COMMENTARY

Is Precision Oncology Really Precise?

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Hello and welcome. I am Dr George Lundberg and this is At Large at Medscape.

Is precision oncology accurate? The answer is either no or unknown. Precision oncology is not even precise. From my clinical pathology background, "accurate" means correct, as close to a gold standard as you can get regarding sensitivity and specificity.

As of now, there is no gold standard as to:

  • Which cancers should be subjected to molecular analysis, such as next-generation sequencing (NGS)—all or all except nonmelanoma skin cancers? Or only those cancers for which there are US Food and Drug Administration (FDA)–approved therapies determined by molecular definition or those for which there are open relevant clinical trials?

  • When to perform NGS on a cancer—at initial diagnosis or not until after spread, or both?

  • Where to take the test sample from—primary tumor or one or many metastatic sites, or both?

  • How to sample—by liquid biopsy, solid tumor biopsy, fine-needle aspiration cytology, or whole tumor segments after surgical removal?

  • Where to send the sample—local pathology lab, regional reference lab, nearest academic or comprehensive cancer center, or dominant commercial lab companies?[1]

  • How to recognize the variants consistently via bioinformatics and experienced professional judgment?

  • Whether the mutation(s) identified are passengers or drivers.*

  • Whether a particular mutation confers "actionability."*

  • Which FDA-approved single drug or combination of drugs, concurrently or in sequence, would be the best choice?*

  • Which investigational drug might merit a clinical trial with an N of 1, after a fully informed consent, and expanded access (compassionate use)?

  • Who (patient, insurance company, government, drug company, treating institution) will pay?

  • How much will be paid for the NGS testing and for the drug, which can cost $100,000-$200,000 per drug per patient/cancer?

  • What therapeutic strategy* may make scientific sense for that patient's cancer?

  • Whether a positive clinical trial match* constitutes actionability.

  • Whether any current drug is a reasonable choice (estimated 10% of cancers).

  • How frequent and severe are likely adverse clinical effects? (This seems especially unknown and probably greatly underreported.)

  • What outcome can be anticipated (no cures yet reported)? A few months, average, of extended (meaningful, useful, worthwhile, pain-free, desired, comfortable, connected) life seems to me a low bar to measure cost-effective "success."

Meanwhile, is precision oncology precise? No way. Reverting to my clinical pathology background, "precise" means reproducible. Prasad and Gale[2] have recently demonstrated that not even the use of the term "precision oncology" is precise—that is, reproducible year to year in this century. It has changed and changes dramatically.

Replicable against gold standards in virtually all of the parameters described in the previous paragraphs? Not even close.

NEEDED: Gold standards for each step of the "brain-to-brain loop"[3] delineated above.

This is a pretty dreadful scientific and clinical scene, yet some 600,000 Americans with cancer proceed beyond standard of curative care every year. But if not precision oncology and radiology (and immunotherapy), what then for each of them? Will history label "precision oncology" of 2017 as merely "early" or as a well-intentioned wild goose chase, or something worse? Time and tens of billions of dollars for testing and experimental treatment for hundreds of thousands of patients will tell in 1 year, 5 years, or—you tell me—when.

I hope there are some molecular oncologist and molecular pathologist readers out there who can take me on and prove me wrong. If so, light up the comments board for all to see. Or engage me privately at gdlundberg@gmail.com.

That is my opinion. I am Dr George Lundberg, at large for Medscape.

*Disclosure: These are services/products offered by CollabRx, of which I am chief medical officer.

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