Correspondence

Inhibition of Poly(ADP-Ribose) Polymerase in BRCA Mutation Carriers

N Engl J Med 2009; 361:1707-1708October 22, 2009

Article

To the Editor:

Fong et al. (July 9 issue),1 who used the poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor olaparib to treat tumors in patients who were carriers of BRCA mutations, state that two deaths “were deemed unlikely to be related to olaparib.” However, it is possible that the second patient died of impaired immunity induced by olaparib. Chemotactic cytokines, or chemokines, mediate the recruitment of inflammatory cells to inflamed sites. TRPM2, a plasma membrane Ca²⁺-permeable channel, controls chemokine production induced by reactive oxygen species in monocytes.2 TRPM2 channel opening in response to oxidative stress depends on activation of PARP.3,4 Therefore, treatment with a PARP inhibitor may lower levels of cytokines by inhibiting TRPM2 activity, thereby impairing immunity.

Shuzhuang Li, M.D., Ph.D.
Dalian Medical University, Dalian, China
shuzhuangli@126.com

4 References

1. 1

   Fong PC, Boss DS, Yap TA, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 2009;361:123-134
   Full Text | Web of Science | Medline

2. 2

   Yamamoto S, Shimizu S, Kiyonaka S, et al. TRPM2-mediated Ca2+ influx induces chemokine production in monocytes that aggravates inflammatory neutrophil infiltration. Nat Med 2008;14:738-747
   CrossRef | Web of Science | Medline

3. 3

   Fonfria E, Marshall IC, Benham CD, et al. TRPM2 channel opening in response to oxidative stress is dependent on activation of poly(ADP-ribose) polymerase. Br J Pharmacol 2004;143:186-192
   CrossRef | Web of Science | Medline

4. 4

   Buelow B, Song Y, Scharenberg AM. The poly(ADP-ribose) polymerase PARP-1 is required for oxidative stress-induced TRPM2 activation in lymphocytes. J Biol Chem 2008;283:24571-24583
   CrossRef | Medline

Author/Editor Response

Li raises the possibility that olaparib contributed to a fatal infection in a 64-year-old patient with advanced ovarian cancer. In her case, the administration of multiple regimens of chemotherapy were followed by the development of drug-resistant metastatic disease, with necrotic cutaneous tumor nodules that were colonized by multiple organisms, including klebsiella species. These nodules did not respond to treatment with olaparib. Gram-negative sepsis developed 28 days after olaparib was started, and blood cultures grew klebsiella and other organisms, a finding consistent with the idea that the infection had arisen from the tumor nodules. Although it is not possible to exclude drug involvement, the incidence of drug-related infections in this phase 1 trial and in all other patients treated with olaparib alone is low. In addition, preclinical studies in PARP1-deficient knockout mice suggest that the mice are resistant to lipopolysaccharide-induced, gram-negative sepsis, a finding that supports our interpretation of the outcome in this case.1 Nonetheless, more extensive evaluation of the safety of olaparib and other PARP inhibitors remains critical to their clinical development.

Timothy A. Yap, M.D.
Stan B. Kaye, M.D.
Johann S. de Bono, M.D., Ph.D.
Institute of Cancer Research, Sutton, United Kingdom
johann.de-bono@icr.ac.uk

1 References

1. 1

   Oliver FJ, Menissier-de Murcia J, Nacci C, et al. Resistance to endotoxic shock as a consequence of defective NF-kappaB activation in poly (ADP-ribose) polymerase-1 deficient mice. EMBO J 1999;18:4446-4454
   CrossRef | Web of Science | Medline