(UroToday.com) The 2023 SUO annual meeting included a session on urothelial cancer, featuring a presentation by Dr. Helen Hougen discussing risk-stratification, biomarkers, and surgical management of upper tract urothelial carcinoma (UTUC). Dr. Hougen started her presentation by asking: Why do we need biomarkers for risk stratification in upper tract UC? Currently, ureteroscopic biopsies have two main disadvantages:
- Understaging and undergrading - Ureteroscopic biopsies understage up to 46% of tumors, and undergrade up to 32% of tumors
- The process of obtaining these biopsies places a high burden on our patients, from the procedural burden with the need for general anesthesia, cost, and time, to the risk of lower urinary tract seeding and procedural complications such as strictures and ureteral perforation
Due to these diagnostic limitations, Dr. Hougen emphasized that we are not accurately selecting patients for effective therapies, such as neoadjuvant chemotherapy, which has good clinical activity in high risk disease. A recent prospective study from Coleman et al. assessed neoadjuvant chemotherapy in 57 patients, with a 63% pathologic response, as well as improved progression free and overall survival:
With more accurate staging we may also avoid over treating a patient with a nephroureterectomy instead of providing appropriate nephron-sparing therapies and avoiding the medical and financial burden of chronic kidney disease:
As such, we need biomarkers that are diagnostic (minimizes procedural burden), predictive (predicts benefit from therapies, ie. neoadjuvant chemotherapy), and prognostic (accurate risk stratification). Dr. Hougen then discussed several of the currently available biomarkers for UTUC. The oldest and most commonly used biomarker is urine cytology, and based on the Paris system we have 4 classifications to inform us of risk:
However, even in a surgical cohort of patients who underwent extirpative surgery, the sensitivity of selective ureteral washings for high grade or muscle invasive disease is only ~70% and PPV is only 40%-50%.
Second, multi florescence in site hybridization (FISH) detects aneuploidy in chromosomes 3, 7, 17, and 9p21 loss. FISH has reasonable sensitivity and specificity, particularly if tumors have high risk features. In one cohort of 30 patients with voided samples, the sensitivity of invasive disease was 100%. Furthermore, using ureteral washings also improves the diagnostic ability. However, Dr. Hougen cautions that FISH is not very good at distinguishing between high vs low grade disease:
Third, Bladder EpiCheck test is a methylation test of 15 genes currently approved in the US for detecting NMIBC recurrence. Interestingly, in a surgical cohort of 82 patients prior to nephroureterectomy, with final pathology mostly HG T1 disease, the sensitivity of this test was 97%. There are also potential tissue biomarkers, such as a panel of cell cycle regulators (p53, p21, p27, cyclin E) and proliferative markers (Ki-67), with genomic alterations potentially predicting cancer specific survival.
Arguably, the most exciting potential biomarker is cell free DNA, which is derived either from the plasma or urine. The main advantage is that cfDNA is easily available and with a short half life it offers “real time” insight into the tumor biology. Studies in bladder urothelial carcinoma have demonstrated that these tumor-derived DNA have good concordance with tumor DNA, and the alteration and levels offer promising reflections of disease burden and prognosis. Furthermore, urinary tumor DNA, assessing a urinary DNA panel of 17 genes for methylation status, in patients with UTUC prior to surgery has also shown good concordance between urine and final tissue genetic variants. In a study from China, Ouyang and colleagues2 developed models based on variables including methylation level, gene mutation level, age, and TERT promoter status. The final model, combining methylation status, age, TERT promotor status had a sensitivity of 94% and AUC of 0.957 for the diagnosis of UTUC:
However, similar to in bladder cancer, certain gene signatures were present for high grade and muscle invasive disease, such as TP53, where there was a significantly higher mutation count in the muscle invasive group compared with the non-muscle invasive group:
A recent study from the Moffitt Cancer Center used circulating tumor DNA to predict invasion.3 This study prospectively enrolled 30 patients, of whom 14 had invasive disease, prior to nephroureterectomy or ureterectomy without neoadjuvant chemotherapy. Using a 152 gene panel to sequence plasma cell free DNA, they found a significantly higher number of genomic alterations with a median of 3 in the invasive group versus 0 in the non-invasive group. Using a cutpoint of 2, variants had a sensitivity of 71% and specificity of 94% with an AUC of 0.92 for predicting invasion. If in addition a copy number burden score threshold of 6.5 is used, the sensitivity of the predictive model increases to 79%:
As expected, patients with ctDNA positivity preoperatively had worse survival outcomes than those without ctDNA:
Dr. Hougen concluded her presentation by discussing risk-stratification, biomarkers, and surgical management of UTUC with the following take-home points:
- Looking ahead, there may be a future where we have a patient with UTUC and can use a combination of imaging and liquid biopsies to accurately diagnose a patient’s grade and stage
- If indicated, the patient can get neoadjuvant systemic therapy and we can repeat a liquid biopsy to risk stratify the patient for a nephron-sparing ablative treatment or radical nephroureterectomy
- Subsequently, we may be able to use biomarkers to survey these patients, ultimately decreasing invasiveness and increasing the accuracy of our diagnostic tools by incorporating biomarkers for patients with UTUC
Presented by: Helen Y. Hougen, MD, University of Iowa Hospitals and Clinics, Iowa City, IA
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2023 Society of Urologic Oncology (SUO) Annual Meeting, Washington, D.C., Tues, Nov 28 – Fri, Dec 1, 2023.
References:
- Coleman JA, Yip W, Wong NC, et al. Multicenter phase II clinical trial of gemcitabine and cisplatin as neoadjuvant chemotherapy for patients with high-grade upper tract urothelial carcinoma. J Clin Oncol. 2023 Mar 10;41(8):1618-1625.
- Ouyang W, Luo L, Zhang J, et al. Urine cellular DNA point mutation and methylation for identifying upper tract urinary carcinoma. Cancers. 2022;14:3537.
- Huelster HL, Gould B, Schiftan EA, et al. Novel use of circulating tumor DNA to identify muscle-invasive and non-organ confined upper tract urothelial carcinoma. Eur Urol. 2023 Oct 4:S0302-2838(23)03144-03145.