The Use of Pharmacogenomics for Selection of Therapy in Non-Small-Cell Lung Cancer

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For patients with non-small cell lung cancer, performance status is the only predictor of clinical outcome that is currently known.

It is thought that pharmacogencomic markers may also be able to predict outcome, so researchers sought to prove this by linking clinical and pharmacogenomic measures with overall survival. The researchers conducted a retrospective analysis that included the records of 50 patients with advanced non-small cell lung cancer between the years of 1998 and 2008.

In addition to noting the gender, race, performance status, and chemotherapy regimen for each patient, researchers also measured the stromal expression of pharmacogenomic markers such as VEGFR, ERCC1, 12-3-3σ, pAKT, and PTEN. A Cox proportional hazards model was used to compare overall survival with pharmacogenomics markers and clinical factors. The median age of patients being studied was 65 years. Platinum-based therapy was administered in 40 patients.

The researchers found factors such as female gender, performance status, and having received gemcitabine therapy were significantly association with longer overall survival (P=0.04, P=0.004, P=0.003, respectively). The age of a patient was not found to have a correlation with length of survival.

The researchers also indicated that race had an effect on overall survival, they observed that Caucasians had a median overall survival of 14.8 months compared to African Americans whose median survival was 10.4 months (P=0.1).

The researchers also found that patients who received platinum-based chemotherapy had a median 15 months survival compared to 8 months in patients who did not receive platinum-based therapy (P=0.01).

Importantly, the researchers found no association between any of the pharmocogenomic markers and a patients overall survival in patients who were treated with platinum (for which ERCC1 negativity was strongly associated with longer survival [P=0.01]).

Performance status is the only known clinical predictor of outcome in patients with advanced non-small-cell lung cancer.
Performance status is the only known clinical predictor of outcome in patients with advanced non-small-cell lung cancer.

Abstract

Introduction: Performance status (PS) is the only known clinical predictor of outcome in patients with advanced non-small-cell lung cancer (NSCLC), although pharmacogenomic markers may also correlate with outcome. The aim of our study was to correlate clinical and pharmacogenomic measures with overall survival.

Methods: This was an IRB approved, retrospective study in which the medical records of 50 patients with advanced NSCLC from 1998–2008 were reviewed, and gender, race, PS, and chemotherapy regimens were documented.

Stromal expression of pharmacogenomic markers (VEGFR, ERCC1, 14-3-3σ, pAKT, and PTEN) was measured. Clinical factors and pharmacogenomics markers were compared to overall survival using a Cox proportional hazards model.

Results: Forty patients received platinum-based therapy. Median age was 65 years. Improved PS, female gender, and gemcitabine therapy were signifi-cantly associated with longer overall survival (P = 0.004, P = 0.04, and P = 0.003, respectively). Age was not associated with survival.

Caucasians had better overall survival in comparison to African Americans with median survival of 14.8 months versus 10.4 months (P = 0.1). Patients treated with platinum-based therapy had better survival of 15 months versus 8 months for non-platinum based therapy (P = 0.01).

There was no significant association between any of the pharmacogenomics markers and overall survival other than in patients treated with platinum, in whom ERCC1 negativity was strongly associated with longer survival (P = 0.007).

Conclusion: ERCC1 negativity with platinum therapy, gemcitabine therapy, good PS, and female gender all correlated with improved overall survival in patients with advanced NSCLC. 


KEYWORDS: pharmacogenomics, selection of therapy, non-small-cell lung cancer

CITATION: Karim et al. The Use of Pharmacogenomics for Selection of Therapy in Non-Small-Cell Lung Cancer. Clinical Medicine Insights: Oncology 2014:8 139–144 doi: 10.4137/CMO.S18369.

RECEIVED: July 3, 2014. RESUMBITTED: September 21, 2014. ACCEPTED FOR PUBLICATION: September 24, 2014.

ACADEMIC EDITOR: William CSCho, Editor in Chief

TYPE: Original Research

FUNDING: Authors disclose no funding sources.

COMPETING INTERESTS: Authors disclose no potential conflicts of interest.

COPYRIGHT: © the authors, publisher and licensee Libertas Academica Limited. This is an open-access article distributed under the terms of the Creative Commons CC-BY-NC 3.0 License.

CORRESPONDENCE: karimnf@ucmail.uc.edu

Paper subject to independent expert blind peer review by minimum of two reviewers. All editorial decisions made by independent academic editor. Upon submission manuscript was subject to anti-plagiarism scanning. Prior to publication all authors have given signed confirmation of agreement to article publication and compliance with all applicable ethical and legal requirements, including the accuracy of author and contributor information, disclosure of competing interests and funding sources, compliance with ethical requirements relating to human and animal study participants, and compliance with any copyright requirements of third parties. This journal is a member of the Committee on Publication Ethics (COPE). 


Introduction

Lung cancer is the leading cause of cancer-related deaths in the United States. Even after 30 years of improved therapeutic approaches, the 5-year mortality of lung cancer remains alarmingly high at 86%.1

The emerging application of pharmacogenomics offers the potential to identify drugs and drug combinations in the treatment of lung cancer according to an individual's unique genetic makeup.

A series of randomized clinical trials have demonstrated that survival of patients with stage III or IV non-small-cell lung cancer (NSCLC) is improved with the use of chemotherapy compared to best supportive care.2,3 Among the initial chemotherapeutic agents that demonstrated reproducible activity in NSCLC was the non-classical alkylating agent cisplatin.

More recently, newer agents such as gemcitabine and taxanes have been combined with cisplatin; however, the ability to predict which patients are likely to benefit from chemotherapy remains a challenging dilemma with no uniformly reliable clinical predictors other than performance status (PS) and weight loss.

Several studies have linked cisplatin resistance to high expression of the DNA repair gene excision repair cross-complementation group 1 (ERCC1).4–7

ERCC1 is 1 of 16 genes that encodes the nucleotide excision repair complex. ERCC1 is a nucleotide excision repair enzyme playing an important role in DNA repair mechanism that removes the therapeutic platinum–DNA adducts from the tumor DNA. NSCLC patients with surgically removed early stage tumors, who received no further therapy, had a better survival if their tumors were ERCC1 positive.8

These studies also have emphasized that patients with lowest levels of mRNA expression of ERCC1 tend to have better response to cisplatin-based therapy. This indicates the importance of considering ERCC1 mRNA expression as a predictive marker for the effectiveness of cisplatin-based chemotherapy.

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