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EGFR mutations predict lung-cancer response to gefitinib
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Two research groups have identified why only some patients with nonsmall-cell lung cancer (NSCLC) respond to treatment with gefitinib, an inhibitor of epidermal growth-factor receptor (EGFR). Patients who respond have specific mutations in EGFR—a finding that could help clinicians decide which patients will benefit most from gefitinib treatment. NSCLC accounts for 85% of cases of lung cancer. Prognosis for patients with NSCLC is poor, and for nonresectable tumours conventional chemotherapy is done with palliative, rather than curative, intent. High expression of EGFR in malignant tissue compared with healthy lung tissue suggests EGFR inhibitors might be beneficial in NSCLC. As a result, the US Food and Drug Administration approved gefitinib in May, 2003, for third-line treatment of NSCLC, even though only 10–19% of patients responded to gefitinib in phase III trials. Senior researcher Daniel Haber (Massachusetts General Hospital Cancer Center, Harvard, USA) and colleagues analysed EGFR in tumours of nine patients who had responded to gefitinib. Eight patients had small in-frame deletions or aminoacid substitutions in the ATP-binding pocket of EGFR, which is also the site where gefitinib binds. Samples of tumour tissue from seven non-responders had no EGFR mutations (N Eng J Med, published online April 29, 2004; DOI: 10.1056/NEJMoa040938). William Sellers (Dana-Farber Cancer Institute, Boston, MA, USA) and his group have also identified similar mutations in EGFR (Science, published online April 29, 2004; DOI: 10.1126/science.1099314). These researchers were systematically screening common human tumours for mutations in protein tyrosine kinases when they noticed that the pattern of EGFR mutations in NSCLC matched patient responsiveness to gefitinib in clinical trials. For example, says Sellers, the occurence of mutations in tumours from Japanese patients was much higher than in tumours from US patients. There was also a direct correlation between gefitinib sensitivity THE LANCET Oncology Vol 5 June 2004
and presence of EGFR mutations in patients treated at Sellers’ institution. “These two studies are a breakthrough”, says Guiseppe Giaccone (Vrije Universiteit Medical Center, Amsterdam, The Netherlands), “even though this important finding comes from a limited number of patients”. Clinical trials are needed to test whether patient selection on the basis of EGFR mutation will improve the response to gefitinib in NSCLC. However, says Sellers, “some clinicians may immediately move gefitinib up front in a patient who has an EGFR mutation”. Haber adds, “it may be possible to design an inhibitor that is specific for the mutant receptor and that works
© Digital Vision; modified by S Wood
EGFR mutations predict lung-cancer response to gefitinib
Who would gain most benefit from gefitinib?
better against tumours, but has even fewer side effects than gefitinib”. Jane Bradbury
Pancreas-preserving D2 dissection offers promise to patients with gastric cancer D2 dissection to preserve the pancreas in patients with gastric cancer could improve survival if done in experienced centres, according to the Italian Gastric Cancer Study Group (Br J Cancer 2004; 90: 1727–32). This finding contradicts two previous studies (N Engl J Med 1999; 340: 908–14 and Br J Cancer 1999; 79: 1522–30) that did not show survival benefit for D2 gastrectomy compared with D1 resection. In previous studies, limited hospital capacity and routine application of pancreas resection in the case of total gastrectomy might have lead to these results, says co-author Mitsuru Sasako (National Cancer Center Hospital, Tokyo, Japan). “D2 showed unacceptably high mortality in both the Dutch and British trials without significant improvement in survival”, says Sasako. In Japan, D2 dissection might lead to a higher 5-year survival than is seen in western countries. “The biggest problem with D2 dissection in prior studies has been a large morbidity and a perioperative mortality of over 10%”, says Jeffrey Drebin (Abramson Cancer Center, University of Pennsylvania, Philadelphia, USA). These figures are
related to lack of physician expertise, he adds. Sasako and colleagues did a phase II study on 191 patients with gastric cancer based on Japanese criteria for standard D2 gastrectomy and postoperative management. Overall 5-year survival was 55·0%; overall morbidity was 20·9%; and postoperative inhospital mortality was 3·1%. The Italian Group has shown “that pancreas preservation, together with much higher hospital [capacity] in [the] trial, could improve morbidity, mortality, and survival”, says Sasako. But, whether the results are beacuse of D2 dissection or a result of the investigator’s surgical expertise remains to be seen, cautions Drebin. Completion of a phase III trial has been difficult because of slow accrual, says Sasako, who adds that an interim analysis by an independent researcher to avoid unnecessary randomisation might be helpful. Drebin awaits the results of phase III trials, but questions whether positive outcomes could be generalised to all surgical settings. “If results show the procedure is beneficial, it still requires training and focus”, he says. Heather Lindsey
http://oncology.thelancet.com
For personal use. Only reproduce with permission from The Lancet.
