Measurement of serum prostate cancer markers using a nanopore thin film based optofluidic chip - Beyond the Abstract

Prostate Cancer (PC) is the second most common cancer and the sixth leading cause of cancer death among men worldwide [1]. The global incidence of PC has increased dramatically in recent years, largely due to aging of the population and the practice of prostate-specific antigen (PSA) testing [2]. The worldwide PC burden is expected to grow to 1.7 million new cases and 499 000 new deaths by 2030 [1].

PCs display a wide range of clinical characteristics, from slow-growing tumors of no or little clinical significance to aggressively metastatic and lethal diseases. Extensive knowledge of the etiology and progression of PC makes it an ideal disease for cancer detection, prognosis and prevention. Despite the availability of PSA as an established marker for over two decades, routine pathological parameters (such as Gleason score, number or percentage of positive cores and the maximum percentage of tumor involvement in any core) are the only parameters used to assess prognosis at biopsy [2]. This is because PSA is not cancer-specific and is also produced in normal prostate; its levels increase in several benign conditions such as benign prostatic hyperplasia (BPH), prostate inflammation besides PC. Population-based studies suggest that PSA screening overdiagnoses PC, where a large number of detected prostate tumors are either benign or indolent [3]. Because of its unreliability, PSA-based diagnosis requires confirmation by invasive, repetitive and costly procedures such as transrectal ultrasound (TRUS-guided biopsy [4]. Serum PSA levels ≤ 4.0 ng/ml are used as a cut-off point for cancer. However, the levels between 4.1-10 ng/ml are considered “grey zone” because BPH patients often display serum PSA levels of up to 10 ng/ml [5, 6]. All “grey zone” PSA patients are advised to undergo TRUS-guided biopsies. Moreover, TRUS-guided biopsies often miss the tumor and detect cancer in only 40-60% of clinically significant cancers, necessitating several repetitions [7-9]. It is estimated that around 1 million prostate biopsies were performed in the United States alone in 2007 [10-12]. Considering that a total of 186,000 new cases of prostate cancer were reported in 2007, it appears that out of every 5 prostate biopsies, at least 4 were cancer-negative and unnecessary. Dr. Shah’s laboratory has cloned a novel transcript (referred as neuroendocrine marker or NEM) that is selectively expressed in malignant prostate [13].


File 001Comparison of ROC curve analysis of same set of patients suggest that NEM is a more reliable PC marker than PSA (Figure 1).


File 000More importantly, PSA-based grey zone patients were clearly stratified by NEM into cancer and non-cancer ones (Figure 2). Based on these results, it appears that combined NEM+PSA test can significantly improve reliability of PC detection and significantly reduce the number of diagnostic biopsies.

Early detection still remains essential for good PC prognosis and treatment options. Localized PC can be effectively treated with prostatectomy, radiation therapy, or other local treatments. Advanced PC that has recurred or spread beyond the prostate is difficult to treat. On the other hand, aggressive treatment of indolent PC causes major side effects and reduces a patient’s quality of life for little to no benefit. As the vast majority of men diagnosed with PC elect to undergo definitive therapy, over-diagnosis leads to over-treatment, associated morbidity and adverse effects on the quality of life. NEM has displayed a significant correlation with Gleason score, suggesting that NEM will also help determine prognosis of prostate tumor at the time of detection. This should greatly help in stratifying the patients into those that require aggressive treatment from those who do not.

Hence, the measurements of cancer biomarkers such as NEM and PSA are generally carried out for the following two purposes: (1) to screen the risk populations for the possibility of cancer; and (2) to determine the efficacy of the therapy in patients undergoing cancer treatment. For both purposes, a large number of clinic samples are needed to be tested. Ideally the cancer biomarker screening can be done at a high accurate and a rapid manner, preferably with automation and low cost at the point-of-care.

