Candidate pathway-based genetic association study of platinum and platinum–taxane related toxicity in a cohort of primary lung cancer patients
Introduction
Combination chemotherapy with a platinum drug or a platinum drug combined with a taxane is used for many types of cancer including ovarian, testicular, lung, breast, and colorectal [1], [2]. Chemotherapy-induced peripheral neuropathy (CIPN) is a common toxicity associated with this treatment [3]. It is typically a sensory neuropathy that may necessitate dose reduction and lead to impaired quality of life [3], [4], [5]. Treatment and preventive strategies have had limited success [6], [7], [8], [9], [10]. CIPN is the major dose limiting toxicity for this common chemotherapy regime. The mechanism underlying neurotoxicity is not understood. Apoptosis of primary sensory dorsal root ganglion (DRG) neurons due to formation of platinum adducts in nuclear and mitochondrial DNA is a central mechanism in rodent models [11], [12], [13], [14], [15], [16], [17], [18], [19]. This results in mitochondrial dysfunction and disruption in cell cycle [14], [15], [19]. Thus the mechanisms of neurotoxicity and cancer cytotoxicity have many similarities and separating the beneficial cytotoxic effect from the neurotoxic effect may be difficult.
A different approach to preventing neurotoxicity may result from understanding why some patients develop CIPN, while others do not. This can be approached from an epidemiological and genetic perspective. A large study using Medicare insurance records identified that the number of cycles of chemotherapy, patient age and cumulative drug dose, were associated with the risk of developing CIPN [2], [20], [21], [22]. Genetic risk factors have been associated with polymorphisms in glutathione-S-transferase (GST) gene family isoforms [2], [20], [21], [22], especially GSTP-1 [2], [20], [21], [22] signaling pathways, metal transporters, growth factors, and DNA repair genes [2], [11], [23], [24], [25], [26], [27].
We now report both an epidemiological and multi-gene association study in a cohort of 950 primary lung cancer patients who received platinum and platinum–taxane chemotherapy. Medical records were available for identifying demographic and epidemiologic data for all of these patients. DNA samples were available for the genetic study. We used a candidate pathway-based approach because it is a hypothesis driven approach to the use of single nucleotide polymorphism data. This contrasts with genome-wide association studies (GWAS) that may identify polymorphisms in genes not mechanistically known to be associated with metabolism of the specific drug but also identify many more false-positive associations. The genes and pathways chosen were based on their known involvement with metabolism that focuses on glutathione, cell cycle, cell signaling, apoptosis, and DNA repair pathways, all of which have been implicated in animal model studies of CIPN [2], [11], [23], [24], [25], [26], [27].
Section snippets
Patient cohort and inclusion criteria
Patients included in this study were chosen from a previously described, larger cohort of primary lung cancer patients [28], [29], [30], [31], [32]. Patients had a diagnosis of primary lung cancer in the electronic medical record system and were seen at Mayo Clinic between 1997 and 2006. Patients who were treated with at least one dose of platinum chemotherapy were included. A Mayo Clinic chest pathologist verified lung cancer diagnoses. All patients consented to participate in the study and to
Epidemiological study
Of the 950 patients included in this cohort, a total of 279 patients had CIPN, 456 patients did not have CIPN, and 215 patients had unknown CIPN status (Fig. 1). Table 2 shows the p values and odds ratios of CIPN in each group compared to the reference group with no comorbidities. Patients who had diabetes mellitus were more than twice as likely to have CIPN [p = 0.0002, OR = 2.41 (1.51–3.86)]. Neither the CNS metastases nor neurological disease groups were significantly associated with the
Discussion
Peripheral neuropathy is the most common dose-limiting toxicity for many chemotherapy agents. It occurs in 30–40% of patients treated with platinum and taxane drugs [3]. Using data from IMS Health (Danbury, Connecticut) it has been calculated that between 390,470 and 465,441 patients develop CIPN each year with an annual cost of $2.39–2.73 billion dollars. Multiple treatment approaches to protect against CIPN have failed [10]. An alternative approach is to examine risk factors for an individual
Conflict of interest
There is no conflict of interest.
Acknowledgments
We thank Mayo Clinic CCaTS (Center for Clinical and Translational Science) for support for this manuscript. We also thank Susan Ernst and Jane Meyer for their help in preparation and submission of this manuscript.
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