West China Hospital of Sichuan University
West China Hospital of Sichuan University
The American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium (ASCO-GU 2023) was held in San Francisco, USA, from February 16th to 18th, 2023. Dr. Qiang Wei and Dr. Hao Zeng’s team had multiple findings selected for academic exchange at this ASCO-GU symposium. Their work addressed prostate cancer, urinary tract carcinoma, and kidney cancer, covering prospective clinical trials, retrospective studies, and translational research. They shared and conveyed the “West China Experience” and “West China Plan” on the international stage.
Prostate Cancer
Abs198:
Prognostic value of lung immunity prognosis index before treatment in metastatic hormone-sensitive and castration-resistant prostate cancer patients
This study reviews 660 cases of late-stage metastatic prostate cancer treated at the Urology Department of West China Hospital of Sichuan University from January 2008 to August 2021. For the first time, it was found that the Lung Immunity Prognosis Index (LIPI) constructed based on the derived neutrophil-to-lymphocyte ratio (dNLR) and lactate dehydrogenase (LDH) has good prognostic value in late-stage metastatic hormone-sensitive and castration-resistant prostate cancer patients.
In 2018, Laura and others first established the LIPI score based on dNLR ≥3 and high LDH levels in an article published in JAMA Oncology. The research confirmed the correlation of the LIPI score with the survival prognosis of advanced non-small cell lung cancer immunotherapy based on multicenter large-sample data. Subsequently, the predictive effectiveness of LIPI was proven not only for immunotherapy but also for lung cancer patients receiving targeted therapy or chemotherapy. Even further research found that the predictive value of LIPI is not limited to lung cancer; LIPI also has good predictive value in stomach cancer, esophageal cancer, and bladder cancer. To date, no studies have explored the prognostic value of the LIPI indicator in the field of prostate cancer.
The study’s results showed that in metastatic hormone-sensitive prostate cancer, the castration-resistant-free survival (CFS) and overall survival (OS) of patients in the good, medium, and poor LIPI groups gradually decreased. For patients with castration-resistant prostate cancer treated with abiraterone as first-line therapy, the LIPI grouping also showed prognostic differences, with the prostate-specific antigen (PSA) response rate, PSA progression-free time, and overall survival showing a gradually decreasing trend for the good, medium, and poor LIPI groups. In summary, LIPI has excellent prognostic value for both metastatic hormone-sensitive and castration-resistant prostate cancer.
Researchers believe that the reason LIPI can gradually expand its application and is not limited to a specific cancer type or treatment method is fundamentally because LIPI reflects the inflammation and metabolism inside a cancer patient’s body. It’s well known that inflammation is closely related to the occurrence and progression of tumors. Rapidly proliferating tumors are often related to an increased anaerobic glycolysis metabolism pathway. Therefore, considering these two aspects, LIPI, an indicator built based on the derived neutrophil-to-lymphocyte ratio and lactate dehydrogenase, has a logically mechanistic explanation for its expanded application. It’s worth noting that the LIPI index is easily calculated based solely on a patient’s routine blood parameters and blood biochemistry parameters, ensuring its widespread applicability and high clinical translational value. Especially for doctors in grassroots hospitals, this easily obtainable LIPI indicator can provide a valuable reference for predicting the survival prognosis of late-stage prostate cancer patients.
Abs215:
The Evolutionary Relationship and Genomic Characteristics of Prostatic Intraductal Carcinoma (IDC-P) and Acinar Adenocarcinoma (PAC)
Prostatic Intraductal Carcinoma (IDC-P) is a highly malignant pathological subtype of prostate cancer. It usually coexists with Acinar Adenocarcinoma (PAC) but exhibits unique biological characteristics such as poor prognosis and subpar response to standard treatments. To date, our understanding of the genomic characteristics and evolutionary origins of IDC-P remains limited. To delve into these unknowns and seek effective treatments for IDC-P, we conducted this study. Previous research predominantly compared tumors containing IDC-P (essentially a mix of IDC-P and PAC) with PAC, a comparison that might dilute the differences between IDC-P and PAC. Thus, we manually dissected IDC-P, PAC, and adjacent control tissues from 22 high-risk prostatectomy specimens, and subsequently conducted whole-exome, transcriptome, and methylation sequencing.
