Abstract
Background. A 58-year-old woman presented with metastatic endometrioid endometrial adenocarcinoma after being previously treated with surgery and adjuvant radiotherapy for early-stage endometrial cancer. She had received several lines of chemotherapy for multiple relapses over 9 years and displayed a profound sensitivity to platinum-containing regimens.
Investigation. CT scans demonstrated progressing liver, lung and peritoneal metastases and MRI detected multiple intracerebral metastases.
Diagnosis. New brain metastases secondary to progressive endometrioid endometrial carcinoma.
Management. On the basis of her sensitivity to repeated platinum treatment she was treated with the oral poly(ADP)-ribose polymerase (PARP) 1 inhibitor olaparib as part of a phase I trial. Repeat MRI scan at week 10 of treatment showed a significant reduction in the size of the brain metastases without steroid treatment or radiotherapy and the patient reported subjective improvement in tumor-related symptoms. After 8 months of olaparib treatment the patient developed objective disease progression. The tumor biopsy was negative for somatic BRCA1 and BRCA2 mutations, but displayed loss of PTEN, which has been suggested to be another predictive marker for sensitivity to PARP inhibitors. The patient remained alive for 10 months after completing olaparib, having gone on to derive further clinical benefit from repeat exposure to platinum-based therapy.
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Acknowledgements
We thank Ruth Riisnaes and Susan Miranda at the Institute of Cancer Research, Sutton, UK for immunohistochemical staining of tumor tissue; Ann Curtis at NewGene, Newcastle upon Tyne, UK for BRCA1 and BRCA2 mutation screening of tumor tissue biopsied on study; Jorge Reis-Filho, Christopher J. Lord and Johann de Bono at the Institute of Cancer Research (ICR; London and Sutton) for their input into the translational work; and James Carmichael at AstraZeneca, Macclesfield for sponsoring the clinical trial. The Drug Development Unit of the Royal Marsden NHS Foundation Trust and ICR is supported in part by a program grant from Cancer Research UK, and by funding from the Experimental Cancer Medicine Centre (to the ICR), and the National Institute for Health Research Biomedical Research Centre (to the Royal Marsden NHS Foundation Trust and the ICR). A. Ashworth is funded in part by Breakthrough Breast Cancer and Cancer Research UK; K. J. Dedes is funded by the Swiss National Science Foundation; B. Weigelt is funded by a Cancer Research UK postdoctoral fellowship; M. D. Forster and R. Kristeleit are now supported in part by the UCL and UCLH Comprehensive Biomedical Research Center.
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M. D. Forster, K. J. Dedes, S. Sandhu, S. Frentzas, R. Kristeleit, C. J. Poole, B. Weigelt and L. R. Molife researched the data for this article. M. D. Forster, K. J. Dedes, S. Sandhu, A. Ashworth, C. J. Poole, B. Weigelt, S. B. Kaye and L. R. Molife provided a substantial contribution to the discussion of the content. M. D. Forster, K. J. Dedes, S. Sandhu, S. Frentzas, R. Kristeleit, A. Ashworth, S. B. Kaye and L. R. Molife contributed to writing the article and all authors reviewed and/or edited the manuscript before submission.
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A. Ashworth is a patent holder with AstraZeneca and L. R. Molife receives grants or research support from AstraZeneca. The other authors and the Journal Chief Editor L. Hutchinson declare no competing interests.
Supplementary information
Supplementary Figure 1
PTEN-sequencing and PTEN protein levels of MDA-MB 415 breast cancer cell line. (DOC 923 kb)
Supplementary Figure 2
Polymerase chain reaction (PCR) based microsatellite instability (MSI) analysis using primers for the microsatellite loci BAT26 and BAT40 in tumor DNA of the patient and control DNA. (DOC 93 kb)
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Forster, M., Dedes, K., Sandhu, S. et al. Treatment with olaparib in a patient with PTEN-deficient endometrioid endometrial cancer. Nat Rev Clin Oncol 8, 302–306 (2011). https://doi.org/10.1038/nrclinonc.2011.42
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DOI: https://doi.org/10.1038/nrclinonc.2011.42
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