EDITORIAL

Erlotinib in Gliomas: Should Selection Be Based on EGFR and Akt Analyses?

Federico Cappuzzo

Affiliation of author: Division of Medical Oncology, Bellaria Hospital, via Altura 3, 40139-Bologna, Italy

Correspondence to: Federico Cappuzzo, MD, Division of Medical Oncology, Bellaria Hospital, via Altura 3, 40139-Bologna, Italy (e-mail: federico.cappuzzo{at}ausl.bo.it).

Gliomas are the most common primary malignant neoplasm of the central nervous system in adults. Despite tangible progress, results remain disappointing, and median survival is 10–12 months (1). Several new drugs have been developed that interfere with specific cellular targets in cancer cells. Among them, small-molecule inhibitors of the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) were shown to be effective in the treatment of solid malignancies. Gefitinib (Iressa; AstraZeneca, Wilmington, DE) and erlotinib (Tarceva; Genentech, South San Francisco, CA) are both orally active, selective EGFR tyrosine kinase inhibitors (EGFR-TKIs) that have produced impressive responses in a small subgroup of lung cancer patients (25), with a statistically significant improvement in survival compared with best supportive care in the case of erlotinib (6). EGFR represents a particularly attractive target in malignant gliomas because the receptor is expressed, amplified, or mutated in most cases (79). Moreover, because intracranial delivery of many agents is limited, small-molecule TKIs offer a pharmacologic advantage for brain malignancies (10,11). A phase II trial, evaluating efficacy and tolerability of gefitinib in 53 recurrent glioblastoma patients not selected for any biologic characteristic showed that the drug may have modest activity (12). Thirteen percent of patients had no disease progression at 6 months, suggesting a potential benefit in a small, and so far undefined, subgroup of patients. In non–small cell lung cancer (NSCLC), mechanisms underlying TKI sensitivity have been described recently, allowing clinicians to select patients with the highest probability of a clinical response. The presence of activating EGFR gene mutations and/or EGFR gene amplification has been shown to be associated with TKI sensitivity (1315), particularly in patients with EGFR-dependent activation of the antiapoptotic phosphatidylinositol 3-kinase (PI3K)–Akt pathway (1517). In other diseases, the best procedure to select patients for EGFR-TKI therapy remains unknown. No EGFR gene mutations have been described in glioma cell lines (13) or in specimens from glioma patients (13,18), indicating that these mutations have probably no role in the sensitivity of gliomas to EGFR-TKIs.

In this issue of the Journal, Haas-Kogan et al. (19) reported their experience in 41 glioma patients treated with erlotinib within a phase I study. Erlotinib was administered alone or in combination with the alkylating agent temozolomide. In this study, no EGFR gene mutation was found, confirming the limited role of EGFR gene sequencing as a predictive test for response to EGFR-TKIs in gliomas. Response to erlotinib was more frequently observed in patients with EGFR expression (P = .07) or EGFR amplification (P = .08); in patients with glioblastoma multiforme, these associations were statistically significant (P = .03 and .02, respectively). Nevertheless, among the 10 patients with EGFR gene amplification, six did not respond to the therapy, suggesting that other mechanisms are involved. In lung cancer studies (1517), activation of the PI3K–Akt pathway has been shown to play an important role in EGFR-TKI sensitivity. Therefore, the statistically significant inverse association between Akt phosphorylation and response to erlotinib reported in this study (19) is surprising. None of the 22 tumors expressing phosphorylated Akt responded to the drug, whereas all tumors responding to the drug lacked phosphorylated Akt. Based on these findings, the authors concluded that, in patients with glioblastoma multiforme, high levels of EGFR expression and low levels of phosphorylated Akt are associated with a better response to erlotinib therapy.

How then should we select glioma patients for EGFR-TKI therapy?

The association of EGFR gene amplification and expression with response to erlotinib in glioblastoma multiforme is probably the most interesting finding of this study. These findings are corroborated by a recent study (16) of NSCLC patients reporting that EGFR gene amplification, detected by fluorescence in situ hybridization, and EGFR expression, detected by immunohistochemistry, were statistically significantly associated with improved response and survival. Unfortunately, the small number of patients and the potentially confounding effect of temozolomide therapy do not allow firm conclusions to be drawn. Statistical analysis was conducted in the whole population regardless of whether patients did or did not receive temozolomide therapy, and the effect of chemotherapy on response was not considered. Although pharmacokinetic analysis showed that temozolomide did not modify the level of erlotinib in plasma (19), we cannot exclude a positive effect of temozolomide in responding patients treated with both drugs. The inverse association with Akt activation and the evidence that six of 10 patients with EGFR gene amplification did not respond to the therapy suggest that EGFR is critical for glioma cell survival in only a small fraction of patients. Because specimens were collected at the time of primary diagnosis or of resection of recurrent disease, it is also not possible to assess the impact of previous or concurrent therapies on the EGFR pathway activations (20). Therefore, we cannot exclude the possibilities that Akt was only apparently not phosphorylated in the four responding tumors with EGFR gene amplification and that the PI3K–Akt pathway remained inactive or Akt activation was not EGFR dependent in the six tumors with EGFR amplification that were refractory to the therapy. Preclinical data showed that Akt could be activated by a non–EGFR-dependent mechanism, such as loss of PTEN or insulin-like growth factor receptor 1 (IGFR-1) gene expression. Data from cell lines suggest (21) that IGFR-1 mediates resistance to anti-EGFR therapy through continued activation of the PI3K–Akt pathway. Although, in this study (19), the authors determined whether PTEN mutations were present, loss of PTEN function is often due to promoter methylation (22).

In conclusion, erlotinib may be active in a small fraction of gliomas with EGFR expression or amplification. Although there is an inverse association between Akt activation and response to erlotinib, it seems unlikely that sensitive patients have no EGFR-dependent Akt activation. The results of this preliminary study, thus, should stimulate further prospective studies to identify predictive markers for EGFR-TKI sensitivity in gliomas before their use in clinical decisions.

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