Predictors of Complete Pathologic Response (pT0) to Neoadjuvant Chemotherapy in Muscle-invasive Bladder Carcinoma

Original Study

Predictors of Complete Pathologic Response (pT0) to Neoadjuvant Chemotherapy in Muscle-invasive Bladder Carcinoma Venkata K. Pokuri,1 Johar R. Syed,2 Zhengyu Yang,3 Erinn P. Field,2 Susanna Cyriac,4 Roberto Pili,5 Ellis Glenn Levine,1 Gissou Azabdaftari,6 Donald L. Trump,7 Khurshid Guru,2 Saby George1 Abstract No predictors of a complete pathologic response (pT0) to neoadjuvant chemotherapy (NAC) in muscle-invasive bladder carcinoma have been established. We performed a retrospective analysis of 50 patients to identify potential predictors. Our results showed that the presence of additional transitional cell variants on pathologic examination (mixed tumors) predicted against pT0, suggesting the avoidance of NAC and its morbidity in these patients with mixed tumors. Background: Randomized trials have supported the use of cisplatin-based neoadjuvant chemotherapy (NAC) in muscleinvasive bladder carcinoma (MIBC) owing to the survival advantage, which has correlated with downstaging of the cancer to pT0. Only 30% to 40% of patients receiving NAC have attained a pT0 response at cystectomy; the remaining have either residual disease or progression. We aimed to identify the factors that could predict a pT0 response to NAC. Patients and Methods: Of 336 patients who had undergone robotic cystectomy at our institute from May 2007 to March 2014, we identified 50 patients who had undergone NAC for MIBC. We conducted a retrospective study, dividing these 50 patients into 2 groups, those with and without a pT0. Factors, including age, histologic features, hydronephrosis at initial presentation, and chemotherapy type, were examined by both univariate and multivariate logistic regression analysis. Results: Of the 50 patients, 14 (28%) had pT0 at cystectomy, 20 (40%) had progressive disease, and 16 (32%) had residual disease. The median age was 67.5 years, the median glomerular filtration rate at presentation was 87.5 mL/min, the patients had undergone a median of 3 NAC cycles, and the median time from the end of chemotherapy to surgery was 4 weeks. The odds of a pT0 response for pure urothelial carcinoma (UC) were approximately 11 times greater relative to cancers with transitional cell variant histologic features or mixed tumors (odds ratio 0.09, 95% confidence interval 0.021-0.380; P ¼ .0011), including squamous, glandular differentiation, small cell, micropapillary, sarcomatoid, nested component, lymphoepithelioma-like, and plasmacytoid variants. Conclusion: The presence of pure UC favored a pT0 response to NAC compared with those with variant histologic features or mixed tumors. These potential predictors warrant prospective validation to allow the ideal selection of patients for NAC. Clinical Genitourinary Cancer, Vol. -, No. -, --- ª 2015 Elsevier Inc. All rights reserved. Keywords: Complete pathological response, Mixed tumors, Muscle-invasive, Neo-adjuvant chemotherapy, Predictors, Urothelial carcinoma, Variant histology

Introduction Bladder cancer (BC) is the fourth most common cancer in men, accounting for 4% of all cancer-related deaths in the United States.1 1

Department of Medical Oncology, Roswell Park Cancer Institute, Buffalo, NY Department of Urologic Oncology, Roswell Park Cancer Institute, Buffalo, NY 3 Department of Biostatistics and Bioinformatics, Roswell Park Cancer Institute, Buffalo, NY 4 Department of Pathology, Case Western Reserve University, Cleveland, OH 5 Department of Medical Oncology, Indiana University Simon Cancer Center, Indianapolis, IN 6 Department of Pathology, Roswell Park Cancer Institute, Buffalo, NY 2

1558-7673/$ - see frontmatter ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clgc.2015.09.013

It has been estimated that 74,000 new patients (56,320 men and 17,680 women) will be diagnosed with BC in the United States in 2015, with 16,000 expected deaths.1 Most deaths occur among 7 Department of Medical Oncology, Inova Comprehensive Cancer Research Institute, Falls Church, VA

