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.

  • Perspective
  • Published:

A framework for understanding and targeting residual disease in oncogene-driven solid cancers

Nature Medicine volume 22, pages 472–478 (2016)Cite this article

Subjects

Abstract

Molecular targeted therapy has the potential to dramatically improve survival in patients with cancer. However, complete and durable responses to targeted therapy are rare in individuals with advanced-stage solid cancers. Even the most effective targeted therapies generally do not induce a complete tumor response, resulting in residual disease and tumor progression that limits patient survival. We discuss the emerging need to more fully understand the molecular basis of residual disease as a prelude to designing therapeutic strategies to minimize or eliminate residual disease so that we can move from temporary to chronic control of disease, or a cure, for patients with advanced-stage solid cancers. Ultimately, we propose a shift from the current reactive paradigm of analyzing and treating acquired drug resistance to a pre-emptive paradigm of defining the mechanisms that result in residual disease, to target and limit this disease reservoir.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Defining residual disease.

Kim Caesar/Nature Publishing Group

Figure 2: Therapeutic strategies to combat residual disease73.

Kim Caesar/Nature Publishing Group

Similar content being viewed by others

References

  1. Collins, F.S. & Varmus, H. A new initiative on precision medicine. N. Engl. J. Med. 372, 793–795 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Varmus, H. Ten years on—the human genome and medicine. N. Engl. J. Med. 362, 2028–2029 (2010).

    Article  CAS  PubMed  Google Scholar 

  3. Sawyers, C.L. The 2011 Gordon Wilson lecture: overcoming resistance to targeted cancer drugs. Trans. Am. Clin. Climatol. Assoc. 123, 114–123, discussion 123–125 (2012).

    PubMed  PubMed Central  Google Scholar 

  4. Sawyers, C.L. Lessons learned from the development of kinase inhibitors. Clin. Adv. Hematol. Oncol. 7, 588–589 (2009).

    PubMed  Google Scholar 

  5. Sawyers, C.L. Shifting paradigms: the seeds of oncogene addiction. Nat. Med. 15, 1158–1161 (2009).

    Article  CAS  PubMed  Google Scholar 

  6. de Bono, J.S. & Ashworth, A. Translating cancer research into targeted therapeutics. Nature 467, 543–549 (2010).

    Article  CAS  PubMed  Google Scholar 

  7. Garraway, L.A. & Jänne, P.A. Circumventing cancer drug resistance in the era of personalized medicine. Cancer Discov. 2, 214–226 (2012).

    Article  CAS  PubMed  Google Scholar 

  8. Blumenthal, G.M. et al. Overall response rate, progression-free survival, and overall survival with targeted and standard therapies in advanced non-small-cell lung cancer: US Food and Drug Administration trial-level and patient-level analyses. J. Clin. Oncol. 33, 1008–1014 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  9. Boxer, R.B., Jang, J.W., Sintasath, L. & Chodosh, L.A. Lack of sustained regression of c-MYC-induced mammary adenocarcinomas following brief or prolonged MYC inactivation. Cancer Cell 6, 577–586 (2004).

    Article  CAS  PubMed  Google Scholar 

  10. Zhang, Z. et al. Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer. Nat. Genet. 44, 852–860 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Hrustanovic, G. et al. RAS–MAPK dependence underlies a rational polytherapy strategy in EML4–ALK-positive lung cancer. Nat. Med. 21, 1038–1047 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Yu, H.A. et al. Analysis of tumor specimens at the time of acquired resistance to EGFR–TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin. Cancer Res. 19, 2240–2247 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Van Allen, E.M. et al. The genetic landscape of clinical resistance to RAF inhibition in metastatic melanoma. Cancer Discov. 4, 94–109 (2014).

    Article  CAS  PubMed  Google Scholar 

  14. Ahronian, L.G. et al. Clinical acquired resistance to RAF inhibitor combinations in BRAF-mutant colorectal cancer through MAPK pathway alterations. Cancer Discov. 5, 358–367 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Poulikakos, P.I., Zhang, C., Bollag, G., Shokat, K.M. & Rosen, N. RAF inhibitors transactivate RAF dimers and ERK signaling in cells with wild-type BRAF. Nature 464, 427–430 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Lito, P., Rosen, N. & Solit, D.B. Tumor adaptation and resistance to RAF inhibitors. Nat. Med. 19, 1401–1409 (2013).

    Article  CAS  PubMed  Google Scholar 

  17. Poulikakos, P.I. et al. RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAFV600E. Nature 480, 387–390 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Lito, P. et al. Relief of profound feedback inhibition of mitogenic signaling by RAF inhibitors attenuates their activity in BRAFV600E melanomas. Cancer Cell 22, 668–682 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Prahallad, A. et al. Unresponsiveness of colon cancer to BRAFV600E inhibition through feedback activation of EGFR. Nature 483, 100–103 (2012).

