Disease persists or recurs:
Why do disease treatments fail, in the treatment of AML et al if the residual tumor cells are antigenically similar progeny of the originals? Simply the effect of mutagenic chemotherapy? Or subclones of the blast or progenitor population? Or do the blasts evolve and develop subsequent resistance to any and all therapeutic agents? AML is the best suited model for laboratory investigation as the disease mimics the accepted cancer stem cell model.
Controversially the definition of cancer stem cells (CSC) is not yet settled: is the CSC an initiating cell, a propagating cell, or a stem-like cell?
Evolutionary changes in the body, dependent on both the external and internal environment (chemo and immune-therapy), allow diseases to escape natural controls i.e. the immune system, and provide shields to further treatment. Sequencing of paired initial and relapse AML cells reveal relapse is reflected in minor genetic subclones initially present which survive chemotherapy. What are these cells?
Similarly, in lymphoma, tumor cells evolve to become refractory to chemotherapy, loss of responsiveness to treatment with monoclonal antibodies (mAbs) such as rituximab and that is a serious complication during therapy of B-cell malignancies, but the mechanisms responsible for it are not well understood.11
This is what one would expect from natural kinds such as ourselves; we evolve to survive ambient cultures e.g. obesity and Type II diabetes may be considered evolutionary alterations22 a shift from simpler diets and activities.
The most important advance provided for in the concept of precision medicine initiative will be a more specific way to define and thus to understand disease, but it will not finally be therapeutically effective since natural kinds will not easily succumb to alteration of the interior milieu i. e. the treatment that will try to change this interior state.3312 Natural kinds will adapt to interventions as quickly as they can.
As precision medicine is aimed at understanding disease, we must be able to take advantage of survival distributions; if every disease is unique, there is no purchase for induction, nor path to generalize treatment If each case of lung cancer will require different immunomodulating drugs,1344 and the cost for one year exceeds $150,000, or CART therapy with axicabtagene costing $373,000 for a single injection, how shall equitable distribution be established in the non-insured population?55 667714
“There is a grandeur in this view of life (and disease) with its several powers, having been originally breathed into a few forms or into one; and that whilst the planet has gone cycling on according to the fixed law of gravity, from so simple a beginning endless forms most beautiful and most wonderful have been, and are being, evolved.”88 15
Declarations:
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2. Nagen M., Chen Y., Lovejoy CA., Artificial intelligence versus clinicians : systematic review of design, reporting standards, and claims of deep learning studies. BMJ 25 March 2020 p 368-381
3 Quine WVO. “Natural Kinds” from Ontological Relativity and Other Essays.1969, pp.134-138
4 Manrai AK. Ioannidis JPA Kohan eIS Clinical Genomics from Pathogenicity Claims to Quantitative Risk Estimates JAMA March 22/29, 2016 Vol 315.No. 12
5. Laplane, Lucie “Cancer Stem Cells: philosophy and therapies” HUP 2016
6.Tannock IF, Hickman Ja “Limits to Personalized Cancer Medicine, NEJM.375:13 1259-1294.
7. Dilley RL, Verma, P, Cho NM et al: Break-induced telomere synthesis underlies alternative telomere maintenance. Nature 2016 ;53.9 54-58
8. Hoffman EP Skipping toward Personalized Molecular Medicine NEJM 357; 26 December 27, 2007.
9. MacConaill LE. Brave-ish New World-What’s needed to make precision oncology a practical reality, JAMA Oncology July 16, 2015
10. Joyner MJ Seven Quesitons for Personalized Medicine. JAMA sept 8, 2015 999-1000
11. Jamal-Hanjani M et al tracking the Evolution of Non-Small Cell Lung cancer NEJM 376;22 June 1, 2017
12. Shlush L. Tracing the origins of relapse in acute myeloid
leukaemia to stem cells Ieukemia Nature 547, 104-108 July 6, 2017
12. Hoffman E.P. Skipping toward Personalized Molecular Medicine. NEJM 357:26, Dec. 2020