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Ying Zhou, Chenchen Zhu, Zhen Shen, Yanhu Xie, Wei Zhang, Jing Zhu, Tianjiao Zhang, Min Li, Jiwei Qin, Shuai Yin, Rongzhu Chen, Wei Wei, Sinan Sun, Guihong Wang, Zheng Zhou, Hanhui Yao, Dabao Wu, and Björn Nashan

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Wei Nie, Jie Qian, Mi-Die Xu, Kai Gu, Fang-Fei Qian, Jun Lu, Xue-Yan Zhang, Hui-Min Wang, Bo Yan, Bo Zhang, Shu-Yuan Wang, Fang Hu, Chang-Hui Li, Hua Zhong, and Bao-Hui Han

Background: Biomarkers for chemotherapy efficacy in non–small cell lung cancer (NSCLC) are lacking. This retrospective study assesses the association between blood-based tumor mutational burden (bTMB) and clinical benefit of chemotherapy. Methods: Clinical and targeted next-generation sequencing data from the OAK trial (training set; n=318) and POPLAR trial (validation set; n=106) in the docetaxel arm were analyzed. The cutoff value of bTMB for outcome prediction was determined based on a time-dependent receiver operating characteristic curve in the training set, and propensity score matching (PSM) was conducted. The primary outcome was overall survival (OS). Durable clinical benefit (DCB) was defined as OS lasting >12 months. Interaction between treatment and bTMB was assessed in the combined set. Results: A lower bTMB was observed in patients with DCB compared with no durable benefit, and in those with a partial response and stable disease compared with progressive disease. The optimized cutoff value of bTMB for predicting OS was 7 single-nucleotide variants per megabase. In the training set, a low bTMB was significantly associated with longer OS and progression-free survival (PFS). The prognostic value of bTMB was confirmed in the validation set and PSM set. The interaction between bTMB and treatment was significant for PFS (interaction P=.043) in the combined set. Mutations in KEAP1 were associated with high bTMB and a lack of benefit from chemotherapy. Conclusions: Low bTMB is associated with a survival advantage in patients with NSCLC treated with docetaxel, suggesting the prognostic and predictive potential of bTMB for determining chemotherapy efficacy.

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Baijun Dong, Liancheng Fan, Bin Yang, Wei Chen, Yonghong Li, Kaijie Wu, Fengbo Zhang, Haiying Dong, Huihua Cheng, Jiahua Pan, Yinjie Zhu, Chenfei Chi, Liang Dong, Jianjun Sha, Lei Li, Xudong Yao, and Wei Xue

Background: This study aimed to describe the aberrations of DNA damage repair genes and other important driving genes in Chinese patients with metastatic castration-resistant prostate cancer (mCRPC) using circulating tumor (ctDNA) sequencing and to evaluate the associations between the clinical outcomes of multiple therapies and key genomic alterations in mCRPC, especially DNA damage repair genes. Patients and Methods: A total of 292 Chinese patients with mCRPC enrolled from 8 centers. Multigene targeted sequencing was performed on 306 ctDNA samples and 23 matched tumor biopsies. The frequency of genomic alterations were compared with the Stand Up to Cancer–Prostate Cancer Foundation (SU2C-PCF) cohort. The Kaplan-Meier method was used to evaluate progression-free survival (PFS) following standard systemic treatments for mCRPC. Cox regression analyses were performed to determine prognostic factors associated with PFS resulting from treatments for mCRPC. Results: In total, 33 of 36 (91.7%) mutations were found consistently between ctDNA and paired biopsy samples. The most common recurrent genomic alterations were found in AR (34.6%), TP53 (19.5%), CDK12 (15.4%), BRCA2 (13%), and RB1 (5.8%). The frequency of CDK12 alterations (15.4%) in our cohort was significantly higher than that in Western populations (5%–7%). AR amplification and TP53 and/or RB1 alterations were associated with resistance to abiraterone or docetaxel. Patients with a CDK12 defect showed rapid disease progression after abiraterone treatment. However, the clinical outcome after docetaxel treatment was similar between patients with and without CDK12 defects. In multivariate Cox regression analysis, a CDK12 defect was significantly associated with inferior PFS after abiraterone treatment. Patients with a BRCA2 defect showed marked response to both PARP inhibitors and platinum-based chemotherapy. Conclusions: Our study explored the genomic landscape of Chinese patients with mCRPC at different treatment stages using minimally invasive methods and evaluated the clinical implications of the driver genomic alterations on patients’ response to the most widely used therapies for mCRPC. We observed a significantly higher alteration frequency of CDK12 in our cohort compared with the SU2C-PCF cohort.

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Kavea Panneerselvam, Rajan N. Amin, Dongguang Wei, Dongfeng Tan, Phillip J. Lum, Hao Chi Zhang, David M. Richards, Mehmet Altan, Petros Grivas, John A. Thompson, Anusha S. Thomas, and Yinghong Wang

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Kavea Panneerselvam, Rajan N. Amin, Dongguang Wei, Dongfeng Tan, Phillip J. Lum, Hao Chi Zhang, David M. Richards, Mehmet Altan, Petros Grivas, John A. Thompson, Anusha S. Thomas, and Yinghong Wang

Background: Although immune checkpoint inhibitors (ICIs) have provided practice-changing outcomes in treating many cancers, ICI-related gastrointestinal toxicity can limit their use. Upper gastrointestinal toxicity is not common nor as well described as lower gastrointestinal toxicity. We aimed to characterize the clinical presentation, endoscopic and histologic features, treatment response, and outcomes of ICI-related esophagitis. Methods: We retrospectively studied patients at The University of Texas MD Anderson Cancer Center in whom esophagitis developed after receiving ICIs from June 2011 through January 2020. We included patients with endoscopic evidence of esophagitis and excluded those with other obvious causes of esophagitis. A chi-square test was used to assess associations between categorical variables. The Mann-Whitney U test was used to compare differences between continuous variables. Results: Of 657 consecutive patients who underwent esophagogastroduodenoscopy (EGD) during or within 6 months of completing ICI-based therapy, 21 (3%) had esophagitis deemed to be from ICIs. Of these patients, 1 (5%) received an inhibitor of CTLA-4 alone, 15 (71%) received anti–PD-1 or PD-L1 monotherapy, and 5 (24%) received a combination of these. Median time from ICI initiation to onset of esophagitis was 4 months. Upon evaluation with EGD, only 3 patients (14%) had isolated esophageal involvement; 18 (86%) had concurrent involvement of the stomach, duodenum, or both. Most patients (67%) were treated with proton pump inhibitors, and 4 (19%) received steroids (prednisone or budesonide). The mortality rate was 38% (median follow-up, 15 months). Conclusions: Esophagitis associated with ICI use is rare. The diagnosis is one of exclusion because its clinical presentation appears similar to that of inflammation resulting from other causes. It often occurs in conjunction with other upper gastrointestinal toxicity. Symptoms are mild and respond well to nonimmunosuppressive treatment, with few severe complications.

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Fangwen Zou, Hamzah Abu-Sbeih, Weijie Ma, Yuanzun Peng, Wei Qiao, Jianbo Wang, Amishi Y. Shah, Isabella C. Glitza Oliva, Sarina A. Piha-Paul, John A. Thompson, Hao Chi Zhang, Anusha S. Thomas, and Yinghong Wang

Background: Immune-mediated diarrhea and colitis (IMDC) is a common immune-related adverse effect related to immune checkpoint inhibitors. We aimed to identify risk factors for chronic IMDC and its prognostic value in cancer outcomes. Methods: We retrospectively collected data on patients with a diagnosis of IMDC between January 2018 and October 2019 and grouped them based on disease duration into acute (≤3 months) and chronic (>3 months) categories. A logistic regression model and the Kaplan-Meier method with log-rank tests were used for biostatistical analysis. Results: In our sample of 88 patients, 43 were in the chronic group and 45 were in the acute group. Genitourinary cancer and melanoma accounted for 70% of malignancies. PD-1/L1 monotherapy (52%) was the more frequently used regimen. We showed that chronic IMDC was associated with proton pump inhibitor use (odds ratio [OR], 3.96; P=.026), long duration of IMDC symptoms (OR, 1.05; P<.001) and hospitalization (OR, 1.07; P=.043), a histologic feature of chronic active colitis (OR, 4.8; P=.025) or microscopic colitis (OR, 5.0; P=.045), and delayed introduction of selective immunosuppressive therapy (infliximab/vedolizumab; OR, 1.06; P=.047). Chronic IMDC also reflected a better cancer response to immune checkpoint inhibitors (30% vs 51%; P=.002) and was accompanied by improved overall survival (P=.035). Similarly, higher doses of selective immunosuppressive therapy were associated with better overall survival (P=.018). Conclusions: Chronic IMDC can develop among patients with a more aggressive disease course and chronic features on colon histology. It likely reflects a prolonged immune checkpoint inhibitor effect and is associated with better cancer outcome and overall survival.

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Sanjeev Kumar Gupta, Nitin Jain, Guilin Tang, Andrew Futreal, Sa A. Wang, Joseph D. Khoury, Richard K. Yang, Hong Fang, Keyur P. Patel, Rajyalakshmi Luthra, Mark Routbort, Bedia A. Barkoh, Wei Chen, Xizeng Mao, Jianhua Zhang, L. Jeffrey Medeiros, Carlos E. Bueso-Ramos, and Sanam Loghavi

RNA-seq was used to identify the partner gene and confirm the presence of a BCR-PDGFRB fusion. Identification of this fusion product resulted in successful treatment and long-term remission of this myeloid neoplasm. Based on our results, we suggest that despite current WHO recommendations, screening for PDGFRB rearrangement in cases of leukocytosis with eosinophilia and no other etiologic explanation is necessary, even if the karyotype is normal.