Tuesday, November 11th, 2008.

Annals of Surgical Oncology. 2009 Jan;16(1):152-8. Epub 2008 Nov 8. [Link]

Foster JM, Gatalica Z, Lilleberg S, Haynatzki G, Loggie BW.

Division of Surgical Oncology, Creighton University Medical Center, Creighton University, Omaha, NE 68131, USA. jasonfoster@creighton.edu

Abstract

Malignant peritoneal mesotheliomas (MPM) are rare tumors representing 20% of all malignant mesothelioma cases. The median survival for these tumors is less than a year, and like other peritoneal surface malignancies, this is due primarily to intra-abdominal recurrence and progression. Currently there is a paucity of information about the biology of these tumors and molecular perturbations that are involved in tumor formation. Elucidation of mutations and biological pathways active in these tumors may identify valuable prognostic markers, as well as facilitate the development of novel therapies. In this study, we investigate the predictive value of epidermal growth factor receptor (EGFR) mutations in achieving optimal resectability. Twenty-nine patients with MPM were evaluated at a single tertiary care center and their tumors were probed for point mutations in the catalytic TK domain of epidermal growth factor receptor (mut+). All specimens were examined for somatic mutations by polymerase chain reaction amplification, and all variants were confirmed by multiple independent amplifications. Twenty-five patients were treated with cytoreductive surgery with or without intraperitoneal hyperthermic chemotherapy and complete clinical data including age, sex, cytoreductive score, mutation, and survival were available for comparison of the mut+ and mut- groups. The median age was 56 years, 71% of the patients were male, and the median follow-up time was 14.5 months. Mutations were found in 31% (9 of 29) of the tumors. Seven of these mutations were novel, and one was the L858R mutation described in non-small-cell lung cancer. Of the 25 patients managed surgically, 7 had mut+ and 18 wild type (mut-) disease. Optimal resectability was achieved in 7 (100%) of 7 of mut+ group and 9 (50%) of 18 mut- (p = .026). All mut+ patients are alive with a mean follow-up time of 24 months, whereas 5 (28%) of 18 of the mut- group are dead of disease with a mean follow-up time of 7 months (p = .27). In an analysis of covariance model, only optimal resectability (p = .04) was found to be predictive of survival. EGFR-TK seems to be a common site for mutation in MPM, with mutations being identified in 31% of patients. The EGFR mutations identified included the L858R activating mutation, as well as eight novel EGFR-TK catalytic domain point mutations. These mutations were predictive of optimal resectability, which was the only variable found to be predictive of survival. With longer follow-up, mut+ may not only be predictive of survival but may represent a subset of patients whose disease may be responsive to TK-inhibitor therapy. Experiments confirming the activating properties of the novel mutations are warranted.

Glossary

therapy

any of the measures taken to treat a disease. Unproven therapy is any therapy that has not been scientifically tested and approved. Use of an unproven therapy instead of standard (proven) therapy is called alternative therapy. Some alternative therapies have dangerous or even life-threatening side effects. For others, the main danger is that a patient may lose the opportunity to benefit from standard therapy. Complementary therapy, on the other hand, refers to therapies used in addition to standard therapy. Some complementary therapies may help relieve certain symptoms of cancer, relieve side effects of standard cancer therapy, or improve a patient's sense of well-being. The ACS recommends that patients considering use of any alternative or complementary therapy discuss this with their health care team.

recurrence

cancer that has come back after treatment. Local recurrence is when the cancer comes back at the same place as the original cancer. Regional recurrence is when the cancer appears in the lymph nodes near the first site. Distant recurrence is when it appears in organs or tissues (such as the lungs, liver, bone marrow, or brain) farther from the original site than the regional lymph nodes. Metastasis means that the disease has recurred at a distant site.

oncology

(on-call-o-jee) the branch of medicine concerned with the diagnosis and treatment of cancer.

mutation

a change; a change in a gene.

chemotherapy

(key-mo-THER-uh-pee) treatment with drugs to destroy cancer cells. Chemotherapy is often used with surgery or radiation to treat cancer when the cancer has spread, when it has come back (recurred), or when there is a strong chance that it could recur.

cell

the basic unit of which all living things are made. Cells replace themselves by splitting and forming new cells (mitosis). The processes that control the formation of new cells and the death of old cells are disrupted in cancer.

cancer

malignancy; a group of diseases typified by abnormal, generally out-of-control, cell growth.

tumor

an abnormal lump or mass of tissue. Tumors can be benign (not cancerous) or malignant (cancerous).

mesothelioma

a tumor derived from mesothelial tissue, such as the peritoneum (lining the abdomen) or pleura (lining the lungs). More on mesothelioma.

peritoneal

(pair-uh-tuh-nee-al) the serous membrane that lines the cavity of the abdomen. (More on Peritoneal Mesothelioma.)

epidermal growth factor receptor

The process of cell division, growth, differentiation and death is a highly regulated process. Several class of trans membrane receptors play a pivot role in this process, of these, epidermal growth factor receptor (EGFR) a member of Receptor Tyrosine Kinase (RTK) family are best known. These comprises of four receptors Erb B1/HER 1, Erb B2 / HER 2, Erb B3/ HER 3, and Erb B4 / HER 4. Of these HER 2 is the most favoured target. (Source: Manoj Pandey and K Chandramohan)

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