LAUSR

Precision medicine is the concept of tailoring treatment to individual patients based on the presence or absence of certain objectively measurable parameters known as biomarkers. These biological markers can be predictive (ie, tell whether a given drug will work) or prognostic (ie, tell how better or worse the cancer outcomes will be regardless of treatment) or both. Precision medicine (ie, personalized therapy or tailored treatment) has gained enormous popularity because it aims to improve the benefit/risk profile of cancer treatment. Providing the drug only to patients who are likely to benefit and avoiding the drug in those who are not is certainly an attractive concept. In reality, however, we don’t seem to be achieving as much tangible result from this approach as promised. Experts have openly questioned the value of precision medicine—and rightly so, because the only randomized controlled trial (RCT) of precision medicine to date has provided negative results.1,2 Why has such an attractive approach failed to improve outcomes? This is a logical question to ask. Although it may well be that the concept of precision medicine is fallacious, it would be prudent to first look at biomarkers, because if there are errors in measurement of a biomarker or questions about its validity, the whole framework of precision medicine crumbles. Precision medicine is impossible without precision in the measurement and validation of biomarkers. However, accurate measurement of biomarkers is not easy. There are many potential avenues for errors. The case history of excision repair cross-complement group 1 protein (ERCC1) as a biomarker for platinum therapy in non–small cell lung cancer (NSCLC) illustrates these problems very well. ERCC1 has been touted as a predictive biomarker for platinum therapy in NSCLC for many years, and is now even available commercially, but no evidence supports or refutes this claim. A recent study mapped all the research activities concerning ERCC1 over the past 12 years.3 During this period, 28 studies of ERCC1 as a predictive biomarker for platinum therapy in NSCLC were reported. Of these, only 2 were prospective studies. Putting all the studies over 12 years together using what the authors called the “Accumulating Evidence and Research Organization” (AERO) model helped recognize major flaws in the ERCC1 research: most studies were poorly designed, the studies used different methods to measure ERCC1 levels, the cutoff points used were different across studies, the chemotherapy regimens were not uniform, and there has been little replication or validation of techniques. Thus, despite considerable investment in terms of time, money, human power, and logistics for this research over 12 years, we are unable to derive any conclusions. In this context, the ERCC1 Trial was an important study; it was the first prospective phase III study assessing both the predictive and prognostic utility of ERCC1 for squamous and nonsquamous NSCLC.4 This study found no utility of ERCC1 as a predictive or prognostic marker for platinum therapy in NSCLC. Although at first look the results suggest that this properly conducted phase III RCT settled the question of whether ERCC1 is a predictive marker of benefit from platinum therapy in NSCLC, a problem remains: this study measured ERCC1 levels using 8F1 assay. However, the accuracy of 8F1 assay in measuring ERCC1 levels has been questioned. Experiments have shown that ERCC1 is not the principal antigen recognized by the 8F1 antibody and that 8F1 does not discriminate between ERCC1-positive and Bishal Gyawali, MD