Investigators have identified genomic alterations that appear to be associated with prognosis in men with metastatic castration-sensitive prostate cancer (mCSPC).

A study of 424 patients with mCSPC treated at a tertiary care center revealed that alterations in the androgen receptor (AR), TP53, cell-cycle, MYC oncogenic signaling pathways occur more commonly in tumors with worse overall survival and decreased time to castration-resistant disease, whereas alterations in the SPOP and MNT pathways occur more frequently in tumors with a better prognosis, according to findings published in Clinical Cancer Research.

“The genomics of metastatic castration-sensitive prostate cancer have not been well characterized in the literature, but it is now clear that upfront treatment intensification with taxanes or next-generation AR-directed therapies offer benefit in the overall patient population,” said the study’s co-senior author Wassim Abida, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York. “The question remains whether treatment selection or targeted therapies can be employed based on genomic characteristics.”

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The association between alterations in cell-cycle genes and TP53 and MYC pathway genes and worse outcomes “may pave the way for targeted therapy in these higher-risk groups,” Dr Abida said.

The study compared genomic alterations according to clinical phenotypes: high- vs low-volume disease and de novo vs metastatic recurrence. Of the 424 patients in the study, 213 men (50%) had high-volume disease (4 or more bone metastases or visceral metastases) and 211 (50%) had low-volume disease; 65% had de novo metastases and 35% had metastatic recurrence. At the time of sample collection, patients had a median age of 66 years. The investigators conducted gene sequencing from May 2015 to September 2018.

High- vs low-volume disease

In adjusted analyses, men with higher-volume disease had significant 1.8- and 3.7-fold increased risks of castration-resistant disease and death, respectively, compared with men who had low-volume disease. Tumor specimens from men with high-volume disease had more copy number alterations.

Among men with high-volume disease, the highest-ranking pathways were the NOTCH, cell-cycle, and epigenetic modifiers pathways.

Although the prevalence of CDK12 alterations differed between patients with de novo metastatic and those with metastatic recurrences, the groups had similar prognoses. “I was actually surprised there were not more dramatic genomic differences between de novo and relapsed disease,” said study co-senior author Philip Kantoff, MD, a medical oncologist and Chair of the Department of Medicine at Memorial Sloan Kettering Cancer Center in New York.

After adjusting for disease volume and other genomic pathways, the researchers found that the rates of castration resistance differed by 1.5-fold and up to 5-fold according to alterations in the AR, SPOP (inverse), TP53, cell-cycle, WNT (inverse), and MYC pathways. Overall survival (OS) rates varied from 2- to 4-fold according to alterations in the AR, SPOP (inverse), WNT (inverse), and cell-cycle pathways. PI3K pathway alterations were not associated with prognosis.

Docetaxel and next-generation AR axis-directed therapies have been shown to prolong OS, but it remains uncertain which patients benefit the most from intensified therapies. “We did not find any obvious genomic reason to explain the differences in docetaxel sensitivity between high- and low-volume disease,” Dr Kantoff said.

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The authors pointed out that genomic landscape studies of tumor DNA profiling in prostate cancer in general have excluded metastatic castration-sensitive tumors. Instead, most studies have focus on localized disease or metastatic castration-resistant disease.

Dr Abida and his colleagues acknowledged that their study has inherent biases because it was hospital based and enrolled patients at an academic referral center.

This article originally appeared on Renal and Urology News