Monday, November 18, 2013

Controversy over the PGx of Cisplatin-Induced Hearing Loss in children

Hearing loss is a common side effect in cancer patients treated with cisplatin, with significant effects on quality of life. Age, dosage, cranial irradiation and concomitant vincristine use are all established risk factors for cisplatin ototoxicity. However, there is debate surrounding genetic variants associated with risk and the clinical utility of this knowledge. This controversy is highlighted in a new commentary available online in Clinical Pharmacology & Therapeutics.

Openly published history:

•    Ross et al, 2009: TPMT rs12201199 allele T (+ strand) and COMT rs9332377 allele T (+ strand) are significantly associated with an increased risk of ototoxicity (discovery and replication cohorts combined = 162 Canadian children in total, statistically significant after Bonferroni multiple testing correction). 
•    Pussegoda et al, 2013 (members of the same group): TPMT variants; rs12201199, rs1142345, rs1800460, COMT variants; rs4646316, rs9332377, and ABCC3 rs1051640 are significantly associated with risk of ototoxicity (previous cohort + replication cohort combined, total of 317 Canadian children, adjusted for age, vincristine treatment, germ-cell tumor and cranial irradiation). Of note, the COMT variants were not significantly associated in the replication cohort alone.
•    Yang et al, 2013 (same issue of CP&T): no association between the 3 TPMT variants and 2 COMT variants with risk of cisplatin ototoxicity (an independent cohort, total of 213 children enrolled in clinical trials at St Jude’s Hospital). No association with cisplatin cytotoxicity in vitro with human cell lines carrying the variants,  and no differences in hearing loss or cochlea hair cell damage between TPMT knockout and wild-type mice treated with cisplatin.

The controversy

Members of the group who published the positive genetic association findings submitted provisional patents for the analytical approach of looking for genetic variants highly predictive of cisplatin-induced hearing loss as early as 2006, but these have never been disclosed in their publications. After the Ross et al, 2009 publication, they were invited to speak at the FDA’s Drug Safety Oversight Board in 2010. In April 2011 members of the same group published an article regarding the economic benefits of testing for these genetic variants in children before cisplatin treatment. Later the same year, the FDA added information to the cisplatin drug label regarding an increased risk of hearing loss in children with certain genetic variants of TPMT.

Issues regarding data discrepancies and statistical methodology are also raised in the commentary, including significant differences in concomitant vincristine use in cases compared to controls not disclosed in the original analysis. High variation in allele frequencies between different populations exists for some of the SNPs examined, which authors of the commentary argue were not correctly addressed. In addition, p-values given in Pussegoda et al, 2013 for this original cohort are those before Bonferroni correction, whereas Ross et al, 2009 report only two statistically significant variants after correcting for multiple testing.

Transparency is key
The authors of this commentary appeal for openness and availability of data from these cohorts so they can be re-analyzed by others. They also argue for publishers to require disclosure of patents filed by authors that could be regarded as a conflict of interest. They request that the FDA revoke its amendments to the cisplatin drug label regarding TPMT genetic variants and ototoxicity. This tale also raises the issue of the difficulty in publishing negative results but the importance of this information in assessing evidence for associations.

In light of this controversy, the PharmGKB clinical annotations for TPMT and COMT variants & cisplatin in children are assigned a level of evidence of 3, as they lack clear evidence:

Read the commentary:
Challenges in Interpreting the Evidence for Genetic Predictors of Ototoxicity.
Mark J. Ratain, Nancy J. Cox, Tara O. Henderson.
Clinical Pharmacology & Therapeutics. 2013 Dec;94(6):631-5. doi: 10.1038/clpt.2013.178.

Also read:
Genetics of cisplatin ototoxicity: confirming the unexplained?
Boddy, A.V.
Clinical Pharmacology & Therapeutics. 2013 Aug;94(2):198-200.

Other genetic variants that have been reported with an association with risk of cisplatin-induced toxicity:
•    GSTP1       rs1695
•    LRP2         rs2075252
•    XPC           rs2228001
•    SLC31A1  rs10981694