According to estimates from the International Agency for Research on Cancer, in 2012 there were 14.1 million new cancer cases and 8.2 million cancer deaths worldwide. In 2016, the American Cancer Society expected about 1.7 million new cancer cases to be diagnosed in the United States alone. This U.S. estimate does not include noninvasive cancer of any site except urinary bladder, nor does it include basal cell or squamous cell skin cancers, because these are not required to be reported to cancer registries.
The most common types of cancer with annual diagnoses over 40,000 in the United States include breast cancer, followed by lung, prostate, colorectal and bladder cancers.
There is no one cause, nor is there one treatment or therapy. Within each of these cancer types there are many causal variations. Tumors are highly heterogeneous and, as one can expect, sampling by traditional tissue biopsy may be precluded by tumor size or location. Liquid biopsies, using blood or urine, have been positioned as a cost-effective method for minimally invasive, systemic assessment of metastatic cancers using an easily obtainable sample from the patient.
In 2004, the CELLSEARCH system was introduced as the first FDA-cleared method designed for predicting the prognosis and monitoring the clinical outcome of patients with metastatic breast, prostate and colorectal cancers by enumerating circulating tumor cells (CTCs). Although a breakthrough technology at the time, enumerating CTCs in these select types of metastatic cancers has yet to be accepted as the standard of care for monitoring disease progression, prognosis and treatment efficacy.
Perhaps the technology was introduced before its time or, perhaps, there are more efficient and reproducible ways to retrieve and analyze CTCs.
Over a decade later, scientific and technical advancements have turned up the excitement factor on the concept of liquid biopsies and opened the doors to a vast array of new approaches, including quantification and analysis of CTCs, circulating tumor DNA (ctDNA) and exosomes.
Will these emerging technologies suffer the same acceptance problems as the initial CELLSEARCH platform? As cancer cases increase, it is clear that there is a need to utilize new technologies to find new ways to decrease monitoring costs as well as to adjust therapies that either do not work or cease to work due to evolving resistance.
What market challenges must be overcome for liquid biopsies to become the universally accepted standard of care in monitoring metastatic cancer?
The scientific community continues to debate which approach—CTCs, ctDNA or exosomes—will provide the most usable information to the clinician. Most likely, no one approach will provide all the answers needed in each particular circumstance and a yet-unknown combination of the three approaches will be the front winner of the future.
For example, CTCs and ctDNA have been investigated for clinical application in cancer screening/early detection, estimating prognosis/risk for metastatic relapse, stratification and real-time monitoring of therapy, identification of therapeutic targets and resistance mechanisms.
So far, the number of patients included in ctDNA studies is much smaller than in CTC-based studies. Although many studies have shown utility for CTCs or ctDNA individually, few studies have performed analyses of both CTC and ctDNA, especially using the most up-to-date technology and methods to allow fair comparison.
However, several clinical trials which aim to quantify both CTC and ctDNA in a variety of tumors and treatment settings are underway, and may provide clearer evidence of their relative utility, strengths and weaknesses as tumor samples (ClinicalTrials.gov, NCT02771314, NCT02364557, NCT02735252, NCT02588105, NCT02269982, NCT02220556, NCT02370355).
Enumeration and single-cell analysis of CTCs are powerful tools, as they provide a whole-cell perspective and allow cellular and molecular analysis. The biggest hurdle the technologies face is capture efficiency and comprehensive, easy-to-perform single-cell analysis. ctDNA is rarer and even more fragile than CTCs, and requires sophisticated knowledge of sequencing and data analysis. Exosomes will also face challenges but may also impart important information as this avenue of liquid biopsies develops.
As each of these technologies evolve, they will likely have overlapping as well as distinct clinical advantages, based on their biologic and technologic strengths and weaknesses. Yet the ongoing debate and positioning of one approach against the other has the potential user understandably confused as to which avenue to choose. The goal should be to isolate all three of the markers—CTCs, ctDNA and exosomes—in one system to better understand the biology of the cancer and to determine the next best steps for each patient.
Of course, this is easier said than done. Ease of use, efficiency and reproducibility of all assays must be demonstrated to allow the dissemination of liquid biopsy beyond large traditional well-funded and well-staffed medical institutions to hospitals in less-populated geographical areas, or those not affiliated with a research medical institution.
There are even more market challenges to be overcome for liquid biopsies to become the universally accepted standard of care in metastatic cancer. Although there are some existing U.S. reimbursement codes, private insurer coverage is spotty. Performing the clinical trials necessary to collect the clinical data that will convince private insurers about the cost effectiveness of liquid biopsy is yet another large costly and time-consuming hurdle.
To illustrate this point, according to a June 2016 policy statement from Health Net Inc., a wholly owned subsidiary of Centene, the company considers circulating tumor cells investigational for any indication. Although CTCs may help to predict disease progression and survival in some patients with metastatic cancer, Health Net believes that there is no conclusive data in the published peer-reviewed medical literature to indicate that this testing can be used to alter the therapy that is offered to patients and to improve outcomes.
Hundreds of clinical trials—active, recruiting and completed—are listed at ClinicalTrials.gov to generate data to prove private insurers wrong. But, as we well know, clinical trials and the resultant data analysis take time, especially when a clinical trial follows patients over time to determine prognosis.
Unfortunately, we are still in a mode of imprecision medicine; every day, millions of people take medications that will not help them. The top 10 highest-grossing drugs in the United States help between one in 25 and one in four of the people who take them. These drugs may not pertain to cancer treatment, but the message is clear: As healthcare costs continue to skyrocket, along with the cost of pharmaceuticals, this approach cannot continue.
Perhaps a better way of conducting clinical trials is needed, such as the N-of-1 trials advocated by Nicholas Schork in “Personalized medicine: Time for one-person trials” published in Nature in April 2015.
Despite hurdles, when the excitement factor gets turned on, discoveries happen more rapidly simply due to the increased number of participants and the more rapid discovery kinetics. The liquid biopsy excitement factor will continue and will drive the industry to come up with better, more simplified, yet sophisticated technology to accomplish the aim.
Precision medicine must be the wave of the future, and liquid biopsies are poised to be part of this in predicting the prognosis and monitoring the clinical outcome of metastatic cancer patients. Strategic partnerships between industry players will be a key component to accelerate acceptance of the technology.
Throughout his career, Grant Howes, vice president of commercial operations for Celsee Diagnostics, has focused on the medical device and life-sciences research/cell-analyses marketplaces. Prior to joining Celsee Diagnostics, he was director of marketing at BD Biosciences, where he had global responsibilities for personal cell-analysis systems in addition to the HIV/AIDS Initiative.