EGFR and KRAS mutations as criteria for treatment with tyrosine kinase inhibitors: retro- and prospective observations in non-small-cell lung cancer

Zandwijk, Nico van; Mathy, Alexandre; Boerrigter, Lucie; Ruijter, Henrique J.; Tielen, Ivon H. G.; Jong, Daniëlle de; Baas, Paul; Burgers, Sjaak A.; Nederlof, Petra M.

doi:10.1093/annonc/mdl323

Cited by 131 publications

(85 citation statements)

References 27 publications

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“…Phase II clinical trails have revealed that deletion of exon 19 and L858R mutations are major markers of response to treatment in advanced non small cell lung cancer. [30][31][32] In the present series of epithelioid sarcomas, no mutations or deletions were detected. These findings suggest that, based on current paradigms of assessing responsiveness to EGFRtargeted therapies in carcinomas, it is uncertain whether epithelioid sarcomas would show a meaningful response to EGFR tyrosine kinase inhibitors.…”

Section: Discussionmentioning

confidence: 41%

Epithelioid sarcoma expresses epidermal growth factor receptor but gene amplification and kinase domain mutations are rare

2010

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Epithelioid sarcoma is a rare, malignant, soft tissue neoplasm that can be classified into proximal, distal and fibroma-like subtypes. Regardless of subtype, epithelioid sarcoma often shows morphologic and immunophenotypic evidence of epithelial differentiation. Current therapeutic strategies include surgical resection, amputation, radiation or chemotherapy, although the overall prognosis remains poor. The epidermal growth factor receptor (EGFR) is a novel therapeutic target in carcinomas. In some carcinomas, EGFR kinase domain mutations or gene amplification may correlate with response to specific inhibitors. EGFR expression has been reported in some sarcoma types, but expression, amplification and mutations have not been studied in epithelioid sarcoma. We evaluated 15 cases of epithelioid sarcoma from 14 patients for EGFR expression using immunohistochemistry, EGFR copy number aberration using fluorescence in situ hybridization and screened for mutations in the tyrosine kinase domain of the EGFR gene using direct sequencing. In all, 14 of the 15 epithelioid sarcomas (93%) showed expression of EGFR by immunohistochemistry. A majority of the cases (n ¼ 11, 73%) showed strong (2 þ to 3 þ ) and homogeneous (475% of cells) membrane staining. No amplification or polysomy of the EGFR gene or mutations of the tyrosine kinase domain of EGFR (exons 18-21) were detected. These results imply that although EGFR is expressed in most epithelioid sarcomas regardless of subtype, gene amplification and activating mutations in the tyrosine kinase domain appear to be rare or absent. Thus, the benefit of targeted therapy against EGFR in patients with epithelioid sarcoma remains to be determined.

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Section: Discussionmentioning

confidence: 41%

Epithelioid sarcoma expresses epidermal growth factor receptor but gene amplification and kinase domain mutations are rare

2010

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“…32 Several studies have shown that increased EGFR gene copy number by FISH and/ or EGFR gene mutations are reliable markers for the prediction of clinical benefit from anti-EGFR drugs such as gefitinib, erlotinib, or cetuximab in typical NSCLC. 13,[15][16][17][18][19][20][21][22][23][24][25][26][27][28] The rare occurrence of these molecular events in lung SC suggests that these tumors are not ideal candidates for anti-EGFR therapy. This is consistent with the high rate of KRAS mutations observed in our series (38%).…”

Section: Discussionmentioning

confidence: 99%

“…There are several lines of evidence indicating that biomarkers such as EGFR protein expression, 13,14 EGFR gene copy number, 13,[15][16][17][18][19][20] EGFR mutations 13,15,[21][22][23][24][25][26][27][28] and KRAS mutations 22,[28][29][30] may be used to predict which patients with NSCLC will respond to EGFR tyrosine kinase inhibitors.…”

mentioning

confidence: 99%

EGFR and KRAS status of primary sarcomatoid carcinomas of the lung: Implications for anti‐EGFR treatment of a rare lung malignancy