We discovered for the first time that there are three evolutionary relationships between IDC-P and PAC: independent origins, early differentiation, and late differentiation. Tumors with independent origins and early differentiation exhibited higher genomic and pathological heterogeneity between IDC-P and PAC. In contrast, tumors showing late differentiation displayed more similarities on various levels. Compared to PAC, IDC-P overexpresses more genes associated with poor prognosis. Furthermore, we found that IDC-P transcriptionally resembled the ISUP grade group 5 tumors. This finding was validated in an independent cohort, with survival data supporting our conclusion. At the signaling pathway level, IDC-P showed abnormally activated cell cycle and androgen receptor pathways, which could be attributed molecularly to the activation of main cell cycle regulatory factors and intratumoral androgen biosynthesis-related genes.
Thus, our study lays a robust molecular foundation for further exploration into the malignant behavior of IDC-P. This research represents a crucial step towards understanding the biological features of IDC-P, potentially aiding the development of targeted therapies for this pathological subtype.
Abs216:
Predictive Value of Neuroendocrine Differentiation (NED) for First-line Treatment with Abiraterone and Docetaxel in Patients with Metastatic Castration-Resistant Prostate Cancer
Androgen receptor pathway inhibitors and cytotoxic drugs are currently the primary first-line treatment options for patients with metastatic castration-resistant prostate cancer (mCRPC). Representative drugs include abiraterone, enzalutamide, and docetaxel. Due to the inherent heterogeneity of prostate cancer, different patients have widely varied responses to treatments. Identifying precise and effective biomarkers is of significant clinical importance for guiding mCRPC treatment strategies. Neuroendocrine differentiation (NED) is a major cause of resistance to anti-androgen treatment in prostate cancer. Its characteristic manifestations are decreased expression of androgen receptor (AR) and prostate-specific antigen (PSA), while neuroendocrine-related marker expressions, like chromogranin A (CgA) and synaptophysin (syn), rise. Current research on the predictive value of NED for advanced prostate cancer is limited. In this study, we included 262 mCRPC patients treated with first-line abiraterone or docetaxel and assessed NED related markers in their prostate biopsy samples taken when progressing to mCRPC. We found a strong correlation between positive NED expression, especially at high proportions (≥10%), and poor outcomes in first-line mCRPC treatments. Both abiraterone and docetaxel showed reduced benefits in NED-positive patients, with associated shorter bPFS, rPFS, and OS. Furthermore, as the NED proportion increased, the prognosis further deteriorated. There was no significant difference between the efficacy of abiraterone and docetaxel in NED-positive patients, suggesting future research should focus on developing effective treatments targeting NED. These results suggest that for mCRPC patients treated with abiraterone or docetaxel, NED and its proportion are essential predictive factors. Testing for NED can help predict mCRPC patient outcomes and optimize clinical treatment decisions.
Abs222:
Liquid Biopsy Suggests Epigenetic Regulator KMT2C Mutation is Associated with Poor Prognosis in Prostate Cancer Patients
Prostate cancer is one of the most common malignant tumors in the male urogenital system and is highly heterogeneous. Advanced sequencing technologies offer a deeper understanding of prostate cancer and provide insights into its genomic heterogeneity. However, the challenge is to identify the truly clinically relevant genomic changes among numerous alterations. Studying the effects of specific gene mutations on patient prognosis and treatment response can help tailor personalized treatment plans. The lysine methyltransferase (KMT2) family enzymes primarily regulate gene expression through epigenetic mechanisms. Specifically, KMT2C is involved in histone 3 lysine 4 (H3K4) methylation at promoters or enhancers, thereby activating gene transcription. KMT2C is one of the most frequently mutated genes in cancers, accounting for 6.6% across all types. While KMT2C mutations have been linked to the prognosis of various cancers, there’s limited research on its association with prognosis in prostate cancer. Our study found that the mutation rate of KMT2C was 7.24% (16/221). Compared to KMT2C wild-type patients, those with KMT2C mutations progressed faster to the castration-resistant stage (P=0.015) and had a shorter overall survival (OS) (P=0.012), representing an independent risk factor for prognosis (OS: HR 3.815, P=0.006). We also found that KMT2C mutations were associated with mutations in serine/threonine kinase 11 (STK11, P=0.004) and catenin beta 1 (CTNNB1, P=0.008). In patients undergoing endocrine therapy, KMT2C mutations were associated with earlier biochemical relapse (PSA-PFS: mutant 9.9 months vs. wild-type 17.6 months, P=0.014). These findings indicate that KMT2C mutations detected in liquid biopsies correlate with poor prognosis and suboptimal response to endocrine therapy, suggesting potential clinical value as a molecular marker for patient stratification.
