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New markers help predict melanoma outcome.

WAIKOLOA, HAWAII -- DNA microarray analysis of melanomas has identified several key genes whose over- or underexpression provides novel independent prognostic markers for melanoma outcome.

"We think that markers like these could be used (a) to understand melanoma biology, and (b), to select patients for appropriate management," Dr. Mohammed Kashani-Sabet said at the annual Hawaii dermatology seminar sponsored by Skin Disease Education Foundation.

"The molecular signature of metastasis can be present in very early melanoma," emphasized Dr. Kashani-Sabet of the University of California, San Francisco, Comprehensive Cancer Center. Two of the best-studied of these novel prognostic markers are osteopontin and nuclear receptor coactivator 3 (NCOA3).

Osteopontin, also known as SPP1, is an integrin-binding protein implicated in the progression of a variety of solid tumors. It activates the NF-kappaB signaling pathway. That constitutes guilt by association, as NF-kappaB is one of the most important signaling pathways in cancer, according to Dr. Kashani-Sabet.

Four earlier gene expression profiling studies conducted by various investigators suggested osteopontin might be a marker of disease progression in melanoma patients. Dr. Kashani-Sabet and associates tested this hypothesis in a retrospective study involving tissue specimens from 345 patients with primary cutaneous melanoma.

They found that high osteopontin expression in the primary tumor was associated with a 51% rate of subsequent relapse, compared with 32% in tumors with low or no osteopontin expression.

Death due to melanoma occurred in 33% of patients with high osteopontin expression in their primary tumor, significantly greater than the 22% rate in tumors with little or no osteopontin.

Osteopontin expression was a significant predictor both of sentinel lymph node metastasis and of sentinel lymph node tumor burden as reflected in the mean number of positive sentinel nodes, Dr. Kashani-Sabet said. High osteopontin expression was also associated with greater Clark level, tumor thickness, and mitotic index, which are among the key factors in the American Joint Committee on Cancer staging criteria.

In a multivariate Cox regression analysis, the only independent predictors of sentinel lymph node status were osteopontin expression, younger age, and tumor thickness. The other AJCC staging criteria--Clark level, ulceration, sex, and site--failed to achieve significance (Cancer 2008;112:144-50).

The NCOA3 gene is located on a region of chromosome 20 that's often amplified in human breast cancer. Its amplification has been shown to correlate with tamoxifen resistance and poor outcome in women with breast cancer. NCOA3 functions enzymatically as a histone acetyltransferase. It is also an activator of NF-kappaB.

Dr. Kashani-Sabet and coinvestigators conducted a retrospective cohort study entailing tissue microarray analysis of 343 primary melanomas with 2 or more years of follow-up. NCOA3 immunostaining was scored by a dermatopathologist blinded as to patient outcome.

The relapse rate was 52% in patients whose primary tumors had high NCOA3 expression, compared with 36% in those with low or no NCOA3. The 32% rate of death due to melanoma in the group with high NCOA3 was nearly twice that in the low or no NCOA3 group.

In a multivariate Cox regression analysis, NCOA3 expression was an independent predictor of both disease-specific survival and sentinel lymph node status. In fact, said Dr. Kashani-Sabet, it was the most powerful predictor of disease-specific survival, beating out all six of the standard AJCC staging criteria.

How might these novel prognostic markers be employed in clinical practice? One example might be in deciding who should undergo the morbidity of sentinel node biopsy.

At present that's not a straightforward decision in patients with primary tumors less than 1.0 mm thick or with a desmoplastic melanoma because their risk of metastasis to lymph nodes is considerably lower than in other melanoma patients, he said. But with overexpression of NCOA3 and osteopontin providing two new predictors of lymph node metastasis, it becomes possible to identify a subset of patients with thin or desmoplastic melanoma in whom sentinel node biopsy is warranted.

He and his colleagues have used a biologic agent targeting NCOA3 overexpression to treat mice with melanoma. They demonstrated that therapy inhibited metastasis.

In other work, Dr. Kashani-Sabet and his coworkers have shown that radial growth phase melanoma can bypass the vertical growth phase and progress directly to metastasis in a small but clinically meaningful percentage of cases. Preliminary studies suggest expression of the adhesion molecule cadherin 3 and matrix metallo-proteinase 10 may have considerable prognostic value in identifying these expresslane lesions.

One such circumstance in which cadherin 3 and matrix metalloproteinase 10 might prove useful is in patients with melanoma in situ with extensive regression. Those tumors don't have the uniformly favorable prognosis of melanoma in situ without regression. Indeed, they are capable of metastasis, the dermatologist noted.

Dr. Kashani-Sabet disclosed he is a consultant to and on the speakers bureau of Schering-Plough. He is also a shareholder in Melanoma Diagnostics, a UCSF spin-off company developing commercial applications for osteopontin, NCOA3, and various other novel prognostic indicators.

SDEF and this publication are wholly owned subsidiaries of Elsevier.


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Title Annotation:Dermatology
Author:Jancin, Bruce
Publication:Internal Medicine News
Article Type:Clinical report
Geographic Code:1USA
Date:Apr 1, 2008
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