335
Two research groups have identified why only some patients with nonsmall-cell lung cancer (NSCLC) respond to treatment with gefitinib, an inhibitor of epidermal growth-factor receptor (EGFR). Patients who respond have specific mutations in EGFR—a finding that could help clinicians decide which patients will benefit most from gefitinib treatment. NSCLC accounts for 85% of cases of lung cancer. Prognosis for patients with NSCLC is poor, and for nonresectable tumours conventional chemotherapy is done with palliative, rather than curative, intent. High expression of EGFR in malignant tissue compared with healthy lung tissue suggests EGFR inhibitors might be beneficial in NSCLC. As a result, the US Food and Drug Administration approved gefitinib in May, 2003, for third-line treatment of NSCLC, even though only 10–19% of patients responded to gefitinib in phase III trials. Senior researcher Daniel Haber (Massachusetts General Hospital Cancer Center, Harvard, USA) and colleagues analysed EGFR in tumours of nine patients who had responded to gefitinib. Eight patients had small in-frame deletions or aminoacid substitutions in the ATP-binding pocket of EGFR, which is also the site where gefitinib binds. Samples of tumour tissue from seven non-responders had no EGFR mutations (N Eng J Med, published online April 29, 2004; DOI: 10.1056/NEJMoa040938). William Sellers (Dana-Farber Cancer Institute, Boston, MA, USA) and his group have also identified similar mutations in EGFR (Science, published online April 29, 2004; DOI: 10.1126/science.1099314). These researchers were systematically screening common human tumours for mutations in protein tyrosine kinases when they noticed that the pattern of EGFR mutations in NSCLC matched patient responsiveness to gefitinib in clinical trials. For example, says Sellers, the occurence of mutations in tumours from Japanese patients was much higher than in tumours from US patients. There was also a direct correlation between gefitinib sensitivity THE LANCET Oncology Vol 5 June 2004
and presence of EGFR mutations in patients treated at Sellers’ institution. “These two studies are a breakthrough”, says Guiseppe Giaccone (Vrije Universiteit Medical Center, Amsterdam, The Netherlands), “even though this important finding comes from a limited number of patients”. Clinical trials are needed to test whether patient selection on the basis of EGFR mutation will improve the response to gefitinib in NSCLC. However, says Sellers, “some clinicians may immediately move gefitinib up front in a patient who has an EGFR mutation”. Haber adds, “it may be possible to design an inhibitor that is specific for the mutant receptor and that works
© Digital Vision; modified by S Wood
EGFR mutations predict lung-cancer response to gefitinib
Who would gain most benefit from gefitinib?
better against tumours, but has even fewer side effects than gefitinib”. Jane Bradbury
Pancreas-preserving D2 dissection offers promise to patients with gastric cancer D2 dissection to preserve the pancreas in patients with gastric cancer could improve survival if done in experienced centres, according to the Italian Gastric Cancer Study Group (Br J Cancer 2004; 90: 1727–32). This finding contradicts two previous studies (N Engl J Med 1999; 340: 908–14 and Br J Cancer 1999; 79: 1522–30) that did not show survival benefit for D2 gastrectomy compared with D1 resection. In previous studies, limited hospital capacity and routine application of pancreas resection in the case of total gastrectomy might have lead to these results, says co-author Mitsuru Sasako (National Cancer Center Hospital, Tokyo, Japan). “D2 showed unacceptably high mortality in both the Dutch and British trials without significant improvement in survival”, says Sasako. In Japan, D2 dissection might lead to a higher 5-year survival than is seen in western countries. “The biggest problem with D2 dissection in prior studies has been a large morbidity and a perioperative mortality of over 10%”, says Jeffrey Drebin (Abramson Cancer Center, University of Pennsylvania, Philadelphia, USA). These figures are
related to lack of physician expertise, he adds. Sasako and colleagues did a phase II study on 191 patients with gastric cancer based on Japanese criteria for standard D2 gastrectomy and postoperative management. Overall 5-year survival was 55·0%; overall morbidity was 20·9%; and postoperative inhospital mortality was 3·1%. The Italian Group has shown “that pancreas preservation, together with much higher hospital [capacity] in [the] trial, could improve morbidity, mortality, and survival”, says Sasako. But, whether the results are beacuse of D2 dissection or a result of the investigator’s surgical expertise remains to be seen, cautions Drebin. Completion of a phase III trial has been difficult because of slow accrual, says Sasako, who adds that an interim analysis by an independent researcher to avoid unnecessary randomisation might be helpful. Drebin awaits the results of phase III trials, but questions whether positive outcomes could be generalised to all surgical settings. “If results show the procedure is beneficial, it still requires training and focus”, he says. Heather Lindsey
http://oncology.thelancet.com
For personal use. Only reproduce with permission from The Lancet.
335