Molecular predictive and prognostic markers in non-small-cell lung cancer

doi:10.1016/S1470-2045(09)70155-X

The Lancet Oncology

Volume 10, Issue 10, October 2009, Pages 1001-1010

https://doi.org/10.1016/S1470-2045(09)70155-X Get rights and content

Summary

Non-small-cell lung cancer (NSCLC) remains the leading cause of cancer death in the developed world. Platinum-based chemotherapy is the therapeutic foundation of treatment both in the metastatic and adjuvant setting and targeted therapies are entering standard treatment paradigms. However, many patients do not obtain benefit from cytotoxic agents or newer targeted therapies, but are still exposed to their toxic effects. Reliable biomarkers to select treatments for patients most likely to obtain benefit have, therefore, been an important focus for many research groups. In this paper, we review current predictive and prognostic biomarkers in NSCLC. We assess their potential clinical use and explore recent data pertaining to genome-wide approaches for treatment selection in NSCLC.

Introduction

Non-small-cell lung cancer (NSCLC) is the leading cause of cancer death in the developed world, with less than 15% of patients surviving beyond 5 years. Cytotoxic chemotherapy remains the key component of treatment in both the adjuvant and metastatic settings, although newer molecularly targeted treatments have shown activity in advanced stages.1, 2, 3, 4 Because many patients do not respond to treatment for NSCLC, personalising therapy to select those most likely to benefit promises to limit toxic effects and maximise efficacy.

Molecular analysis has evolved from simple histological characterisation of tumours, to microarray-based interrogation of thousands of genes. These advances have enabled researchers to focus on molecular pathways that are constitutively active in NSCLC, and to correlate levels of activity with clinical outcome (figure). In this paper, we review the key predictive and prognostic biomarkers that have been described in NSCLC.

Section snippets

Defining predictive and prognostic markers

A prognostic factor is a patient or tumour characteristic that identifies a better outcome for the patient regardless of treatment. A predictive factor is a patient or tumour characteristic that identifies a better outcome from treatment. Outcomes can be defined in terms of response to treatment or survival benefit from treatment. In other words, a prognostic factor determines the effect of the tumour on the patient and a predictive factor determines the effect of the treatment on the tumour.

The nucleotide excision repair (NER) pathway

The NER pathway is important in repairing DNA damage, and its components have been assessed in lung cancer and other cancers as potential biomarkers of response and resistance to treatment.

Cell-cycle regulators

Abnormalities of the key proteins controlling the cell cycle are common in human cancers.²⁵ They are, therefore, attractive targets for therapy and investigation for their potential use as biomarkers. Additionally, the cell cycle is intimately linked to DNA repair, especially via the ataxia telangiectasia-mutated pathway.

Beta-tubulin class III

Microtubules are dynamic polymers that play a part in cell division. Microtubule-interacting agents, including the taxanes and vinca alkaloids, inhibit spindle dynamics, thereby blocking mitosis. Altered expression of the beta-tubulin class III gene has been shown to correlate with paclitaxel resistance in NSCLC cell lines.¹⁸

At the clinical level, an analysis of 265 samples of NSCLC from the JBR.10 trial showed that high beta-tubulin expression, shown by immunohistochemistry,³³ correlated with

Epidermal growth factor receptor (EGFR)

The EGFR pathway is a regulator of cellular proliferation, angiogenesis, apoptosis, and migration, and EGFR is frequently overexpressed in NSCLC. EGFR protein expression can be assessed semiquantitatively by immunohistochemistry. Gene copy number can be evaluated by several methods, including fluorescence in-situ hybridisation (FISH; figure) and qRT-PCR. Finally, gene mutations can be detected by several methods including direct sequencing.

