Many Companies Join Race to Create Novel CTC Technology

This breast cancer circulating tumor cell culture was isolated from a patient’s blood sample using the CTC-iChip and expanded in the laboratory for drug testing. Researchers at the Massachusetts General Hospital Cancer Center at Harvard Medical School and the Harvard Center for Bioengineering in Medicine are developing the CTC-iChip through a collaboration funded partly funded by Janssen Diagnostics.(Courtesy of Min Yu, PhD, MD/Newswise)

At least 30 companies are seeking to develop the next generation of circulating tumor cell (CTC) technology, part of an emerging focus on analyzing the biofluids of patients with cancer as a “liquid biopsy,” particularly for solid tumors.

Fueled in part by the National Cancer Institute, the research efforts concentrate on creating methods of extracting CTCs from blood samples so that they can be analyzed on a molecular level.¹

Thus far, the CellSearch system is the only in vitro CTC diagnostic to gain the FDA’s approval, although other assays are available commercially as laboratory developed tests. Initially approved in 2004, CellSearch is indicated for detecting the presence of CTCs and monitoring disease progression through CTC levels in patients with metastatic breast, colorectal, and prostate cancer.

Although the enumeration of CTCs has demonstrated analytical and clinical validity in these tumor types, the CellSearch test has not yet been established as a means of selecting therapies for these patient populations, hampering its incorporation into treatment guidelines. Medicare covers CTC testing, but the reimbursement picture in the private insurance industry is spotty.

Janssen Diagnostics, which owns the CellSearch technology, is actively seeking to validate its clinical utility through large studies in the United States and Europe. In addition, Janssen is developing the CTC-iChip, which isolates CTCs suitable for both standard clinical diagnostic cytopathology and advanced genetic and molecular analysis, through a collaboration with researchers at the Massachusetts General Hospital Cancer Center.

Similarly, major pharmaceutical companies and emerging biotechnology firms have partnered with each other and with academic institutions to develop CTC technology.

“These companies are not all ‘me too’ companies trying to just harvest the cells,” Enal Razvi, PhD, managing director of Select Biosciences US, a market research and life sciences conference company, said in an interview. “That's been done. Now, the challenge is to go to the next level—capture the cells and then ask the question: What do these cells do in the body, what is their potential to metastasize, and are they truly going to seed a new tumor? That’s the belief, but the proof remains.

“Just counting the number of cells gives you very basic information. It doesn't provide you with the details and that’s been a challenge of CTCs,” added Razvi. “For CTCs to have their full impact in the clinic, you need to have more depth and that depth comes from a molecular analysis of these tumor cells that had been harvested from the patient.”

The Competitive Landscape

Razvi said about 30 companies are working on CTC technology. He values the current market for CTC diagnostics at $200 million to $250 million annually, with most of the testing being performed in the United States. That market, however, is likely to expand internationally.

“China, for example, is embracing a lot of this work with biofluid biopsies and, in in fact, Chinese companies are offering these CTC tests, so the market number is surely going to increase and grow,” said Razvi.

Indeed, Biocept Inc, a molecular diagnostics company based in San Diego, California, announced in September that the company has obtained a patent in China for its microfluidic technology that captures CTCs.² In the United States, the company is collaborating with The University of Texas MD Anderson Cancer Center to study its OncoCEE device for evaluating HER3 expression in ovarian cancer CTCs.³ Biocept has launched an OncoCEE test for breast cancer and plans to introduce tests for lung, colorectal, prostate, and other solid tumors.³

Biocept was among 10 companies that respondents to an industry survey cited as those whose technologies hold the most promise for improving the ability to study and measure CTCs. ⁴

Janssen Diagnostics led the field by a wide margin, according to the survey, conducted last year as part of the Circulate: Circulating Cancer Biomarkers conference held in Boston. Also making the list were Fluidigm, Fluxion, Miltenyi Biotec’s MACS system, ScreenCell, Advanced Cell Diagnostics, CytoTrack, BioFluidica, and SRI Biosciences’ FASTcell system.

Other companies whose technology has attracted attention in research circles include Epic Sciences and Cynvenio Biosystems.

Based in San Diego, Epic Sciences has partnered with Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, and the University of Michigan to study the use of its technology for the molecular characterization of CTCs in prostate cancer.⁵ Industry investors include Roche and Pfizer venture funds.⁶

Cynvenio trademarked the term LiquidBiopsy for its system of deriving CTC cell populations that can be captured on a microfluidic chip and analyzed molecularly directly from the chip. The company’s clinical advisory board includes noted CTC researcher Massimo Cristofanilli, MD, director of the Jefferson Breast Care Center at the Sidney Kimmel Cancer Center at Thomas Jefferson University in Philadelphia.

For his part, Razvi declined to characterize any particular developing technology as more promising than that of a potential competitor, citing his desire to remain an unbiased analyst of the industry. Select Biosciences is hosting the Biofluid Biopsies and Companion Diagnostics conference in San Diego on October 27-28 and will hold the 2nd Annual SELECTBIO Circulating Biomarkers World Congress 2015 in Boston in March.

“A lot of these companies have interesting results but let's see how they shake out and how the data come out over the coming years in the clinic,” said Razvi. “Ultimately, the technology might look promising but if it doesn't have robustness across patient samples, for example, then its clinical utility and appeal is significantly diminished.”

Next Steps for Existing Technology

Amid such a crowded field, Janssen Diagnostics is seeking to advance the use of its current CellSearch technology, which already has been widely employed.

