2021 ASCO GU | Professor Sheng Xinan's interpretation: Research progress of upper urinary tract urothelial cancer

Urothelial carcinoma of the upper urinary tract (UTUC) accounts for about 5%-10% of urothelial carcinoma (UC), but 60% of UTUC is aggressive when first diagnosed.
In contrast, the bladder originates from the lower urinary tract.
Urothelial carcinoma (UBC) has only 15-25% of invasive disease at first diagnosis 1; therefore, UTUC brings greater clinical harm than lower urinary tract urothelial carcinoma (LTUC).

Moreover, epidemiology shows that the incidence of UTUC in Asian populations represented by China is significantly higher than that in Western populations2.
In recent years, clinical studies of advanced urothelial cancer in China have found that nearly half of the cases derived from UTUC.

Therefore, more attention is paid to the diagnosis and treatment of UTUC in China.

The following will progress UTUC study from the General Assembly this year's ASCO-GU make combing and presented to the reader: Author: Li Siming Sheng Xinan Hospital of Peking University, a tumor, UTUC peri-operative progress 1.
Where does postoperative adjuvant treatment go from POUT research updated data is the only UTUC research that entered and discussed the Poster Highlight session of this year's ASCO-GU conference.

The POUT study, first reported in 2018, opened a new chapter in adjuvant chemotherapy after UTUC.

At that time, the study randomly assigned 261 postoperative UTUC patients with pT2-4N0-3M0 staging from 56 centers to the adjuvant chemotherapy group and the observation group.

Adjuvant chemotherapy regimens include: GP regimen (requires eGFR>50ml/min) or GC regimen (eGFR: 30-49ml/min) postoperative adjuvant chemotherapy for 4 cycles.

The results showed that compared with the observation group, the adjuvant chemotherapy group significantly improved disease-free survival (DFS) and metastasis-free survival (MFS) time.
At that time, the overall survival (OS) data was not mature, but the HR was 0.
55, which is conducive to adjuvant Chemotherapy group.The POUT study was the only phase III clinical study of UTUC at that time.
The evidence level of evidence-based medicine was strong.
The results of the study basically confirmed the status of adjuvant chemotherapy after UTUC.

The design of the study, but then the doubts about the POUT study began to appear, including: 1.
It is believed that the change in renal function after radical renal ureterectomy (RNU) may affect the choice of postoperative chemotherapy, so that neoadjuvant chemotherapy (The renal function reserve at this time is good) Push to the forefront of UTUC treatment; 2.
The subgroups of the POUT study have inconsistent benefits (N+ or resection margin + patients have no clear benefit); 3.
The previous study (EORTC 30994) 3 shows surgery Post-adjuvant chemotherapy did not significantly improve OS compared with delayed (until relapse) chemotherapy.

Accompanied by doubts, this year’s ASCO-GU reported updated data from the POUT study after a median follow-up of 49.
2 months, in which the HR value of the two DFS comparisons was 0.
51 (95%CI: 0.
35-0.
76; p = 0.
0006), MFS The compared HR value was 0.
52 (95%CI: 0.
36-0.
77; p = 0.
0007).

The 3-year OS rate of the adjuvant chemotherapy group and the observation group were 79% (95%CI: 71%-86%) and 67% (95%CI: 58%-75%), while the 5-year OS rate was 65%, respectively (95%CI: 54%-74%) and 57% (95%CI: 46%-66%).

The risk of death in the adjuvant chemotherapy group was 30% lower than that in the observation group, but there was no statistical difference (HR = 0.
70, 95% CI: 0.
46-1.
06; p = 0.
09).

Efficacy data This updated data maintains the results reported in 2018 for UTUC patients to obtain DFS and MFS benefits from postoperative adjuvant chemotherapy, but ultimately did not obtain statistical OS benefits.

Regarding the problem that adjuvant chemotherapy did not achieve significant OS benefits, the author explained in the conference report: The sample size of the study was originally 345 cases, but the main study endpoint was DFS, and DFS had reached 261 patients when enrolled Statistical difference, which was stopped early by the independent data monitoring committee.