File 000_1

To this end, Dr. Que’s laboratory recently has developed an optofluidic chip-based diagnostic system (Figure 3). This type of chip offers 50-100 fold more sensitivity compared with the traditional ELISA for PSA and NEM. In addition, this type of chip not only can be made disposable thereby avoiding any possible cross-contamination during the test, but also can offer many advantages such as elimination of the labeled antigen, the need of the sophisticated equipment and the highly trained individuals. These advantages make the technology suitable for point-of-care application to screen elderly male populations for PC and to monitor the progress of patients undergoing PC treatment. 

Written by:

Long Que, Ph. D.
Associate Professor
Department of Electrical and Computer Engineering


Read the Abstract

Ferlay, J., H.R. Shin, F. Bray, D. Forman, C. Mathers, and D.M. Parkin, Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer, 2010. 127(12): p. 2893-917.
Schroder, F.H., Words of wisdom. Re: Screening for prostate cancer: a review of the evidence for the U.S. Preventive Services Task Force. Eur Urol, 2012. 61(2): p. 423-4.
Force, U.P.S.T., Final Recommendation Statement: men, Screening with PSA. Ann Internal Med, 2012(May 22).
Vickers, A.J., A.M. Cronin, G. Aus, C.G. Pihl, C. Becker, K. Pettersson, P.T. Scardino, J. Hugosson, and H. Lilja, Impact of recent screening on predicting the outcome of prostate cancer biopsy in men with elevated prostate-specific antigen: data from the European Randomized Study of Prostate Cancer Screening in Gothenburg, Sweden. Cancer, 2010. 116(11): p. 2612-20.
Klotz, L., Active surveillance for prostate cancer: overview and update. Curr Treat Options Oncol, 2013. 14(1): p. 97-108.
Schroder, F.H. and M.J. Roobol, Defining the optimal prostate-specific antigen threshold for the diagnosis of prostate cancer. Curr Opin Urol, 2009. 19(3): p. 227-31
Freedland, S.J., W.J. Aronson, G.S. Csathy, C.J. Kane, C.L. Amling, J.C. Presti, Jr., F. Dorey, and M.K. Terris, Comparison of percentage of total prostate needle biopsy tissue with cancer to percentage of cores with cancer for predicting PSA recurrence after radical prostatectomy: results from the SEARCH database. Urology, 2003. 61(4): p. 742-7.
Crawford, E.D., D. Hirano, P.N. Werahera, M.S. Lucia, E.P. DeAntoni, F. Daneshgari, P.N. Brawn, V.O. Speights, J.S. Stewart, and G.J. Miller, Computer modeling of prostate biopsy: tumor size and location--not clinical significance--determine cancer detection. J Urol, 1998. 159(4): p. 1260-4.
Kitagawa, Y., S. Ueno, K. Izumi, Y. Kadono, H. Konaka, A. Mizokami, and M. Namiki, Cumulative probability of prostate cancer detection in biopsy according to free/total PSA
ratio in men with total PSA levels of 2.1-10.0 ng/ml at population screening. J Cancer Res Clin Oncol, 2013.
Cool, D.W., M.J. Connolly, S. Sherebrin, R. Eagleson, J.I. Izawa, J. Amann, C. Romagnoli, W.M. Romano, and A. Fenster, Repeat prostate biopsy accuracy: simulator-based comparison of two- and three-dimensional transrectal US modalities. Radiology, 2010. 254(2): p. 587-94.
Djavan, B., M. Remzi, C.C. Schulman, M. Marberger, and A.R. Zlotta, Repeat prostate biopsy: who, how and when?. a review. Eur Urol, 2002. 42(2): p. 93-103.
Song, L., Y. Zhu, P. Han, N. Chen, D. Lin, J. Lai, and Q. Wei, A retrospective study: correlation of histologic inflammation in biopsy specimens of Chinese men undergoing surgery for benign prostatic hyperplasia with serum prostate-specific antigen. Urology, 2011. 77(3): p. 688-92
Shah, G., A. Srivastava, and K. Iczkowski. Neuroendocrine marker: a novel, reliable early stage marker for prostate cancer. in 100th AACR Annual Meeting. 2009. Denver, CO.