For example, the technology has been used to perform 151,600 tests for patients in clinical settings from 2010 through mid-2014 alone, and an additional 156,000 tests as part of research studies, according to Mark C. Connelly, PhD, scientific director of cellular research and site director at the company’s Huntingdon Valley, Pennsylvania, laboratory.

Connelly said the presence of CTCs above certain thresholds (≥5 CTCs/7.5 mL blood for prostate and breast cancer and ≥3 CTCs/7.5 mL blood for colorectal cancer) is predictive of shorter progression-free survival and shorter overall survival.

He said this information is useful to oncology specialists when evaluated in conjunction with other clinical indicators to manage patients, particularly when tumor specimens are unavailable.

Connelly said Janssen is seeking to establish the clinical utility of CellSearch technology in five trials now under way, all involving patients with metastatic breast cancer:

• CirCeO1, which assesses the value of CTC enumeration in improving outcomes for patients with multiple treatment switches in advanced third-line therapy
• STIC, which evaluates the utility of baseline CTC count in choice of first-line therapy
• DETECT, which studies CTCs as a decision tool for treating patients with HER2-negative primary breast cancer that expresses HER2-positive CTCs during progression
• CirCe T-DM1, which investigates whether patients with HER2-negative breast cancer who have HER2-amplified CTCs will respond to the HER2-targeting ado-trastuzumab emtansine (Kadcyla)
• COMETI, which evaluates a CTC endocrine therapy index for patients with tumors that are estrogen receptor—positive and HER2-negative.

Data from these trials are expected to mature within the next three to four years. Meanwhile, CellSearch has not been incorporated into cancer treatment guidelines in the United States, although it is included in a set of gynecological guidelines in Germany, said Connelly.

“We continue to work with guideline organizations in the United States to collect the kind of data that we need to answer their questions,” said Connelly.

The acceptance of a therapy into treatment guidelines is “hugely influential” when it comes to whether insurance payers will reimburse for an assay, noted Bruce Quinn, MD, PhD, a national healthcare policy and reimbursement expert with the Foley Hoag strategic advisory law firm.

Quinn said payers increasingly look for either one or both of two elements: “evidence that there are improved patient outcomes when that test is used as opposed to when it’s not used, and then a clear position for the test in guidelines.”

As it stands now, Medicare will reimburse for CTC testing at a national rate of $337 for assays in a category that includes laboratory-developed tests as well as CellSearch, noted Quinn. Private insurance coverage varies, however, with several major companies considering the tests as investigational and thus declining coverage.

Connelly put the CellSearch reimbursement issues into the context of a difficult healthcare environment, and said Janssen is continuing its dialogue with payers and providers. “We’re living in time of a lot of challenges but bringing this test to the market in the first place was a significant challenge, so we’re not afraid of the challenge,” he said.

Moving Toward the “Liquid Biopsy”

Although CTCs have garnered most of the attention, they are part of a class of biological material that researchers are seeking to exploit for analysis as a “liquid biopsy,” and the importance of translating such elements for clinical use is expected to grow in the coming years.

Razvi prefers the term “biofluid biopsy” to describe this emerging category. “Circulating tumor cells are one way to characterize circulating biomarkers,” said Razvi, adding that exosomes, cerebrospinal fluid, and urine are also being investigated for this purpose. “Biofluid biopsy is a more all-encompassing term that we feel characterizes the space—CTCs are a class of analytes that can enable you to perform biofluid biopsies.”

In terms of blood-based biomarkers, Quinn anticipates the emergence of assays that analyze circulating DNA as well as tests for CTCs. “This area of molecular medicine is evolving very rapidly,” said Quinn. “People are looking at cancer genes in blood, cancer genes in circulating tumor cells, looking at panels of cancer cells… But I don’t think it’s far enough published for payers to be on board yet.”

At Janssen Diagnostics, the company is planning for a future that includes a variety of new technologies.

“We believe that the whole field of dynamic fluid monitoring is going to be a huge advantage for personalizing therapies and personalizing directed therapies into the future because it’s essentially noninvasive,” said Connelly. “Technologies such as CellSearch, such as our next-generation [sequencing] technology, molecular diagnostics—all of these will be brought to the bear to provide real-time, patient- specific information.”

References

1. US Department of Health and Human Services. The National Cancer Program: An Annual Plan and Budget Proposal for FY 2013. National Cancer Institute. Published NIH Publication No. 13-7957. November 2012. Accessed October 13, 2014.
2. Biocept granted patent in China for its microfluidic channel technology used to capture circulating tumor cells [press release]. San Diego, CA: Biocept, Inc; September 18, 2014. http://ir.biocept.com/releases.cfm. Accessed October 13, 2014.
3. Biocept expands collaboration with MD Anderson Cancer Center [press release]. San Diego, CA: Biocept, Inc; October 7, 2014. http://ir.biocept.com/releases.cfm. Accessed October 13, 2014.
4. Survey results: annual CTC industry overview. Circulate: Circulating Cancer Biomarkers website. http://circulate-europe.com/resources. Published 2013. Accessed October 13, 2104.
5. Epic Sciences and collaborators to present six novel abstracts at ASCO GU addressing the clinical applicability of Epic's CTC technology in prostate cancer [press release]. San Diego and San Francisco, CA: Epic Sciences, Inc; January 29, 2014. http://goo.gl/CSVzaM. Accessed October 13, 2014.
6. Epic Sciences announces Series C financing to advance essential cancer diagnostics for personalized medicine [press release]. San Diego, CA: Epic Sciences, Inc; July 30, 2014. http://goo.gl/UK7Z6p. Accessed October 13, 2014.