Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Case Study
  • Published:

Treatment with olaparib in a patient with PTEN-deficient endometrioid endometrial cancer

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

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

Figure 1: CT scan images showing extracranial metastatic disease (lesions of interest circled red).
Figure 2: MRI of cerebral metastases (lesions of interest circled in red; edema in green).
Figure 3: Immunohistochemical and FISH findings of the on-study biopsy.
Figure 4: PTEN-sequencing of cDNA derived from RNA that was extracted from a microdissected peritoneal deposit.
Figure 5: 14-day colorimetric assay for in vitro cytotoxicity to a PARP inhibitor (KU0058948).

References

  1. Turner, N., Tutt, A. & Ashworth, A. Hallmarks of 'BRCAness' in sporadic cancers. Nat. Rev. Cancer 4, 814–819 (2004).

    Article  CAS  Google Scholar 

  2. 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).

    Article  Google Scholar 

  3. 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).

    Article  CAS  Google Scholar 

  4. He, L. Posttranscriptional regulation of PTEN dosage by noncoding RNAs. Sci. Signal 3, pe39 (2010).

    PubMed  PubMed Central  Google Scholar 

  5. Salmena, L., Carracedo, A. & Pandolfi, P. P. Tenets of PTEN tumor suppression. Cell 133, 403–414 (2008).

    Article  CAS  Google Scholar 

  6. 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).

    CAS  Google Scholar 

  7. 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).

    Article  CAS  Google Scholar 

  8. 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).

    Article  CAS  Google Scholar 

  9. Farmer, H. et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434, 917–921 (2005).

    Article  CAS  Google Scholar 

  10. 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).

    Article  CAS  Google Scholar 

  11. 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).

    Article  CAS  Google Scholar 

  12. 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).

    Article  CAS  Google Scholar 

  13. 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).

    Article  CAS  Google Scholar 

  14. 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).

    Article  CAS  Google Scholar 

  15. 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).

    Article  Google Scholar 

  16. Dedes, K. J. et al. PTEN deficiency in endometrioid endometrial adenocarcinomas predicts sensitivity to PARP inhibitors. Sci. Transl. Med. 2, 53ra75 (2010).

    Article  Google Scholar 

  17. 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).

    Article  CAS  Google Scholar 

  18. Mendes-Pereira, A. M. et al. Synthetic lethal targeting of PTEN mutant cells with PARP inhibitors. EMBO Mol. Med. 1, 315–322 (2009).

    Article  CAS  Google Scholar 

  19. Li, J. et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 275, 1943–1947 (1997).

    Article  CAS  Google Scholar 

  20. Samuels, Y. & Velculescu, V. E. Oncogenic mutations of PIK3CA in human cancers. Cell Cycle 3, 1221–1224 (2004).

    Article  CAS  Google Scholar 

  21. Stambolic, V. et al. Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell 95, 29–39 (1998).

    Article  CAS  Google Scholar 

  22. Hecht, J. L. & Mutter, G. L. Molecular and pathologic aspects of endometrial carcinogenesis. J. Clin. Oncol. 24, 4783–4791 (2006).

    Article  CAS  Google Scholar 

  23. 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).

    Article  CAS  Google Scholar 

  24. 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).

    Article  CAS  Google Scholar 

  25. Shen, W. H. et al. Essential role for nuclear PTEN in maintaining chromosomal integrity. Cell 128, 157–170 (2007).

    Article  CAS  Google Scholar 

Download references

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

Authors

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

Correspondence to L. Rhoda Molife.

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

Reprints 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

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrclinonc.2011.42

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing