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Lung cancer is still the leading cause of morbidity and mortality by cancer among men, according to the latest epidemiological data in China. Anaplastic lymphoma kinase (ALK) rearrangements act as key oncogenic drivers of non-small cell lung cancer (NSCLC) and have been identified in 5–6% of NSCLC. Although ALK inhibitors (ALK-TKIs) were proven to be more effective than chemotherapy in ALK-positive NSCLC patients and the safety profile of these drugs was favorable, novel ALK fusions NSCLC might discontinue or switch treatment because of adverse events (AEs) have rarely previously been reported. Here, we describe a male patient with stage IV lung adenocarcinoma who carried a novel PTH2R-ALK fusion identified by next-generation sequencing (NGS). The patient first took crizotinib but switched to alectinib due to gastrointestinal AEs. Although alectinib remained effective on tumors, ceritinib (450 mg) was replaced after the AEs of hyperbilirubinemia occurred. After reducing the dose to 300mg, the diarrhea AEs caused by ceritinib were effectively relieved, and the patient obtained sustained clinical benefit with progression-free survival nearly 12 months. Our findings offer valuable information for the safety management of NSCLC patients with a novel PTH2R-ALK fusion treated by ALK-TKIs.

Background: RNF43, a single transmembrane circular E3 ubiquitin ligase, has been identified as a tumor suppressor for a variety of cancers, including ovarian cancer, gastric cancer, pancreatic cancer, endometrial cancer and colorectal cancer. It is even considered to be carcinogenic driver mutations in cholangiocarcinoma, ovarian cancer, gastric cancer, endometrial cancer and colorectal cancer (CRC). However, the correlation between RNF43 mutation and CRC immunotherapy has not been reported yet. Methods: We evaluated the role of RNF43 in CRC using publicly available data from The Cancer Genome Atlas (TCGA) and Memorial Sloan Kettering Cancer Center (MSKCC). An in-house Chinese CRC cohort (n=2290) was used for the analysis of immune-related markers. The relationship between clinical pathologic features and RNF43 were analyzed with using the two-sided chi-squared test or the Fisher exact test. Clinicopathologic characteristics associated with overall survival using Cox regression and the Kaplan-Meier method. Results: In the MSKCC cohort, a total of 108 CRC patients receiving immunotherapy were enrolled, of which 38 (34.9%) were over 60-year-old and 61 (56.0%) were male. RNF43 mutation was significantly associated with high TMB and high MSI score (all p 1% (p=0.0110) in the in-house Chinese RCC cohorts. Citation Format: Changjun Yu, Weibiao Kang, Yu Yuan, Junling Zhang, Mengli Huang, Yanan Chen, Xihua Xia, Yuezong Bai. RNF43 mutation as a predictor of immunotherapeutic efficacy in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5089.

Background: NOTCH, as an oncogene, has been shown to be closely associated with radiation and chemotherapy, hormone therapy, and other molecular targeted therapies (such as anti-EGFR and anti-PI3K molecular targeted therapies) in a variety of tumors, and even in drug resistance mechanisms. However, the correlation between NOTCH mutations and immunotherapy in colorectal cancer (CRC) has not been reported. Methods: We retrospectively identified NOTCH mutation and treatment outcomes. The relationship between clinical pathologic features and NOTCH were analyzed with using the two-sided chi-squared test or the Fisher exact test. Clinicopathologic characteristics associated with overall survival using Cox regression and the Kaplan-Meier method. Results: We retrospectively analyzed 108 CRC patients who received immunotherapy, including 31 patients with NOTCH mutation (MUT) and 78 patients with NOTCH wide-type (WT). NOTCH mutation was discovered to be enriched in MSI instable and associated with significant better overall survival (HR, 0.4; 95% CI, 018-0.9; P=0.0272). Although compared with NOTCH WT, no association was observed between NOTCH1/2/4 MUT and overall survival, Kaplan-Meier survival analysis showed that patients with NOTCH3 MUT obtained better OS (not reach vs. 14 months, HR, 0.17; 95% CI 0.04-0.74; P=0.0176). In addition, in an in-house Chinese CRC cohort (n=1968), we found 322 (16.4%) patients with NOTCH mutations, including NOTCH1/2/3/4 mutation frequency were 43.5%, 32.9%, 46.9% and 12.1%, respectively. 206 (60.4%) patients had one NOTCH mutation, and only 20 (6.2%) patients had more than four mutations. NOTCH mutations were significantly associated with higher TMB levels (P Conclusions: Our results suggest that NOTCH1/2/3/4 mutation may be a potential predictor to favorable ICI response in CRC patients. The exact mechanisms underlying NOTCH mutations are needed to be further evaluated. Citation Format: Xiaoyang Xia, DongShan You, Jing Cao, JingHui Huang, Junling Zhang, Mengli Huang, Yanan Chen, Xihua Xia, Yuezong Bai. Identification of NOTCH mutation as novel predictor to efficacious immunotherapy in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5088.