Submitted: Aug 5, 2015; Revised: Sep 17, 2015; Accepted: Sep 25, 2015 Address for correspondence: Venkata K. Pokuri, MD, Department of Medical Oncology, Roswell Park Cancer Institute, Buffalo, NY E-mail contact: [email protected]

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pT0 Predictors in Muscle-Invasive Bladder Carcinoma those with muscle-invasive BC (MIBC), and approximately 35% of patients will present with MIBC.2,3 Radical cystectomy (RC) with pelvic lymph node dissection is the reference standard treatment of clinically localized MIBC (stage  T2).4 However, many patients develop a relapse after surgery. The recurrence rates have been reported to be 30% to 50%, and the recurrences are most likely related to micrometastases present at surgery.5 Disease recurrence after surgery is rarely curable.6 In randomized trials, the use of neoadjuvant chemotherapy (NAC) has been shown to downstage the primary tumor, likely eradicating micrometastases before surgery, and improve survival.7-12 A metaanalysis of these trials showed a 5% improvement in the average 5year survival with the addition of platinum-based NAC to local definitive treatment.13 The survival benefit of NAC was shown to be strongly associated with downstaging of the tumor to pT0 (complete pathologic response), and the probability of pT0 with platinum-based NAC at cystectomy was 38%.7,14,15 To date, no definitive clinicopathologic variables have been reported to predict pT0 response to NAC. The present study aimed at determining the factors that could predict a pT0 response to NAC that could improve the selection of patients best treated with chemotherapy before cystectomy.

Patients and Methods The prospectively maintained, institutional review boardeapproved, robot-assisted radical cystectomy (RARC) database was queried for our retrospective analysis. The database included 336 patients who had undergone RARC at our comprehensive cancer care center from May 2007 to March 2014. Of these 336 patients, 50 had undergone NAC before surgery (Figure 1).

Figure 1 Retrospective Study Design

2

-

Abbreviation: NAC ¼ neoadjuvant chemotherapy.

Clinical Genitourinary Cancer Month 2015

Using the final histopathologic findings at cystectomy, the patients receiving NAC were divided into 2 groups: those with a pT0 (complete response) and those without a pT0 (residual or progressive disease). Both groups were compared in terms of the basic characteristics (eg, age, gender, smoking status, initial renal function), clinical stage as determined by cystoscopy with transurethral resection of bladder tumor (TURBT) and imaging (computed tomography), tumor histopathologic findings, chemotherapy (type and number of cycles received), and the duration from the end of chemotherapy to cystectomy. A complete pathologic response (pT0) was defined as no residual tumor in the cystectomy specimen. Patients with residual carcinoma in situ alone at cystectomy were included in the pT0 group. The non-pT0 group had disease at cystectomy (after NAC). The residual disease subgroup of the non-pT0 group was defined as those with the same or lower T stage after NAC, and the progressive disease subgroup of the non-pT0 group was defined as those with a higher T stage after NAC. The histopathologic review of the TURBT specimen and cystectomy specimen was initially completed by the pathologists at our institute. These pathologic reports were reviewed again at the present analysis. The tumor grade and pathologic stage were determined using the 2002 American Joint Committee on Cancer TNM staging system and the 2004 World Health Organization/International Society of Urologic Pathologists classification of papillary urothelial neoplasms.16

Statistical Analysis The data are presented as the median for continuous variables and the percentage in each group for the categorical variables. A

Venkata K. Pokuri et al comparative analysis of the NAC patients with and without pT0 was performed using Fisher’s exact tests for categorical data and Wilcoxon rank sum tests for continuous data. The odds ratios of the factors were assessed by univariate and multivariate logistic regression analysis (with 95% confidence intervals [CIs]), modeling the probability of residual or progressive disease as a function of the covariates listed. Statistical significance in the present study was set at an a-level of 0.05, and the reported P values were 2-sided. All analyses were performed in Statistical Analysis Systems, version 9.3 (SAS Institute, Cary, NC).

