Genomic Differences in Prostate Cancer Stages Are Coming Into Focus

Jane de Lartigue, PhD
Published: Tuesday, Sep 13, 2016
Prostate cancer is slow-growing and readily curable in many cases, but the propensity for some tumors to develop into an aggressive, metastatic form that becomes resistant to androgen-targeting therapies continues to present a significant obstacle.

The current methods for definitively identifying patients who are at risk of progression to metastatic disease are based on histological and clinical differences and the expression of specific biomarkers.

But these strategies are imperfect, and researchers are turning to genome sequencing to tease out molecular differences that might underlie the clinical heterogeneity in prostate cancer progression. They hope to identify new markers to guide diagnosis and treatment and new targets for drug development.

The Prostate Cancer Challenge

Understanding what drives the variability in clinical behavior in prostate cancer and developing effective treatments for patients with metastatic disease are among the greatest challenges today.

Measurement of prostate-specific antigen (PSA) levels, a protein produced by the epithelial cells of the prostate gland, is the gold standard for determining which patients are at risk for developing aggressive disease and therefore require aggressive treatment. But the use of PSA to guide treatment remains controversial because of the tendency for overdiagnosis that often leads to unnecessary treatment and significant morbidity.

The treatment of advanced prostate cancer has been shaped by the knowledge that it is driven by the androgens testosterone and its more active metabolite, 5-dihydroxytestosterone (5-DHT). Reducing the circulating levels of androgens or blocking their cellular effects by inhibiting the activity of the androgen receptor (AR) has become the cornerstone of treatment via surgical or medical castration, the latter through the use of androgen-deprivation therapy (ADT).

Despite initial response, castration-resistant prostate cancer (CRPC) inevitably develops, in which the tumor progresses in spite of low circulating levels of androgens or inhibition of the AR signaling pathway. Insight into the mechanisms underlying the development of CRPC revealed, somewhat surprisingly, that the disease had not become androgen-independent as many suspected, but that the AR pathway is still highly activated in these cancers.

This knowledge has spurred the development of numerous second-generation AR-targeting drugs that are more potent and selective or have novel mechanisms of action, including the AR antagonist enzalutamide (Xtandi) and the CYP17A inhibitor abiraterone acetate (Zytiga). Yet patients still continue to develop resistance to these drugs and there is a pressing need for new therapeutic options.

Genomic Highlights of Primary Prostate Cancer

The Primary Prostate Cancer Landscape

Genome-level studies are starting to provide a comprehensive picture of the molecular basis of prostate cancer at different stages. The first sequencing study was published in 2011 and since then several research entities have added their contributions to the field, including The Cancer Genome Atlas (TCGA) research network. The TCGA analyzed 333 primary prostate cancer samples and reported findings in 2015 (Figure 1).

Chromoplexy

Studies have highlighted significant heterogeneity in the molecular makeup of prostate cancer and have also revealed that the types of genomic aberrations involved are quite unique. The gain or loss of whole chromosomes is relatively rare and the number of individual “spelling errors” in the DNA of key driver genes is also low compared with other solid tumors.

The TCGA study found a median mutation rate of just 0.94 mutations per megabase (range, 0.02-28 per megabase), which is comparable with cancers at the bottom end of the spectrum of mutational load, such as acute myeloid leukemia.

Instead, prostate cancers are a prime example of a class of complex DNA rearrangements called chromoplexy. This is where whole “paragraphs” of DNA break off and move to another part of the genome, creating numerous rearranged or deleted genes as the DNA is stuck back together in new configurations. Since chromoplexy can generate multiple disrupted genes, this can result in numerous oncogenic events occurring in a single cell cycle, giving the cancer cell a significant proliferative advantage.


View Conference Coverage
Online CME Activities
TitleExpiration DateCME Credits
Community Practice Connections™: Personalized Sequencing in Castration-Resistant Prostate Cancer: Bridging the Latest Evidence to the Bedside in Clinical ManagementAug 25, 20181.5
Community Practice Connections™: Precision Medicine for Community Oncologists: Assessing the Role of Tumor-Testing Technologies in Cancer CareNov 30, 20181.0
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