Precision Medicine Approaches to the Diagnosis and Management of Prostate Cancer

Substantial evidence exists that prostate cancer arises and progresses by core genetic alterations that activate cancer-promoting genes and inactivate tumor suppressors. These changes result most commonly from epigenetic and structural genomic changes, including promoter hyper- and hypo-methylation, gene amplification, chromosomal deletions, somatic copy number aberrations, and chromosomal rearrangements that result in gene fusions with novel biologic properties. Interestingly, and unlike in many metabolic diseases, the incidences of point and missense mutations resulting in altered proteins are quite low in prostate cancer. A comprehensive, integrated model of the genetic events that underlie the genesis and progression of prostate cancer from germline susceptibility to castrate resistant metastatic disease is now emerging, and the explosion in genomic analysis of prostate tumors has now allowed genomic science to be brought to the clinic. In their article in this issue of ONCOLOGY, Drs. Crawford, Ventii, and Shore have nicely summarized commercially available tests that can influence decision making in men at risk of harboring prostate cancer, indicating who needs a second biopsy after an initially negative one and identifying who may be the best candidate for active surveillance.[1]

For those undergoing screening for the presence of previously undiagnosed prostate cancer, the major challenge for new tests is to avoid the overdetection of indolent cancers that limits the clinical utility of the prostate-specific antigen (PSA) test. Both the Prostate Health Index (phi) and prostate cancer antigen 3 (PCA3) tests have improved specificity for finding higher-grade cancers, and their use is likely to result in fewer men undergoing biopsy but a higher likelihood that a biopsy will be positive for biologically significant disease. This apparent paradox is actually good news, because if used properly, these tests should reduce both the number of biopsies performed and the overdiagnosis and overtreatment of nonlethal cancers. PCA3 is of particular interest biologically, because it was the first non–PSA-based marker that has value for screening. The clinical assay measures levels of a cancer-specific long noncoding RNA (lncRNA), a class of molecules that have recently come under the spotlight as important epigenetic regulators of prostate cancer progression. Another test on the horizon is a panel of four kallikrein markers that in initial reports further improve identification of men harboring higher-grade cancers.

Another common clinical dilemma is when to re-biopsy a patient with an initially negative biopsy despite a concerning PSA level. Undersampling is a known limitation of standard biopsy schemes, and while older studies suggested that a second biopsy resulted in a cancer diagnosis in about 20% of patients, there are clear data showing that repeated biopsy also increases the risk of overdetecting nonlethal disease. The new markers available for helping clinicians to decide who is at risk of harboring a cancer that was missed by initial biopsy are based on the emerging understanding of the biology of early-stage prostate cancer, generally testing for the presence of genomic alterations that are absent in benign disease but present in cancer or precancerous lesions. These measured biologic events include promoter hypermethylation (ConfirmMDx), the presence of a cancer-specific lncRNA (PCA3), deletions in mitochrondrial DNA (assessed by the prostate core mitomic test [PCMT]), the presence of cancer-specific gene fusions (TMRPSS2:ERG), or the presence of inactivating mutations in a known oncogene (PTEN). All of these mechanisms are well-established events in early-stage cancer. If they are accurately measured by these assays, then the number of repeat biopsies should diminish because of their high negative predictive values.

Finally, the authors consider new biomarkers for assessing disease aggressiveness in newly diagnosed men. These attempt to address perhaps the most pressing issue in prostate cancer today, namely identifying men with biologically indolent disease who are good candidates for active surveillance. This management strategy is substantially underutilized for a variety of reasons, most especially uncertainty on the part of patients and physicians over whether a biopsy showing only low-grade tumor is representative of the entire biology of the cancer-bearing prostate. Preliminary studies suggest that measuring gene expression (using Oncotype DX, Prolaris, or ProMark) in needle biopsies from men who meet clinical criteria for surveillance can predict clinical outcomes such as adverse pathology at radical prostatectomy and long-term disease-free survival. However, none of the existing assays have actually been tested or validated, in a contemporary series of patients managed by surveillance, for their ability to predict progression or a need for therapy. The Decipher test measures the likelihood of adverse clinical outcomes after a biochemical recurrence following prostatectomy, with the suggestion that those at low risk for an event may be spared the cost and morbidity of adjuvant or salvage radiation; however, the hypothesis that radiation in those determined to be at higher risk based on this test can actually be beneficial has not been studied. Finally, circulating tumor cells (CTCs) represent a promising way to monitor response to systemic therapies, but they have not yet been validated in prospective clinical trials.

In sum, all of these tests are based on a sound understanding of prostate cancer biology and well-developed laboratory platforms. They hold promise for moving the management of prostate cancer into the sphere of precision medicine, where clinical decisions are based on the molecular characteristics specific to an individual patient’s cancer, in much the same way that new therapeutic agents targeting specific molecular defects have advanced treatment for many other tumors. The upfront cost of these tests is an issue for some clinicians and payors, although it is instructive to remember that managing a problem correctly from the outset is always the least expensive option. As a group, the available tests represent first-generation assays that are likely to provide incremental improvement in clinical decisionmaking now and will serve as the basis for more precise diagnostics in the future.

Financial Disclosure:Dr. Klein has received research support from and served as a consultant to GenomeDx Biosciences, Genomic Health, and Metamark.

References:

1. Crawford ED, Ventii K, Shore ND. New biomarkers in prostate cancer. Oncology (Williston Park). 2014;28:135-42.