Targetable mutations in UTUC: At the Fred Hutchinson Cancer Research Center and the University of Washington, Dr. Brian R. Winters, Dr. Andrew C. Hsieh, and their colleagues reported the results of a rapid autopsy evaluation consisting of whole-exome sequencing of primary and metastatic tumor samples from patients with UTUC or lower tract urothelial carcinoma (LTUC). The UTUC samples showed a wider variety of both deleterious mutations and copy number variations (that is, discrepancies in repetitive regions of DNA). In contrast, the LTUC specimens had a more substantial but also more homogeneous mutational burden.
This study also identified mutations that are potentially targetable with drug therapy. Importantly, approximately 70% of potentially targetable mutations were detected in all metastatic tissue specimens from any given patient with UTUC. Mutations from metastatic UTUC tissues were also present in primary tumors, but at much lower frequencies, suggesting that metastases usually arose from seeding by nondominant clones. These findings, which were published in JCI Insight,1 suggest that therapy for metastatic UTUC should not be selected based on the sequencing of archival (primary) tumor tissue. Material from metastatic sites may possess the genetic changes that are currently driving the disease process and thus could be more effectively targeted.
In another study published this summer, whole-exome and RNA sequencing data from UTUC specimens indicated that UTUCs are primarily luminal-papillary and are characterized by a T-cell deleted immune microenvironment that correlates with high FGFR3 expression. The study by Dr. Brian D. Robinson, Dr. Olivier Elemento, Dr. Bishoy M. Faltas, and their colleagues at Weill Cornell Medicine and New York-Presbyterian provides a biological rationale for combining FGFR3 inhibitor therapy with immunotherapy to provide a dual boost to the antitumor immune response.2
To evaluate this approach, a multicenter phase 1/2 study (NCT03473743) is recruiting patients to evaluate the safety and anti-tumor activity of the FGFR inhibitor erdafitinib alone or in combination with cetrelimab, an investigational anti-PD-1 monoclonal antibody, in patients with metastatic or locally advanced urothelial cancer with selected FGFR3 alterations. This study continues the evaluation of erdafitinib, which was approved by the FDA in the spring of 2019.
Variant histology UTUC
Urothelial carcinoma with variant histology is associated with a poor prognosis. At Vanderbilt University Medical Center, investigators this year reported that patients with variant histology UTUC had a median survival time of 30 months, compared with 68 months for patients with non-variant histology UTUC, and that this difference persisted even after controlling for disease stage. Adjuvant chemotherapy appeared to improve survival in both histologic subgroups. Other experts this year performed a comprehensive systematic review and meta-analysis of 26 studies of survival outcomes in UTUC with or without variant histology. Variant histology in UTUC was associated with a significantly increased risk of disease recurrence, cancer-specific death, and overall mortality, with respective estimated hazard ratios of 1.64, 2.0, and 1.76. These findings are available online in the Journal of Urology.3 As in the case with variant histology bladder (LTUC) lesions, the optimal therapy for these tumor types remains unknown.
Neoadjuvant chemotherapy
Urine molecular profiling is of interest for identifying optimal strategies for neoadjuvant therapy in UTUC, which is crucial because many patients are ineligible for adjuvant treatment following radical nephroureterectomy. Ideally, urine-based UTUC biomarkers could also help monitor tumor response to UTUC therapy. Currently, a multi-institutional collaboration led by Drs. Eugene J. Pietzak, Bernard H. Bochner, and Jonathan C. Coleman of Memorial Sloan Kettering Cancer Center (MSKCC) are studying the potential of a urine-based assay. Their early findings have not been published but were discussed in a breakout session at BCAN 2019 led by Dr. Coleman and Dr. Surena F. Matin of MD Anderson Cancer Center. We look forward to hearing more results from this group soon.
At this year’s AUA meeting, Dr. Nathan C. Wong of MSKCC and his associates presented preliminary data on neoadjuvant chemotherapy for high-grade nonmetastatic UTUC. In a multicenter phase 2 trial, more than 50 patients with high-grade UTUC received neoadjuvant therapy with gemcitabine and cisplatin, the primary endpoint of pathologic response (>pT1N0) was 60% (95% CI, 47% to 75%). The regimen also was well tolerated, resulting in minimal delays to surgery and no significant increase in the risk of perioperative complications (all patients underwent either radical nephroureterectomy or distal ureterectomy plus ipsilateral retroperitoneal lymph node dissection). Two-year progression-free survival was 75%, and overall survival was 89%--promising findings in this high-risk group. During his talk, Dr. Wong asserted that neoadjuvant chemotherapy and definitive surgery with lymph node dissection should be considered a standard treatment option for high-grade UTUC. Although treating physicians have favored neoadjuvant therapy, these data support the efficacy of this approach. Longer follow-up results will be forthcoming and should help further validate this treatment paradigm.
