Determinants of Tumor Response and Survival With Erlotinib in Patients With Non—Small-Cell Lung Cancer

Pérez-Soler, Román; Chachoua, Abraham; Hammond, Lisa A.; Rowinsky, Eric K.; Huberman, Mark S.; Karp, Daniel D.; Rigas, James R.; Clark, Gary M.; Santabárbara, P.; Bonomi, Philip

doi:10.1200/jco.2004.11.057

Cited by 1,000 publications

(590 citation statements)

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“…Indeed, although some authors reported a relationship between EGFR protein expression assessed by IHC and clinical benefit from EGFR tyrosine kinase inhibitors in NSCLC, 13,14 such a correlation was not confirmed by others. 11,36,37 Therefore, the predictive value of EGFR IHC in NSCLC care remains to be validated.…”

Section: Discussionmentioning

confidence: 99%

“…These inhibitors produce objective response in about 12-27% of unselected patients with NSCLC. [9][10][11][12] Erlotinib has also been shown to improve the survival of patients with advanced NSCLC after a first-or secondline chemotherapy in a multicenter randomized placebo-controlled trial conducted by the National Cancer Institute of Canada. 12 Therefore, this drug has been approved by both the Food and Drug Administration and the European Medicines Agency as monotherapy for the treatment of patients with locally advanced or metastatic non-NSCLC after failure of at least 1 prior chemotherapy regimen.…”

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confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

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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“…Although the reason for this discrepancy is unknown, the occurrence of skin rash has been of particular clinical relevance since several studies have correlated it with antitumour activity (Cohen et al, 2003;Saltz et al, 2003;Perez-Soler et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Epidermal growth factor receptor dimerization status determines skin toxicity to HER-kinase targeted therapies

Laux

Jain

Singh³

et al. 2005

Br J Cancer

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Skin toxicity, a common drug-related adverse event observed in cancer patients treated with epidermal growth factor receptor (EGFR)-directed therapies is rarely seen with therapies targeting HER2. This study reports the significance of the EGFR and HER2 dimerization status in skin with regard to these dermatologic side effects. We demonstrate the differential effect of HER-directed therapies on the ligand driven activation status of EGFR, HER2 and MAPK in normal human epidermal keratinocytes. EGFR-directed therapies, such as gefitinib and cetuximab, inhibited ligand-induced activation of EGFR and MAPK in human keratinocytes. Pertuzumab, an antibody interfering with functional HER2 heterodimerization, failed to block ligand-induced HER signaling in primary keratinocytes. Using a novel proximity-based dimerization assay (eTagt) we show that EGFR homodimers are the predominant HER dimer pair in normal primary kertinocytes and in normal skin tissue from 16 patients with solid malignancies. The presence of [p]EGFR and [p]MAPK, but the absence of [p]HER2, demonstrates productive signaling via EGFR but not HER2 in human skin. These data illustrate the importance of the EGFR dimerization partner in human skin and suggests that inhibition of EGFR homodimer signaling rather than EGFR/HER2 heterodimer signaling maybe the key molecular event determining dermatologic toxicity discrepancies observed between EGFR-targeted versus HER2-targeted therapies.

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“…However, although the presence of an EGFR mutation may increase responsiveness to erlotinib, it is not indicative of survival benefit. Phase II trials for erlotinib and gefitinib have reported correlations between responsiveness to EGFR inhibition and patient characteristics such as gender, histologic type, race or ethnic origin, and smoking status (109,(116)(117)(118)(119).…”

Section: Egfr Inhibitionmentioning

confidence: 99%

The Role of VEGF and EGFR Inhibition: Implications for Combining Anti–VEGF and Anti–EGFR Agents

Tabernero

2007

Molecular Cancer Research

383

266

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Determinants of Tumor Response and Survival With Erlotinib in Patients With Non—Small-Cell Lung Cancer

Abstract: Erlotinib was active and well tolerated in this patient population, and further clinical development is clearly warranted. Cutaneous rash seems to be a surrogate marker of clinical benefit, but this finding should be confirmed in ongoing and future studies.

Cited by 1,000 publications

References 30 publications

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

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

Epidermal growth factor receptor dimerization status determines skin toxicity to HER-kinase targeted therapies

The Role of VEGF and EGFR Inhibition: Implications for Combining Anti–VEGF and Anti–EGFR Agents

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