Prognostic and genomic implications of HER2 expression in metastatic prostate cancer.

Abstract

Background: Evidence regarding the prevalence and clinical or biological relevance of Her2 expressioninmetastaticprostatecancer(mPC)remainslimited.Methods: 52patients(pts)withmPC (48 mCPHS, 4 mCRPC) were retrospectively analyzed. HER2 IHC was performed on FFPE primary and/ormetastaticsamplesusingtheDakoHercepTest(Agilentplatform),scoredpergastric/solidtumor criteria (0, 1+, 2+, 3+). Clinical and laboratory parameters were correlated with HER2 status (0 vs $1+). Genomic profiling included TP53, RB1, PTEN, and BRCA1/2. Progression-free survival (PFS) was defined from 1st-line therapy start to progression or death; overall survival (OS) from metastatic diagnosis. Survival was estimated by Kaplan–Meier and compared by log-rank test. Results: HER2 $1+ was observed in 59.6% of pts (IHC 1+ = 17%, 2+ = 21%, 3+ = 21%). Baseline characteristics are summarized in Table 1. HER2 0 tumors showed numerically higher rates of adverse clinical features, including ISUP 5 (50% vs 26%), ECOG $2 (21% vs 11%), visceral metastases (29% vs 16%), elevated LDH (43% vs 26%), and high-volume disease (57% vs 53%), none reachedstatistical significance (all p . 0.1). Molecularly, HER20 tumorswereenrichedforBRCA1/2 (24%vs11%,p=0.18),TP53(58%vs29%,p=0.11),RB1(42%vs14%,p=0.09),andPTEN(37%vs 7%,p=0.04)alterations.TheonlyTP53/RB1/PTENtriple-hitoccurredinaHER20tumor.NoERBB2 mutations were detected. Median PFS with 1st-line therapy in M1-HSPC pts was numerically shorter for HER2 0 versus HER2 $1+ (11.2 vs 16.8 months; HR 1.42, p = 0.18), with consistent trends across chemotherapy and non-chemotherapy regimens. OSwas immature(medianfollowup 17 months; 26% deaths). None of the pts received HER2-directed ADCs. At the time of submission, genomic results were available for 22 pts; sequencing of 20 additional cases is ongoing, while 10werenotevaluableduetotissuelimitations.Conclusions: HER2expression(IHC$1+)was present in approximately 60% of mPCcases. Although not statistically significant, HER2 0 tumors showed enrichment in TP53/RB1/PTEN/BRCA1/2 alterations and a trend toward shorter PFS, consistent across treatment subgroups. These findings suggest that loss of HER2 expression may define a genomically adverse subset of mPC that warrants further validation.