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Antibody May Detect Early Lung Cancer in Lambert–Eaton Myasthenic Syndrome Patients

ARTICLE IN BRIEF

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SOX1 antibodies in patients with Lambert-Eaton myasthenic syndrome predict the presence of small cell lung cancer.

An international team of researchers may have discovered an immune system biomarker for a type of lung cancer that is common among patients with the Lambert–Eaton myasthenic syndrome (LEMS), an autoimmune disorder of the neuromuscular junction.

Between 40–60 percent of all patients with LEMS have a small cell lung carcinoma (SCLC), an aggressive cancer that has usually metastasized by the time it is diagnosed. Although initially responsive to chemotherapy, SCLC is often fatal, with a median survival of only eight to 10 months and a five-year survival of less than 10 percent.

In the March 18 Neurology, investigators led by Francesc Graus, MD, professor of neurology at the University of Barcelona Hospital Clinic in Spain, reported that the antigen SOX1 was detected in more than 60 percent of LEMS-SCLC patients studied, but not in LEMS patients who did not have cancer, or in a group of patients with other paraneoplastic syndromes. (See “More About SOX1 Antibodies.”)

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To detect SOX1 antibodies in human samples, filters were cut into four pieces and used to screen patients sera. The right lower quadrant was incubated with normal human serum and the others with three different anti-glial nuclear antibody-positive sera.Both graphics: Neurology 2008;70:906–907.

In a 2005 paper in the Journal of Neuroimmunology, the investigators had reported that 43 percent of patients with LEMS and SCLC have an antibody called anti-glial nuclear antibody (AGNA), which targets the nuclei of Bergmann glial cells in the cerebellum.

In the current study, the investigators used AGNA-positive sera from 105 LEMS patients, half of whom had SCLC, and probed samples in a fetal brain DNA library, looking for antibodies against the isolated antigen. They also compared responses in blood from 50 patients with paraneoplastic neurologic syndromes: both SCLC and anti-Hu antibodies, and 50 patients with SCLC alone.

According to Dr. Graus, antibodies were detected in 64 percent of patients with LEMS with SCLC, but in none of 50 patients with non-paraneoplastic LEMS. The frequency of SOX1 antibodies was significantly lower in patients with Hu antibodies (32 percent, p = 0.002) and in those with only SCLC (22 percent).

The findings hold promise for much earlier diagnosis of SCLC in LEMS patients, Dr. Graus said in an e-mail message to Neurology Today.

“Presently, when neurologists diagnose LEMS, they cannot predict if the patient has an underlying lung cancer,” he said. “A patient's age, if older than 50 years, and smoking status may help, but these tend to be poor predictors. The presence of SOX1 antibodies appears specific for lung cancer. Patients with the antibody must be followed closely, even if there is no radiological evidence of a tumor.”

SOX1 antibodies could also be used by neurologists during initial workups to identify LEMS patients before there is any evidence of cancer, he added.

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The presence of anti-glia nuclear antibody (AGNA) seropositivity was defined first by staining the nuclei of Bergmann glia in a rat cerebellum. Row A shows the rat cerebellum incubated with AGNA positive serum; Row B, the AGNA positive serum eluted from Sox1; and C, the irrelevant clones. The IgG eluted from the SOX1 clone immunoreacts with the nuclei of Bergman glia with the same pattern produced by the AGNA-positive serum.

The study did have limitations, according to Dr. Graus. “The antibody is present in approximately 60 percent of patients with LEMS and lung cancer, so a negative result does not exclude the presence of a tumor. It also does not indicate whether the antibody appears early in the evolution of the tumor, or if it is a late event — when the tumor already is evident on the chest CT.”

Preliminary evidence, however, shows that the antibody may develop when the tumor is at a microscopic stage, he said.

EARLY CANCER SCREENING

In an editorial accompanying the report, Bethan Lang, PhD, of the department of clinical neurology at the University of Oxford and Weatherall Institute of Molecular Medicine in the UK, noted that while the exact immune process in LEMS-SCLC patients remains unknown, the findings should help improve early cancer diagnosis and survival.

“SOX-1 antibody detection was also associated with an increased median survival time, suggesting that the tumor itself is involved in provoking an immune response that may be beneficial to the patient,” wrote Dr. Lang and Amelia Evoli, MD, of the neuroscience department at Catholic University in Rome, Italy.

They noted that in LEMS-SCLC patients, neurologic symptoms often predate detection of cancer “by months or years,” while clinical improvement or complete remission of the neurologic syndrome often occurs after chemotherapy or radiotherapy. Further, survival time in LEMS-SCLC patients is significantly longer than in patients who have the tumor alone.

“It is not entirely clear whether this is due to early detection of an underlying tumor or to a vigorous autoimmune attack on the tumor itself,” they wrote. “All patients with LEMS should be routinely screened for an underlying tumor, which, even if present, may be below the resolution of the scanning device and not immediately detected.”

The authors also said that the high incidence of SCLC in LEMS patients suggests that a highly effective immune response to proteins is expressed both on the surface and in the nucleus of SCLC cells.

Although it was unclear if the LEMS-SCLC serum samples tested were obtained before tumor detection, they noted, it is not known whether the SOX1 antibodies might be detected by immunochemical methods.

“SOX1 antibodies can be detected only by immunohistochemical screening on mammalian brain tissue or by screening on a phage display library, both technically demanding procedures. Before the relevance of this new paraneoplastic marker can be fully evaluated, it will be necessary to develop a more amenable assay system,” they observed.

Still, the study is interesting for several reasons, said Nick Willcox, PhD, professor of neurosciences at the Oxford Weatherall Institute. “First, it implies that a subset of SCLC tumors is more than averagely immunogenic, and that the autoimmune responses may be partly protective, as we have long suspected,” he told Neurology Today in an e-mail.

“As always, one wonders why these responses consistently single out certain targets,” he said. “One Holy Grail has long been to devise assays for early detection of occult SCLCs. While this study still falls short of that goal, it does reinforce hopes of developing analogous but even more sensitive assays and more informative targets; surface epitopes amenable to scanning would be ideal.”

MORE ABOUT SOX1 ANTIBODIES

The study investigators explain that SOX1 belongs to a family of developmental transcription factors, proteins that bind to DNA and play a role in regulating gene expression by promoting transcription. The human SOX gene family is classified in groups from A to H. SOX1 belongs to group B1 — genes that are strongly expressed in the early neuroectoderm and the developing nervous system. In the adult nervous system, SOXB1 genes are down-regulated but remain active in adult neural stem cells and selected groups of differentiated neurons.

PODCAST INTERVIEW WITH STUDY AUTHOR ON NEUROLOGY ONLINE

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Dr. Francesc Graus discusses his latest findings on SOX1 antibodies and LEMS in an interview with Dr. Michael Benatar and Dr. Bethan Lang in a podcast available online at neurology.org. Neurologists can earn 0.5 AMA PRA Category 1 CME Credits™ by answering the multiple-choice questions in the online podcast quiz.