignant phenotypes in the context of a reciprocally coevolving tumor microenvironment (TME) comprising immune and stromal cells. 2-4 CRC patients are staged using the well-established tumor-nodemetastases (TNM) classification. 5,6 However, there is significant variability in patient outcomes within each stage. For example, CRC will recur in up to 30% of Stage II patients despite complete tumor resection, no residual tumor burden and no signs of metastasis. 7 In contrast, more advanced CRC has been known to show stability or indeed even to spontaneously regress. 7,8 The intrinsic plasticity of the TME underlying this variability in outcome is controlled by complex network biology emerging from the spatial organization of diverse cell types within the TME and their heterogeneous states of activation. 3,[9][10][11] The important role of the TME in CRC progression and recurrence has recently been highlighted by the identification of four consensus molecular subtypes (CMS) 12,13 , functional studies defining the critical role of stromal cells in determining overall survival, 14 and the development of Immunoscore® 14 which quantifies tumorinfiltrating T-lymphocytes in different regions of the tumor and associates their infiltration with CRC recurrence. 15,16 However the TME can be further harnessed to significantly improve CRC prognosis through the identification of biomarkers mechanistically linked to disease progression and the development of novel therapeutic strategies.Deeper understanding of the TME may arise from imaging methods capable of labeling > 7 cellular and tissue components in the same sample (hyperplexed 17 (HxIF) fluorescence and other imaging modalities). [17][18][19][20][21] To...

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Targeting HER2 in colorectal cancer: The landscape of amplification and short variant mutations in ERBB2 and ERBB3

Cited by 170 publications

References 94 publications

HER2 Positivity Predicts Unresponsiveness to EGFR-Targeted Treatment in Metastatic Colorectal Cancer

HER2 Positivity Predicts Unresponsiveness to EGFR-Targeted Treatment in Metastatic Colorectal Cancer

Proteogenomics of Colorectal Cancer Liver Metastases: Complementing Precision Oncology with Phenotypic Data

Spatial domain analysis predicts risk of colorectal cancer recurrence and infers associated tumor microenvironment networks

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