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How The Liquid Biopsy Could Speed Up Oncology Clinical Trials

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5 May 2014

The realization of Precision Oncology involves developing many low-toxic therapeutics to specifically target genetic weak points in a patient’s cancer. The requisite technology for tumor genomic analysis will likely not be a limiting factor in a few years’ time, especially with the advent of sequencing platforms like HiSeq X Ten by Illumina. The remaining rate-limiting step is the clinical trial phase; clinical trials are immensely expensive to conduct, and measures that can reduce the costs (and time) of oncology clinical trials will allow new molecular scalpels to reach the clinic at a quicker pace.

The pivotal I-Spy1 trial (1) established a strong correlation between observed radiographic reduction of tumor size in the neoadjuvant (before surgery) setting, and long-term survival irrespective of surgery:

Primary objectives were to evaluate whether response to therapy—as measured by imaging (magnetic resonance imaging [MRI] volume) response and pathologic complete response (pCR)—would predict recurrence-free survival (RFS), overall and within biologic and imaging subsets.

I-Spy1 provided the ethical framework for use of radiographic imaging pCR as a surrogate for Survival, and opened the door for neoadjuvant testing of new targeted therapies. I-Spy1 paved the way for the transformative I-Spy2 clinical trial in progress (2). The result is a roughly six-month knowledge turn, instead of a knowledge turn on the order of magnitude of years.

However, radiographic / pathological monitoring of tumor burden is far from optimal. There is a level of subjectivity and noise that can flummox even the most skilled pathologist / radiologist. Also, mammograms, CT Scans, MRI’s are all highly invasive procedures, and very expensive ones at that. The use of these scanning techniques is a contributing factor to the immense cost of clinical trials in oncology.

The Liquid Biopsy has great potential for cancer diagnosis, risk assessment, and therapy. Its advantages are many: compared to more traditional forms of tumor monitoring like PET, MRI, x-ray and mammogram, a blood draw is much less invasive to the patient with much greater ease of re-biopsy and longitudinal monitoring, and potentially much less expensive. But, its technological hurdles are great. That said, they are not insurmountable, and it’s an area of technology that I can see greatly helping many facets of oncology.

Retrospective analyses indicate that numeration of circulating tumor cells (CTC’s) can be a strong prognostic factor, and might be able to predict tumor relapse and / or provide clinically actionable genetic and phenotypic information (3-5).

Perhaps CTC detection technology could be adapted for use in neoadjuvant monitoring of tumor burden? Would a clinical trial similar to I-Spy1, except using a CTC metric in lieu of radiographic tumor size reduction, enable the introduction of less invasive disease monitoring that might shorten clinical trial length and reduce cost? Could this enable a quicker turnaround for therapies to find their way into the clinic?

In the adjuvant (after surgery) setting, might a longitudinal increase in CTC burden indicate impending relapse? Such an increase in CTC number (or perhaps another metric?) could be detectable long before metastatic outgrowths become visible via PET, MRI, X-ray, etc. CTC’s could provide a quicker endpoint for clinical trials? For this to happen, a prospective clinical trial could be structured to establish longitudinal CTC-based metric (such as CTC number, gene expression, size, density, morphological shape, etc.) that strongly indicates impending relapse. Such information could then be used to reduce knowledge turn time for adjuvant clinical trial results, not to mention spare patients from additional chemotherapy for which their cancer is refectory, and begin alternative therapeutic regiments before establishment of radiographically visible tumors.

Ryon

References:

1. Esserman LJ, Berry DA, DeMichele A, Carey L, Davis SE, Buxton M, et al. Pathologic complete response predicts recurrence-free survival more effectively by cancer subset: results from the I-SPY 1 TRIAL–CALGB 150007/150012, ACRIN 6657. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2012 Sep 10;30(26):3242-9. PubMed PMID: 22649152. Pubmed Central PMCID: PMC3434983. Epub 2012/06/01. eng.
2. DeMichele A, Berry DA, Zujewski J, Hunsberger S, Rubinstein L, Tomaszewski JE, et al. Developing safety criteria for introducing new agents into neoadjuvant trials. Clinical cancer research : an official journal of the American Association for Cancer Research. 2013 Jun 1;19(11):2817-23. PubMed PMID: 23470967. Epub 2013/03/09. eng.
3. Wallwiener M, Hartkopf AD, Baccelli I, Riethdorf S, Schott S, Pantel K, et al. The prognostic impact of circulating tumor cells in subtypes of metastatic breast cancer. Breast cancer research and treatment. 2013 Jan;137(2):503-10. PubMed PMID: 23271327. Epub 2012/12/29. eng.
4. Yu M, Bardia A, Wittner BS, Stott SL, Smas ME, Ting DT, et al. Circulating breast tumor cells exhibit dynamic changes in epithelial and mesenchymal composition. Science. 2013 Feb 1;339(6119):580-4. PubMed PMID: 23372014. Epub 2013/02/02. eng.
5. Friedlander TW, Premasekharan G, Paris PL. Looking back, to the future of circulating tumor cells. Pharmacol Ther. 2014 Jun;142(3):271-80. PubMed PMID: 24362084. Epub 2013/12/24. Eng.

Edit 5/16/2014: Embarrassing spelling errors

Written by Ryon

May 5th, 2014 at 7:01 pm

Posted in Science Blog