    Article  CAS  PubMed  Google Scholar 

  20. Alizadeh, A.A. et al. Toward understanding and exploiting tumor heterogeneity. Nat. Med. 21, 846–853 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. de Bruin, E.C. et al. Spatial and temporal diversity in genomic instability processes defines lung cancer evolution. Science 346, 251–256 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Hiley, C., de Bruin, E.C., McGranahan, N. & Swanton, C. Deciphering intratumor heterogeneity and temporal acquisition of driver events to refine precision medicine. Genome Biol. 15, 453 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  23. Burrell, R.A. & Swanton, C. Tumor heterogeneity and the evolution of polyclonal drug resistance. Mol. Oncol. 8, 1095–1111 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Turke, A.B. et al. Preexistence and clonal selection of MET amplification in EGFR-mutant NSCLC. Cancer Cell 17, 77–88 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Rosell, R. et al. Pretreatment EGFRT790M mutation and BRCA1 mRNA expression in erlotinib-treated advanced non-small-cell lung cancer patients with EGFR mutations. Clin. Cancer Res. 17, 1160–1168 (2011).

    Article  CAS  PubMed  Google Scholar 

  26. Lin, L. et al. The Hippo effector YAP promotes resistance to RAF- and MEK-targeted cancer therapies. Nat. Genet. 47, 250–256 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Janku, F. et al. PIK3CA mutations frequently coexist with RAS and BRAF mutations in patients with advanced cancers. PLoS One 6, e22769 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Hata, A.N. et al. Tumor cells can follow distinct evolutionary paths to become resistant to epidermal growth factor receptor inhibition. Nat. Med. 22, 262–269 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Müller, J. et al. Low MITF/AXL ratio predicts early resistance to multiple targeted drugs in melanoma. Nat. Commun. 5, 5712 (2014).

    Article  PubMed  CAS  Google Scholar 

  30. Straussman, R. et al. Tumor microenvironment elicits innate resistance to RAF inhibitors through HGF secretion. Nature 487, 500–504 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Blakely, C.M. et al. NF-κB-activating complex engaged in response to EGFR oncogene inhibition drives tumor cell survival and residual disease in lung cancer. Cell Rep. 11, 98–110 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Sharma, S.V. et al. A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell 141, 69–80 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Lee, H.J. et al. Drug resistance via feedback activation of Stat3 in oncogene-addicted cancer cells. Cancer Cell 26, 207–221 (2014).

    Article  CAS  PubMed  Google Scholar 

  34. Haq, R. et al. Oncogenic BRAF regulates oxidative metabolism via PGC-1α and MITF. Cancer Cell 23, 302–315 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Wilson, T.R. et al. Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors. Nature 487, 505–509 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Obenauf, A.C. et al. Therapy-induced tumor secretomes promote resistance and tumor progression. Nature 520, 368–372 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Bollag, G. et al. Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature 467, 596–599 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Szmulewitz, R.Z. & Ratain, M.J. Vemurafenib oral bioavailability: an insoluble problem. J. Clin. Pharmacol. 54, 375–377 (2014).

    Article  PubMed  CAS  Google Scholar 

  39. Undevia, S.D., Gomez-Abuin, G. & Ratain, M.J. Pharmacokinetic variability of anticancer agents. Nat. Rev. Cancer 5, 447–458 (2005).

    Article  CAS  PubMed  Google Scholar 

  40. Neesse, A., Algül, H., Tuveson, D.A. & Gress, T.M. Stromal biology and therapy in pancreatic cancer: a changing paradigm. Gut 64, 1476–1484 (2015).

    Article  CAS  PubMed  Google Scholar 

  41. Jain, R.K. Antiangiogenesis strategies revisited: from starving tumors to alleviating hypoxia. Cancer Cell 26, 605–622 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Jänne, P.A. et al. Phase 1 safety and pharmacokinetic study of the PI3K–mTOR inhibitor SAR245409 (XL765) in combination with erlotinib in patients with advanced solid tumors. J. Thorac. Oncol. 9, 316–323 (2014).

    Article  PubMed  CAS  Google Scholar 

  43. Lin, N.U. Targeted therapies in brain metastases. Curr. Treat. Options Neurol. 16, 276 (2014).

    Article  PubMed  Google Scholar 

  44. Thompson, C.B. Targeting the anti-apoptotic signaling pathway. Clin. Adv. Hematol. Oncol. 7, 819–822 (2009).

    PubMed  Google Scholar 

  45. Shaw, A.T. et al. Ceritinib in ALK-rearranged non-small-cell lung cancer. N. Engl. J. Med. 370, 1189–1197 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Sequist, L.V. et al. Rociletinib in EGFR-mutated non-small-cell lung cancer. N. Engl. J. Med. 372, 1700–1709 (2015).

