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Conference News Update

American Association for Cancer Research 2009 Annual Meeting—Denver

• Gene Responsible for Familial Pleuropulmonary Blastoma Identified
• Metabolite in Urine May Predict Lung Cancer in Smokers
• Mutational Background May Be Used to Diagnose Lung Lesions
• Novel Lung Cancer Biomarker Identified
• Combination Therapy Shows Promise for Non–Small Cell Lung Cancer

Gene Responsible for Familial Pleuropulmonary Blastoma Identified

The search for the cause of an inherited form of a rare, aggressive childhood lung cancer has uncovered important information about how the cancer develops and potentially sheds light on the development of other cancers.

The study shows that some children with the rare cancer PPB are born with a deleterious mutation in DICER1, a master controller gene that helps regulate the expression of other genes. The children studied came from families with a history of PPB or related disorders.

The finding by researchers at Washington University School of Medicine in St. Louis, Children's National Medical Center in Washington, DC, the International Pleuropulmonary Blastoma (PPB) Registry at Children’s Hospitals and Clinics of Minnesota, and other collaborating institutions adds the final link to the chain connecting the gene DICER1 to cancer development.

"PPB is the first malignancy found to be directly associated with inherited DICER1 mutations, making the cancer an important model for understanding how mutations and loss of DICER1 function lead to cancer," Dana Ashley Hill, MD, chief of pathology at Children’s National Medical Center stated. "Additionally, we now believe that PPB tumors arise from an unusual mechanism in which cells carrying mutations induce nearby cells to become cancerous without becoming cancerous themselves."

All the children studied with PPB carried damaging mutations in one of their DICER1 genes, the study authors found, giving them one functional and one nonfunctional DICER1 gene in all their body's cells. PPB lung tumors probably originate when one or more cells in the lung acquire a harmful mutation in their functional copy of the DICER1 gene, they hypothesized.

In addition, PPB lung tumors appear to result from a novel cancer induction mechanism not previously demonstrated, Dr. Hill and colleagues observed. Loss of DICER1 protein specifically in lung airway cells appears to deregulate signals to nearby cells and somehow causes those cells to transform into malignant cells, they found. However, the cells with the loss of DICER1 do not progress to malignancy.

Metabolite in Urine May Predict Lung Cancer in Smokers

Researchers may have uncovered why lung cancer afflicts some smokers and not others.

“A history of smoking has always been thought of as a predictor of lung cancer, but it is actually not very accurate,” Jian-Min Yuan, MD, PhD, Associate Professor in Epidemiology at the University of Minnesota. “Smoking absolutely increases your risk, but why it does so in some people but not others is a big question.”

Dr. Yuan and colleagues hypothesized that the presence of the metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) in a patient’s urine might predict risk of lung cancer. This metabolite has been shown to induce lung cancer in laboratory animals, but the effect in humans had not yet been studied.

Researchers collected data from 18,244 men enrolled in the Shanghai Cohort Study and 63,257 men and women from the Singapore Chinese Health Study. In addition to conducting in-person interviews to assess levels of cigarette smoking, dietary and other lifestyle factors, researchers collected blood and urine samples from more than 50,000 patients.

To evaluate the impact of NNAL, Dr. Yuan and colleagues identified 246 current smokers who later developed lung cancer and 245 smokers who did not develop lung cancer during the 10 years after the initial interview and collected urine samples. The samples were divided into three groups based on levels of NNAL in the urine.

Compared to patients with the lowest NNAL levels, patients with a mid-range level of NNAL had a 43% increased risk of lung cancer, while those at the highest level had a more than two-fold increased risk of lung cancer, after adjustment for the number of cigarettes smoked per day, the number of years of smoking, and urinary levels of cotinine.

Levels of nicotine in the urine were also calculated. Patients with the highest levels of nicotine and NNAL had an 8.5-fold increase in the risk of lung cancer compared with smokers who had the lowest levels after accounting for smoking history.

“Smoking leads to lung cancer, but there are about 60 possible carcinogens in tobacco smoke, and the more accurately we can identify the culprit, the better we will become at predicting risk,” Dr. Yuan stated.

Mutational Background May Be Used to Diagnose Lung Lesions

Accurate differential diagnosis of synchronous multiple lung lesions may be done through mutational background—especially in patients with multiple adenocarcinoma (AD), according to researchers.

