Genetic Biomarker for Taxane-Induced Neuropathy

Maurie Markman, MD


November 01, 2012

A Genome-Wide Association Identifies Novel Loci for Paclitaxel-Induced Sensory Peripheral Neuropathy in CALGB 40101

Baldwin RM, Owzar K, Zembutsu H, et al
Clin Cancer Res. 2012;18:5099-5109


The Cancer and Leukemia Group B (CALGB) 40101 study evaluated the ideal duration of adjuvant paclitaxel or doxorubicin/cyclophosphamide for patients with lower-risk primary breast cancer.[1] As an adjunct to this study, the CALGB investigators conducted a prospective analysis of 855 patients of European ancestry who participated in the 40101 study and who received paclitaxel in an effort to determine whether there is an association between specific germline nucleotide polymorphisms and the risk for paclitaxel-associated neuropathy. In the initial (discovery) phase of this effort, a rather striking association was found between a specific polymorphism in FGD4 (rs10771973) and the development of early-onset neuropathy (hazard ratio [HR], 1.57; P = 2.6 x 10-6) following paclitaxel therapy. A confirmatory study undertaken in a separate group of 154 patients with a similar ancestry as well as in a group of African American patients (n = 117) who also received the drug, and the relationship was observed in both the confirmatory European (HR, 1.72; P = .013) and African American (HR, 1.93; P =.0067) populations. Of note, mutations in FGD4 have already been implicated in Charcot-Marie-Tooth neuropathy type 4, a group of inherited progressive motor and sensory neuropathies.[2]


Paclitaxel is one of the most useful antineoplastic agents in the oncologist's armamentarium and is a common component of effective primary chemotherapy for advanced cancers of the breast, lung, ovary, and endometrium. Evidence also supports the potential utility of the continuation of paclitaxel as a maintenance strategy for 12 months in patients with advanced ovarian cancer who have achieved a clinically defined complete response to front-line platinum/paclitaxel chemotherapy.[3] Unfortunately, the major toxicity of the agent is peripheral neuropathy that can develop during or following the completion of therapy. This treatment side effect can have a very serious negative impact on a patient's quality of life, and although the symptoms may improve over a period of many months in some patients, they may persist in others for the remainder of the individual's life.

The ability to identify patients who are at increased risk for experiencing this toxicity prior to the initiation of treatment could be highly beneficial to oncologists as they decide how to manage a particular patient in whom paclitaxel is an option. This information might also be useful in the decision regarding how long treatment should be continued.

An effort similar to this was done with a cohort from the ongoing Eastern Cooperative Oncology Group E5103 study that is comparing doxorubicin/cyclophosphamide followed by paclitaxel with or without concurrent or sequential bevacizumab in patients with early-stage breast cancer. In the genetic substudy of 2204 patients, associations were found between paclitaxel-induced neuropathy and polymorphisms in RWDD3 and TECTA,[4] but further study of these genes in other patient populations was not able to confirm the association.[5]

The validity of the association between the FGD4 polymorphism and the development of paclitaxel-related peripheral neuropathy is supported by 2 factors: first, the same FGD4 polymorphism was identified in the CALGB 40101 cohort and in the 2 confirmatory populations, and second, the FGD4 had previously been shown to be related to the development of a neuropathy. While it will be important for these results to be confirmed in another large patient cohort, the observation has the realistic potential to be very useful in routine cancer management in the near future.