ERCC1, toxicity and quality of life in advanced NSCLC patients randomized in a large multicentre phase III trial

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Abstract

Aim

Excision repair cross complementation group 1 (ERCC1) is a promising biomarker in advanced non-small cell lung cancer (NSCLC). However, current evidence regarding the impact of ERCC1 on toxicity and quality of life (QOL) is limited.

Patients and methods

Four hundred and forty three patients with advanced NSCLC were enroled in a phase III trial and randomized to triplet chemotherapy or standard doublet regimen. Immunohistochemical evaluation for ERCC1-status was mainly performed on bioptic material. Toxicity and patient-reported QOL were correlated to ERCC1-status.

Results

We observed a significantly improved outcome in patients with ERCC1-negative (ERCC1-neg) tumours and demonstrated interaction between ERCC1-status and adenocarcinomas. Numerically more toxicity was observed in the entire population of ERCC1-neg tumours and reached significance in patients with adenocarcinomas regarding leukopenia (P = 0.015), nausea/vomiting (P = 0.040) and neurotoxicity (P = 0.037). Mean change in QOL in the entire population was −13.33 (ERCC1-neg; P = 0.001) and −2.25 (ERCC1-positive (ERCC1-pos): P = 0.607) and −14.86 (ERCC1-neg; P = 0.006) and 0 (ERCC1-pos) in patients with adenocarcinomas.

Conclusions

Patient-reported QOL deteriorated significantly among survival-favourable ERCC1-neg patients possibly due to increased toxicity especially in patients with adenocarcinomas. Our novel findings emphasise strict demands for careful patient selection, proper methodology and prospective validation of ERCC1 to prove a true survival benefit before clinical implementation.

Introduction

Translational research has provided unique knowledge in molecular cancer biology and thereby paving the way for new treatment options. Customising anti-cancer treatment by the use of biomarkers has improved outcome in a variety of malignant diseases beginning with hormone receptor status in breast cancer predicting sensitivity to anti-oestrogen therapy. During the same period Imatinib was approved for chronic myelogenous leukaemia (CML) characterised by the fusion gene Bcr-ABL. In recent years several other similar discoveries have emerged: e.g. the KRAS-mutation predicting resistance to Cetuximab in Colorectal Cancer (CRC).

Lung cancer has killed around 160.000 people in 2009 in the United States (US) alone (http://www.cancer.gov/cancertopics/types/lung) and is the leading cancer-related cause of death in the western world. Non-small cell lung cancer (NSCLC) accounts for the majority of the patients (80%) and is a relatively chemotherapy-resistant disease with response rates (RR) of 25–30% and median overall survival (OS) of 10–12 months in patients with advanced disease (70%).1 The dismal prognosis has warranted intensive translational research leading to the discovery of biomarkers with the potential to identify patient subgroups and improve outcome: Patients with mutations in the EGFR-gene are likely to benefit from Erlotinib,2 histopathology and possibly low thymidylate synthase (TS)-levels may increase response to Pemetrexed3 and the excision cross complementation group 1 (ERCC1) predicts sensitivity to Cisplatin.4

ERCC1 plays a key role in nucleotide excision repair (NER) pathway. NER repairs DNA-adducts and other DNA helix-distorting lesions including those associated with Cisplatin.5 ERCC1 works together with its XP group F (XPF) partner by a ‘cut and paste mechanism’ where it nicks the damaged DNA strand at the 5′ site of the helix-distorting Cisplatin lesion6 as well as by being involved in homologous repair of interstrand crosslinks.7 Low expression of the ERCC1-gene (ERCC1-neg) may predict increased sensitivity to platinum-based chemotherapy possibly due to saturation of the enzyme complex, which is supported by a number of studies.4, 8, 9, 10, 11

However, only few studies4, 12, 13 have explored the correlation between ERCC1-status and toxicity in advanced NSCLC and reported different results. Toxicity is an important issue if the biomarker is to be clinically applied. The increased effect of Cisplatin-based chemotherapy regimens in ERCC1-neg patients could potentially increase the toxicity and deteriorate quality of life (QOL). To our knowledge no research groups have explored the impact of ERCC1-status on QOL. In ovarian and gastro-intestinal (GI) cancer ERCC1 also appears to be a promising predictive marker and the impact of different ERCC1 single nucleotide polymorphisms (SNP) has been correlated with toxicity but with conflicting results.14, 15, 16, 17

Taken together, the impact of ERCC1-status on toxicity is far from elucidated and dominated by heterogenous studies, using different methodologies and reporting varying conclusions. The objective of this study was to explore the correlation between immunohistochemically evaluated ERCC1-status, toxicity and QOL in a large homogeneous population of advanced NSCLC patients randomized in a chemotherapy trial.18 Our group has previously shown an interaction between ERCC1-neg status and adenocarcinomas yielding a favourable Hazard Ratio (HR) in predicting Cisplatin sensitivity in advanced NSCLC patients.19 Accordingly, we explored the toxicity profile and QOL in this subgroup of patients.

Section snippets

Patients and treatment

A total of 443 chemotherapy-naive patients aged 18–75 years with histologically verified inoperable NSCLC, performance status 0–2 and normal organ function where included in the study (LU2007) and randomized to regimen A (Paclitaxel 180 mg/m2 and cisplatin 100 mg/m2 day 1 with Gemcitabine 1000 mg/m2 day 1 and 8 every 3 weeks) or regimen B (Cisplatin 100 mg/m2 day 1 every 3 weeks and weekly intravenously (i.v.) Vinorelbine for a maximum of 6 cycles) to examine for superiority in the intensive regimen.

Characteristics of the population

A total of 443 patients were randomized in the chemotherapy trial (LU2007) without statistical significant survival difference between the triplet regimen and the standard doublet regimen. Two hundred and sixty four patients (59.5%) of the 443 patients originally randomized to the two treatment arms could be immunohistochemically evaluated for ERCC1-status. The remaining 40.5% of patients could not be evaluated for ERCC1 due to unavailable tissue samples, no tumour tissue left, etc. (Fig. 1).

No

Discussion

ERCC1 has previously been shown to be a promising biomarker in NSCLC4, 10 and in other malignancies such as ovarian cancer23, 24 and GI-cancer.25, 26 However, the evidence regarding the role of ERCC1-status in toxicity and QOL is sparse and heterogenous, especially in patients with advanced NSCLC. A tolerable toxicity profile is of great importance if clinicians are to customise chemotherapy treatment based on ERCC1-status and the survival benefit should be weighted against a possible

Conflict of interest statement

None declared.

Acknowledgements

We thank Kell Østerlind and Søren Astrup Jensen for excellent assistance in the statistical analysis and Lone Svendstrup, Michelle S. Lage, Camilla C. Mortensen and Maria Anderberg for expert technical assistance. We also thank Claus B. Andersen for excellent assistance in design and conception. The Harboe foundation, Augustinus foundation and the Research Council of Rigshospitalet supported this study.

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