Multi-Marker Testing for Cancer: What can we Learn from Modern Prenatal Testing for Trisomy-21

Abstract

A recent report in the New England Journal of Medicine on prenatal screening for Down’s syndrome (Malone et al 2005) received much attention in the non-scientific press, such as Time (Wallis 2005) and Forbes (Gordon 2005) magazines. This paper describes the results from a multicenter study that showed that, when an integrated, multi-marker approach was combined with a specific algorithm, it was possible to detect 90–95% of fetuses affected with trisomy 21 relatively early in a pregnancy with high accuracy, giving the prospective parents time to make appropriate choices. This study represents the culmination of over 25 years of research that has gradually increased the utility of prenatal screening for chromosomal defects. This effort started in the 1970s with the observation that there was an increased risk for chromosomal abnormalities, primarily trisomy 21, in mothers of advanced age at the time of pregnancy (Hook 1976a, b). In the mid 1980s it was shown that combining age with the results from AFP (alpha-fetoprotein) and beta-hCG (human chorionic gonadotropin) measurements in the maternal serum could increase the detection rate from below 40% to around 50–55% (Bogart et al 1987; Cuckle et al 1987). By 1990, the so-called triple test was developed, which takes into account the maternal age in combination with the levels of AFP, beta-hCG, and uE3 (unconjugated estriol) in the maternal serum during the second trimester of pregnancy, thereby achieving a detection rate of up to 70% for trisomy 21 (Cuckle et al 1988; Wald et al 1989). This detection rate was further improved a few years later with the addition of dimeric inhibin A measurement to form the quadruple test, which increased the detection rate to almost 80% (Wald et al 1994a; Aitken et al 1996). Today, either the triple or quadruple test is the standard of prenatal care for expectant mothers and their unborn child. At the same time that the quadruple test was introduced, various groups started to develop tests that could be used earlier in a pregnancy, i.e, during the first trimester, which led to the combination of the levels for the biochemical serum markers PAPP-A (pregnancy-associated plasma protein A) and free beta-hCG with the physical marker of nuchal translucency determined by ultrasound (Wald et al 1994b; Wald et al 1995; Wald and Hackshaw 1997). These developments finally culminated in two landmark studies, one in England (SURUSS) (Wald et al 2003), the other in the USA (FASTER) (Dugoff et al 2004; Malone et al 2005), that demonstrated that a combination or integration of second trimester screening with first trimester screening gives the highest sensitivity for the prenatal detection of chromosomal defects, while at the same time keeping the false-positive rate low.