Association of treatment-induced decrease of tumor chromosome Y and prognosis.

3136 Background: Loss of chromosome Y (LOY) in cancer has been linked to increased mortality. Since tumors that are not completely eradicated often harbor additional molecular changes which may alter biological behavior, here we sought to examine if therapy has any impact on tumor chromosome Y content and if so, the relevance this has on patient outcome. Changes in chromosome Y content with therapy would impact clinical decision making in patients with persistent or recurrent tumors since tumors with LOY have also been shown to be more responsive to specific therapies. Methods: Male patients with >=2 sequential tumor samples profiled at Caris Life Sciences (Phoenix, AZ) who received systemic therapy between collections were included. RNASeq was performed using NovaSeq platform. Chromosome Y score (YChr score) was calculated using ssGSEA (log-rank normalization) based on a previously published 9-gene signature ( Nature 2025). Change in YChr score between pre and post treatment paired samples (ΔYChr) was computed per patient. A decrease in YChr score in post sample compared to pre sample was defined as ΔYChr ≥0.029 (cohort mean) and called progressive LOY (pLOY) while the remainder were called no-pLOY. Real-world clinical data were obtained from insurance claims. Overall survival (OS) was defined from first sample collection to last contact. Hazard ratios (HRs) were estimated using Cox proportional hazards models, with log-rank p values reported. Results: Among 1,343 patients with paired samples, pLOY was associated with shorter OS compared with no-pLOY (median OS [mOS]: 33.2 vs. 36.0 months; HR 1.168, 95% CI 1.028–1.326; p=0.0167). Tumor-specific analyses demonstrated significantly worse OS in pLOY versus no-pLOY for colorectal cancer (CRC; N=124 vs. 157; mOS 38.9 vs. 50.6 months; HR 1.535, p=0.0038), bladder cancer (N=26 vs. 41; mOS 25.7 vs. 37.7 months; HR 1.992, p=0.0204), NSCLC (N=100 vs. 134; mOS 27.6 vs. 32.7 months; HR 1.379, p=0.0379), and gastric cancer (N=13 vs. 16; mOS 17.6 vs. 28.5 months; HR 2.603, p=0.0223), with a trend observed in melanoma (N=17 vs. 27; mOS: 31.4m vs. inf, HR: 2.231 [0.922-5.4], p=0.075). No association was observed in other tumor types. Treatment distributions for mentioned cancer types did not differ between pLOY and no-pLOY groups (p>0.05). Among CRC patients with primary-to-metastatic paired samples (57%), pLOY remained significantly associated with worse OS (mOS 39.5 vs. 56.3 months; HR 1.647; p=0.0112). pLOY was not associated with specific therapies or combinations across the full cohort. Conclusions: In a large real-world clinico-genomic cohort, longitudinal decrease in Chromosome Y score is independently associated with poor prognosis across multiple cancer types supporting further investigation into the biological and clinical relevance of Y chromosome loss and providing insights on novel treatment selection strategies.