Tissue-based PCa assays not robust to multifocality

Chicago-Tissue-based prognostic biomarker assays for prostate cancer are not robust to tumor multifocality and heterogeneity, according to research presented at the American Society of Clinical Oncology annual meeting in Chicago.

This finding speaks to the need for further studies to enable better identification of the biologically dominant lesion in patients with multifocal disease and/or the development of better prognostic techniques, said first author Simpa S. Salami, MD, clinical lecturer and urologic oncology fellow, department of urology, University of Michigan, Ann Arbor, working with Ganesh Palapattu, MD, and co-authors.

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“Our research challenges the claim that in men with multifocal prostate cancer, analysis of a single biopsy specimen using an expression-based prognostic test can accurately predict the overall biologic trajectory of the disease,” Dr. Salami told Urology Times.

“This is an important issue because an estimated 60% to 80% of patients with prostate cancer have multifocal disease.”

To determine whether commercially available tissue expression-based prognostic tests are robust to multifocality, Dr. Salami and colleagues analyzed and compared the genetic profiles of 67 biopsy-derived primary tumor foci and 17 lymph node metastasis foci. The samples were obtained from 14 patients with grade-discordant multifocal disease, of whom 10 had N1 disease.

They were submitted for high-depth, targeted DNA and RNA next-generation sequencing using a customized panel of markers encompassing those included in commercially available prognostic tests.

Next: Significant DNA heterogeneity observed

Significant DNA heterogeneity observed

The results showed significant DNA heterogeneity comparing the molecular profiles of primary tumor foci obtained from individual patients. The RNA analyses indicated that low-grade foci tended to cluster together and separately from high-grade foci.

As an example, analyses of samples obtained from one patient who had five primary tumor foci (four high-grade, one low-grade) and two lymph node metastases showed that the primary tumor foci near the positive margin exhibited higher concordance with the lymph node metastases than intraprostatic foci. Comparisons of copy number alterations found in lymph node metastases and primary tumor foci indicated that the biologically dominant nodule that gave rise to metastasis was not necessarily the largest primary lesion or the one with the highest Gleason score.

“Our findings suggest that the expression profile of a low-grade focus cannot predict the presence or lack thereof of a high-grade focus within the same patient,” said Dr. Salami.

“They also indicate that a specific molecular profile might confer metastatic risk more so than lesion grade or size.”

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The authors plan to enroll a total of 50 patients in the study and hope data from the larger population might allow them to identify genes that are informative for predicting metastases in individual patients and subsequently the development of a prognostic signature that might be robust to multifocality.

In addition, they are investigating whether magnetic resonance imaging might be helpful for identifying the most biologically significant tumor. Based on the idea that tumor cells found in peripheral blood or urine may reflect the heterogeneity of multiple foci within the prostate, they are conducting studies to see if DNA and RNA sequencing of those fluids, rather than prostate biopsy samples, could provide a better-performing prognostic assay.

Two of Dr. Salami’s co-authors have a financial or other relationship with multiple pharamecutical companies.

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