Dana-Farber / Brigham and Women's Cancer Center

Novel Tests Determine Prognosis and Confirm Diagnosis in Mesothelioma

Dr. Bueno

Gene expression ratio tests, developed and validated by Raphael Bueno, MD, Associate Chief of Thoracic Surgery at Brigham and Women’s Hospital and thoracic surgeon in the Center for Thoracic Oncology at Dana-Farber/Brigham and Women’s Cancer Center, confirm differential diagnosis and predict survival in patients undergoing surgical treatment for mesothelioma. These tests are expected to be available for clinicians in 2013.

“This work of Dr. Bueno’s laboratory is a game-changer in the surgical management of this disease”, said Dr. David Sugarbaker, Chief of Thoracic Surgery at Brigham and Women’s Hospital and thoracic surgeon in the Center for Thoracic Oncology at Dana-Farber/Brigham and Women’s Cancer Center and the Director of the International Mesothelioma Program (IMP).

“Current treatment for mesothelioma usually requires aggressive surgery to remove all the tumor and perform complete macroscopic cytoreduction. This concept and surgical approach were developed and refined by David Sugarbaker, MD, and surgery is on occasion associated with a long recovery period,” said Dr. Bueno. “Being able to identify which patients will most likely benefit from this therapy is extremely valuable in the clinical management of patients with mesothelioma, helping clinicians and patients to make more informed decisions regarding care.”

Demonstrated Robust Predictive Value

In a validation study published in the Journal of the National Cancer Institute (J Natl Cancer Inst. 2009 May 6; 101(9): 678–686.), clinical data were obtained prospectively from 120 consecutive patients with malignant pleural mesothelioma who underwent debulking surgery at Brigham and Women’s Hospital. Specimens were obtained at the time of surgery and by pleural biopsy examination. Expression data for four genes were collected from tumor specimens, and three ratios of gene expression (TM4SF1/PKM2, TM4SF1/ ARHGDIA, and COBLL1/ARHGDIA) were determined by quantitative reverse transcriptase–polymerase chain reaction. Patients were assigned to good or poor outcome groups by the gene ratio test.

Combined predictions algorithm: patients with malignant pleural mesothelioma after surgery (ie, extrapleural pneumonectomy)*
combined predictions algorithm

Overall survival of patients with malignant pleural mesothelioma after surgery from combined prediction models (as defi ned in Table 4 ). A ) Model for four subgroups of patients. B ) Model for three subgroups of patients . Hash marks = censored patients; N = number of patients at risk; S = Kaplan – Meier survival point estimate as percent; 95% CI = 95% confidence interval for the survival estimate.

The prognostic test accurately predicted overall survival and cancer-specific survival in a highly significant manner. The test was reproducible within patients and repeatable between two determinations for specimens with widely varying tumor cell contents. Combining the gene ratio prognostic test and other prognostic factors allowed prospective discrimination between patients at high risk (median survival = 6.9 months and 3-year survival = 0 percent) and low risk (median survival = 31.9 months and 3-year survival = 42 percent).

A second gene ratio test serves as a diagnostic assay, which confirms mesothelioma and distinguishes it from other potential confounding diagnoses that may present clinically in a similar manner. These two tests are licensed by Castle Biosciences, and availability is anticipated in 2013.

Based on the results of these tests and other genomic sequencing studies, specialists at Dana-Farber/Brigham and Women’s Cancer Center, led by David Sugarbaker, MD and Raphael Bueno, MD, are designing novel neoadjuvant and adjuvant therapies for subsets of mesothelioma patients with specific genetic mutations. Clinical trials are expected to open in the first half of 2013.

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