Just say no to “de novo resistance”

Precisely-defined terminology is essential for clear scientific communication. But technical jargon isn’t always the best way to convey meaning. Real trouble arises when the same term comes to mean different things in allied specialties.

An example from my research is “migration”. In ecology and population genetics, migration is an umbrella term for movement between environments; to a cell biologist, the term more specifically implies orchestrated movement; an ornithologist, on the other hand, will likely think first of seasonal journeys. In my research applying popgen methods to cell biology, I’ve opted to avoid misunderstanding by ditching the term in favour of “dispersal”.

Worst of all is when a term means either one thing or its exact opposite, depending on the subfield. Such is the case of “de novo resistance”.

In germline evolution, “de novo mutation” has a well-established, unambiguous definition. It is, as the National Cancer Institute puts it, “a genetic alteration that is present for the first time in one family member as a result of a variant (or mutation) in a germ cell (egg or sperm) of one of the parents, or a variant that arises in the fertilized egg itself during early embryogenesis.”

By extension, a de novo mutation in somatic and microbial evolution is one that arises during the study period, as opposed to a pre-existing mutation. And if a new mutation confers drug resistance then a tumour or a pathogen population may acquire “de novo resistance”. This use is consistent with the literal translation of “de novo” as “of new”.

But “de novo” is also used in English to mean “from the beginning”, and this is the sense preferred by clinicians. In particular, “de novo resistance” is understood in medicine to be synonymous with intrinsic (primary) resistance, defined as no initial response to a drug in a patient who’s received no previous treatment. In the clinic — where resistance is principally classified according to when, not how, it arises — de novo resistance is the opposite of acquired (secondary) resistance.

Due to these different interpretations, the cancer and infectious disease research literature abounds with papers using “de novo resistance” to mean either pre-existing resistance [e.g. 1-5] or non-pre-existing resistance [e.g. 6-9]. And as evolutionary biology increasingly addresses medical questions, this particular bit of jargon is apt to confuse more than it clarifies.

NEJM editor Lorraine Loviglio once wrote, “For the nonstandard use of de novo as an adjective — frequently to mean very nearly the opposite of its standard definition as an adverb — there seems to be no excuse.” Most of all, please let us ditch “de novo resistance”.

References

  1. Hazlehurst L.A., Dalton W.S. (2006) De Novo and Acquired Resistance to Antitumor Alkylating Agents. In: Teicher B.A. (eds) Cancer Drug Resistance. Cancer Drug Discovery and Development. Humana Press
  2. Syn N.L., et al. (2017) De-novo and acquired resistance to immune checkpoint targeting. Lancet Oncology 18(12):e731-e741
  3. Xhao X., et al. (2017) Unification of de novo and acquired ibrutinib resistance in mantle cell lymphoma. Nature Communications 8:14920
  4. Aas T., et al. (1996) Specific P53 mutations are associated with de novo resistance to doxorubicin in breast cancer patients. Nature Medicine 2(7):811-4
  5. Kramer R.A., et al. (1988) Role of the glutathione redox cycle in acquired and de novo multidrug resistance. Science 241(4866):694-7
  6. Fu F., Nowak M.A., Bonhoeffer S. (2015) Spatial Heterogeneity in Drug Concentrations Can Facilitate the Emergence of Resistance to Cancer Therapy. Plos Computational Biology 11(3): e1004142
  7. Yamamoto K.N., et al. (2014) Evolution of Pre-Existing versus Acquired Resistance to Platinum Drugs and PARP Inhibitors in BRCA-Associated Cancers. Plos ONE 9(8): e105724
  8. Basanta D., Gatenby R.A., Anderson A.R.A. (2013) Exploiting evolution to treat drug resistance: Combination therapy and the double bind. Molecular Pharmaceutics 9(4):914-21
  9. Farrell F.D., et al. (2017) Mechanical interactions in bacterial colonies and the surfing probability of beneficial mutations. Journal of the Royal Society Interface 14(131). pii: 20170073

Author: Rob Noble

I use mathematical and computational models to investigate evolutionary and ecological systems. I am currently working, in close collaboration with laboratory scientists, on models of cancer evolution and the development of drug resistance. My methods include game theory, analysis of dynamical systems, spatially structured models, and Bayesian inference. During my PhD at the University of Oxford (2009-2013) I used mathematical models, informed by statistical analysis of laboratory data, to understand the immune evasion mechanisms of the malaria parasite Plasmodium falciparum.

5 thoughts on “Just say no to “de novo resistance””

  1. I was not aware of this terminology clash. I had assumed that it was always the former meaning, and never seen the clinical use. Thank you for warning me. It would definitely be easier for me to use something like “a priori resistance” for the clinical sense; at least if we insist on Latin. Alternatively we can just stick to English and use “pre-existing resistance” or just “unresponsive to treatment”.

    But I can also understand how the clinicians might have arrived at their terminology. It feels less reductive than the genetics terminology, especially since in practice it can be very difficult to detect if a certain mutation was pre-existing (at extremely low levels) or not. And to the clinician, the mechanism of resistance being genetic or not can also be irrelevant; especially in cases where they have no effective means to test for the corresponding genetic marker.

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    1. Yes, I can see why clinicians have a different way of categorizing things, but it’s unfortunate they chose to use this particular term. As noted in the article cited in the final paragraph, de novo is also “used, for example, to distinguish primary leukemia from leukemia secondary to ionizing radiation or certain drugs.” In such contexts, it would be much clearer to always say “primary”.

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