Proveri tests will be based on biomarkers derived from the tumor microenvironment, i.e. stroma tissue that surrounds cancerous lesions. This circumvents applicability problems arising from using biomarkers derived from tumors, which may have occurred by heterogeneous and polyclonal genetic changes that are not uniform across a biopsy sample or not present in all cases and therefore only apply to a subset of the patient population. The stroma advantage is of particular importance to our Diagnostic Biopsy Test designed to increase diagnostic accuracy for prostate biopsies.
The main advantages of this approach are:
- Changes in gene and protein expression in the stroma surrounding a tumor are due to interaction of cancer cells with the surrounding tissue and due to “field effects”. These changes are independent of the genetic changes that lead to tumor formation. As cancer arises by genetic changes that can differ widely from patient to patient, reliable biomarkers derived from tumor cells per se have been wrought with difficulties regarding reproducibility and applicability to the general male population. Stroma biomarkers are more stable and therefore provide more reliable signatures for the presence and aggressiveness of the disease.
- There is usually more stoma tissue in any given patient tissue sample than actual tumor tissue (unless of course in a very advanced cancer case). The stroma approach is therefore of particular advantage for the diagnostic biopsy test as it will provide a highly accurate assessment of the presence of cancer on the patient’s FIRST biopsy samples.
- A subset of our biomarkers are capable of detecting gene expression changes in tumor-surrounding tissue at several mm away from the tumor, which allows the diagnosis of cancer in cases where tumor is missed by the prostate biopsy core. This powerful diagnostic feature is especially critical for early detection of prostate cancer because early stage cancers are small and often missed even by saturation biopsy procedures.
Prostate biopsy procedures usually involve the harvesting of 12 tissue cores. If the tumor is small there is a high likelihood that the tumor is missed, schematically represented in the left panel of the figure below. Published data indicate that the false negative rates can be as high as 30% – 40%. The figure below illustrates the issue. The panels show two hypothetical needle tracks. The needle on the left side of the panels reached the tumor indicated by the ovals. This biopsy core will therefore be diagnostic for the presence of tumor. Should the needle miss the tumor as illustrated by the needle on the right side in the panels, Proveri biomarkers are still capable of indicating the presence of tumor: the right panel in the figure below shows a tissue section stained with one of the Proveri stroma markers (red) demonstrating that the core that missed the tumor (indicated by the needle on the right) is diagnostic for tumor despite no tumor cells (stained green) are present in this core. The left panel shows the same tissue section stained with the traditional procedure (H & E stain). The traditional stain would not be indicative for the presence of tumor in the biopsy tissue harvested by the needle on the right.
An additional advantage, equally important for improved diagnostic accuracy, is the extended diagnostic “reach” effected by applying stroma biomarkers. The stroma biomarkers have the potential for virtually increasing the prostate sample volume that can be assayed on each biopsy track: The standard biopsy procedure needle has a diameter of 0,89 mm (18 gauge) and the average biopsy tissue length is 14 mm: yielding a total volume of 0,19 cm3 retrieved by the standard 12-core prostate biopsy procedure. The range of the sizes of prostate glands for men between 40 and 70, depending on multiple factors, is between 12 cm3 to 200 cm3. For the purpose of illustrating the effect of stroma sampling, three sizes are selected: 27.5 cm3 (average small), 35 cm3 (average medium), and 60 cm3 (average large). The figure below shows calculated volume coverage of biopsy cores and extended volume coverage with stroma signals. The left figure shows the volume coverage of prostate glands as a function of a modeled stroma signal. The inset shows the corresponding volume coverage of a prostate (examples shown for average small, medium and large prostates) under a standard biopsy procedure, at 0,67%, 0,53%, and 0,31%, respectively. A 5 mm stroma signal for example would provide theoretical sample volume coverage of 100% for a small prostate and 89% and 52%, respectively, for medium and large prostates; these numbers indicate a two orders of magnitude increase in diagnostic detection power. The panel on the right illustrates how the volume coverage of model prostates increases as the stroma signal distance increases. Applying stroma-derived biomarkers to biopsy cores will thus significantly increase the chance of identifying the presence of cancer.
- More reliable diagnostic indicators of the presence of cancer – Stroma biomarker changes are independent from various genetic changes occurring in individual tumors
- Increase of the diagnostic “reach” for biopsy samples – Expression changes of stroma biomarkers are measurable 8-15 mm distant from the tumor
- Stroma is usually more abundant in biopsy samples – Major advantage for the reduction of false negatives due to biopsy needles missing tumors