Therefore, the author believes that such a sample size of 261 cases can achieve a DFS difference, but it is not enough to achieve a statistical difference in OS; compared with the adjuvant chemotherapy group, there is a higher proportion of patients in the observation group (65.
1% vs.
45.
0%).
Received systemic treatment when the disease relapsed, and in the current background of new immunotherapy, a high proportion of systemic treatment may mean better survival, which has a great impact on the OS results of the POUT study.

The author's explanation seems reasonable, but it still does not give a reasonable answer to the previous questions about "the subgroups have inconsistent benefits, postoperative renal function affects chemotherapy options, and whether neoadjuvant chemotherapy is more suitable".

Therefore, whether the adjuvant treatment of UTUC should be selected with reference to the results of the POUT study may be a matter of opinion.

2.
Advantages and disadvantages of preoperative diagnostic examination.
The visibility of ureteroscopy (URS) provides the feasibility for exploring the complete upper urinary tract and reduces the rate of misdiagnosis.
The information provided by the URS examination can also assist in the risk stratification of UTUC However, the potential tumor dissemination that URS operation brings to UTUC patients and the risk of recurrence in the bladder are also concerned by everyone4.

Meta-analysis shows that receiving diagnostic URS before RNU is associated with recurrence in the bladder after surgery.

At ASCO-GU this year, a study from the MD Anderson Cancer Center in the United States further evaluated the impact of preoperative diagnosis on the risk of recurrence in the bladder after UTUC.

A total of 878 patients who received RNU from a single center from 1995 to 2019 were included in the study, and they were divided into four groups.
The main research endpoint was to compare the intravesical recurrence rate of the four groups after RNU.
The details are as follows: Univariate analysis shows age, female, and history of bladder cancer Factors such as current smoking status and multifocal lesions of the primary lesion are related to recurrence in the bladder.

Multivariate analysis further clarified: Compared with the non-biopsy group, the risk of intravesical recurrence in the URS and microscopic biopsy group was increased (HR=1.
41, p=0.
03). Compared with the URS but no microscopic biopsy group (HR=1.
18, p=0.
45) and the percutaneous biopsy group (HR=1.
11, p=0.
79), there was no significant difference in the risk of intravesical recurrence in the URS and microscopic biopsy group .

On the surface, the results of the study, whether biopsy or not, as long as URS (group 1 and group 2) is done, it seems that the recurrence rate in the bladder is higher; but from the results of multivariate analysis, unless preoperative biopsy is not done, then The risk of bladder recurrence after surgery is reduced; as long as a preoperative biopsy is done, whether it is percutaneous biopsy or URS biopsy, the risk of bladder recurrence after surgery is similar.

From this point of view, although the results of the study showed the risk of bladder recurrence caused by URS plus biopsy, but at the same time because of the important microscopic tumor information provided by URS, the author actually rejected other biopsy methods such as percutaneous biopsy.

It seems that for a long period of time in the future, the controversy over preoperative diagnostic procedures will continue.

2.
Progress in immunotherapy of advanced UTUC.
Although it is now believed that upper urinary tract and lower urinary tract urothelial carcinoma have many differences in origin, biological behavior, characteristics of recurrence and metastasis, chemotherapy sensitivity, molecular changes, etc.
, they are even considered to be Two different diseases.

However, there is no obvious difference in treatment between the two.

The treatment of UTUC is mainly based on the model of LTUC, and traditional chemotherapy is still the main choice in clinical practice.

In recent years, the application of immune checkpoint inhibitors (ICI) in UC has gradually deepened.

However, the majority of patients included in large-scale clinical studies involving ICI are basically LTUC.
Whether UTUC is equally effective for ICI treatment is currently uncertain.

This year's research progress on UTUC immunotherapy is mainly reflected in the following two aspects: 1.
The basic research of UTUC with the aid of molecular detection methods has continued to deepen.
Past molecular lineage studies using gross specimens of tumor tissue have shown that UTUC is mainly classified as lunimal subtype and T cell depletion subtype, and FGFR3 mutations are considered to be related to UTUC T cells.
The depletion phenotype has a great relationship5. This also suggests that UTUC may not be sensitive to immunotherapy, while target inhibitors represented by FGFR may have certain therapeutic advantages.