Abs485:
Analysis of Incidence and Prognosis of Different Histological Subtypes of Urothelial Tumors Based on the SEER Database
Urothelial tumors are among the most common tumors of the urogenital system, which can be divided into bladder cancer and upper urinary tract tumors (renal pelvis cancer and ureteral cancer) based on their origin. Histological characteristics remain the gold standard for classification and diagnosis of urothelial tumors. According to the 2016 WHO classification, urothelial tumors can be divided into nine subtypes, including urothelial carcinoma, squamous cell carcinoma, urachal carcinoma, adenocarcinoma, neuroendocrine carcinoma, Müllerian tumor, and mesenchymal tumors, among others. Urothelial carcinoma is the most common, accounting for 90%~95% of all urothelial tumors. While other non-urothelial carcinoma subtypes are relatively rare, most related studies are either based on overall non-urothelial carcinoma or a specific non-urothelial carcinoma subtype, with few studies analyzing multiple histological subtypes. Using the SEER database, our study analyzed the incidence, clinical pathological characteristics at diagnosis, and prognosis of various histological subtypes of urothelial tumors (both bladder cancer and upper urinary tract tumors) from 2004 to 2016. A total of 93,200 patients met the inclusion and exclusion criteria, with 87,323 having bladder cancer and 5,877 with upper urinary tract tumors. The included histological subtypes were urothelial carcinoma, squamous cell carcinoma, urachal carcinoma, adenocarcinoma, neuroendocrine carcinoma, Müllerian tumor, and mesenchymal tumors. Urothelial carcinoma accounted for 96.65% of all urothelial tumors, with the incidence of non-urothelial carcinoma subtypes differing between bladder cancer and upper urinary tract tumors. Patients with non-urothelial carcinoma subtypes and those with upper urinary tract tumors presented with higher stages at diagnosis. Different histological subtypes also had varied tendencies for distant metastasis. Using propensity score matching, we conducted survival analysis in multiple grouping scenarios before and after scoring. In general, for overall urothelial tumors and bladder cancer, urothelial carcinoma had a better prognosis than non-urothelial carcinoma. However, in metastatic urothelial tumors and upper urinary tract tumors, the prognosis differences among various histological subtypes were not significant.
Abs516:
A Phase II Open-label Study on Bladder-Preserving Treatment with Neoadjuvant Chemotherapy Combined with Tirreli Monoclonal Antibody Followed by Radiotherapy for High-risk/Locally Advanced Muscle Invasive Bladder Urothelial Carcinoma (HOPE-02)
Bladder preserving trimodality therapy (TURBT + chemotherapy + radiotherapy, TMT) is an alternative to radical cystectomy, suitable for a subset of muscle invasive bladder cancer (MIBC) patients who wish to retain their bladder. This Phase II study aims to explore the efficacy and safety of neoadjuvant chemotherapy combined with tirreli monoclonal antibody followed by radiotherapy as a bladder preserving treatment for high-risk/locally advanced MIBC (Trial Registration Number: ChiCTR2100045213). Patients diagnosed pathologically and radiologically as cT2-4bN0-3M0-1a MIBC were enrolled. They underwent 3-4 cycles of neoadjuvant chemotherapy (gemcitabine + cisplatin or carboplatin) combined with tirreli monoclonal antibody treatment (200mg, q3w, for 1 year). Those who didn’t progress post neoadjuvant treatment underwent further radiotherapy (bladder 60.4-64.4 Gy /1.8Gy/33-35f, pelvis 50.4 Gy/1.8Gy/28f). The primary endpoint of the study was complete response rate (CR), with secondary endpoints being progression-free survival (PFS), bladder intact disease-free survival (BI-DFS), overall survival (OS), and toxicity.
