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May 1, 2011 (Vol. 31, No. 9)

Cancer Detection Improved with Noninvasive Testing

Search for Novel Biomarkers Detectable in Accessible Bodily Fluids Proves Promising

  • Lung Cancer Protection

    Charles Birse, Ph.D., associate director at Celera, talked about serum biomarker panels that detect lung cancer in never-smokers. He noted that about 20% of lung cancers occur in never-smokers, and that figure is expected to increase. About 62% of these tumors are adenocarcinomas and 18% squamous cell carcinomas, compared to 19% and 53%, respectively, among smokers.

    Dr. Birse envisions serum biomarkers being used as an adjunctive diagnostic tool either applied before a CT scan to determine the need for imaging or post-CT to stratify patients with evidence of a pulmonary nodule according to their risk for a malignant lesion and to assess the need to perform a lung biopsy.

    Dr. Birse and colleagues analyzed tumor tissue and cell lines using mass spectrometry to identify cell surface and secreted proteins differentially expressed in cancer versus healthy samples. The team then prioritized the markers identified from the MS data and validated them using ELISA immunoassays. They studied a biomarker panel in more than 600 specimens from patients (smokers) with non-small-cell lung cancer (NSCLC) and control subjects, which they divided into a set of training serum samples and a set of test samples, using the data to develop an algorithm for lung cancer detection.

    A subsequent independent, case/control, validation study using a six-marker model was performed in 80 never-smokers, 40 with lung cancer and 40 matched controls. The study yielded promising results and demonstrated the ability of the blood test to distinguish samples from the smoker cohort with malignancy (all stages), with an AUC for the training set of 0.877 and AUC for the test set of samples of 0.868. When the model was applied to the never-smoker patient population, the algorithm was again able to discriminate the malignant cases with an AUC of 0.906, at 83% sensitivity and 83% specificity.

    Allen Taylor, Ph.D., research fellow at Fred Hutchinson Cancer Research Center, presented studies aimed at detecting autoantibodies to angioprotein-like protein 2 (ANGPTL3), a growth factor involved in regulating angiogenesis that is elevated in the serum of a mouse model of NSCLC and in plasma collected from newly diagnosed patients with NSCLC. Circulating autoantibodies to tumor antigens such as ANGPTL3 may be produced during the early stages of tumor development and could, therefore, contribute to early diagnosis, even before tumor antigens are detectable in serum.

    The study showed that the circulating concentration of and autoantibody reactivity to ANGPTL3 were significantly elevated in the sera of patients with NSCLC that was collected up to 12 months before their diagnosis, compared to healthy controls. These measures were also significantly elevated in the sera of newly diagnosed NSCLC patients compared to control samples.

    Dr. Taylor presented data showing an inverse correlation between autoantibody reactivity to ANGPTL3 and antigen concentration in individual serum samples. He proposed that autoantibodies represent an alternative type of biomarker that could be used in combination with tumor antigen detection to improve the predictive performance of a test for early detection of NSCLC.

    Men are commonly screened for prostate cancer risk using measurements of prostate specific antigen (PSA); however, the PSA test suffers from relatively low specificity and sensitivity as a diagnostic tool. Most men with an elevated PSA test result are found not to have cancer. According to the U.S. National Cancer Institute (NCI), only 25–35% of men who have a biopsy performed as follow-up to an elevated PSA level have prostate cancer.

    Scott Tomlins, M.D., Ph.D., a resident at the University of Michigan Health System, presented work done in collaboration with Gen-Probe, University of California at San Diego Medical Center, Université Laval, and Dianon Systems to develop a urine-based test to detect the TMPRSS2:ERG gene fusion, which is present in about 50% of prostate cancers, and which Dr. Tomlins describes as the most specific prostate cancer biomarker currently identified.

    Urinary TMPRSS2:ERG scores have been shown to correlate with positive findings of clinically significant prostate cancer on biopsy and prostatectomy. The scores are significantly higher in samples from patients with cancerous versus benign prostate lesions.

    Dr. Tomlins concluded that this new biomarker may improve on the predictive power of the PCA3 assay, which detects the messenger RNA of prostate cancer gene 3 (PCA3) in male urine after a digital rectal examination. PCA3 assay results are used to guide decisions to perform a biopsy following a positive PSA test.

    Urinary TMPRSS2:ERG in combination with PCA3 can enhance the utility of serum PSA for predicting prostate cancer and the presence of clinically relevant cancer on biopsy. TMPRSS2:ERG has not yet been evaluated for its utility as a screening tool.

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