Discussion:
There is only limited literature for chemotherapy toxicity in XP patients, owing to its rarity. Sumiyoshi et al(9) reported 2 elderly patients with XP variant with mutations in POLH gene encoding DNA polymerase η that is involved in the trans-lesion DNA synthesis (TLS). Both developed severe toxicity with cisplatin involving liver, kidney, cochlea, gastrointestinal tract and bone marrow ultimately resulting in death. Carneiro et al(10) reported another lethal nephrotoxicity following cisplatin in a young oral squamous cell carcinoma patient with XP. Gilbar et al(11) reported a similar toxicity with cisplatin in a patient who seems to be the only patient that survived the fatal toxicity. Both the later authors postulated the defective XPC gene to be the underlying genetic defects in these 2 patients. Our index case is the first such toxicity reported after carboplatin as per the current literature (Table-1).
XP is characterized by defective nucleotide excision repair (NER) pathway, that leads to excessive DNA damage by UV radiation. Booton etal(12) found that polymorphism in XPD gene is associated with platinum toxicity in lung cancer patients. Though in their cohort none had XP, this observation highlights the pharmacogenomic interaction involving the XP gene expression and platinum chemotherapy.
Platinum-DNA adduct formation is an important mechanism of its antineoplastic activity(13). Repair of these adducts occurs by NER, involving genes like XPA, XPB, and ERCC1-XPF(14). Recent in-vitro models suggest that XPC gene expression increases susceptibility of colorectal cancer cell lines to chemotherapy(15) and XPC mutations in fibroblasts increases oxidative DNA damage(16). In most of the XP subtypes one of the above loci are constitutionally defective and non-neoplastic cells are also at risk of exaggerated DNA damage by Platinum compounds, leading to toxicity.
Although the genetic subtype of the index case is not known, due to complete absence of neurological symptoms she was clinically labelled as XPC. Current evidence is insufficient to conclude if one or the other XP subtype is associated with more severe toxicity to chemotherapy. Also, it is not known whether similar toxicity is observed with anticancer drugs other than platinum compounds. In vitro studies of cells of various subtypes of XP can shed more light into their relative susceptibility to anticancer agents. In conclusion, we would recommend to withheld platinum compounds in XP patients and to closely monitor for toxicity of other anticancer drugs if at all used.
Conflict of Interest statement: The authors declare no conflict of interest.
Acknowledgement: We sincerely acknowledge the family of the patient for giving us the consent to publish the case
Funding: None