The planned sample size was 43 participants. To date, 28 patients were enrolled, with 23 undergoing radiotherapy. Out of these, 16 had therapeutic efficacy evaluated through imaging and cystoscopy post radiotherapy. Median follow-up time was 14.2 months. Post-radiotherapy, out of 16 patients, 2 were Tis, and 14 were T0 (initial CR rate of 100%). The 2 Tis patients received BCG vaccine bladder instillation and reached T0 upon the second therapeutic evaluation. No patient deaths were reported, with only one instance of distant metastasis. 1-year PFS rate, 1-year BI-DFS, and 1-year OS were all 100%. Grade 3 and 4 hematological adverse events occurred at rates of 23.3% and 2.3% respectively. One patient exhibited reduced bladder capacity, while 3 had symptoms of increased frequency, urgency, nocturia, and dysuria. Three patients presented with grade 1 immunotherapy-related thyroid dysfunction, and another three with grade 2 myositis. This phase of the HOPE-02 study analysis suggests that neoadjuvant chemotherapy combined with tirreli monoclonal antibody followed by radiotherapy offers satisfactory efficacy and tolerable toxicity. This treatment may be an ideal strategy for high-risk/locally advanced MIBC patients wishing to preserve their bladder.
Kidney Cancer
Abs685:
Phase II Multicenter Study of Xindili Monoclonal Antibody Combined with Axitinib in the Treatment of Advanced Fumarate Hydratase-deficient Renal Cell Carcinoma
Fumarate hydratase-deficient renal cell carcinoma (FH-RCC) is a rare and highly invasive subtype of kidney cancer, which was officially listed as an independent subtype by the WHO classification of urological and male reproductive system tumors in 2022. Despite numerous significant studies exploring its potential pathogenesis, therapies targeting these discovered mechanisms have been less effective. Clinical treatment options remain somewhat chaotic, such that there is still no standard treatment strategy. Our team’s previous research found that FH-RCC is highly immunogenic, characterized by increased tumor T cell infiltration and high expression of immune checkpoint molecules in the tumor, and proposed for the first time the clinical concept of immune combination therapy. To further validate the efficacy and safety of the immune combination treatment strategy in FH-RCC, our team registered and conducted the world’s first prospective IIT study of FH-RCC immune combination treatment and reported preliminary results at the 2023 ASCO GU annual meeting.
All participants were diagnosed through FH immunohistochemistry and next-generation sequencing or MLPA. After enrollment, they received first-line treatment with Xindili monoclonal antibody (200mg, intravenous injection every three weeks) combined with Axitinib (5mg, orally, once daily) until disease progression or intolerance to treatment. The primary study endpoints were ORR (Objective Response Rate) and PFS (Progression-Free Survival). This study was registered on ClinicalTrials.gov, with the identifier NCT04387500. As of October 2022, 21 participants from 8 centers were enrolled. In this preliminary analysis, the median follow-up was 9 months (0.9~15.2 months). Out of 19 evaluable participants, CR (Complete Response) was 15.8% (3/19), ORR was 63.1% (12/19), and DCR (Disease Control Rate) was 89.4% (17/19). Median PFS has not been reached, with 12-month PFS being as high as 72.3%. Treatment-related adverse events of all grades and ≥ grade 3 occurred in 95% (20/21) and 23.8% (5/21) of patients, respectively.
These results suggest that the combination of Xindili monoclonal antibody and Axitinib has efficacy and controllable safety. This study is an ongoing clinical trial, aiming to enroll 41 participants from 8 centers. The study began on June 2, 2021.
Abs686:
Value of Metastatic Lesion Resection in the Prognosis of Metastatic Non-clear Cell Carcinoma
In recent years, studies have shown that for patients with metastatic clear cell renal cell carcinoma (ccRCC), the removal of metastatic lesions can improve prognosis to some extent. However, whether patients with metastatic non-clear cell renal cell carcinoma (non-ccRCC) can benefit from the resection of metastatic lesions is still unknown.
