Clin Cancer Res
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Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, gefitinib and erlotinib, lead to significant tumor regressions in 10% to 15% of non-small cell lung cancer (NSCLC) patients with EGFR activating mutations. However, 30% to 40% of NSCLC patients, majority of whom are EGFR wild-type, develop stable disease following EGFR tyrosine kinase inhibitor therapy. EGFR-directed antibodies (cetuximab) are effective treatments for head and neck squamous cell carcinomas, which seldom contain EGFR mutations. The determinant(s) of efficacy of EGFR-targeted therapies in EGFR wild-type cancers is not well defined. ⋯ Amphiregulin expression may help select EGFR wild-type patients who are likely to develop stable disease from EGFR-targeted therapies.
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Most lung cancers with activating epidermal growth factor receptor (EGFR) mutations respond to gefitinib; however, resistance to this tyrosine kinase inhibitor (TKI) invariably ensues. The T790M mutation occurs in 50% and MET amplification in 20% of TKI-resistant tumors. Other secondary mutations (D761Y and L747S) are rare. Our goal was to determine the effects of erlotinib 150 mg/d in EGFR mutated patients resistant to gefitinib 250 mg/d, because the EGFR TKI erlotinib is given at a higher biologically active dose than gefitinib. ⋯ In EGFR mutated tumors resistant to gefitinib 250 mg/d, a switch to erlotinib 150 mg/d does not lead to responses in most patients. These findings are consistent with preclinical models, because the common mechanisms of TKI resistance (T790M and MET amplification) in vitro are not inhibited by clinically achievable doses of gefitinib or erlotinib. Alternative strategies to overcome TKI resistance must be evaluated.
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Multicenter Study
Phase I combination study of trabectedin and doxorubicin in patients with soft-tissue sarcoma.
To determine the dose of trabectedin plus doxorubicin with granulocyte colony-stimulating factor support associated with manageable neutropenia and acceptable dose-limiting toxicities (DLT) in patients with recurrent or persistent soft-tissue sarcoma. ⋯ The combination of doxorubicin 60 mg/m(2) followed by trabectedin 1.1 mg/m(2) every 21 days is safe and active in patients with soft-tissue sarcoma.
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Many cancer treatments benefit only a minority of patients who receive them. This results in an enormous burden on patients and on the health care system. The problem will become even greater with the increasing use of molecularly targeted agents whose benefits are likely to be more selective unless the drug development process is modified to include co-development of companion diagnostics. ⋯ The challenges are numerous and substantial but are not primarily technological. They involve organizing publicly funded diagnostics of deregulated pathways, adopting new paradigms for drug development, and developing incentives for industry to incur the complexity and expense of co-development of drugs and companion diagnostics. This article reviews some designs for phase III clinical trials that may facilitate movement to a more predictive oncology.
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Comparative Study Clinical Trial
Letrozole is superior to anastrozole in suppressing breast cancer tissue and plasma estrogen levels.
To evaluate the influence of the third-generation aromatase inhibitor letrozole (Femara) on breast cancer tissue levels of estrone (E(1)), estradiol (E(2)), and estrone sulfate (E(1)S) in postmenopausal women undergoing primary treatment for locally advanced estrogen receptor/progesterone receptor-positive breast cancers. ⋯ Our data reveals that letrozole (2.5 mg o.d.) is more effective compared with anastrozole (1.0 mg o.d.) with respect to tissue as well as plasma estrogen suppression in patients with postmenopausal breast cancer.