According to the ASCO-GU report this year, researchers from MSKCC in the United States used single-cell RNA sequencing (scRNA-seq) technology, which is different from the detection of gross tumor specimens, to analyze the tumor immune microenvironment (TME) of UTUC.

They found that just like the results of previous studies, all the UTUC samples they tested also expressed the luminal gene phenotype.
Among them, the high-grade UTUC samples had higher expression of squamous markers, but they were also in the high-grade UTUC.
Significant macrophage infiltration was seen in the TME of UTUC, indicating that the tumor immune microenvironment of UTUC has significant heterogeneity.
This heterogeneity suggests that high-grade UTUC may still benefit from immunotherapy.

Coincidentally, in this year’s ASCO-GU report, other researchers used next-generation sequencing (NGS) and whole exome sequencing (WES) to analyze UTUC samples, and used immunohistochemistry (IHC), fragment analysis and NGS technology to detect Mismatch repair status (dMMR or pMMR) and microsatellite instability (MSI-H or MSS).

PD-L1 expression was detected by IHC method for the 22c3 PD-L1 antibody (CPS cutoff value ≥ 10) and SP142 PD-L1 antibody (IC cutoff value ≥ 5%).

TMB takes 10muts/MB as the cutoff value, and ≥10 is defined as TMB-high.

The study analyzed a total of 538 UTUC samples, of which dMMR/MSI-H accounted for 3.
9% and TMB-high accounted for 22.
7%.

The positive expression rates of PD-L1 shown by 22c3 and SP142 antibody detection were 33.
2% and 28.
4%, respectively. Compared with MSS tumors, the proportion of TMB-high in dMMR/MSI-H tumors is significantly higher (100% vs.
19%; p = 0.
0003), and chromatin remodeling is related to dMMR/MSI-H tumors Genes (ASXL 82.
4%, CREBBP 60%, SMARCA4 40%, KMT2D 95%, ARIDIA 100%, KMT2A 20%, KMT2C 35.
3%, NSD1 20%), DNA damage repair genes (FANCG 10%, ATM 45%, ATRX 40 %) and other biosignaling pathway genes (RNF43 10%, PTCH1 21.
4%, ERBB3 30%, CDKN2A 25%, TSC2 15%, FLNC 15%, HNF1A 20%, CIC 15%, DNMT3A 17.
6%) mutation ratio is also obvious Higher (p value <0.
05), but there is no difference in the positive expression rate of PD-L1 in dMMR/MSI-H and MSS tumors.

The study also detected pathological gene fusion mutations in 3.
8% of UTUC samples, of which FGFR3 fusion mutations were the most common (2.
7%).

In addition, the study did not find significant molecular differences between primary and metastatic lesions, and between men and women.

This study should be the largest molecular detection study for UTUC so far.
From the results, the TMB-high ratio of UTUC is relatively high, which is basically in line with the previous UC-related literature results.

The main focus of the study is MSI-H, which accounts for only 3.
9%.
It does not seem to provide any help for UTUC based on molecular expression.
However, it can still be seen that all MSI-H UTUC have high levels of TMB.
Pembrolizumab's pan-tumor indications for MSI-H and the above-mentioned scRNA-seq research results from MSKCC provide a theoretical basis for UTUC to receive immunotherapy represented by PD-1 monoclonal antibody. In addition, FGFR3 fusion mutation, MSI-H UTUC contains these high mutation ratios of chromatin remodeling genes and DNA damage repair genes, etc.
, which may provide potential therapeutic targets for future targeted drug therapy.

2.
The background of molecular-based immunotherapy for advanced UTUC is still in the ascendant.
The background of basic research will ultimately be verified in clinical practice.

Coincidentally, another team on ASCO-GU this year published a small-sample clinical retrospective study that specifically analyzed the results of ICI treatment for dMMR/MSI UTUC patients.

The study included only 10 patients with unresectable locally advanced and metastatic UTUC.
All patients were detected as dMMR by IHC (7 cases) or PCR-detected as MSI status (3 cases), and received ICI treatment (including Par Bolizumab, nivolizumab, and atelizumab), half of the patients have received systemic chemotherapy in the past.