To explore the value of metastatic lesion resection in the prognosis of non-ccRCC patients, our research team conducted a retrospective study on all 114 patients pathologically diagnosed with metastatic non-ccRCC who were treated at West China Hospital of Sichuan University from September 2008 to July 2021. Of the 114 patients, all received systemic treatment; 14 underwent resection of metastatic lesions. In the overall population analysis, the resection of metastatic lesions significantly increased the patients’ progression-free survival (PFS) (7.1 vs 12.4 months; HR 0.352, 95%CI: 0.108~1.143, P=0.046). To further identify more suitable patient populations for metastatic lesion resection, our research team conducted further subgroup analyses. For patients with metastasis at initial diagnosis, nephrectomy based on systemic treatment significantly prolonged both PFS (HR 0.363, 95%CI: 0.179~0.737, P=0.005) and overall survival (OS) (HR 0.172, 95%CI: 0.080~0.371, P<0.001). For patients with asynchronous metastasis, resection of metastatic lesions significantly extended PFS (HR 0.124, 95%CI: 0.016~0.956, P=0.045) and OS (HR 0.250, 95%CI: 0.059~0.971, P=0.043). Moreover, the Clavien-Dindo classification of postoperative complications for all patients who underwent metastatic lesion resection did not exceed grade 3.
The above results suggest that patients with metastatic non-ccRCC, especially those with asynchronous metastasis, may benefit from the resection of metastatic lesions. This can help formulate the best personalized treatment decisions for patients with metastatic non-ccRCC.
The Urological Oncology Multidisciplinary Team (MDT) of West China Hospital of Sichuan University was established in 2013 and is among the first in China to align with international advanced concepts of tumor treatment. After nearly a decade of development, under the leadership of Dr. Qiang Wei and Dr. Qiao Zhou, the West China Urological Oncology MDT has become one of the four major demonstration bases for MDT in urological oncology in China. With the team’s ethos of “Collaborate for growth and innovate for the future”, they engage in interactive clinical diagnoses and treatments centered on “patient services” and “clinical exploration”. This approach offers many patients individualized and precise comprehensive treatment solutions, maximizing benefits in survival and quality of life.
The Urological Oncology MDT now encompasses 16 specialist areas, with 47 team members covering Urological Surgery, Oncology Radiotherapy, Oncology Chemotherapy, Pathology, Radiology, Nuclear Medicine, Endocrinology, Vascular Surgery, Anesthesiology, Cardiology, Nephrology, Hematology, Mental Health Center, and Oncology Nursing. In the last five years, the team has served 1,582 urological oncology patients, with a year-on-year growth rate of 22.5%. Leveraging the hospital’s nationwide influence and the team’s formidable diagnostic and treatment capabilities, they’ve set up patient follow-up systems for specific tumors like prostate cancer, renal cancer, and urothelial cancer. They’ve also gradually built comprehensive clinical and biological databases for each of these. Notably, as one of the world’s five major medical centers focusing on intraductal carcinoma of the prostate (IDC-P), the prostate cancer sub-team has developed the world’s largest integrated database module for IDC-P patient clinical information, radiomics, and genomics, covering the entire lifecycle management of prostate cancer patients. The median survival time for late-stage prostate cancer patients approaches 80 months, surpassing international standards.
In 2020, the West China Urological Oncology MDT took the lead in establishing the CACA-GU Rare Renal Cancer Cooperative Group. With the support of domestic peers, they built the world’s largest integrated clinical and biological database for fumarate hydratase-deficient renal cell carcinoma and TFE3 rearranged renal cell carcinoma. They conduct precision imaging alerts and pathological diagnoses for special pathological types of renal cancer and conduct several prospective clinical explorations for these rare types, greatly improving the lives of these patient groups.
Collaboratively, the West China Urological Oncology MDT has secured over 30 National Natural Science Foundation projects and led 18 tumor-related clinical studies. Over the past five years, they’ve published over 130 papers in prestigious journals, including Cancer cell, Nature Comm, Genome Med, PNAS, Clin Cancer Res, Cancer Res, Eur Urol, J Urol, and others. They’ve presented 48 translational research results at significant international urological oncology conferences like ASCO-GU, ASCO, AUA, EAU, and ESMO, continuously voicing the advances of urological oncology from West China.