Results The data from 50 patients (14.8% of all RARC patients) with stage cT2N0M0 to cT4N0M0 MIBC who had undergone NAC were analyzed. Of the 50 patients, 14 demonstrated a complete response (pT0) and 36 did not (16 with residual and 20 with progressive disease). The characteristics between the pT0 and non-pT0 groups are listed in Table 1. Of the 50 patients, 41 were men and 9 were women, with a median age of 67.5 years (range, 47-84 years). The Eastern Cooperative Oncology Group performance status of all patients was  1. Of the 50 patients, 31 (62%) had cT2N0 disease, 11 (22%) had cT3N0, and 8 (16%) had cT4N0 disease. Approximately 86% of the cohort were smokers (either current or former), and one third of the patients had hydronephrosis (either unilateral or bilateral) at the initial presentation. The median glomerular filtration rate (GFR) was 87.5 mL/min (range, 33-170 mL/min). The smoking status and median GFR were comparable between the pT0 and non-pT0 groups. The TURBT and cystectomy histologic types were classified into 2 groups: pure urothelial carcinoma (PUC) and mixed tumors (urothelial plus variant histologic features). PUC and mixed tumors received either cisplatin-based chemotherapy (either GC [gemcitabine/cisplatin] or MVAC [methotrexate/vinblastine/doxorubicin/ cisplatin]) or nonecisplatin-based chemotherapy (gemcitabine/carboplatin, carboplatin/docetaxel) because of relative contraindications to cisplatin. All but 2 patients received cisplatin-based NAC. The median number of chemotherapy cycles received by the whole cohort was 3, and the median time from the end of NAC to cystectomy was 4 weeks.

Histopathologic Differences Predicted pT0 Mixed tumors are those with urothelial plus variant histologic features. The variant histologic features included squamous, glandular differentiation, small cell, micropapillary, sarcomatoid differentiation, nested variant, lymphoepithelioma-like, and plasmacytoid variants. Stratified by the TURBT histologic types, in the pT0 group, 9 patients (64%) had PUC and 5 (36%) had mixed tumors. In the nonpT0 group, 19 patients (53%) had mixed tumors and 17 (47%) had PUC. However, agreement was lacking between the TURBT and cystectomy specimen histologic types in the non-pT0 group (Table 2 and Figure 2). Approximately 50% of the non-pT0 group had PUC found on TURBT, but only 14% (5 patients) had PUC found at cystectomy. Twelve patients from the non-pT0 group who had PUC found at TURBT had additional variant histologic types found at cystectomy after NAC. Both univariate and multivariate logistic regression analysis was performed. The final analysis yielded histopathologic type as the

Table 1 Distribution of Patient Characteristics Stratified by Treatment Response Characteristic Patients Median age (years)

pT0

Non-pT0

Total

14 (28)

36 (72)

50 (100)

67.5

67

67.5

Gender Female Male

2 (14)

7 (20)

9 (18)

12 (86)

29 (80)

41 (82)

2 (14)

5 (14)

7 (14)

12 (86)

31 (86)

43 (86)

Smoking status Nonsmoker Smoker Histologic type (TURBT for both pT0 and non-pT0) PUC

9 (64)

17 (47)

26 (52)

Mixed

5 (36)

19 (53)

24 (48)

cT2

9 (64)

22 (61)

31 (62)

cT3

3 (22)

8 (22)

11 (22)

cT4

2 (14)

6 (17)

8 (16)

Clinical T stage at diagnosis

GFR at presentation (mL/min) Median

90

86

87.5

Range

56-116

33-170

33-170

Hydronephrosis at presentation No

12 (86)

23 (64)

35 (70)

Yes

2 (14)

13 (36)

15 (30)

14 (100)

34 (94)

48 (96)

2 (6)

2 (4)

Chemotherapy Cisplatin based Non-cisplatin based Chemotherapy cycles Median

3

3

3

Range

2-4

2-6

2-6

Median

4

4

4

Range

3-8

2-9

2-9

Time from TURBT to chemotherapy (wk)

Time from end of chemotherapy to surgery (wk) Median

4

4.5

4

Range

2-36

1-46

1-46

Data presented as n (%), unless otherwise noted. Abbreviations: GFR ¼ glomerular filtration rate; PUC ¼ pure urothelial carcinoma; TURBT ¼ transurethral resection of bladder tumor.

