Researchers at the Wistar Institute Cancer Center have discovered a new potential circulating biomarker for nonâ€“small cell lung cancer. It is a cancer testis antigen expressed by a cancer/testis gene called AKAP4. The exciting prospect this heralds is the development of an accurate, quick blood test for early-stage NSCLC.
Qihong Huang, MD, PhD
A team of researchers led by Qihong Huang, MD, PhD, associate professor of the Tumor Microenvironment and Metastasis Program at the Wistar Institute Cancer Center in Philadelphia, have discovered a new potential circulating biomarker for nonsmall cell lung cancer (NSCLC).1,2This protein is a cancer testis antigen (CTA) expressed by a cancer/testis gene calledAKAP4. The exciting prospect this heralds is the development of a very accurate, quick blood test for early-stage NSCLC.
“Qihong and his colleagues have found a target that could result in a more accurate test than any method that’s been used to screen for nonsmall cell lung cancer to date,” said Dario C. Altieri, MD, president and CEO of The Wistar Institute and director of Wistar’s Cancer Center. “With the government recommending annual screening for high-risk populations, the identification of a promising target likeAKAP4comes at a critical time. Early detection is needed in order to have a meaningful impact on this devastating disease.”1
AKAP4is one of 130 cancer/testis genes on the human X chromosome.2,3,4These genes are commonly expressed as CTAs in tumor tissues, circulating tumor cells, and tumor-derived exosomes, usually endocytosed by tumor infiltrating lymphocytes and macrophages.2Together with his colleagues, Huang analyzed peripheral blood mononuclear cells from patients with NSCLC (n = 12) versus patients with smoking-related, benign lung diseases (n = 7) to establish whether or not CTA mRNAs could be detected. Using a highly sensitive nested polymerase chain reaction the researchers detected the mRNAs expressed fromCTAgenes, then proceeded, with a larger number of patients, to demonstrate that the expression of oneCTAgene,AKAP4, accurately separated patients with NSCLC from the control group.2
They then analyzed combined samples from two cohorts of patients, comprising 264 patients with NSCLC and 135 controls. They foundAKAP4expression was highly discriminative for the detection of NSCLC, with a value of 0.9714 for the area under the curve (AUC) of the receiver operating characteristic (ROC) curve, (a perfect score would be 1.0, and a score of 0.90-1.0 is regarded as excellent5). Furthermore, the variation coefficient was just 0.10% for the AUC and 0.16% for accuracy.1,2
The patients who benefit the most from early detection are those with stage I disease, and 136 of the 264 patients with NSCLC were at stage I. Once again, usingAKAP4expression levels as the NSCLC classifier, the AUC of the ROC curve was excellent, at 0.9795, showing that the test was capable of detecting even early disease. As shown in the table,AKAP4expression (plotted as mean log10expression) was found to increase as NSCLC stage advanced.1,2
Fold Difference vs Stage 1
Stage 2 (n = 42)
Stage 3 (n = 74)
Stage 4 (n = 12)
When the team followed up with a small number of patients who had been given surgery,AKAP4levels remained low in those who were in remission, but increased in those who relapsed. The expression ofAKAP4was significantly associated only with cancer stage on linear regression analysis when histology, stage, smoking history, gender, and age were the independent variables.2
Benjamin P. Levy, MD, assistant professor at the Icahn School of Medicine, medical director of the Thoracic Oncology Program, Mount Sinai Health Systems, and associate director of the Cancer Clinical Trials Office at Mount Sinai Hospital in New York, said, “The main strength of this study is the exceptional accuracy of the circulating biomarker, which had a ROC curve of 0.97. Importantly, this accuracy not only held in patients with stage I disease, but also when factoring in healthy controls (n = 27) with histologically confirmed benign tumor nodules. Furthermore, the presence of theAKA4P signal seemed to correlate with either remission or recurrence of disease in a small number of patients.” Levy also remarked that the diagnostic platform used by Huang and colleagues, had the advantage of being relatively noninvasive and potentially inexpensive.
“The results of this study exceeded our expectations,” said Huang toTargeted Oncology. “AKAP4 appears to be a highly effective biomarker for the detection of non-small cell lung cancer. If we are able to confirm these results in a more robust study, then we have the potential for a new, more accurate screening method that could help save many, many lives.”1
Further testing ofAKAP4is planned, “While this was a fairly large sample size for a pilot study at 399 total samples, we are currently pursuing a larger cohort of patient samples for a validation study. We’ve already secured partnerships with multiple hospitals in the region to get the samples we need,” said Huang.
Levy was also very positive about the potential of the biomarker, “If this strategy is verified in a larger study, the clinical impact could be profound,” adding, “…this test would undoubtedly have utility in detecting early stage disease.”
Considering possible clinical scenarios for screening with the biomarker, Levy said, “Possible strategies include as a stand-alone diagnostic for high-risk patients (current or former smokers) similar to low dose CT scan or, in conjunction with CT imaging to help better define benign versus malignant nodules. There may also be an opportunity to detect recurrences earlier than traditional imaging postcurative intent treatment (surgery or chemoradiation). Hopefully, diagnostic approaches like this will aid in our efforts to accurately identify cancers at an earlier stage where the goal is cure.”
Huang too is optimistic about the role of the test, “It can be potentially used to monitor the therapy efficacy in NSCLC patients. Because altered AKAP4 expression occurs early in the treatment, if a particular therapy is not effective, physicians can immediately change treatment.”