“Due to recent advances in imaging, the incidence of patients with synchronous multiple lung nodules, which are often AD, are increasing,” said Teruhisa Takuwa, MD, of the Hyogo College of Medicine in Nishinomiya, Japan, and colleagues. “Lung lesions can be a pulmonary metastasis or a synchronous secondary primary lung cancer. For the appropriate therapy, accurate differential diagnosis is important.”

To analyze genetic mutations in the cases of multiple AD, bronchioloalveolar carcinoma (BAC), and atypical adenomatous hyperplasia (AAH) lesions, the investigators assessed 135 patients who underwent surgical resection between January 2006 and August 2008.

Twenty-two patients had synchronous multiple AD, BAC, and AAH lesions, the study authors observed. Multiple lesions were sampled in 18 patients: five patients had multiple AD lesions, five patients had multiple AD and BAC lesions, four patients had AD and AAH lesions, two patients had BAC and AAH lesions, one patient had multiple AAH lesions, and one patient had all three types of lesions, Dr. Takuwa and colleagues reported.

A total of 42 lesions were obtained (22 AD, 10 BAC, and 10 AAH). Of these, genetic mutations were detected in 10 of 22 AD lesions and none in BAC and AAH lesions. Of the patients with multiple AD lesions (n = 5), three had genetic mutations. “Among the three patients, two patients had genetic mutations in only one of the two lesions,” the study authors noted. “Through mutational background, we diagnosed them as a double primary lung cancer.” One other patient had K-ras mutations in each of the lesions and was diagnosed with pulmonary metastasis, Dr. Tukawa and colleagues reported.

Of the patients with AD and BAC lesions (n = 6), four cases had genetic mutations only in the AD lesions, and were diagnosed with double primary lung cancer.

Novel Lung Cancer Biomarker Identified

A heavy methyl–sensitive detection assay of the SHOX2 gene may be used in the work-up of patients with suspected lung cancer, researchers reported.

“Confirming malignancy often remains a challenge, because the tumor may not be accessible for biopsy by bronchoscopy and cytology is inconclusive,” the investigators explained. “This potentially triggers additional diagnostic procedures bearing risks for the patient and eventually causing a delay in diagnosis.”

In a retrospective study analysis, John K. Field, PhD, of the University of Liverpool Cancer Research Center in Liverpool, United Kingdom, and colleagues evaluated the use of the recently developed assay to diagnose suspected bronchial carcinoma. Of 423 patients with suspected lung cancer, 237 patients had lung cancer and 186 patients had benign lung disease (controls). Flexible bronchoscopy with bronchial lavage of the specimens taken from suspicious regions was performed.

Sixty-three of 84 patients (75%) with squamous cell lung cancer were positive for SHOX2 methylation, with 99% sensitivity. Stage-specific analysis of the patients showed a sensitivity of 70%, 89%, and 76% for International Union Against Cancer stages I, II, and II, respectively.

There was a 59% sensitivity and a 99% specificity for all lung carcinomas (ie, 84 squamous carcinomas, 98 adenocarcinomas, 12 small–cell lung cancers, and 43 other types), the study authors found.

Combination Therapy Shows Promise for Non–Small Cell Lung Cancer

In a study of patients with advanced non–small cell lung cancer, combination therapy with bevacizumab and erlotinib improved progression-free survival compared with erlotinib treatment alone, researchers reported. There was no improvement in overall survival, they noted.

In the BeTa lung study, investigators randomized patients to receive erlotinib (150 mg/daily) with bevacizumab (15 mg/kg), or erlotinib with placebo (15 mg/kg), intravenously for every three weeks. Of 477 patients who provided tissue samples, investigators reported progression-free survival and overall survival of 0.63 and 1.03 for patients EGFR immunohistochemistry. In addition, patients with EGFR fluorescence in situ hybridization results had 0.62 and 1.24 for progression-free survival and overall survival, respectively, compared with patients with EGFR mutation (0.62 and 1.09). In patients with K-ras mutations, progression-free survival was 0.63 and overall survival was 1.10.

“These patients were representative of the overall enrolled patient population,” Roy S. Herbert, Chief of the Section of Thoracic Oncology at the University of Texas, and colleagues concluded. “The progression-free survival and overall survival results for biomarker defined subgroups were consistent with the overall results of the trial.”