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OPINION

Going to extremes: determinants of extraordinary response and survival in patients with cancer

Nature Reviews Cancer volume 19, pages 339–348 (2019)Cite this article

Subjects

Abstract

Research into factors affecting treatment response or survival in patients with cancer frequently involves cohorts that span the most common range of clinical outcomes, as such patients are most readily available for study. However, attention has turned to highly unusual patients who have exceptionally favourable or atypically poor responses to treatment and/or overall survival, with the expectation that patients at the extremes may provide insights that could ultimately improve the outcome of individuals with more typical disease trajectories. While clinicians can often recount surprising patients whose clinical journey was very unusual, given known clinical characteristics and prognostic indicators, there is a lack of consensus among researchers on how best to define exceptional patients, and little has been proposed for the optimal design of studies to identify factors that dictate unusual outcome. In this Opinion article, we review different approaches to identifying exceptional patients with cancer and possible study designs to investigate extraordinary clinical outcomes. We discuss pitfalls with finding these rare patients, including challenges associated with accrual of patients across different treatment centres and time periods. We describe recent molecular and immunological factors that have been identified as contributing to unusual patient outcome and make recommendations for future studies on these intriguing patients.

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Fig. 1: Classification of patients with an extraordinary treatment response or survival.
Fig. 2: Contrasting patterns of survival in breast and lung cancer.
Fig. 3: Examples of factors influencing exceptionally favourable response to therapy and/or long-term survival.

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Acknowledgements

F.A.M.S. is supported by a Swiss National Foundation Early Postdoc Mobility Fellowship (P2BEP3-172246), Swiss Cancer Research Foundation grant BIL KFS-3942-08-2016 and a Professor Dr Max Cloëtta and Uniscientia Foundation grant. B.H.N., A.dF., C.L.P., M.C.P., D.W.G. and D.D.L.B. are supported by US Army Medical Research and Materiel Command grant W81XWH-16-2-0010. D.D.L.B. is supported by National Health and Medical Research Council of Australia (NHMRC) grants APP1092856 and APP1117044 and by the US National Cancer Institute U54 programme (U54CA209978). The authors acknowledge additional support from Margaret Rose AM and the Rose family, The WeirAnderson Foundation, Border Ovarian Cancer Awareness Group, donors to the Garvan Institute of Medical Research Ovarian Cancer Research Program, the Peter MacCallum Cancer Foundation, Wendy Taylor and Arthur Coombs and family. The Australian Ovarian Cancer Study (AOCS) was supported by the US Army Medical Research and Materiel Command under DAMD17-01-1-0729.

Reviewer information

Nature Reviews Cancer thanks A. Biankin, S. Percy Ivy and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Author information

Authors and Affiliations

  1. Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

    Flurina A. M. Saner, Alan Herschtal, Ahwan Pandey, Jessica A. Beach, Sian Fereday, Dale W. Garsed & David D. L. Bowtell

  2. Deeley Research Centre, British Columbia Cancer Agency, Victoria, British Columbia, Canada

    Brad H. Nelson

  3. Department of Gynaecological Oncology, Westmead Hospital, Westmead, New South Wales, Australia

    Anna deFazio

  4. The University of Sydney, Sydney, New South Wales, Australia

    Anna deFazio

  5. Centre for Cancer Research, The Westmead Institute for Medical Research, Sydney, New South Wales, Australia

    Anna deFazio

  6. Department of Health Science Research, Division of Epidemiology, Mayo Clinic, Rochester, MN, USA

    Ellen L. Goode

  7. School of Women’s and Children’s Health, University ofNew South Wales, Sydney, New South Wales, Australia

    Susan J. Ramus

  8. Garvan Institute of Medical Research, Sydney, New South Wales, Australia

    Susan J. Ramus

  9. Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC, USA

    Andrew Berchuck

  10. Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Canada

    Stephanie Lheureux

  11. Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI, USA

    Celeste Leigh Pearce

  12. Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK

    Paul D. Pharoah

  13. Department of Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK

    Paul D. Pharoah

  14. Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Malcolm C. Pike

  15. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Victoria, Australia

    Dale W. Garsed & David D. L. Bowtell

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Contributions

F.A.M.S., D.W.G. and D.D.L.B. wrote the manuscript and prepared the figures. B.H.N. wrote the section on immunology, and C.L.P. wrote the section on epidemiology. F.A.M.S., A.P. and M.C.P. performed data analyses for the article. A.H., A.dF., E.L.G., S.J.R., J.A.B., S.F., A.B., S.L., P.D.P. and M.C.P. provided a substantial contribution to discussions of the content. D.W.G. and D.D.L.B. contributed equally to supervision of the project. All authors contributed to the review and editing of the article before submission.

Corresponding authors

Correspondence to Dale W. Garsed or David D. L. Bowtell.

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The authors declare no competing interests.

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Related links

Surveillance, Epidemiology and End Results Program: http://www.seer.cancer.gov

Glossary

Complete response

(CR). The disappearance of all target lesions in response to treatment.

Genome-wide association studies

(GWAS). Studies that compare genetic markers across the genome in individuals with and without disease traits.

Hyper-progression

Accelerated disease progression associated with immune checkpoint inhibitor therapy.

Hypomorphic germline alleles

Also called hypomorphic mutations; inherited genetic variants that cause partial (not complete) loss of gene function through reduced expression or function.

Maintenance therapy

Treatment provided following initial therapy to prevent relapse.

Multivariable analyses

Statistical models taking into account the impact of multiple explanatory variables that may influence a single outcome.

Partial response

(PR). A decrease of at least 30% in the sum of the diameters of target lesions in response to treatment.

Polygenic risk

A genetic susceptibility score based on the combination of multiple, often low-penetrance, disease susceptibility alleles.

Synthetic lethality

A phenomenon in cells or organisms whereby two gene or pathway defects occurring in isolation have little or no effect on survival but for which the combination of both leads to death.

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Saner, F.A.M., Herschtal, A., Nelson, B.H. et al. Going to extremes: determinants of extraordinary response and survival in patients with cancer. Nat Rev Cancer 19, 339–348 (2019). https://doi.org/10.1038/s41568-019-0145-5

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