One of the best ways to truly understand the staggering advances and potential impact of medical innovations is to talk to the individuals who lead the organizations responsible for developing them. So, I was thrilled to sit down with Mike Hoerres, the CEO of Cernostics. The company is on a mission is to develop better cancer diagnostics through a unique approach to tissue analysis.
Cernostics first product focuses on an important question related to esophageal cancer, a malignancy that often has a poor prognosis:
How can clinicians know which patients with Barrett’s esophagus will progress from this non-malignant precursor condition to outright esophageal cancer?
Facts about Barrett’s esophagus and esophageal cancer
Esophageal cancer is relatively uncommon, accounting for only 1% of cancers diagnosed in the U.S. However, it is one of the worst cancers to live with and is often deadly. Overall, the five-year survival rate is ~20% although cancers diagnosed early have a better prognosis.1https://www.cancer.org/cancer/esophagus-cancer/about/key-statistics.html Risk factors for esophageal cancer include the following2https://www.cancer.org/cancer/esophagus-cancer/causes-risks-prevention/risk-factors.html:
- Tobacco use
- Chronic gastroesophageal reflux (GERD)
- Heavy alcohol use
- Barrett’s esophagus
Barrett’s esophagus occurs when stomach acid backs up into the esophagus. This causes cellular and molecular changes that lead the esophageal lining to resemble that of the intestines. About 10-15% of people with chronic GERD will end up with Barrett’s esophagus3https://www.asge.org/home/for-patients/patient-information/understanding-gerd-barrett-39-s. But less than 1% of them will develop esophageal adenocarcinoma.4https://blog.dana-farber.org/insight/2016/01/five-things-you-need-to-know-about-barretts-esophagus/
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A key clinical question
As I mentioned above, a key clinical question is which of the three to four million people living with Barrett’s in the US alone will progress to esophageal adenocarcinoma (EAC)? It is an important question because traditional diagnostic methods, tissue biopsy analyzed with chemical stains (i.e., traditional histopathology), fail to predict the risk of progression.
The inability to determine that risk leaves gastroenterologists and their patients without complete information to determine the most clinically and cost-effective treatment. This may lead to unnecessary surveillance involving multiple endoscopies and biopsies. And, of course, it causes needless worry on the part of patients and families.
Cernostics is looking to change all that with their “next generation cancer diagnostics and prognostics.” Their patented TissueCypher® Barrett’s Esophagus Assay offers deeper tissue insights than regular anatomical pathology.
What is Cernostics unique approach?
The company describes its unique approach as “tissue analysis, digital pathology, and healthcare delivery re-engineering.” According to the company:
“Until now, there has been no adequate way to determine the risk level of patients with Barrett’s esophagus. There is no single biomarker that can sufficiently diagnose the grade of dysplasia or predict malignant progression since multiple pathways play a role in disease progression.”
In contrast to traditional diagnostic methodologies. Cernostics combines their tissue assay with a technology platform for what they call “high dimensional analysis of tissue biopsies.”
Intended use for Cernostic’s technology
The technology is designed to use with those patients who are at the “early end of the Barrett’s spectrum” and have one of the following findings on histology:
- non-dysplastic (ND)
- indefinite for dysplasia (IND)
- low-grade dysplasia (LGD)
The goal is to eliminate uncertainty related to the treatment of Barrett’s esophagus in patients who meet those criteria.
Why focus on Barrett’s esophagus and esophageal cancer?
Theoretically, according to CEO Mike Hoerres, Cernostics could focus on most types of cancer. They selected Barrett’s and preventing esophageal cancer as their first priority for multiple reasons:
- The treatment of Barrett’s esophagus – the ablation of the abnormal tissue – is effective at preventing later development of esophageal cancer.
- The growth rate of the esophageal cancer
- Esophageal cancer is also one of the worst possible cancers
- The challenge of understanding which of the millions of patients will progress to cancer
- A detailed risk prognosis offers actionable information to doctors and patients
Also, says Hoerres, Barrett’s is a big market: U.S. estimates are more than $1 billion dollars are spent on the disorder. It is $2 billion if you include the Western European market.
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Additionally, there is an opportunity to improve patient care in major ways. The product will improve practice and treatment and it’s likely to be financially viable. Most important of all, it may make a real difference in preventing this deadly form of cancer.
Anatomic Pathology vs. Advanced Tissue Assay Platform
There are important differences between anatomic pathology which gastroenterologists currently depend on and the advanced Cernostics approach. With anatomic pathology, a pathologist views a section of tissue through a microscope and makes a subjective assessment of the state of the tissue (e.g., is it malignant or not?)
Instead, the Cernostics tissue assay analyzes at molecular, cellular and proteomic levels. The company describes what they do as a “tissue systems biology approach to anatomic pathology.”
Their patent-protected technology platform, TissueCypher™, “analyzes whole slide digital images with multiplexed fluorescence.” This offers substantially more information and accuracy than traditional subjective tissue diagnostics.
The platform simultaneously evaluates multiple tumor, immune, and stromal cells processes as well as biomarkers on a single slice of tissue. The company states this will provide a “new path for the development of novel diagnostic tests for digital and anatomic pathology.”
How it works
Cernostics states that their product combines “quantitative analysis of multiple protein-based biomarkers with tissue structure information to predict the risk of progression to high-grade dysplasia (HGD) and esophageal adenocarcinoma (EAC) in patients with Barrett’s esophagus.”
