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  • Perspective
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OPINION

Integrated molecular and clinical staging defines the spectrum of metastatic cancer

Abstract

The elimination of metastases remains one of the major challenges in the curative treatment of patients with cancer. Therefore, most patients with metastatic disease typically receive systemic agents, which prolong survival and alleviate symptoms but are rarely curative. The oligometastatic paradigm challenges the prevailing view of metastasis as a disseminated process and proposes the existence of a spectrum of biological virulence within metastatic lesions. In this Perspectives article, we present evidence supporting our hypothesis that integrated clinical and molecular classification of metastases along the spectrum of disease influences the staging and treatment of patients with cancer.

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Fig. 1: Mechanistic determinants of metastatic heterogeneity.
Fig. 2: Personalized treatment along the metastasis spectrum.

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References

  1. Hellman, S. & Weichselbaum, R. R. Oligometastases. J. Clin. Oncol. 13, 8–10 (1995).

    Article  CAS  Google Scholar 

  2. Weichselbaum, R. R. & Hellman, S. Oligometastases revisited. Nat. Rev. Clin. Oncol. 8, 378–382 (2011).

    Article  CAS  Google Scholar 

  3. Ost, P. et al. Surveillance or metastasis-directed therapy for oligometastatic prostate cancer recurrence: a prospective, randomized, multicenter phase II trial. J. Clin. Oncol. 36, 446–453 (2018).

    Article  CAS  Google Scholar 

  4. Gomez, D. R. et al. Local consolidative therapy versus maintenance therapy or observation for patients with oligometastatic non-small-cell lung cancer without progression after first-line systemic therapy: a multicentre, randomised, controlled, phase 2 study. Lancet Oncol. 17, 1672–1682 (2016).

    Article  CAS  Google Scholar 

  5. Iyengar, P. et al. Consolidative radiotherapy for limited metastatic non-small-cell lung cancer: a phase 2 randomized clinical trial. JAMA Oncol. 4, e173501 (2018).

    Article  Google Scholar 

  6. Gomez, D. R. et al. Local consolidative therapy vs. maintenance therapy or observation for patients with oligometastatic non–small-cell lung cancer: long-term results of a multi-institutional, phase II, randomized study. J. Clin. Oncol. https://doi.org/10.1200/JCO.19.00201 (2019).

    Article  Google Scholar 

  7. Ruers, T. et al. Radiofrequency ablation combined with systemic treatment versus systemic treatment alone in patients with non-resectable colorectal liver metastases: a randomized EORTC Intergroup phase II study (EORTC 40004). Ann. Oncol. 23, 2619–2626 (2012).

    Article  CAS  Google Scholar 

  8. Ruers, T. et al. Local treatment of unresectable colorectal liver metastases: results of a randomized phase II trial. J. Natl Cancer Inst. 109, djx015 (2017).

    PubMed Central  Google Scholar 

  9. Palma, D. A. et al. Stereotactic ablative radiotherapy versus standard of care palliative treatment in patients with oligometastatic cancers (SABR-COMET): a randomised, phase 2, open-label trial. Lancet https://doi.org/10.1016/S0140-6736(18)32487-5 (2019).

    Article  Google Scholar 

  10. Palma, D. A. et al. Stereotactic ablative radiotherapy for comprehensive treatment of oligometastatic tumors (SABR-COMET): study protocol for a randomized phase II trial. BMC Cancer 12, 305 (2012).

    Article  CAS  Google Scholar 

  11. Singh, D. et al. Is there a favorable subset of patients with prostate cancer who develop oligometastases? Int. J. Radiat. Oncol. Biol. Phys. 58, 3–10 (2004).

    Article  Google Scholar 

  12. deSouza, N. M. et al. Strategies and technical challenges for imaging oligometastatic disease: Recommendations from the European Organisation for Research and Treatment of Cancer imaging group. Eur. J. Cancer 91, 153–163 (2018).

    Article  Google Scholar 

  13. Joice, G. A. et al. Oligometastatic prostate cancer: shaping the definition with molecular imaging and an improved understanding of tumor biology. Curr. Opin. Urol. 27, 533–541 (2017).

    Article  Google Scholar 

  14. Wong, H. S. et al. Comparative study between (68) Ga-prostate-specific membrane antigen positron emission tomography and conventional imaging in the initial staging of prostate cancer. J. Med. Imaging Radiat. Oncol. 62, 816–822 (2018).

    Article  Google Scholar 

  15. Ashworth, A. B. et al. An individual patient data metaanalysis of outcomes and prognostic factors after treatment of oligometastatic non-small-cell lung cancer. Clin. Lung Cancer 15, 346–355 (2014).

