From bench to bedside... but when?

Abstract

Prior to September 1994, we physicians in Cancer Family Clinic sat in front of patients who had family histories of breast cancer, prophesying, albeit cautiously, that we would be practicing clinical cancer genetics differently once the first breast cancer susceptibility gene, BRCA1 was cloned. In the autumn of 1994, BRCA1 was delivered into an expectant world of scientists, clinical cancer geneticists, patients, and curious onlookers (Miki et al. 1994). In rapid succession, thanks to the Human Genome Project and its fallout technology and information, the second breast cancer susceptiblity gene BRCA2 was mapped and isolated (Wooster et al. 1994, 1995); other genes that may lend susceptiblity to breast cancer, ATM (ataxia-telangiectasia) and PTEN (Cowden syndrome), ensued (Savitsky et al. 1995; Nelen et al. 1996; Liaw et al. 1997). The era of molecular oncology had arrived. But what makes cutting-edge genetic findings of today clinical practice tomorrow? The most important criterion is benefit or potential benefit to the patient—that genetic tests result in altered clinical management. Other criteria (Table 1) include ease of mutation detection, the majority of people with a specific inherited cancer syndrome contain mutations within the same gene, the mutation analysis allows prediction of cancer risk, and effective surveillance or effective prophylactic procedures are available. Two inherited cancer syndromes illustrate the agony and ecstasy—apologies to Michelangelo—of translating the latest molecular genetic findings into clinical practice: the hereditary breast cancer (HBC) syndromes and multiple endocrine neoplasia type 2 (MEN 2). As highlighted in a Lancet Grand Round convened at the Royal Marsden Hospital, Sutton, UK (Eng et al. 1994), the differences between these syndromes were obvious even before the identification of BRCA1.