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Role of SPOP Mutations in Prostate, Endometrial Cancer Come Into Focus in Retrospective Analysis

prostate cancer

NEW YORK – An analysis of thousands of tumor samples from Caris Life Sciences' database has sharpened researchers' understanding of the prevalence of SPOP mutations in prostate and endometrial cancers and how these mutations might impact patient outcomes on standard treatments.

The retrospective analysis, published in JCO Precision Oncology earlier this month, included more than 7,000 prostate tumor samples and 19,000 endometrial tumor samples with accompanying next-generation sequencing, immunohistochemistry, and whole-transcriptome sequencing data collected within the Caris Precision Oncology Alliance research program. The Caris database includes information on patient survival from insurance claims data from the time of sample collection to when patients were last contacted. The database also contains information on how patients fared on treatments they received such as chemo or immunotherapy. Drawing on this claims data, the researchers estimated how long patients lived after beginning treatment.

Prostate and endometrial cancers have the highest frequency of SPOP mutations. In this analysis, 9 percent of prostate cancer samples and 4 percent of endometrial cancer samples had a mutation in this gene. Clear cell endometrial tumors had some of the highest rates of SPOP mutations at 16 percent, while about 4 percent of endometrioid tumors, serous tumors, and carcinosarcomas had them.

The researchers hoped to characterize the genomic and immune landscape of prostate and endometrial tumors harboring SPOP mutations and examine the different roles these mutations play in these cancers. Ludimila Cavalcante, lead author of the study and a medical oncologist at Novant Health Cancer Institute in Charlotte, North Carolina, said her team found that SPOP mutations appeared to have very different functions in these tumors.

For example, the analysis showed that SPOP-mutated prostate tumors appeared to be more immunosuppressed, while SPOP-mutated endometrial tumors were more immunostimulated. Prostate tumors with SPOP mutations also had elevated prostate-specific antigen (PSA) levels, suggesting they were more hormonally regulated.

She and her colleagues speculated that the different genomic and immune characteristics of SPOP-mutant prostate and endometrial tumors may be due to the location of the mutation in the meprin and TRAF-C homology (MATH) domain, which is associated with regulation of protein processing and ubiquitination. "When we compared the hotspots between prostate and endometrial [cancers], we saw that the hotspot clusters were in different locations in the MATH domain of the crystal structure of SPOP," Cavalcante said. "That could be the reason for the different mechanisms of action for the different tumor types."

Different genes were enriched in SPOP-mutant prostate and endometrial tumor types. In prostate cancer, SPOP-mutated samples had fewer mutations in the TP53, TMPRSS2, AR, and ETV1 genes but more mutations in the APC and BCOR genes, compared to SPOP-wild type samples. Endometrial tumors with SPOP mutations had fewer PIK3CA mutations in clear cell and serous subtypes and fewer PTEN mutations compared with SPOP-wild type tumors.

The researchers also found that SPOP-mutant prostate tumors appeared to be more resistant to BET inhibitors than wild-type tumors due to lower expression of BRD2, a protein in the BET family. The authors noted that immunotherapy may not benefit patients with SPOP-mutant prostate cancer because these mutations are associated with an immunosuppressed microenvironment. They also found that patients with SPOP-mutant prostate cancer appeared to have longer survival on androgen deprivation therapies and chemotherapy.

"This could potentially guide treatment early on, even in the castration-sensitive metastatic setting," Cavalcante said. "Patients that are diagnosed with metastatic disease and SPOP mutations, they could preferentially get hormone-directed therapy first versus chemotherapy. But we would obviously need a lot more data in trials to support that."

SPOP mutations may also be more prevalent in Black patients with prostate cancer, and knowledge of these mutations may help improve treatment decisions for this group. Cavalcante noted that Caris' database did not include demographic information about patients' race. However, when researchers homed in on samples that expressed ANPEP, a gene known to be associated with prostate cancer in African American patients, they found a higher incidence of SPOP mutations. Previous studies have also described a higher incidence of SPOP mutations in Black men with prostate cancer.

The findings and potential clinical implications for SPOP mutations were less clear for endometrial cancer, Cavalcante said, likely due to the small numbers of SPOP-mutant samples for each endometrial subtype. There were small differences in survival, such as serous patients with SPOP mutations having generally worse outcomes, and SPOP-mutant endometrioid patients having prolonged survival. The mutation did not appear to affect survival outcomes on any specific administered treatment such as chemo, endocrine therapies, or immunotherapy.

Researchers did identify that SPOP-mutant endometrial carcinosarcoma tumors were more immune-rich than SPOP wild-type tumors with higher PD-L1 expression and tumor mutational burden, suggesting that immunotherapy may be a good choice for these patients. They also confirmed that clear cell endometrial cancer had the highest frequency of SPOP mutations but did not find that the mutations were associated with any different treatment outcomes. The immune-rich nature of SPOP-mutant endometrial tumors could provide further evidence to support the use of immunotherapy for these patients.

"The clear cell subtype didn't have specifically better survival, so we don't know whether that means that SPOP is more of a passenger in that subtype or what it's actually doing there," Cavalcante said, adding that further research is needed in larger populations to explore SPOP's potential effect on outcomes.

According to Cavalcante, future clinical trials based on this research could focus on studying whether combination therapies can sensitize SPOP-mutant prostate tumors to BET inhibitors or on prospectively evaluating whether SPOP-mutant prostate tumors have better outcomes on hormone therapies. Additional studies exploring the role of SPOP mutations in endometrial cancer subtypes are also needed to better understand the role of these mutations, Cavalcante said.