There are unique tumorigenic risk factors endemic to countries such as China and Taiwan that make for an appealing comparison against UTUC cases arising in the US. Whereas tobacco exposure overwhelmingly accounts for the majority of cases in the latter, consumption of aristolochic acid (AA)-containing herbal medicines and arsenic exposure have been associated with UTUC carcinogenesis in East Asia. Exposure to AA notably creates nephrotoxic aristolactam-DNA adducts that persist in the proximal convoluted tubule of the renal cortex and give rise to tumors with signature TP53 mutations3 that are not evident in other sporadic forms of UTUC. Whether these differences hold implications for targeted therapies warrants further evaluation. Nonetheless, the apparent clinicopathologic differences that may arise from such risk factors are important to consider when designing clinical trials, particularly those that draw from an international catchment.
We observed from the literature that body mass index (BMI) had inconsistent, and even conflicting, prognostic implications in UTUC based on the origin of the patient population studied. In our most recent work,4 we explored this notion further via an international, multi-institutional cohort derived from Taiwan and the US. Interestingly, we found that, unlike in US patients, Taiwanese patients with greater BMI exhibited better oncological outcomes than those with lower BMI. This finding is akin to the so-called “obesity paradox” seen in multiple immunogenic malignancies such as renal cell carcinoma, non-small cell lung cancer, and melanoma.5 Future studies will need to focus on elucidating whether these observed differences may be influenced by inherent genetics or exposure to certain risk factors. Clinically, this also begs the question of whether such observations hold therapeutic implications, such as in the use of immune checkpoint inhibitors. Notably, UTUC arising in the setting of Lynch syndrome may respond well to immunotherapy by virtue of its high microsatellite instability and tumor mutational burden, implicating a potential link between genetics and tumor response.6
In an era increasingly defined by precision oncology, the molecular basis of pathogenesis will undoubtedly prove to be paramount in predicting outcomes and stratifying patients to the most appropriate therapies. Furthermore, as our study highlights,4 interethnic differences may be important to consider in preoperative counseling or predictive modeling in patients with UTUC.
Written by: Nirmish Singla, MD, MSCS, Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York; Hsin-Chih Yeh, MD, PhD, Department of Urology, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
1. Singla, Nirmish, Dong Fang, Xiaohong Su, Zhengqing Bao, Zhenpeng Cao, Syed M. Jafri, Gengyan Xiong et al. "A multi-institutional comparison of clinicopathological characteristics and oncologic outcomes of upper tract urothelial carcinoma in China and the United States." The Journal of urology 197, no. 5 (2017): 1208-1213.
2. Singla, Nirmish, Dong Fang, Xiaohong Su, Zhengqing Bao, Zhenpeng Cao, Haley Robyak, Gengyan Xiong et al. "Preoperative predictors of nonorgan-confined disease in upper-tract urothelial carcinoma differ between China and the United States." In Urologic Oncology: Seminars and Original Investigations, vol. 36, no. 3, pp. 88-e11. Elsevier, 2018.
3. Stiborová, M., E. Frei, and H. H. Schmeiser. "Biotransformation enzymes in development of renal injury and urothelial cancer caused by aristolochic acid." Kidney international 73, no. 11 (2008): 1209-1211.
4. Yeh, Hsin-Chih, Ching-Chia Li, Tsu-Ming Chien, Chia-Yang Li, Yen-Chen Cheng, Solomon L. Woldu, Haley Robyak et al. "Interethnic differences in the impact of body mass index on upper tract urothelial carcinoma following radical nephroureterectomy." World Journal of Urology (2020): 1-10.
5. Singla, Nirmish. "Re: Alejandro Sanchez, Helena Furberg, Fengshen Kuo, et al. Transcriptomic Signatures Related to the Obesity Paradox in Patients with Clear Cell Renal Cell Carcinoma: A Cohort Study. Lancet Oncol 2020; 21: 283-93: Unraveling the Obesity Paradox in Immunogenic Malignancies: A Step Toward Precision Oncology?." European urology (2020).
6. Sharma, Padmanee, Arlene Siefker-Radtke, Filippo de Braud, Umberto Basso, Emiliano Calvo, Petri Bono, Michael A. Morse et al. "Nivolumab alone and with ipilimumab in previously treated metastatic urothelial carcinoma: CheckMate 032 nivolumab 1 mg/kg plus ipilimumab 3 mg/kg expansion cohort results." Journal of Clinical Oncology 37, no. 19 (2019): 1608-1616.
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