Finally, investigators are evaluating novel approaches to neoadjuvant therapy. Padeliporfin (WST11) is a relatively recent addition to the family of photosensitizing drugs and has shown promise in the treatment of low-risk prostate cancer. Currently, a phase 1 trial (NCT03617003) at Memorial Sloan Kettering Cancer Center (MSKCC) is evaluating the safety and optimal fluence rate of laser light treatment of UTUC carcinoma in combination with intravenous padeliporfin. Study participants have urothelial carcinoma of the ureter and/or renal pelvis, residual or recurrent disease following prior endoscopic treatment, and are resection-ineligible or refusing.
Adjuvant chemotherapy
As I have mentioned, neoadjuvant therapy shows promise and is of possible preference in the management of UTUC, and many patients also are ineligible for adjuvant platinum-based chemotherapy. However, we do have good evidence supporting adjuvant therapy for selected fit patients. At ESOU 2019, Dr. Robert Jones of the University of Glasgow and his associates reported the final results of the multicenter phase 3 POUT trial, in which adjuvant gemcitabine plus cisplatin-based chemotherapy significantly improved disease-free survival (DFS) compared with standard-of-care surveillance following radical nephroureterectomy for locally advanced or node-positive UTUC. Over a median follow-up of 17.6 months, the hazard ratio for the primary DFS endpoint was 0.49 (95% CI, 0.31-0.76; P=0.001). The effect also remained highly significant after controlling for nodal involvement, microscopic margin status, and type of planned chemotherapy.
The POUT trial (NCT01993979), which enrolled approximately 260 patients at 57 centers in the United Kingdom, was stopped early in November 2017, after an independent review committee determined that the primary DFS endpoint had been met. Treatment compliance was fairly high in this trial (72% of patients received all four cycles of adjuvant chemotherapy). Grade 3 toxicities occurred in 62% of patients who received adjuvant chemotherapy versus 24.8% of those in the surveillance arm. As expected, the most common grade 3 toxicities were hematologic in nature. Chemotherapy also was associated with grade 3 nausea and vomiting, which in turn was associated with decreased patient-reported quality of life, but by 12 months, quality of life was once again comparable between arms.
Overall survival data from the POUT trial remain immature, although the curves have begun to separate. Based on these results, researchers are planning the POUT 2 trial to compare chemotherapy alone or with immunotherapy for the adjuvant treatment of UTUC.
Takeaways
It is remarkable to contrast the scarcity of UTUC studies from just a few years ago with the explosion of research we have seen over the past 12 to 18 months. A growing interest in urothelial cancer of the bladder has sparked great interest and inquiry into possible interventions for upper tract disease, but research so far has only scratched the surface. Additionally, although UTUC and bladder cancer are related, they can differ considerably, which affects current and future management. Given the smaller population of patients affected by UTUC, clinicians are actively recruiting patients for important clinical trials to investigate the many remaining therapeutic and diagnostic questions that are raised every day in the clinic.
Written by: Sam S. Chang, MD, FACS, Professor of Urologic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, United States
Published Date: October 8th, 2019
References:
1. Winters B., Sarkar N. et al. Genomic distinctions between metastatic lower and upper tract urothelial carcinoma revealed through rapid autopsy. JCI Insight. 2019;4(13):e128728. https://doi.org/10.1172/jci.insight.128728.
2. Faltas B., Elemento O. et al. Upper tract urothelial carcinoma has a luminal-papillary T-cell depleted contexture and activated FGFR3 signaling. Nature Communications. 2019 Jul 5;10(1):2977.
3. Mori K, Janisch F, Parizi MK, Mostafaei H, Lysenko I, Kimura S, Enikeev DV, Egawa S, Shariat SF. Prognostic Value of Variant Histology in Upper Tract Urothelial Carcinoma Treated with Nephroureterectomy: A Systematic Review and Meta-Analysis. Journal of Urology. 2019 Sep 3:101097JU0000000000000523. doi: 10.1097/JU.0000000000000523.
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