It quantifies key expression features of 9 unique biomarkers including immune system biomarkers and tissue morphology. With multiplexed immunohistochemistry, there are multiple colors per slide. They look at 4 unique biomarkers per section of tissue performed through immunofluorescence staining.
An image analysis software platform then evaluates the digital images from multichannel fluorescence whole-slide images. Multiple epithelial, immune, and stromal biomarkers are labeled by immunofluorescence on a tissue slide from an esophageal biopsy of Barret’s esophagus.
“This is all about combining molecular and cellular data and information within a spatial context. You can see where something is expressed in the biopsy or if it’s co-expressed in one location. That is important and can play a part in tumor growth, tumor progression, response to therapy, ultimately, in patients’ outcomes.”
Horres says that the evaluation is determined by proprietary algorithms. The result is automatic, objective and with much higher throughput than traditional biopsies. The test algorithm measures 9 markers, 14 features.
The digital whole slide imaging software platform has two sets of algorithms:
- The first set uses algorithms to automatically identify cell-based objects on the biopsy. This includes the nuclei, the cell membrane, the cytoplasm.
- The other set has algorithms that can identify a larger geographic area in the biopsy. For example, the epithelial component of an esophageal biopsy can be automatically identified.
Hoerres notes that understanding protein expression within the context of the tissue’s geography is an important distinction of Cernostic’s TissueCypher Assay’s technology.
“The test gets all this protein expression information and it’s linked to specific geographies on the tumors. We generate a risk score (developed from our 3 studies) from 0 – very low risk to 10.0 – very high risk. That patient would be plotted on a continuous variable curve with cut points for low, intermediate and high risk.”
He goes on to say that “when the Assay calls a patient “high risk” typically the positive predictive value is that their progression rate per year is above 5% – 6%. This is actually higher than the progression rate of low-grade dysplasia.”
And, there is evidence the Assay’s prediction of prognosis works.
Validation through clinical research
Cernostics has conducted independent clinical research. Two multi-institutional independent clinical validation studies on the TissueCypher™ Barrett’s Esophagus Assay have already been published. A third study with the Cleveland Clinic and the University of Pittsburgh – completed at the end of last year – will be published soon.
Results from this latest study were recently presented at the 2019 Digestive Disease Week conference in San Diego. According to Hoerres:
“We’ve been able to confirm through our research that our risk stratification has been accurate in identifying who goes on to develop esophageal cancer — up to 7 years later — and who does not.”
What is the clinical evidence that the approach works?
Here is a summary of the clinical evidence
- TissueCypher™ identified a high-risk subset of patients at 9.4x increased risk of progression to high-grade dysplasia or esophageal carcinoma within 5 years. It had a stronger prognostic power than current clinical variables, including the pathologic diagnosis.
- The assay detected multiple molecular and cellular changes, including stromal changes, that are associated with neoplastic transformation.
- It also identified a subset of patients who have a very low risk of progression within 5 years.
Two European studies are also underway. They are expected to be completed shortly. The results should be published later this year.
Independent studies to date are leading to a much larger prospective clinical study Cernostics hopes to start the second half of this year. They believe it will be “important for establishing TissueCypher as the standard for risk prediction.”
The impact of treating Barrett’s esophagus
Approximately 400,000 upper GI endoscopies performed each year in the US will confirm a diagnosis of Barrett’s. Each case is further assessed by histology and determined to be in one of these diagnostic categories:
- non-dysplastic or indefinite for dysplasia (IND)
- low-grade dysplasia (LGD)
- high-grade dysplasia (HGD)
Currently, only high-grade and low-grade cases are treated with ablation.
Progression rates of patients with non-dysplastic changes are low. This means that very few of these patients will progress to esophageal cancer. Although some of the people in the non-dysplastic category will progress, the question is which ones?
“The irony here is there are treatments…for treating Barrett’s patients that are high risk. You can clean up the inside of the esophagus by doing radiofrequency or cryo-ablation. This leads to an obvious question: if this is such a great treatment, which it is, why don’t we just treat all Barrett’s patients? The answer is that it’s just not cost effective — it would be way too expensive.”
In addition, although there is no mortality from the procedure, ablation has some serious side effects including pain and strictures in the esophagus.
It is not practical to do ablation on all cases of Barrett’s esophagus
Doing ablation on all these patients simply isn’t practical. it has been estimated that it would cost ~$4.5 billion to ablate all of them. So, although it would be clinically effective, it is not cost effective.
Providing risk information from TissueCypher can make a big difference. Although all patients with dysplastic diagnoses would still get ablation, those with non-dysplasia or indeterminant diagnoses could be assessed for their risk of progression instead. Hoerres explains:
“If you do ablations for all the patients who receive positive scores with the TissueCypher it would cost ~$535 million. Treating in advance and preventing the cancer produces a savings of $142 million.”
“This,” he says, “will help identify the right patients for ablation therapy, prevent cancer, save lives, and eliminate unnecessary cost.”
The bottom line
Cernostics TissueCypher™ Assay for Barrett’s Esophagus is a technologic advance over traditional tissue biopsy. It has the potential to pinpoint which patients with indeterminate or non-dysplastic biopsies are low risk for progression to esophageal cancer. They can be spared the pain, expense, and needless worry of surveillance endoscopies. This is a remarkable advance in the field of esophageal cancer.
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Many thanks to healthcare communication and public affairs consultant, Leslie Rose, for her expert assistance in the preparation of this story.