    Article  Google Scholar 

  16. Fong, Y. et al. Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1001 consecutive cases. Ann. Surg. 230, 309–318 (1999).

    Article  CAS  Google Scholar 

  17. Pastorino, U. et al. Long-term results of lung metastasectomy: prognostic analyses based on 5206 cases. J. Thorac. Cardiovasc. Surg. 113, 37–49 (1997).

    Article  CAS  Google Scholar 

  18. Lussier, Y. A. et al. Oligo- and polymetastatic progression in lung metastasis(es) patients is associated with specific microRNAs. PLOS ONE 7, e50141 (2012).

    Article  CAS  Google Scholar 

  19. Hong, J. C. et al. Classification for long-term survival in oligometastatic patients treated with ablative radiotherapy: A multi-institutional pooled analysis. PLOS ONE 13, e0195149 (2018).

    Article  Google Scholar 

  20. Obenauf, A. C. & Massague, J. Surviving at a distance: organ-specific metastasis. Trends Cancer 1, 76–91 (2015).

    Article  Google Scholar 

  21. Massague, J. & Obenauf, A. C. Metastatic colonization by circulating tumour cells. Nature 529, 298–306 (2016).

    Article  CAS  Google Scholar 

  22. Lambert, A. W., Pattabiraman, D. R. & Weinberg, R. A. Emerging biological principles of metastasis. Cell 168, 670–691 (2017).

    Article  CAS  Google Scholar 

  23. Bartel, D. P. Metazoan microRNAs. Cell 173, 20–51 (2018).

    Article  CAS  Google Scholar 

  24. Lussier, Y. A. et al. MicroRNA expression characterizes oligometastasis(es). PLOS ONE 6, e28650 (2011).

    Article  CAS  Google Scholar 

  25. Uppal, A. et al. 14q32-encoded microRNAs mediate an oligometastatic phenotype. Oncotarget 6, 3540–3552 (2015).

    Article  Google Scholar 

  26. Holder, J. L. Jr. et al. A child with an inherited 0.31 Mb microdeletion of chromosome 14q32.33: further delineation of a critical region for the 14q32 deletion syndrome. Am. J. Med. Genet. A 158, 1962–1966 (2012).

    Article  CAS  Google Scholar 

  27. Briggs, T. A. et al. Temple syndrome as a result of isolated hypomethylation of the 14q32 imprinted DLK1/MEG3 region. Am. J. Med. Genet. A 170, 170–175 (2016).

    Article  CAS  Google Scholar 

  28. Kagami, M. et al. Deletions and epimutations affecting the human 14q32.2 imprinted region in individuals with paternal and maternal upd(14)-like phenotypes. Nat. Genet. 40, 237–242 (2008).

    Article  CAS  Google Scholar 

  29. Kagami, M. et al. The IG-DMR and the MEG3-DMR at human chromosome 14q32.2: hierarchical interaction and distinct functional properties as imprinting control centers. PLOS Genet. 6, e1000992 (2010).

    Article  Google Scholar 

  30. Stadtfeld, M. et al. Aberrant silencing of imprinted genes on chromosome 12qF1 in mouse induced pluripotent stem cells. Nature 465, 175–181 (2010).

    Article  CAS  Google Scholar 

  31. Oshima, G. et al. DNA methylation controls metastasis-suppressive 14q32-encoded miRNAs. Cancer Res. https://doi.org/10.1158/0008-5472.CAN-18-0692 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  32. Jamal-Hanjani, M. et al. Tracking the evolution of non-small-cell lung cancer. N. Engl. J. Med. 376, 2109–2121 (2017).

    Article  CAS  Google Scholar 

  33. Haffner, M. C. et al. Tracking the clonal origin of lethal prostate cancer. J. Clin. Invest. 123, 4918–4922 (2013).

    Article  CAS  Google Scholar 

  34. Turajlic, S. et al. Tracking cancer evolution reveals constrained routes to metastases: TRACERx renal. Cell 173, 581–594 (2018).

    Article  CAS  Google Scholar 

  35. Pitroda, S. P. et al. Integrated molecular subtyping defines a curable oligometastatic state in colorectal liver metastasis. Nat. Commun. 9, 1793 (2018).

    Article  Google Scholar 

  36. Guinney, J. et al. The consensus molecular subtypes of colorectal cancer. Nat. Med. 21, 1350−1356 (2015).

  37. Wang, B. et al. Similarity network fusion for aggregating data types on a genomic scale. Nat. Methods 11, 333–337 (2014).

    Article  CAS  Google Scholar 

  38. Van den Eynde, M. et al. The link between the multiverse of immune microenvironments in metastases and the survival of colorectal cancer patients. Cancer Cell 34, 1012–1026 (2018).

