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Journal of Clinical Oncology, Vol 25, No 19 (July 1), 2007: pp. 2648-2649 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.11.3167
ERCC1-Tailored Chemotherapy in Lung Cancer: The First Prospective Randomized TrialDepartment of Medicine, Institute Gustave Roussy, Villejuif, France The cancer death toll is one of the top health problems facing the industrialized world today. Lung cancer is the leading cause of cancer death in men and also increasingly in women.1 Novel therapeutic strategies need to be developed and existing therapies optimized to increase the survival rate of lung cancer patients. Improving systemic chemotherapy will have an impact on virtually 90% of all lung cancer patients, result in the cure of more patients with resected non–small-cell lung cancer (NSCLC), and improve the survival of patients with locally advanced/metastatic lesions. In this regard, rational treatment decision making based on an analysis of biomarkers of response and resistance to cytotoxic drugs seems to be a promising approach. Platinum has long been the mainstay of chemotherapy for lung cancer. Platinum cytotoxicity results from the disruption of the double-stranded DNA molecule in cells, mainly through the formation of intrastrand adducts. Nucleotide excision repair (NER) is the primary DNA repair mechanism that removes platinum-DNA adducts from genomic DNA. Excision repair cross-complementing 1 (ERCC1) is a critical gene on the NER pathway. A growing list of reports links cisplatin, carboplatin, and oxaliplatin resistance to ERCC1 mRNA levels in tumors. This relationship has been suggested for patients with gastric, bladder, ovarian, colorectal, and non–small-cell lung cancers.2-7 We recently showed that immunohistochemically evaluated ERCC1 levels are also predictive for the survival benefit afforded by adjuvant cisplatin-based chemotherapy in patients with totally resected stage I to IIIA NSCLC.8 In the treated group, ERCC1-negative tumors derived a substantial benefit from adjuvant cisplatin-based chemotherapy, whereas their ERCC1-positive counterparts did not. Interestingly, in patients randomly assigned to the observation arm, the subgroup with ERCC1-positive tumors had a better survival compared with those with ERCC1-negative tumors. This paradoxical status of ERCC1 (a good prognostic marker in untreated resected NSCLC patients and a poor predictor of efficient adjuvant chemotherapy) was recently confirmed by Zheng et al.9 The study by Cobo et al10 in this issue of the Journal of Clinical Oncology evaluated ERCC1 mRNA expression prospectively in an attempt to predict response to cisplatin-based or cisplatin-free regimens in stage IIIB or IV in NSCLC patients. In the control arm (no customization), patients received the well-established docetaxel/cisplatin combination. In the genotypic arm, patients were allocated to docetaxel/cisplatin or docetaxel/gemcitabine regimens respectively, according to whether low or high ERCC1 mRNA levels were detected. The study met its primary end point: response rates were significantly higher in the genotypic arm (50.3%) when compared with the control arm (39.3%). However, this difference was no longer significant after a strict intent-to-treat analysis. Most importantly however, the clinical relevance remains limited, given that there was no difference between the two arms in either progression-free survival or overall survival. How can one explain the negative results of such an innovative pioneering trial of customized chemotherapy? Technical issues clearly are crucial in the setting of biomarker-based therapies. The study by Cobo et al10 is based on a series of assumptions. Evaluation of mRNA gene expression by reverse transcriptase polymerase chain reaction may be assessed safely in a convenient material: paraffin-embedded tissue. Laser capture tumor microdissection guarantees optimal tumor enrichment of the analyzed specimen. This quantitative technique produces a ratio of ERCC1 mRNA expression with housekeeping genes, thus simplifying allocation by predefining a threshold. In the trial under consideration, however, approximately 18% of the patients allocated to the genotypic arm were inassessable for ERCC1 due to insufficient tumor material. This percentage, along with patients excluded for other reasons (such as brain metastasis, protocol violations, and so on), led the authors to amend the protocol and increase recruitment by nearly 30%. The 18% dropout rate emphasizes the poor feasibility of this technique when insufficient tumor tissue is available. ERCC1 assessment was performed by Response Genetics (Los Angeles, CA), proprietor of the mRNA extraction procedure. The exact threshold defining high ERCC1 expression levels is unknown, but 43% of the patients were allocated to the high expression arm (high genotypic arm). It is therefore surprising that ranges for ERCC1 expression valve overlap between the high and low genotypic groups. Overall, major improvements of quantitative mRNA assessment are still required in the prospective setting. This technique should be compared and put into perspective with immunohistochemistry, a semiquantitative method that can be performed with a minimum amount of tissue and that has been validated for ERCC1 evaluation by two independent groups in the NSCLC setting.8,9 The design of the study by Cobo et al10 also merits discussion. The underlying hypothesis is that ERCC1 customization should improve clinical outcome (response rate and survival). This