At a median follow-up of 15.
5 months (2 months-43 months), all patients were alive and maintained a non-progressive state.

The overall response rate (ORR) was 90% (95% CI: 55.
5%-99.
8%), including 8 cases of complete response (CR).

Although the study has a small number of cases and is a retrospective study, the excellent clinical remission rate and survival data are still impressive.

For the special patient population of dMMR/MSI, it is necessary to expand the sample size of immunotherapy clinical research.

Excluding the patient population with special molecular expressions, this year there is also a large-sample retrospective study to analyze the ICI efficacy of UTUC and LTUC from the overall level.

The study included data on 746 patients with advanced UC who received ICI treatment from 24 centers in the United States and Europe from 2013 to 2020, including 130 (17.
4%) UTUC patients and 616 (82.
6%) LTUC patients. The median ages of the two groups of patients were 71 years (40-92 years) and 70 years (31-93 years), the proportion of males was 62% and 76%, the proportion of non-smokers were 41% and 29%, previous The percentages of radical resection of primary tumors were 62% and 52%, and the percentages of liver metastases were 29% and 18%.

The study compared the outcomes of UTUC and LTUC after ICI treatment, including ORR, median progression-free survival (PFS) and median OS, as shown in the figure below: From the results, UTUC and LTUC are in overall ORR (24% vs.
28%), median PFS (4.
3 months vs.
4.
1 months) and median OS (9.
8 months vs.
9.
6 months) are almost the same.

However, in the subgroup of UC mixed with other histological components, the ORR of UTUC (11% vs.
29%; OR = 0.
20 [0.
05-0.
91]) and median PFS (2.
2 months vs.
4.
3 months; HR = 1.
66 [1.
06-1.
13]) is significantly lower than LTUC, but there is no significant difference from LTUC in median OS (10.
6 months vs.
7.
6 months; HR = 1.
36 [0.
85-2.
17]).

Whether ICI is used as a first-line treatment or as a follow-up treatment, there is no significant difference in the efficacy of UTUC and LTUC.

The study shows that immunotherapy for UTUC patients is equally effective, but at the same time, we should also see the problems in the study.

For example, a retrospective study of 250 cases of UTUC in our center in China showed that 6: The baseline PS status, LDH level, number of metastatic organs, previous first-line chemotherapy efficacy and number of cycles (all independent prognostic factors) of patients with advanced UTUC will all affect OS time.

However, this year's ASCO-GU study provided incomplete information on patient baseline characteristics including renal function status, PS status, number of metastatic organs, and second-line treatment patients' previous first-line chemotherapy efficacy and chemotherapy cycles.
The interpretation of the research results Had an impact, so its clinical guidance is doubtful.

However, the results of the study still provide some basis for the clinical use of ICI therapy in UTUC patients.

For UTUC mixed with other histological components, the effect of ICI treatment is not satisfactory.
It may still be necessary to select appropriate chemotherapeutic drugs or try a combination of immunochemotherapy according to the specific histological differentiation type.

3.
Summary and Prospects From the above research content, we can see that after many years of research focus focused on the analysis of the clinical characteristics differences between UTUC and LTUC, recent foreign studies have begun to extend their antennae to the field of UTUC immunotherapy, the next step It is possible to analyze the possibility of immune combination therapy and precision treatment through related molecular studies, including the prediction of curative effect and the screening of potential benefit populations of immunotherapy.

Compared with the low incidence of UTUC in Western countries, as Asian countries with a higher incidence of UTUC, our research in the basic and clinical fields of UTUC seems to have a long way to go.

References: 1.
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pdf.
Accessed Feburary 2021.
2.
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Urol Oncol 39:75 e1- 75 e8, 2021and chemosensitivity in patients with metastatic upper tract urothelial carcinoma.
Urol Oncol 39:75 e1-75 e8, 2021and chemosensitivity in patients with metastatic upper tract urothelial carcinoma.
Urol Oncol 39:75 e1-75 e8, 2021