    Article  Google Scholar 

  39. Angelova, M. et al. Evolution of metastases in space and time under immune selection. Cell 175, 751–765 (2018).

    Article  CAS  Google Scholar 

  40. Pages, F. et al. In situ cytotoxic and memory T cells predict outcome in patients with early-stage colorectal cancer. J. Clin. Oncol. 27, 5944–5951 (2009).

    Article  CAS  Google Scholar 

  41. Mlecnik, B. et al. The tumor microenvironment and Immunoscore are critical determinants of dissemination to distant metastasis. Sci. Transl Med. 8, 327ra26 (2016).

    Article  Google Scholar 

  42. Cohen, R. et al. Immunotherapy and metastatic colorectal cancers with microsatellite instability or mismatch repair deficiency. Bull. Cancer 106, 137–142 (2018).

    Article  Google Scholar 

  43. Irahara, N. et al. NRAS mutations are rare in colorectal cancer. Diagn. Mol. Pathol. 19, 157–163 (2010).

    Article  CAS  Google Scholar 

  44. Johnson, D. B. et al. Impact of NRAS mutations for patients with advanced melanoma treated with immune therapies. Cancer Immunol. Res. 3, 288–295 (2015).

    Article  CAS  Google Scholar 

  45. Wu, Y. M. et al. Inactivation of CDK12 delineates a distinct immunogenic class of advanced prostate cancer. Cell 173, 1770–1782 (2018).

    Article  CAS  Google Scholar 

  46. Robinson, D. R. et al. Integrative clinical genomics of metastatic cancer. Nature 548, 297–303 (2017).

    Article  CAS  Google Scholar 

  47. Huang, L. et al. Molecular classification of lymph node metastases subtypes predict for survival in head and neck cancer. Clin. Cancer Res. 25, 1795–1808 (2018).

    Article  Google Scholar 

  48. Huang, S. H. & O’Sullivan, B. Overview of the 8th edn TNM classification for head and neck cancer. Curr. Treat. Opt. Oncol. 18, 40 (2017).

    Article  Google Scholar 

  49. Louis, D. N. et al. The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol. 131, 803–820 (2016).

    Article  Google Scholar 

  50. Parker, C. C. et al. Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled phase 3 trial. Lancet 392, 2353–2366 (2018).

    Article  Google Scholar 

  51. Sweeney, C. J. et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N. Engl. J. Med. 373, 737–746 (2015).

    Article  CAS  Google Scholar 

  52. Gundem, G. et al. The evolutionary history of lethal metastatic prostate cancer. Nature 520, 353–357 (2015).

    Article  CAS  Google Scholar 

  53. Corcoran, R. B. & Chabner, B. A. Application of cell-free DNA analysis to cancer treatment. N. Engl. J. Med. 379, 1754–1765 (2018).

    Article  CAS  Google Scholar 

  54. Radwan, N. et al. A phase II randomized trial of Observation versus stereotactic ablative RadiatIon for OLigometastatic prostate CancEr (ORIOLE). BMC Cancer 17, 453 (2017).

    Article  Google Scholar 

  55. Newton, P. K. et al. Spatiotemporal progression of metastatic breast cancer: a Markov chain model highlighting the role of early metastatic sites. NPJ Breast Cancer 1, 15018 (2015).

    Article  Google Scholar 

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Acknowledgements

This work was supported by the Virginia and D. K. Ludwig Fund for Cancer Research, an NIH National Cancer Institute (NCI) R21 grant (CA195075-01A1) and a generous gift from the Foglia Family Foundation.

Reviewer information

Nature Reviews Clinical Oncology thanks P. Ost, S. Siva and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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Both authors made a substantial contribution to all aspects of the preparation of this manuscript.

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Correspondence to Ralph R. Weichselbaum.

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Competing interests

R.R.W. is a consultant and/or adviser for Aettis, AstraZeneca, Genus, ImmunoVir, Merck Serono, Nano Proteagen, Reflexion Pharmaceuticals, RiMO and Shuttle Pharmaceuticals, has been a guest speaker sponsored by Boehringer Ingelheim and has equity and/or intellectual property rights with Boost Therapeutics, Oncosenescence, Reflexion Pharmaceuticals and RiMO. S.P.P. and R.R.W. have a patent entitled “Methods and kits for diagnosis and triage of patients with colorectal liver metastases” pending.

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Pitroda, S.P., Weichselbaum, R.R. Integrated molecular and clinical staging defines the spectrum of metastatic cancer. Nat Rev Clin Oncol 16, 581–588 (2019). https://doi.org/10.1038/s41571-019-0220-6

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