Inconsistent effects of neoadjuvant chemotherapy?

Introduction: Patients with non-metastatic muscle-invasive bladder cancer (MIBC) who receive cisplatin-based neoadjuvant chemotherapy (NAC) before radical cystectomy (RC) can achieve an absolute survival benefit of 5%-10%
.

Evidence suggests that molecular differences between tumors may influence patient response to therapy, necessitating the need for clinically validated biomarkers to predict patient response to NAC
.

The relevant research results were recently published in THE JOURNAL OF UROLOGY
.

Background studies have confirmed that receiving cisplatin-based NAC before RC surgery can bring an absolute survival benefit of 5%-10% in patients with MIBC
.

Despite Grade 1 clinical evidence and guideline recommendations, the actual application rate of NAC in clinical practice is not high, with only a 20-30% application rate in the United States
.

In practical applications, patient complications, potential chemotherapy toxicity, the risk of disease progression in non-responders, the delay of radical local therapy, and the choice of adjuvant chemotherapy will all affect the application of NAC
.

NAC is recommended for the nonselective treatment of all patients with cT2-T4aN0M0 bladder cancer, although the risk of progression to non-organ-confined disease and the likelihood of benefit from treatment vary widely
.

If the patient has organ-confined (OC) disease or may be unresponsive to NAC, it may be better to avoid NAC and choose RC
.

In addition, patients who received NAC but did not experience a pathological response had a worse prognosis than those who did not
.

There is evidence that molecular differences between tumors may affect treatment outcomes
.

Therefore, clinically validated biomarkers are needed to predict patient response to NAC at the time of diagnosis
.

We conducted a study of more than 800 bladder cancer patients to assess the impact of molecular subtypes on survival in patients who received NAC followed by RC or RC alone
.

Research Methods A total of 4 cohorts of bladder cancer patients were designed
.

Baseline data (age, sex, and clinical tumor stage) were processed using inverse probability weighting (IPW) for NAC-treated and untreated groups to make them more comparable; a genetic subtype classifier (GSC) was used to confirm tumor identities.
Molecular subtypes; survival was assessed using weighted Kaplan-Meier curves; Cox proportional hazards model was used to assess the primary endpoint of the study, overall survival (OS) and secondary endpoints, tumor-specific survival (CSS)
.

RESULTS: Patient cohort demographics and the impact of NAC The study included 828 bladder cancer patients who had undergone RC and a total of 601 eligible patients after screening (Figure 1 and Table 1)
.

There were 247 patients in the NAC group with a median age of 65.
0 years and a median follow-up time of 2.
5 years; 354 ​​patients in the non-NAC group with a median age of 70.
2 years (p<0.
001) and a median follow-up time of 2.
9 years
.

After IPW treatment, the two groups were similar in age, proportion of female patients, and clinical stage
.


Figure 1 Study Design Figure 1 Patient demographics Grouped according to whether or not patients received NAC, the results of the study showed that the 2-year OS and CSS benefits were 6% and 5% in the NAC group compared with the non-NAC group (Figure 2)
.

Figure 2 Analysis of OS and CSS results of patients after IPW treatment.
Patients with Luminal subtype who received NAC had no significant survival benefit.
Patients were divided into luminal subtype group and non-luminal subtype group according to GSC to evaluate whether molecular subtype would affect patients' response to NAC.
's answer
.

Study found that patients with the luminal subtype, with or without NAC, had similar treatment outcomes
.

Patients with the luminal subtype who received NAC had a 2-year OS of 82% and a 3-year OS of 63%
.

Patients with the luminal subtype who did not receive NAC had a 2-year OS of 78% and a 3-year OS of 65% (Figure 3A)
.

In contrast, patients with the non-luminal subtype who received NAC had a 2-year OS of 78% and a 3-year OS of 71%, which was higher than the 69% and 61% of patients with the non-luminal subtype who did not receive NAC (Fig.
3B)
.

Figure 3 OS and CSS results of patients grouped according to molecular subtype and NAC treatment A luminal subtype OS B non-luminal subtype OS C luminal subtype CSS D non-luminal subtype CSS univariate analysis (UVA) results showed that luminal subtype There was no significant improvement in OS in patients receiving NAC (HR 0.
9, 95%Cl 0.
52-1.
55, p=0.
7); OS improved in patients with the non-luminal subtype (HR 0.
62, 95%Cl 0.
42-0.
91, p=0.
02, Table 2)
.

Multivariate analysis (MVA) results were similar, with NAC significantly improving OS in patients with non-luminal subtypes (HR 0.
66, 95%Cl 0.
44-0.
98, p=0.
04), but not in patients with luminal subtypes (HR 0.
91) , 95%Cl 0.
50-1.
63, p=0.
74, Table 2) Table 2 Results of univariate and multivariate analysis of the effect of NAC treatment and molecular subtype on patients' OS The results of CSS were similar to those of OS, for patients with luminal subtype , receiving NAC or not was not associated with improved clinical benefit of CSS; patients with non-luminal subtype receiving NAC improved CSS by 11% at 3 years (77% vs 66% Figure 3C-D)
.

UVA results showed that luminal subtype was not associated with improvement in CSS (HR 1.
10, 95%Cl 0.
6-2.
02, p=0.
76); non-luminal subtype was associated with improvement in CSS (HR 0.
57, 95%Cl 0.
37-0.
88, p= 0.
01, Table 3)
.

MVA results showed that CSS was significantly improved in patients with non-luminal subtype receiving NAC (HR 0.
66, 95%Cl 0.
44-0.
98, p=0.
02), but not in patients with luminal subtype (HR 0.
91, 95%Cl 0.
50-1.
63 , p=0.
76, Table 3)
.

Table 3 Results of univariate and multivariate analysis of the effect of NAC treatment and molecular subtypes on CSS in patients From the results of OS, there was no statistically significant association between luminal classification and receiving NAC (P=0.
3, Figure 4A)
.

Similarly, the association between luminal typing and receiving NAC was inconclusive in the CSS results (p = 0.
1, Figure 4B)
.

Figure 4 2-year predicted rates of OS and CSS for the association between molecular subtypes and NAC (IPW Cox analysis results) Conclusions In this cohort, transcriptome-based analysis showed that patients with the non-luminal subtype received the most benefit from NAC, Patients with the luminal subtype received little or no survival benefit from NAC
.

Selecting MIBC patients suitable for NAC by genotyping can exclude patients who do not benefit from treatment and concentrate potential benefit patients
.

Reference: Yair Lotan, Joep J.
de Jong, Vinnie YT Liu et al.
Patients with Muscle-Invasive Bladder Cancer with Nonluminal Subtype Derive Greatest Benefit from Platinum Based Neoadjuvant Chemotherapy.
THE JOURNAL OF UROLOGY.
Vol.
207, 541-550, March 2022.