    Article  PubMed  Google Scholar 

  47. Jänne, P.A. et al. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N. Engl. J. Med. 372, 1689–1699 (2015).

    Article  PubMed  Google Scholar 

  48. Johnson, D.B. et al. Combined BRAF (dabrafenib) and MEK inhibition (trametinib) in patients with BRAFV600-mutant melanoma experiencing progression with single-agent BRAF inhibitor. J. Clin. Oncol. 32, 3697–3704 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Charakidis, M. & Boyer, M. Targeting MET and EGFR in NSCLC—what can we learn from the recently reported phase 3 trial of onartuzumab in combination with erlotinib in advanced non-small cell lung cancer? Transl. Lung Cancer Res. 3, 395–396 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Riely, G.J. et al. Prospective assessment of discontinuation and reinitiation of erlotinib or gefitinib in patients with acquired resistance to erlotinib or gefitinib followed by the addition of everolimus. Clin. Cancer Res. 13, 5150–5155 (2007).

    Article  CAS  PubMed  Google Scholar 

  51. Wagle, N. et al. MAP kinase pathway alterations in BRAF-mutant melanoma patients with acquired resistance to combined RAF–MEK inhibition. Cancer Discov. 4, 61–68 (2014).

    Article  CAS  PubMed  Google Scholar 

  52. Flaherty, K.T. et al. Combined BRAF and MEK inhibition in melanoma with BRAFV600 mutations. N. Engl. J. Med. 367, 1694–1703 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Long, G.V. et al. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N. Engl. J. Med. 371, 1877–1888 (2014).

    Article  PubMed  CAS  Google Scholar 

  54. Bhang, H.E. et al. Studying clonal dynamics in response to cancer therapy using high-complexity barcoding. Nat. Med. 21, 440–448 (2015).

    Article  CAS  PubMed  Google Scholar 

  55. Bozic, I. et al. Evolutionary dynamics of cancer in response to targeted combination therapy. eLife 2, e00747 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  56. Schwaederle, M. et al. On the road to precision cancer medicine: analysis of genomic biomarker actionability in 439 patients. Mol. Cancer Ther. 14, 1488–1494 (2015).

    Article  CAS  PubMed  Google Scholar 

  57. Crystal, A.S. et al. Patient-derived models of acquired resistance can identify effective drug combinations for cancer. Science 346, 1480–1486 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Gao, D. et al. Organoid cultures derived from patients with advanced prostate cancer. Cell 159, 176–187 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Gingras, I., Salgado, R. & Ignatiadis, M. Liquid biopsy: will it be the 'magic tool' for monitoring response of solid tumors to anticancer therapies? Curr. Opin. Oncol. 27, 560–567 (2015).

    Article  CAS  PubMed  Google Scholar 

  60. Li, X. et al. Oncogenic transformation of diverse gastrointestinal tissues in primary organoid culture. Nat. Med. 20, 769–777 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Karthaus, W.R. et al. Identification of multipotent luminal progenitor cells in human prostate organoid cultures. Cell 159, 163–175 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Piotrowska, Z. et al. Heterogeneity underlies the emergence of EGFRT790 wild-type clones following treatment of EGFRT790-positive cancers with a third-generation EGFR inhibitor. Cancer Discov. 5, 713–722 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Nakasone, E.S. et al. Imaging tumor–stroma interactions during chemotherapy reveals contributions of the microenvironment to resistance. Cancer Cell 21, 488–503 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Mayer, R.J. et al. Intensive postremission chemotherapy in adults with acute myeloid leukemia. N. Engl. J. Med. 331, 896–903 (1994).

    Article  CAS  PubMed  Google Scholar 

  65. Coombs, C.C., Tallman, M.S. & Levine, R.L. Molecular therapy for acute myeloid leukemia. Nat. Rev. Clin. Oncol. (2015).

  66. Condeelis, J. & Weissleder, R. In vivo imaging in cancer. Cold Spring Harb. Perspect. Biol. 2, a003848 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Doebele, R.C. et al. Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non-small-cell lung cancer. Clin. Cancer Res. 18, 1472–1482 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Van Allen, E.M. et al. Whole-exome sequencing and clinical interpretation of formalin-fixed, paraffin-embedded tumor samples to guide precision cancer medicine. Nat. Med. 20, 682–688 (2014).

    Article  CAS  PubMed  Google Scholar 

  69. De Silva, N. et al. Molecular effects of lapatinib in the treatment of HER2-overexpressing oesophago-gastric adenocarcinoma. Br. J. Cancer 113, 1305–1312 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Thress, K.S. et al. Acquired EGFRC797S mutation mediates resistance to AZD9291 in non-small-cell lung cancer harboring EGFRT790M. Nat. Med. 21, 560–562 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Siravegna, G. et al. Clonal evolution and resistance to EGFR blockade in the blood of colorectal cancer patients. Nat. Med. 21, 795–801 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Murtaza, M. et al. Non-invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA. Nature 497, 108–112 (2013).