only significant factor (Table 3). Comparing the non-pT0 cystectomy pathologic findings with the TURBT histologic features of the pT0 group, the patients with PUC had greater odds of attaining pT0 with NAC than the patients with mixed tumors (odds ratio, 0.09; 95% CI, 0.021-0.380; P ¼ .0011). After removal of the 2 patients in the non-pT0 group who had received nonecisplatinbased chemotherapy (carboplatin-based) and performing the analysis again, no difference was found in these results (odds ratio, 0.096; 95% CI, 0.023-0.407; P ¼ .0015), suggesting that those with PUC had approximately 10 to 11 times greater likelihood of achieving a pT0 with cisplatin-based NAC. However, a comparison

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pT0 Predictors in Muscle-Invasive Bladder Carcinoma Table 2 Discrepancy in TURBT and Cystectomy Histopathologic Findings for Non-pT0 Group (n [ 36) Variable At TURBT At cystectomy

Patients With PUC (n)

Patients With Mixed Histologic Features (n)

17 (47) 5 (14)

19 (53) 31 (86)

Data in parentheses are percentages. Abbreviations: PUC ¼ pure urothelial carcinoma; TURBT ¼ transurethral resection of bladder tumor.

of the TURBT histologic findings of both groups showed less likelihood of attaining pT0 in mixed tumors without reaching statistical significance. An absence of hydronephrosis favored a pT0 response without statistical significance. The presence of a higher T stage (T3-T4) at initial presentation did not predict for pT0 with NAC.

Discussion BC is a heterogeneous disease, with a highly variable prognosis, depending on the tumor stage. The use of NAC has been advocated for more than a decade, with prospective trials showing that cisplatin-based NAC followed by RC and pelvic lymph node dissection significantly improved the survival of patients with MIBC.7-12 The intergroup trial (Southwestern Oncology Group [SWOG]-8710) demonstrated that patients randomized to 3 cycles of MVAC followed by RC had improved survival of 77 months compared with 46 months for patients assigned to RC alone. The BA06 30894 trial by the International Collaboration of Trialists showed that with the administration of 3 cycles of CMV (cisplatin/ methotrexate/vinblastine), the estimated 10-year survival improved from 30% to 36% and the median survival from 37 to 44 months compared with RC alone. Both trials showed corresponding

significant reduction in the risk of death of 33% and 16% with NAC. A subsequent meta-analysis showed a 5% improvement in the average 5-year survival with the addition of platinum-based NAC to local definitive treatment.13 However, this modest benefit was associated with notable toxicity. The corresponding rate of grade 3 and 4 toxicities (granulocytopenia, mucositis) reported in these trials was 35% and 37%. This finding was one of the major reasons for the dramatic underusage of NAC, with < 20% of patients receiving the recommended standard of care.17 The absence of a substantial survival benefit with NAC, the unpredictable response, and a delay to definitive surgery were among the other reasons. A recent retrospective analysis18 conducted at our institute demonstrated significantly improving NAC usage rates (from 10.8% to 55% within 1 year from 2011 to 2012) after implementation of a stringent multidisciplinary approach. The survival benefit of NAC has been shown to be strongly related to downstaging of the tumor to a complete pathologic response. The probability of pT0 with MVAC at cystectomy was shown to be 38% by Grossman et al,7 and the median overall survival for pT0 patients was significantly longer than for those with residual disease (13.6 vs. 3.4 years). Also, an updated analysis of the combined Nordic trials showed that the survival benefit was restricted to those who had achieved a pT0 with NAC,19 indicating that NAC-induced downstaging might be a surrogate marker for overall survival. Retrospective and prospective studies using cisplatin-based NAC in MIBC demonstrated pT0 response rates of 20% to 38%.17,20-22 Recently, a large multinational retrospective analysis by Galsky et al23 reported comparable pT0 response rates of 29% and 31% with the NAC regimens GC and MVAC, respectively. The identification of this relatively small group of responders to chemotherapy might result in selective administration of NAC and the avoidance of unnecessary chemotherapy-related morbidity. Many centers use a risk-adapted approach, in which patients with

Figure 2 Graphic Representation of Histologic Features in Both pT0 (at TURBT) and Non-pT0 (at TURBT and Cystectomy) Groups

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Abbreviations: Ca ¼ cancer; TURBT ¼ transurethral resection of bladder tumor.

