Private laboratory oncologists have been making this point for years...finally validated -- in the JCO, no less!
All of these marker studies (including Her2, ER, KRAS, EGFR mutations, OncotypeDx, etc.) are highly artificial, non-real world studies. Everything gets batch processed by the same crack team of technologists, same reagents, same platforms, same pathologists, etc. over a brief period of time. In cell culture studies, they are constrained to "real world conditions." Specimens processed and tested as accessioned, in real time, over days, weeks, months, years.
In this study, the authors got null results, which didn't agree with previous findings, and blamed this on the fact that the present study was "real world," while all the prior studies were "batch processed."
From their discussion:
"Finally, it is important to note, that our study required real- time processing of tumor specimens for ERCC1 and RRM1 in situ protein levels. All prior investigations of these molecules utilized batch processing of tumor samples. Thus, day-to-day variations in the assay reliability may have not affected prior investigations, whereas our investigation suffered from this. During the entire trial, all specimens were processed by one of two investigators using a standardized operating procedure, device, and image anal- ysis application. Reagents were from similar sources and prepared identically; however, different lots of reagents were used during the 3.5-year patient accrual period. In an analysis of ERCC1 and RRM1 values over time, we noticed nonrandom trends in marker levels, suggesting that reagent and processing procedures may have influ- enced the biomarker levels.
In summary, we believe that the survival results and possibly the disease response results are false negative. However, the trial clearly demonstrates feasibility of treatment assignment for patients with advanced NSCLC across countries and academic, nonacademic, and private practice settings. We conclude that further assay development with special attention to reagent specificity, day-to-day assay conditions, and site-specific specimen processing is desirable before another trial is launched."
Randomized International Phase III Trial of ERCC1 and RRM1 Expression–Based Chemotherapy Versus Gemcitabine/Carboplatin in Advanced Non–Small-Cell Lung Cancer
Gerold Bepler, Charles Williams, Michael J. Schell, Wei Chen, Zhong Zheng, George Simon, Shirish Gadgeel, Xiuhua Zhao, Fred Schreiber, Julie Brahmer, Alberto Chiappori, Tawee Tanvetyanon, Mary Pinder-Schenck, Jhanelle Gray, Eric Haura, Scott Antonia, and Juergen R. Fischer
Abstract
Purpose:
We assessed whether chemotherapy selection based on in situ ERCC1 and RRM1 protein levels would improve survival in patients with advanced non–small-cell lung cancer (NSCLC).
Patients and Methods:
Eligible patients were randomly assigned 2:1 to the trial’s experimental arm, which consisted of gemcitabine/carboplatin if RRM1 and ERCC1 were low, docetaxel/carboplatin if RRM1 was high and ERCC1 was low, gemcitabine/docetaxel if RRM1 was low and ERCC1 was high, and docetaxel/vinorelbine if both were high. In the control arm, patients received gemcitabine/ carboplatin. The trial was powered for a 32% improvement in 6-month progression-free sur- vival (PFS).
Results:
Of 331 patients registered, 275 were eligible. The median number of cycles given was four in both arms. A tumor rebiopsy specifically for expression analysis was required in 17% of patients. The median time from informed consent to expression analysis was 11 days. We found no statistically significant differences between the experimental arm and the control arm in PFS (6.1 months v 6.9 months) or overall survival (11.0 months v 11.3 months). A subset analysis revealed that patients with low levels for both proteins who received the same treatment in both treatment arms had a statistically better PFS (P = .02) in the control arm (8.1 months) compared with the experimental arm (5.0 months).
Conclusion:
This demonstrates that protein expression analysis for therapeutic decision making is feasible in newly diagnosed patients with advanced-stage NSCLC. A tumor rebiopsy is safe, required in 17%, and acceptable to 89% (47 of 53) of patients.
J Clin Oncol 31:2404-2412. 2013 by American Society of Clinical Oncology
http://www.ncbi.nlm.nih.gov/pubmed/23690416
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