Rationale and clinical experience with epidermal growth factor receptor inhibitors in gynecologic malignancies

Abstract

The family of epidermal growth factor receptors (EGFRs) is overexpressed in many gynecologic malignancies. Extensive preclinical studies of these receptors demonstrate that they play an important role in supporting the growth of a wide variety of malignancies and that interruption of receptor function or signaling from these receptors leads to inhibition of tumor growth or in certain cases tumor regression. Recently, many therapeutic agents targeting this receptor have entered the clinic and phase II clinical studies have demonstrated activity in lung cancer, colon cancer, and head and neck malignancies. Phase II trials of both small molecule inhibitors of EGFR and antibody-based inhibitors are underway in both cervical and ovarian cancer and emerging data suggests that their activity in unselected women with advanced gynecologic malignancies is very modest. Recently, molecular analysis of lung cancers has identified that the response to small molecule inhibitors of EGFR is highly correlated with activating mutations within the EGFR. It is possible that these agents will be highly effective in a small subset of patients with gynecologic malignancies whose tumors are dependent on EGFR signaling, perhaps through an activating mutation in EGFR or its downstream pathway. Until additional research can identify the subset of patients most likely to benefit from this targeted therapy, treatment for women with gynecologic malignancies with EGFR inhibitors should be limited to investigational trials. It is critical that these trials have access to tissue of responding and nonresponding patients so to determine the rational use of these agents in the treatment of gynecologic malignancies.

Inhibition of the epidermal growth factor receptor by erlotinib prevents immortalization of human cervical cells by Human Papillomavirus type 16

“…Several studies have shown that patients who harbor mutations in the EGFR gene have a high rate of response to erlotinib (Lynch et al, 2004), but these mutations appear to be rare in cervical cancers and dysplasias (Arias-Pulido et al, 2008). In the future, EGFR inhibitors may be most effective therapeutically in patients who are preselected for genetic susceptibility (Carter, Kelly, and Giaccone, 2009; Vaidya, Parnes, and Seiden, 2005), or when they are used in combination with other targeted therapies (Gossage and Eisen, 2010; Johnson and Brown, 2010). …”

Growth factors in tussues of ovarian cancer at various stages

“…От 60 до 98 % всех случаев эпителиального РЯ де-монстрируют высокие уровни EGFR. В то же время в исследовании [20] было показано, что EGFR отражает интенсивность роста опухоли и прогрессию. Две от-дельные группы исследователей показали обратную корреляцию между EGFR и выживаемостью при РЯ [11,14].…”

Prognostic biomarkers in ovarian cancer

“…101, 102 EGFR (HER) – 1,2 and 4 proteins possess tyrosine kinase activities, whereas EGFR(HER)–3 doesn’t, but EGFR(HER3)-3 can dimerize with other EGFR(HER) family members and lead to activation of the EGFR(HER) pathways. 103 …”

“…104 Estimates ranging from 60% to 98% of all epithelial ovarian cancers express high levels of the EGFR (HER), and extensive studies also revealed that EGFR (HER) had significant implication in tumor growth and progression. 103, 105–108 Two separate groups have shown an inverse correlation between EGFR and survival in ovarian cancer. 109, 110 Others have delineated the key role of EGFR in downstream signaling pathways such as the PI3K (phosphatidylinositol-3 kinase)/Akt and ERK (external signal-regulated kinase) pathways.…”