    Article  CAS  PubMed  Google Scholar 

  73. Behbehani, G.K. et al. Mass cytometric functional profiling of acute myeloid leukemia defines cell-cycle and immunophenotypic properties that correlate with known responses to therapy. Cancer Discov. 5, 988–1003 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Macosko, E.Z. et al. Highly parallel genome-wide expression profiling of individual cells using nanoliter droplets. Cell 161, 1202–1214 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Larkin, J. et al. Combined nivolumab and ipilimumab, or monotherapy, in untreated melanoma. N. Engl. J. Med. 373, 23–34 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  76. Sequist, L.V. et al. Randomized phase 2 study of erlotinib plus tivantinib versus erlotinib plus placebo in previously treated non-small-cell lung cancer. J. Clin. Oncol. 29, 3307–3315 (2011).

    Article  CAS  PubMed  Google Scholar 

  77. Spigel, D.R. et al. Final efficacy results from OAM4558g, a randomized phase 2 study evaluating MetMAb or placebo in combination with erlotinib in advanced NSCLC (ASCO Annual Meeting) 7505 (American Society of Clinical Oncology, Alexandria, Virginia, USA, 2011).

  78. Price, K.A. et al. Phase 2 trial of gefitinib and everolimus in advanced non-small-cell lung cancer. J. Thorac. Oncol. 5, 1623–1629 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  79. Witta, S.E. et al. Randomized phase 2 trial of erlotinib with and without entinostat in patients with advanced non-small-cell lung cancer who progressed on prior chemotherapy. J. Clin. Oncol. 30, 2248–2255 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Johnson, M.L. et al. Phase 1/2 study of HSP90 inhibitor AUY922 and erlotinib for EGFR-mutant lung cancer with acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors. J. Clin. Oncol. 33, 1666–1673 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Planchard, D. et al. Interim results of a phase 2 study of the BRAF inhibitor (BRAFi) dabrafenib (D) in combination with the MEK inhibitor trametinib (T) in patients (pts) with BRAFV600E mutated (mut) metastatic non-small-cell lung cancer (NSCLC) (ASCO Annual Meeting) 8006 (American Society of Clinical Oncology, Alexandria, Virginia, USA, 2011).

  82. Yaeger, R. et al. Pilot trial of combined BRAF and EGFR inhibition in BRAF-mutant metastatic colorectal cancer patients. Clin. Cancer Res. 21, 1313–1320 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Hurvitz, S.A. et al. Combination of everolimus with trastuzumab plus paclitaxel as first-line treatment for patients with HER2-positive advanced breast cancer (BOLERO-1): a phase 3, randomized, double-blind, multicenter trial. Lancet Oncol. 16, 816–829 (2015).

    Article  CAS  PubMed  Google Scholar 

  84. Swain, S.M. et al. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N. Engl. J. Med. 372, 724–734 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

T.G.B. acknowledges funding support from the US National Institutes of Health Director's Office and Common Fund (New Innovators Award DP2-CA174497), the National Cancer Institute (R01-CA169338), the HHMI Collaborative Innovation Award Program, the Searle Scholars Program, the Pew Charitable Trust, and the Addario Lung Cancer Foundation. R.C.D. acknowledges funding support from the V Foundation for Cancer Research and the University of Colorado Lung Cancer SPORE.

Author information

Author notes

  1. Trever G Bivona and Robert C Doebele: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medicine, University of California, San Francisco, San Francisco, California, USA

    Trever G Bivona

  2. Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California, USA

    Trever G Bivona

  3. Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, California, USA

    Trever G Bivona

  4. Department of Medicine and Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA

    Robert C Doebele

Authors
  1. Trever G Bivona
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Robert C Doebele
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Trever G Bivona.

Ethics declarations

Competing interests

T.G.B. has ownership in Driver Group, is a consultant to Driver Group, Novartis, Astellas, Natera, Array Biopharma, and Ariad, and is a recipient of research grants from Servier and Ignyta. R.C.D. is a consultant to Array BioPharma and Ariad, and has received honoraria from AstraZeneca, Clovis, and Pfizer, research grants from Loxo Oncology, Mirati Therapeutics, and Abbott Molecular, and licensing fees from Chugai, Ariad, Blueprint Medicines, GVKbio, and Abbott Molecular.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bivona, T., Doebele, R. A framework for understanding and targeting residual disease in oncogene-driven solid cancers. Nat Med 22, 472–478 (2016). https://doi.org/10.1038/nm.4091

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.4091

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer