CDK12 aberrations have been reported as a biomarker of response to immunotherapy for metastatic castration-resistant prostate cancer (mCRPC). Herein, we characterize CDK12mutated mCRPC, presenting clinical, genomic, and tumor-infiltrating lymphocyte data.
Background: Advanced prostate cancer (PC) is invariably fatal and largely insensitive to established immune checkpoint inhibition (ICI). The immune checkpoint, PD-L1 (B7-H1; CD274), is infrequently overexpressed in PC; whilst other B7 family immunomodulatory glycoprotein, B7-H3 (CD276), is overexpressed in many PCs. B7-H3 targeted immunoconjugates are in clinical development. We therefore studied the longitudinal expression of B7-H3 in PC and its associations with advanced PC immunogenomics. Design: We analysed matching, same-patient, formalin-fixed paraffin-embedded (FFPE) metastatic castration resistant PC (mCRPC) (n=98), and treatment-naïve, castration-sensitive PC (CSPC) biopsies (n=43) from patients treated at The Royal Marsden Hospital (UK). Biopsies were analysed by: targeted next-generation sequencing (NGS) for deleterious DNA repair gene alterations; immunohistochemistry (IHC) for ATM, PTEN, B7-H3 and mismatch repair (MMR) proteins using validated antibodies; and multi-color immunofluorescence (IF) assays for T cell surface markers to determine the density of tumour infiltrating T lymphocyte (TIL) subsets. Wilcoxon signed-rank test and Mann-Whitney U test compared B7-H3 expression across matched and unmatched subsets, respectively. Spearman correlation determined associations between continuous variables. Results: Most CRPC and CSPC biopsies had both membranous B7-H3 (mB7-H3) expression (134/141, 95.0%) and cytoplasmic B7-H3 expression (137/141, 97.2%). Analysis of the 43 matched samples sets showed that there was no significant change in mB7-H3 expression as tumours progressed from CSPC to CRPC (median Histoscore [HS] [range]: 130 [5-300] for CSPC vs. 130 [5-290] for CRPC; p=0.6). There was significant interpatient and intratumor heterogeneity in mB7-H3 expression, but a subset of tumour biopsies had very high mB7-H3 expression (HS ≥200: 28/98 [28.6%] CRPC; 14/43 [32.6%] CSPC). mB7-H3 expression strongly associated with the presence of deleterious alterations of genes involved in homologous recombination (HR) repair (p<0.0001), including BRCA2 mutations and homozygous deletions (p=0.0003) as well as ATM loss (p=0.001). mB7-H3 expression did not associate with defective MMR. Interestingly, mB7-H3 expression inversely associated with the density of intra-tumor CD3+ TILs (median: 104.6 TILs/mm2 in B7-H3 low tumors (HS < median) vs. 39.2 TILs/mm2 in B7-H3 high tumours (HS ≥ median), p=0.004) but did not associate with stromal TIL density (p=0.4). Conclusion: mB7-H3 is highly expressed in advanced PC, with higher expression associating with BRCA2 and ATM loss of function alterations and low intratumor TILs. B7-H3 may be an actionable target for treating this disease subset. Citation Format: Christina Guo, Ines Figueiredo, Bora Gurel, Matues Crespo, Jan Rekowski, Suzanne Carreira, Antje Neeb, Adam Sharp, Maria D. Fenor de la Maza, Pasquale Rescigno, Khobe Chandran, Ana Ferreira, Ruth Riisnaes, Susana Miranda, Rita Pereira, Veronica Gil, George Seed, Claudia Bertan, Chloe Baker, Wei Yuan, Johann S. de Bono. B7-H3 as a therapeutic target in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB035.
Background: Genomic analyses describing the molecular landscape of primary prostate cancer (PCa) and metastatic castration-resistant prostate cancer (mCRPC) have identified recurrent CDK12 alterations in 2-4% of primary PCa and 4-11% of mCRPC. These aberrations, as well as high lymphocyte tumor infiltration, could be clinically relevant as putative biomarkers of response to immunotherapies. However, there are few studies looking into whether CDK12 biallelic mutant cases are immune ‘hot'. Here, we describe a cohort of patients with CDK12 aberration and studied the tumor infiltration of those cancers. Methods: Patients with mCRPC and available diagnostic archival and/or CRPC tumor samples were evaluated. Mutation analysis involved custom designed targeted sequencing on MiSeq sequencer. Loss of heterozygosity (LOH) was assessed for the CDK12 cases from exome sequencing using ASCAT, which include single copy lost or copy neutral LOH. Tumor infiltrating lymphocytes were assessed initially with CD3 IHC, using a deep learning-based AI analysis approach. We then subtyped the TILs using a multiplex IF approach, classifying lymphocytes using CD4, CD8 and FOXP3 positivity. Results: Overall 913 samples (between Feb/15 and Oct/19) were sequenced by targeted NGS, 42 patients presented with pathogenic alterations in CDK12 (4.6%), 27 had bi-allelic alterations, 14 mono-allelic, 1 likely biallelic. In these cases, we identified 39 frameshift alterations, 10 missense mutations mainly involving the kinase domain; with 5 having concomitant LOH. One case showed deep deletion of CDK12 and five presented with additional aberrations in other DNA repair related genes. CDK12 biallelic alterations were present in all 3 cases with both diagnostic and matched mCRPC samples available. We studied T cell infiltration in 100 (23 CDK12 biallelic alterations, 7 monoallelic, 70 controls) samples selected from within the initial targeted NGS cohort. Median intratumoral CD3+ cell density was significantly higher in CDK12 biallelic loss samples compared to matched controls in diagnostic biopsies (271.4 vs 104.683 cells/mm2, p=0.026). A similar trend was seen in mCRPC samples (142.130 vs 51.75 cells/mm2, p=0.36). Intratumoral CD4+ cell infiltration was again significantly higher in CDK12 biallelic loss samples compared to controls (98.864 vs 6.188 cells/mm2, p=0.014). Conclusions: In our analysis we show that a proportion of mCRPC patients harbor defects in CDK12, these are often alterations involving both alleles, likely present from the time of diagnosis. A majority of these CDK12 altered cancers has high CD3 infiltration compared to controls. We envision that these CDK12 aberrant ‘hot' tumors could represent a subset of mCRPC likely to respond to immune-checkpoint inhibition. Citation Format: Bora Gurel, Pasquale Rescigno, Wei Yuan, Rita Pereira, Mateus Crespo, Mattia Rediti, Ines Figueiredo, Maialen Barrero, Diletta Bianchini, Maria D. Fenor de la Maza, Khobe Chandran, Juliet Carmichael, Alec Paschalis, Adam Sharp, George Seed, Ruth Riisnaes, Claudia Bertan, Suzanne Carreira, Johann S. De Bono. CDK12-mutated lethal prostate cancers: How hot are these tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-075.
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