Background: Immunotherapy exhibits promising clinical efficacy in treating unresectable esophageal cancer, and several studies have demonstrated that both comutations in DNA damage response (DDR) pathways and tumor immune microenvironment(TIME) could serve as potential biomarkers for immune checkpoint blockade (ICB) treatment. However, the associtation between DDR comutations and TIME remains unclear. Methods: Between April 2020 and September 2020, NGS and TIME analysis of tumor tissue from 22 patients with esophageal cancer were performed by 3D Medicines, Inc., a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory. We retrospectively investigated the association between genomic alterations and immune microenvironment features. Among eight DDR pathways, comutations of check point factors(CPF) plus base excision repair(BER), homologous recombination repair(HRR), mismatch repair(MMR) or Fanconi anemia(FA) were defined as "DDR co-mut+", while mutation of CPF or comutations of CPF plus nucleotide excision repair (NER) were defined as “DDR co-mut-”. In addition, the relationship between comutations of DDR pathways and tumor mutational burden (TMB) was also analyzed. Results: 22 patients with esophageal cancer were included for analysis. 16 of 22 patients (72.7%) were male and the median age was 62 years old(range, 52 to 73 years). Based on the definition of DDR co-mut+ and DDR co-mut-, 13 patients were devided into DDR co-mut+ group, and 9 patients belonged to DDR co-mut- group. Gene alterations and TIME analysis revealed that patients with DDR co-mut+ showed a higher abundance of CD56dim natural killer cells in both tumor(p=0.0161) and stroma(p=0.028) compared with DDR co-mut- patients. No differences were observed in the densities of CD8+ T cells, M1-TAMs, and M2-TAMs between DDR co-mut+ and DDR co-mut- patients. TMB analysis displayed slightly higher in DDR co-mut+ group with no significant difference. Conclusions: Patients with DDR co-mut+ showed better infiltration of CD56dim NK cells in tumor and stroma in esophageal cancer. Combination of DDR comutations with TIME features may be a more promising biomarker to guide immunotherapy. Keywords: esophageal cancer; DNA damage response pathway; tumor immune microenvironment; tumor mutational burden Citation Format: Hao Chen, Xihua Xia, Junling Zhang, Yanan Chen, Mengli Huang. Characteristics of tumor immune microenvironment in patients carrying comutations of DNA damage response pathways in esophageal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5096.

Background: The von Hippel-Lindau (VHL) gene is a tumor suppressor gene. Although VHL gene alterations play a key role in the pathogenesis of renal cell carcinoma (RCC), and several therapies targeting this molecular pathway have been studied, such as sunitinib, pazopanib and axitinib. However, it is not clear whether VHL mutation is a prognostic factor for immunotherapy in renal cell carcinoma. Methods: The impact of VHL mutations on survival outcomes in RCC patients received immunotherapy or non-immunotherapy were verified in the Memorial Sloan Kettering Cancer Center (MSKCC) trials and The Cancer Genome Atlas (TCGA) RCC cohort, respectively. An in-house Chinese RCC cohort (n=950) was used for the analysis of immune-related markers. The relationship between clinical pathologic features and VHL were analyzed with using the two-sided chi-squared test or the Fisher exact test. Clinicopathologic characteristics associated with overall survival using Cox regression and the Kaplan-Meier method. Results: In the MSKCC cohort, a total of 143 RCC patients receiving immunotherapy were enrolled, of which 117 (81.8%) were clear cell RCC and 143 (100%) microsatellite-stable RCC. VHL mutation was significantly associated with high TMB score (P =0.017). Kaplan-Meier survival analysis showed that patients with VHL mutation obtained better OS compared to VHL wild-type (50 months vs. 23 months, HR, 0.36; 95% CI 0.21-0.64; P Conclusions: Our results suggest that VHL mutation may be associated with better OS in RCC patients receiving immunotherapy. The exact mechanisms underlying VHL are needed to be further evaluated. Citation Format: Dong Shen, Yufeng Huang, Zhiwei Wu, Junling Zhang, Mengli Huang, Yanan Chen, Xihua Xia, Yuezong Bai. Prognosis of renal cell carcinoma patients with VHL mutations to immune checkpoint inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5090.

Background: In recent years, the application of immune checkpoint inhibitors (ICIs) therapies targeting the programmed cell death-1 (PD-1)/programmed cell death ligand 1 (PD-L1) or cytotoxic T lymphocyte (CTLA-4) pathway represents a major breakthrough in many types of cancer. However, low response rates has limited the clinical application of ICIs monotherapy for liver cancer.Anti-vascular combined ICIs are the preferred regiments in first-line systemic treatment of hepatocellular carcinoma (HCC) by NCCN. Therefore, strategies to improve efficacy through patient stratification, biomarker-directed therapies or combinations remain urgently needed. The purpose of this study was to explore potential genomic markers associated with “low response rates” in liver cancer with ICIs combination therapy. Methods: Between July 2019 and April 2021, a total of 47 patients with advanced liver cancer treated with ICIs combined anti-vascular or anti-vascular alone therapy were admitted to Drum Tower Hospital. We retrospectively identified genomic markers, abstracted clinicopathologic features and treatment outcomes. Results: 47 patients with advanced liver cancer treated with immunotherapy combined anti-vascular or anti-vascular were included in this analysis. 40 of 47patients (85.1%) were male and the median age was 58 years (range, 32 to 80 years). Most patients (85.1%) were HCC and 12 patients had at least one immune negative gene mutation (including CCND1, FGF19, FGF3, FGF4, KEAP1, JAK1, MDM4, DNMT3A, EGFR and STK11). Median follow-up was 206 days in immunotherapy combined anti-vascular group and 215 days in anti-vascular group. In the immunotherapy combined anti-vascular group, compared with wild-type, patients with immune negative gene mutations were significantly associated with poorer overall survival (P=0.021). In anti-vascular alone group, there was no significant difference in median OS for patients with/without immune negative gene (P=0.94). In addition, patients with immune negative gene mutations, OS of anti-vascular alone was better than immunotherapy combined anti-vascular (P=0.085). Conclusion: Our study revealed that liver cancer with immune negative gene mutations have a worse prognosis than wild-type patients on immunotherapy combined anti-vascular. In addition, in patients with immune negative gene mutations, immunotherapy combined anti-vascular did not significantly improve prognosis compared to anti-vascular alone. Citation Format: Xinhua Zhu, Yanan Chen, Junling Zhang, Mengli Huang, Xihua Xia. Effects of immune negative genes on immunotherapy combined anti-vascular for liver cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5086.