24 October 2013
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Nature magazine recently had a special Insight on tumor heterogeneity, complete with no less than six fantastic review articles on the topic.
Barbara Marte gave an introduction on the matter:
Cancer is not one but many diseases. It is different in each patient and continuously evolves into a progressively complex interplay of diverse tumour cells with their changing environment.
In an insightful and prescient 1976 paper, Peter Nowell proposed the now prevailing view of cancer as a process of clonal evolution, in which successive rounds of clonal selection give rise to tumours with diverse genetic and other molecular alterations that may necessitate ‘personalized’ therapies.
There is great variability between cancers, but it is the variability within tumors that I see as the biggest hurdle for diagnosis, treatment, and resistance even with the multi-faceted revolution in sequencing and targeted therapies.
If every cancer, and perhaps every cancer cell, is unique, and some cancer cell populations are more ‘unique’ than others, this needs to be taken into consideration for the improvement of cancer diagnoses and prognoses, for the treatment and monitoring of each patient and for the design of clinical trials to evaluate new therapies.
I could not agree more. A caveat to every molecular analysis on tumor tissue is that it offers only a spatial and temporal snapshot of the disease. This caveat is seldom acknowledged in oncology literature, almost never directly addressed in discussions, and sometimes completely ignored in experimental methodology that would be greatly affected by the heterogeneous snapshot caveat. What was present at that moment in time might be no more in weeks’ or months’ time. While there is a potential for a malignant tumor to continue to evolve, tremendous spatial heterogeneity already exists in many tumors. (1-4)
Any targeted therapy might not hit every tumor cell even with perfect pharmacodynamics, because a particular target might not be present in every tumor, and it’s difficult to know what other targets exist in other regions of a tumor without a comprehensive survey of tumor heterogeneity. Genetic testing requires biopsies for genomic surveys, and even the most advanced sequencing technologies cannot get past a particular caveat: it is impossible to survey an entire tumor’s genetic heterogeneity. Repeat biopsies are highly invasive to cancer patients and pose logistical and ethical problems. Besides, and if a particular tumor was easily accessible, it would likely be removed surgically anyway.
So, what part of a tumor could or should be biopsied? How much weight should be put on the driver mutations detected in a particular biopsy? What essential molecular targets might evade our notice?
While there is a growing appreciation (apprehension?) at the immense heterogeneity within tumors and the associated hurdles to more effective therapy, there is also a growing interest in cell free DNA (cfDNA). It was recently reported that advanced cancer patients have an order of magnitude higher amount of DNA floating around in their blood plasma than healthy volunteers (5). Furthermore, the amount of cfDNA was shown to correlate with disease progression (6), and to carry tumor-specific mutations that can be used to track genomic evolution of metastatic cancer in response to targeted therapy (7).
The origin of this cfDNA is likely the same cells that will cause the most harm to cancer patients: the ones that escape tumor(s) and seed the bloodstream. Studies from circulating tumor cells (CTC) indicate that the vast majority of CTC’s do not form tumors (8, 9), and the detection of shards of tumor cells along with long strands of genomic DNA is consistent with many of these cells being torn apart by sheer forces in the vasculature. The genomic interrogation of this cfDNA might not be too far away with the current trends in sequencing technology, giving rise to the non-invasive “liquid biopsy” of solid tumor heterogeneity surveyed with a blood draw (7, 10).
Such analyses are amendable to serial biopsies and might give light to the kinetics of tumor heterogeneity over time, portraying patterns of tumor evolution that could be exploited therapeutically, and perhaps even prophylactically.
1. Gerlinger M, Rowan AJ, Horswell S, Larkin J, Endesfelder D, Gronroos E, et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. The New England journal of medicine. 2012 Mar 8;366(10):883-92. PubMed PMID: 22397650. Epub 2012/03/09. eng.
2. Yachida S, Jones S, Bozic I, Antal T, Leary R, Fu B, et al. Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature. 2010 Oct 28;467(7319):1114-7. PubMed PMID: 20981102. Pubmed Central PMCID: PMC3148940. Epub 2010/10/29. eng.
3. De Mattos-Arruda L, Cortes J, Santarpia L, Vivancos A, Tabernero J, Reis-Filho JS, et al. Circulating tumour cells and cell-free DNA as tools for managing breast cancer. Nature reviews Clinical oncology. 2013 Jul;10(7):377-89. PubMed PMID: 23712187. Epub 2013/05/29. eng.
4. Park SY, Gonen M, Kim HJ, Michor F, Polyak K. Cellular and genetic diversity in the progression of in situ human breast carcinomas to an invasive phenotype. The Journal of clinical investigation. 2010 Feb;120(2):636-44. PubMed PMID: 20101094. Pubmed Central PMCID: PMC2810089. Epub 2010/01/27. eng.
5. Perkins G, Yap TA, Pope L, Cassidy AM, Dukes JP, Riisnaes R, et al. Multi-purpose utility of circulating plasma DNA testing in patients with advanced cancers. PloS one. 2012;7(11):e47020. PubMed PMID: 23144797. Pubmed Central PMCID: PMC3492590. Epub 2012/11/13. eng.
6. Dawson SJ, Tsui DW, Murtaza M, Biggs H, Rueda OM, Chin SF, et al. Analysis of circulating tumor DNA to monitor metastatic breast cancer. The New England journal of medicine. 2013 Mar 28;368(13):1199-209. PubMed PMID: 23484797. Epub 2013/03/15. eng.
7. Murtaza M, Dawson SJ, Tsui DW, Gale D, Forshew T, Piskorz AM, et al. Non-invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA. Nature. 2013 May 2;497(7447):108-12. PubMed PMID: 23563269. Epub 2013/04/09. eng.
8. Allard WJ, Matera J, Miller MC, Repollet M, Connelly MC, Rao C, et al. Tumor cells circulate in the peripheral blood of all major carcinomas but not in healthy subjects or patients with nonmalignant diseases. Clinical cancer research : an official journal of the American Association for Cancer Research. 2004 Oct 15;10(20):6897-904. PubMed PMID: 15501967. Epub 2004/10/27. eng.
9. Meng S, Tripathy D, Frenkel EP, Shete S, Naftalis EZ, Huth JF, et al. Circulating tumor cells in patients with breast cancer dormancy. Clinical cancer research : an official journal of the American Association for Cancer Research. 2004 Dec 15;10(24):8152-62. PubMed PMID: 15623589. Epub 2004/12/30. eng.
10. Lianidou ES, Mavroudis D, Georgoulias V. Clinical challenges in the molecular characterization of circulating tumour cells in breast cancer. British journal of cancer. 2013 Jun 25;108(12):2426-32. PubMed PMID: 23756869. Pubmed Central PMCID: PMC3694246. Epub 2013/06/13. eng.