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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
References
Turner, N., Tutt, A. & Ashworth, A. Hallmarks of 'BRCAness' in sporadic cancers. Nat. Rev. Cancer 4, 814–819 (2004).
Molife, L. R. et al. A phase I study to determine the comparative bioavailability of two different oral formulations of the PARP inhibitor, olaparib (AZD2281), in patients with advanced solid tumors [abstract]. J. Clin. Oncol. 28 (Suppl.), a2599 (2010).
Therasse, P. et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J. Natl Cancer Inst. 92, 205–216 (2000).
He, L. Posttranscriptional regulation of PTEN dosage by noncoding RNAs. Sci. Signal 3, pe39 (2010).
Salmena, L., Carracedo, A. & Pandolfi, P. P. Tenets of PTEN tumor suppression. Cell 133, 403–414 (2008).
Salvesen, H. B. et al. PTEN methylation is associated with advanced stage and microsatellite instability in endometrial carcinoma. Int. J. Cancer 91, 22–26 (2001).
Koul, A., Nilbert, M. & Borg, A. A somatic BRCA2 mutation in RER+ endometrial carcinomas that specifically deletes the amino-terminal transactivation domain. Genes Chromosomes Cancer 24, 207–212 (1999).
Ashworth, A. A synthetic lethal therapeutic approach: poly(ADP) ribose polymerase inhibitors for the treatment of cancers deficient in DNA double-strand break repair. J. Clin. Oncol. 26, 3785–3790 (2008).
Farmer, H. et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434, 917–921 (2005).
Arnaudeau, C., Lundin, C. & Helleday, T. DNA double-strand breaks associated with replication forks are predominantly repaired by homologous recombination involving an exchange mechanism in mammalian cells. J. Mol. Biol. 307, 1235–1245 (2001).
Lord, C. J., Garrett, M. D. & Ashworth, A. Targeting the double-strand DNA break repair pathway as a therapeutic strategy. Clin. Cancer Res. 12, 4463–4468 (2006).
Fong, P. C. et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N. Engl. J. Med. 361, 123–134 (2009).
Audeh, M. W. et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial. Lancet 376, 245–251 (2010).
Tutt, A. et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. Lancet 376, 235–244 (2010).
Gelmon, K. A. et al. Can we define tumors that will respond to PARP inhibitors? A phase II correlative study of olaparib in advanced serous ovarian cancer and triple-negative breast cancer [abstract]. J. Clin. Oncol. 28 (Suppl.), a3002 (2010).
Dedes, K. J. et al. PTEN deficiency in endometrioid endometrial adenocarcinomas predicts sensitivity to PARP inhibitors. Sci. Transl. Med. 2, 53ra75 (2010).
McEllin, B. et al. PTEN loss compromises homologous recombination repair in astrocytes: implications for glioblastoma therapy with temozolomide or poly(ADP-ribose) polymerase inhibitors. Cancer Res. 70, 5457–5464 (2010).
Mendes-Pereira, A. M. et al. Synthetic lethal targeting of PTEN mutant cells with PARP inhibitors. EMBO Mol. Med. 1, 315–322 (2009).
Li, J. et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 275, 1943–1947 (1997).
Samuels, Y. & Velculescu, V. E. Oncogenic mutations of PIK3CA in human cancers. Cell Cycle 3, 1221–1224 (2004).
Stambolic, V. et al. Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell 95, 29–39 (1998).
Hecht, J. L. & Mutter, G. L. Molecular and pathologic aspects of endometrial carcinogenesis. J. Clin. Oncol. 24, 4783–4791 (2006).
Mutter, G. L. et al. Altered PTEN expression as a diagnostic marker for the earliest endometrial precancers. J. Natl Cancer Inst. 92, 924–930 (2000).
Gupta, A. et al. Cell cycle checkpoint defects contribute to genomic instability in PTEN deficient cells independent of DNA DSB repair. Cell Cycle 8, 2198–2210 (2009).
Shen, W. H. et al. Essential role for nuclear PTEN in maintaining chromosomal integrity. Cell 128, 157–170 (2007).
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.
Author information
Authors and Affiliations
Contributions
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.
Corresponding author
Ethics declarations
Competing interests
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)
Rights and permissions
About this article
Cite this article
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
Published:
Issue Date:
DOI: https://doi.org/10.1038/nrclinonc.2011.42
This article is cited by
-
New insights for gynecological cancer therapies: from molecular mechanisms and clinical evidence to future directions
Cancer and Metastasis Reviews (2023)
-
Targeting homologous recombination deficiency in uterine leiomyosarcoma
Journal of Experimental & Clinical Cancer Research (2023)
-
PARP Inhibitors in Gynecologic Cancers: What Is the Next Big Development?
Current Oncology Reports (2020)
-
PTEN deficiency sensitizes endometrioid endometrial cancer to compound PARP-PI3K inhibition but not PARP inhibition as monotherapy
Oncogene (2018)
-
Inhibition of PI3K-AKT-mTOR pathway sensitizes endometrial cancer cell lines to PARP inhibitors
BMC Cancer (2017)