Italiano

Cortot

Ilié

et al. 2009

Intl Journal of Cancer

103

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Sarcomatoid carcinomas (SC) of the lung are uncommon malignant tumors composed of carcinomatous and sarcomatous cell components and characterized by a more aggressive outcome than other histological subtypes of nonsmall cell lung cancer (NSCLC). Although epidermal growth factor receptor (EGFR)‐targeted therapies have emerged as a promising therapeutic approach in patients with advanced typical NSCLC such as adenocarcinoma, the potential clinical activity of these drugs in lung SC is still unknown. To investigate this point, we have analyzed the status of 4 EGFR pathways biomarkers in a series of lung SC. EGFR protein expression, EGFR gene copy number, EGFR mutational status and KRAS mutational status were assessed in a series of 22 consecutive cases of primary lung SC. EGFR protein overexpression was observed in all the cases. High level of polysomy (≥4 copies of the gene in >40% of cells) was detected in 5 cases (23%). No EGFR mutation was detected. KRAS mutations were found in 8 patients (38%; Gly12Cys in 6 cases and Gly12Val in 2 cases). The consistent EGFR protein overexpression and the high rate of KRAS mutation may contribute to the poorer outcome of lung SC in comparison with typical NSCLC. The rare incidence of increased EGFR gene copy number, the lack of EGFR mutation and the high rate of KRAS mutation observed in our series also suggest that most patients with lung SC are not likely to benefit from anti‐EGFR therapies. © 2009 UICC

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“…12 The expected product length was 170 bp. Subsequently, 206 PCR products were purified using the QIAquick gel extraction kit (Qiagen, Venlo, the Netherlands) following manufacturer's instructions, whereas 90 PCR products were purified by the enzymatic reaction with ExoSapIT (USB, Staufen, Germany).…”

Section: Kras Pcr and Dideoxy Sequencingmentioning

confidence: 97%

“…12 Subsequently, products were purified with ExoSapIT (USB). Next, the single nucleotide primer extension reaction was performed as previously described 9 by adding four different oligonucleotides for each mutation hotspot and allowing the addition of a specific dideoxynucleotide triphosphate differently labeled ( Figure 1).…”

Section: Kras Snapshotmentioning

confidence: 99%

SNaPshot and StripAssay as Valuable Alternatives to Direct Sequencing for KRAS Mutation Detection in Colon Cancer Routine Diagnostics

Sarasqueta

Moerland

Bruyne

et al. 2011

The Journal of Molecular Diagnostics

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Although direct sequencing is the gold standard for KRAS mutation detection in routine diagnostics, it remains laborious, time consuming, and not very sensitive. Our objective was to evaluate SNaPshot and the KRAS StripAssay as alternatives to sequencing for KRAS mutation detection in daily practice. KRAS exon 2-specific PCR followed by sequencing or by a SNaPshot reaction was performed. For the StripAssay, a mutant-enriched PCR was followed by hybridization to KRAS-specific probes bound to a nitrocellulose strip. To test sensitivities, dilution series of mutated DNA in wild-type DNA were made. Additionally, direct sequencing and SNaPshot were evaluated in 296 colon cancer samples. Detection limits of direct sequencing, SNaPshot, and StripAssay were 20%, 10%, and 1% tumor cells, respectively. Direct sequencing and SNaPshot can detect all 12 mutations in KRAS codons 12 and 13, whereas the StripAssay detects 10 of the most frequent ones. Workload and time to results are comparable for SNaPshot and direct sequencing. SNaPshot is flexible and easy to multiplex. The StripAssay is less time consuming for daily laboratory practice. SNaPshot is more flexible and slightly more sensitive than direct sequencing. The clinical evaluation showed comparable performances between direct sequencing and SNaPshot. The StripAssay is rapid and an extremely sensitive assay that could be considered when few tumor cells are available. However, found mutants should be confirmed to avoid risk of false positives.

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EGFR and KRAS mutations as criteria for treatment with tyrosine kinase inhibitors: retro- and prospective observations in non-small-cell lung cancer

Cited by 131 publications

References 27 publications

Epithelioid sarcoma expresses epidermal growth factor receptor but gene amplification and kinase domain mutations are rare

Epithelioid sarcoma expresses epidermal growth factor receptor but gene amplification and kinase domain mutations are rare

EGFR and KRAS status of primary sarcomatoid carcinomas of the lung: Implications for anti‐EGFR treatment of a rare lung malignancy

SNaPshot and StripAssay as Valuable Alternatives to Direct Sequencing for KRAS Mutation Detection in Colon Cancer Routine Diagnostics

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