clinical study insights

Molecular Characterization of Oligometastatic Disease

by Guru P. Sonpavde, MD

Overview

Clinical Study Title:
The Biology of Prostate Cancer Metastases: Does Oligo Differ From Polymetastatic?

Clinical Study Abstract:
The purpose of this review was to examine the biomedical literature for reports of biological findings in prostate cancer, with specific attention to potential biological differences between oligometastatic and polymetastatic disease. Based on tumor biology studies, data suggest that malignant cells of limited metastatic potential exist, which may represent one possible biological underpinning of oligometastatic disease. In a proportion of cases, it is also possible that oligometastatic disease might merely represent an earlier presentation of a polymetastatic phenotype. Molecular differences between oligometastatic and polymetastatic disease have been identified in some studies, but larger studies are required to validate these findings. In particular, differences in micro-RNA profiles are provocative in that they may serve to regulate gene expression and modulate metastatic potential. Systemic therapy alone has traditionally been the mainstay of therapy for widespread metastatic disease. However, the concept of using ablative therapy in the oligometastitic setting is emerging as a conceptually appealing prospect. Defining the molecular alterations that drive oligometastatic disease may help not only to identify patients with truly oligometastatic phenotypes, but also to select appropriate subsets of patients for tailored therapy.

Reference:
Sonpavde G. The biology of prostate cancer metastases: does oligo differ from polymetastatic? Curr Opin Urol. August 3, 2017. doi:10.1097/MOU.0000000000000434. [Epub ahead of print].

Expert Commentary

Guru P. Sonpavde, MD

Director, Bladder Cancer
Dana Farber Cancer Institute
Genitourinary Oncology
Boston, MA

The concept of a more limited, potentially treatable form of metastatic disease is one that has some support, including anecdotal evidence spanning decades. In the study of malignancies at other sites, there has been confirmation from randomized clinical trials (eg, in non-small cell lung cancer) that local therapies may, indeed, prolong the progression-free survival of patients with 3 or fewer metastases after first-line systemic therapy. As for prostate cancer, multiple prospective randomized trials to investigate the role of metastasis-directed therapy are ongoing. These trials may also serve to further the understanding of the biology of oligometastatic disease.

Historically, patients with metastatic castration-resistant prostate cancer (mCRPC) were believed to harbor microscopic metastases in radiographically silent areas, regardless of the number of metastases. Generally, therefore, systemic therapy alone has been offered to all patients with metastatic disease. Tumor-directed therapy such as radiation or surgery has been reserved for patients with localized disease, or cases of symptomatic metastatic disease. Owing to the lack of prospective randomized trials, metastasis-directed therapy for oligometastatic disease remains somewhat controversial.

The current understanding of how, molecularly, a primary tumor might progress to oligometastasis rather than polymetastases is not well developed. And, although many sources refer to a range of approximately 3-5 metastases in describing oligometastatic disease, no formal cut-off for ‘‘oligo’’ has been defined in the literature. One area of interest has been the potential role of micro-RNAs. Uppal and colleagues found in their review of the known functions of oligometastatic-specific micro-RNAs that there might be regulatory action in the metastatic cascade, including epithelial-mesenchymal transition, tumor invasion, intravasation, distant vascular extravasation, and proliferation in a distant organ.

A better understanding of the molecular characteristics of oligometastatic disease would be especially helpful in concert with other advances in the field such as more sensitive imaging techniques and emerging forms of focal treatment. Indeed, a molecular signature to discriminate between metastatic disease destined to remain oligometastatic and disease destined to progress to polymetastatic disease will inform therapeutic decisions. More sensitive imaging will likely identify more metastases in many patients previously classified as ‘‘oligometastatic’’ by conventional modalities such as computed tomography and bone scintigraphy. Likewise, many patients determined to have M0 disease via conventional imaging may be reclassified as having M1 disease, with an oligometastatic presentation, especially where lower PSA thresholds lead to imaging.

References

Gillessen S, Attard G, Beer TM, et al. Management of patients with advanced prostate cancer: the report of the advanced prostate cancer consensus conference APCCC 2017. Eur Urol. 2017. doi: 10.1016/j.eururo.2017.06.002. [Epub ahead of print].

Gomez DR, Blumenschein GR Jr, Lee JJ, et al. Local consolidative therapy versus maintenance therapy or observation for patients with oligometastatic non-small-cell lung cancer without progression after first-line systemic therapy: a multicenter, randomized, controlled, phase 2 study. Lancet Oncol. 2016;17(12):1672-1682.

Lussier YA, Xing HR, Salama JK, et al. MicroRNA expression characterizes oligometastasis(es). PLoS One. 2011; 6:e28650.

Ost P, Bossi A, Decaestecker K, et al. Metastasis-directed therapy of regional and distant recurrences after curative treatment of prostate cancer: a systematic review of the literature. Eur Urol. 2015;67:852-863. 


Reyes DK, Pienta KJ. The biology and treatment of oligometastatic cancer. Oncotarget. 2015;6:8491-8524.

Tosoian JJ, Gorin MA, Ross AE, et al. Oligometastatic prostate cancer: definitions, clinical outcomes, and treatment considerations. Nat Rev Urol. 2017;14:15-25.

Uppal A, Ferguson M, Posner MC, et al. Towards a molecular basis of oligometastatic disease: potential role of micro-RNAs. Clin Exp Metastasis. 2014;31(6): 735-748.

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