should be achieved by offering cisplatin-based therapy to ERCC1-negative patients and an active platin-free regimen to ERCC1-positive patients. The choice of docetaxel in combination with gemcitabine for ERCC1-positive patients is debatable. Indeed, although docetaxel is a tubulin-interacting agent, gemcitabine is an antimetabolite that will have an influence on the pool of nucleotides available for DNA repair, and thus may interact with the NER pathway. Given that the treatment is different in the high and low genotypic groups, the final result of the present study (either positive or negative) could either be linked to the predictive value of ERCC1 or simply to intrinsic differences related to the chemotherapy regimens selected. It is noteworthy that the authors did not reveal the predictive value of ERCC1 in the control arm in this study. The best way to control for the predictive value of ERCC1 would have been a retrospective analysis of ERCC1 expression in the noncustomized control arm, in which all patients were treated with the same cisplatin-based regimen. Finally, the design of the trial allowed for ERCC1 evaluation in any tumor tissue available. ERCC1 was evaluated in metastatic lesions in only 24% of the patients, whereas 92% of them had stage IV disease. Differential protein expression of specific biomarkers between primary and metastatic lesions has been reported in various tumors including NSCLC.11,12 In colon cancer, thymidylate synthase evaluated in metastatic lesions was shown to be more predictive than thymidylate synthase measured in the primary tumor.11 Other factors may explain interindividual ERCC1 variation, such as the smoking status (the nucleotide excision pathway is involved in tobacco-related adduct clearance), age, or the histologic subtype, but no correlation was provided in the study by Cobo et al.10 Despite these shortcomings, one should keep in mind that it was visionary and extremely audacious to initiate this prospective randomized customized trial in the early 2000s, at a time when the predictive value of selected biomarkers was not yet staunchly advocated. This partly explains the strengths and the weaknesses of the study. Future trials may integrate a combination of biomarkers (rather than a single one), use a design that specifically addresses the issue of the predictive value (rather than a mixture of new biomarkers and different treatments), and integrate individual genomic variations to explore treatment toxicities (it is striking that peripheral neurotoxicity occurred more frequently in the low ERCC1 arm). Overall, Cobo et al10 must be commended for their audacious and pioneering work, which helps pave the way toward providing individualized chemotherapy based on tumor characteristics. This is one of the strongest expectations, not only of the medical community, but also of our fellow citizens. AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. ACKNOWLEDGMENTS I thank Lorna Saint Ange for editing the manuscript. REFERENCES 1. Ruckdeschel JC, Schwartz AG, Bepler G: Cancer of the lung: NSCLC and SCLC, in Clinical Oncology. New York, NY, Elsevier, 2004, pp 1649-1743 2. Kwon HC, Roh MS, Oh SY, et al: Prognostic value of expression of ERCC1, thymidylate synthase, and glutathione S-transferase P1 for 5-fluorouracil/oxaliplatin chemotherapy in advanced gastric cancer. Ann Oncol 18:504-509, 2007 3. Bellmunt J, Paz-Ares L, Cuello M, et al: Gene expression of ERCC1 as a novel prognostic marker in advanced bladder cancer patients receiving cisplatin-based chemotherapy. Ann Oncol 18:522-528, 2007 4. Bepler G, Kusmartseva I, Sharma S, et al: RRM1 modulated in vitro and in vivo efficacy of gemcitabine and platinum in non-small-cell lung cancer. J Clin Oncol 24:4731-4737, 2006 5. Dabholkar M, Bostick-Bruton F, Weber C, et al: ERCC1 and ERCC2 expression in malignant tissues from ovarian cancer patients. J Natl Cancer Inst 84:1512-1517, 1992 6. Lord RV, Brabender J, Gandara D, et al: Low ERCC1 expression correlates with prolonged survival after cisplatin plus gemcitabine chemotherapy in non-small cell lung cancer. Clinical Cancer Res 8:2286-2291, 2002 7. Metzger R, Leichman CG, Danenberg KD, et al: ERCC1 mRNA levels complement thymidylate synthase mRNA levels in predicting response and survival for gastric cancer patients receiving combination cisplatin and fluorouracil chemotherapy. J Clin Oncol 16:309-316, 1998 8. Olaussen KA, Dunant A, Fouret P, et al: DNA repair by ERCC1 in non-small-cell lung cancer and cisplatin-based adjuvant chemotherapy. N Engl J Med 355:983-991, 2006 9. Zheng Z, Chen T, Li X, et al: DNA synthesis and repair genes RRM1 and ERCC1 in lung cancer. N Engl J Med 356:800-808, 2007 10. Cobo M, Isla D, Massuti B, et al: Customizing cisplatin based on quantitative excision repair cross-complementing 1 mRNA expression: A phase III trial in non–small-cell lung cancer. J Clin Oncol 25:2747-2754, 2007 11. Aschele C, Debernardis D, Tunesi G, et al: Thymidylate synthase protein expression in primary colorectal cancer compared with the corresponding distant metastases and relationship with the clinical response to 5-fluorouracil. Clin Cancer Res 6:4797-4802, 2000 12. Italiano A, Vandenbos FB, Otto J, et al: Comparison of the epidermal growth factor receptor gene and protein in primary non-small-cell-lung cancer and metastatic sites: Implications for treatment with EGFR-inhibitors. Ann Oncol 17:981-985, 2006 Related Articles
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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