Molecular profiling as a prognostic tool

By interrogating thousands of genes simultaneously, microarray-derived gene signatures offer potential to correlate transcript expression with survival and to identify genetic pathways that might predict response to individual drugs. The technology used to capture and analyse microarray data is improving rapidly with many different platforms and analysis tools available.⁵²

Several studies have reported prognostic signatures in early stage disease.⁵³ Some have been histology specific, the largest

Conclusions

The question of which molecular markers will prove to be the most useful for selecting treatment for individual patients with NSCLC and which will be validated remains unanswered. In this Review, we have summarised the prognostic and predictive factors of these markers (table 3).

Furthermore, we still do not know whether the molecular profile of a tumour changes at the time of disease recurrence after surgery, or even after therapy for more advanced disease. There is little information as to

Search strategy and selection criteria

References for this Review were found by searches of Medline, the American Association for Cancer Research (AACR), and the American Society of Clinical Oncology (ASCO) 2004–08 meeting abstracts by use of the search terms: “molecular”, “prognostic”, “predictive”, and “non-small-cell lung cancer”. The most frequently occurring markers identified were then subjected to individual literature searches using the same search terms. The articles identified were assessed for clinical relevance by

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ReviewMolecular predictive and prognostic markers in non-small-cell lung cancer

Summary

Introduction

Section snippets

Defining predictive and prognostic markers

The nucleotide excision repair (NER) pathway

Cell-cycle regulators

Beta-tubulin class III

Epidermal growth factor receptor (EGFR)

Molecular profiling as a prognostic tool

Conclusions

Search strategy and selection criteria

Lancet Oncol

Cancer Treat Rev

Chest

Lung Cancer

Lung Cancer

Lancet

Lancet

Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer

N Engl J Med

Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer

N Engl J Med

Adjuvant paclitaxel plus carboplatin compared with observation in stage IB non-small-cell lung cancer: CALGB 9633 with the Cancer and Leukemia Group B, Radiation Therapy Oncology Group, and North Central Cancer Treatment Group Study Groups

J Clin Oncol

Erlotinib in lung cancer—molecular and clinical predictors of outcome

N Engl J Med

Excision repair cross complementing-group 1: gene expression and platinum resistance

Int J Mol Med

DNA repair by ERCC1 in non-small-cell lung cancer and cisplatin-based adjuvant chemotherapy

N Engl J Med

BRCA1: a novel prognostic factor in resected non-small-cell lung cancer

PLoS ONE

Low ERCC1 expression correlates with prolonged survival after cisplatin plus gemcitabine chemotherapy in non-small cell lung cancer

Clin Cancer Res

Prognostic and predictive importance of p53 and RAS for adjuvant chemotherapy in non small-cell lung cancer

J Clin Oncol

Erlotinib in previously treated non-small-cell lung cancer

N Engl J Med

Role of KRAS and EGFR as biomarkers of response to erlotinib in National Cancer Institute of Canada Clinical Trials Group Study BR.21

J Clin Oncol

Overall survival (OS) results from the phase III trial BMS 099: cetuximab taxane/carboplatin as 1st-line treatment for advanced NSCLC

J Thorac Oncol

K-Ras mutations (MT) and EGFR-related markers as potential predictors of cetuximab benefit in 1st line advanced NSCLC: results from the BMS099 study

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Cell cycle regulators and outcome of adjuvant cisplatin-based chemotherapy in completely resected non-small-cell lung cancer: the International Adjuvant Lung Cancer Trial Biologic Program

J Clin Oncol

Class III beta-tubulin expression and benefit from adjuvant cisplatin/vinorelbine chemotherapy in operable non-small cell lung cancer: analysis of NCIC JBR.10

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DNA synthesis and repair genes RRM1 and ERCC1 in lung cancer

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Ribonucleotide reductase messenger RNA expression and survival in gemcitabine/cisplatin-treated advanced non-small cell lung cancer patients

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Spanish customized adjuvant trial (SCAT) based on BRCA1 mRNA levels

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Review
Molecular predictive and prognostic markers in non-small-cell lung cancer