The genomic alterations in prostate cancer were detected from tissue biopsies of primary tumors and metastatic sites as well as from liquid biopsies of circulating tumor DNA, the latter of which has emerged as an increasingly popular method for genomic analyses across various types of cancer.
Researchers recently published findings showing that comprehensive genomic profiling (CGP) in a real-world setting was able to identify genomic alterations that they say could serve as investigational biomarkers in clinical trials for targeted therapies for advanced prostate cancer.
The genomic alterations documented in their study were detected from tissue biopsies of primary tumors and metastatic sites as well as from liquid biopsies of circulating tumor DNA (ctDNA), the latter of which has emerged as an increasingly popular method for genomic analyses across various types of cancer.
Across the analyses were heterogeneity across metastatic sites of disease and ctDNA analyses showed a broad array of alterations similar to those identified among the metastatic site samples. The findings have led the researchers to argue that the combination of metastatic site biopsy and liquid biopsy could identify more patients for targeted therapy in clinical trials.
“Currently, chemotherapy regimens, next-generation AR inhibitors, sipuleucel-T, PARP inhibitors, and radiopharmaceutical agents represent effective therapeutic options. However, a significant proportion of patients ultimately develop primary or secondary resistance to these agents and die of MET CRPC,” wrote the researchers, nothing that this has opened the doors to research on new actionable targets and drug development. “On the basis of the potential efficacy of various targeted therapies, CGP is increasingly used for the routine management of patients with PC.”
The researchers analyzed over 1200 primary tumor and metastatic site tissue samples and over 2400 ctDNA samples, finding a high rate of alterations in TP53, PTEN, RB1, BRCA2, and AR genes and differences in alteration frequencies between the sample types.
Across metastatic sites, 33% had a genomic alteration in AR, which the researchers note was expected as persistent AR signaling is a primary driver of prostate cancer progression; the frequency ranged from 24% in lung metastases samples to 50% among liver metastases samples. Liquid biopsies showed that ctDNA samples carried AR alterations at a similar, albeit slightly lower, rate (31%), but just 2% of primary tumor samples had AR alterations.
“In the case of AR, [genomic alterations] are likely selected in response to androgen deprivation; this enables tumor cells to be activated promiscuously or to simply overcome inhibition through AR amplification,” explained the researchers. “Selective pressure from chemotherapy influencing clonal evolution might possibly explain the observed higher rate of tumor suppressor GAs in visceral organs versus BO or LN; however, we lack information on therapies, and this remains only a hypothesis because there are no data from published trials that may be suitable to test this hypothesis.”
Brain metastases samples showed the highest rate of genomic alterations per tumor and most frequent PTEN genomic alterations. The frequency of BRCA2 genomic alterations, which have approved targeted therapies, ranged from 0% in brain metastases samples to 15% in liver metastases samples. Four percent of primary tumor samples had RB1 genomic alterations.
The study also identified biomarkers associated with anti-PD-L1 response across the samples, including CDK12 alterations, found in 16% of lung metastases samples, and a microsatellite instability-high status, found in 29% of brain metastases samples.
Findings such as these highlight the important information tumor biopsies offer that can’t be reliably captured by liquid biopsies, with the researchers commenting that liquid biopsy can be a complement for genomic profiling.
Necchi A, Cucchiara V, Grivas P, et al. Contrasting genomic profiling profiles from metastatic sites, primary tumors, and liquid biopsies of advanced prostate cancer. Cancer. Published online August 11, 2021. doi:10.1002/cncr.33865