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Venkata K. Pokuri et al Table 3 Predictors of pT0 to NAC Variable

pT0 (n [ 14)

Non-pT0 (n [ 36)

Histologic typea b

Mixed

5

31

Pure transitional

9

5

Mixedb

5

19

Pure transitional

9

17

No

12

23

Yes

2

13

Histologic typec

Hydronephrosis at presentation

T3-T4 disease at initial presentation No

9

22

Yes

5

14

OR (95% CI)

P Value

0.09 (0.021-0.380)

.0011

0.497 (0.139-1.777)

.2822

0.295 (0.057-1.527)

.1455

1.145 (0.318-4.129)

.8356

Abbreviations: CI ¼ confidence interval; NAC ¼ neoadjuvant chemotherapy; OR ¼ odds ratio; TURBT ¼ transurethral resection of bladder tumor. a at TURBT for pT0 group and at cystectomy for non-pT0 group. b Urothelial with variant histologic features. c at TURBT for both pT0 and non-pT0 groups.

high-risk features such as stage  cT3 disease and the presence of hydronephrosis are offered multimodality therapy.24 To date, no definitive clinicopathologic variables have been established to identify responders to NAC. In our study, we found that the odds of a pT0 response for PUC with cisplatin-based NAC were approximately 10 to 11 times greater relative to cancer with additional urothelial variant histologic features. A meta-analysis of several randomized trials revealed the inferiority of carboplatin-based therapy compared with cisplatinbased therapy in attaining a complete response in patients with advanced BC.25 Our results did not change even after eliminating the 2 patients who had received carboplatin-based therapy from the non-pT0 group. These findings suggest that patients with additional variant histologic features could potentially benefit from upfront cystectomy (without NAC), especially because delaying cystectomy for > 3 months from a diagnosis of MIBC has been associated with decreased survival in some patient populations.26 Observational studies in the metastatic BC setting have shown similar high clinical response rates (disappearance of all clinical and radiographic evidence of disease) to platinum-based combination chemotherapy in those with PUC compared with those with mixed tumors.27,28 Logothetis et al27 reported a complete clinical response to platinum-based chemotherapy in 39% of 74 patients with metastatic PUC and 25% of 20 patients with metastatic mixed histologic features (UC with squamous, glandular, or spindle cell components). Kastritis et al28 reported any clinical response (complete or partial) to platinum-based chemotherapy in 44% of 389 patients with metastatic PUC and in 34% of 42 patients with metastatic mixed urothelial and squamous histologic features. This might not be directly applicable to the neoadjuvant setting, because the biology of metastatic disease is likely to be different. Our study findings were in contrast to those from a similar retrospective study by Scosyrev et al,29 in which a secondary analysis of SWOG-8710 patients was conducted to determine whether the presence of additional variant histologic features (squamous and/or glandular differentiation variants only) altered the survival effect of

MVAC NAC in patients with locally advanced MIBC. A total of 307 eligible patients in that study were randomized to either MVAC plus cystectomy (n ¼ 153) or cystectomy alone (n ¼ 154). In the MVAC arm, the pT0 response after chemotherapy was greater among patients with mixed tumors than for patients with PUC (28% vs. 15%, P ¼ .004). Also, evidence of a survival benefit from chemotherapy was seen in patients with mixed tumors (hazard ratio [HR], 0.46; 95% CI, 0.25-0.87; P ¼ .02). Patients with PUC had improved survival in the chemotherapy arm; however, the survival benefit was not statistically significant (HR, 0.90; 95% CI, 0.671.21; P ¼ .48). That study also reported evidence of borderline statistical significance that the survival benefit of chemotherapy in patients with mixed tumors was greater than it was for patients with PUC (statistical interaction, P ¼ .09).29 Scosyrev et al29 included MVAC as the only platinum-based chemotherapy regimen. Squamous and/or glandular differentiation, the most frequent urothelial histologic variants,30 were the only histologic types included in their study. That study was completed before micropapillary and nested variants were routinely reported. In contrast, we included other cisplatin-based regimens (eg, GC) and other histologic variants (eg, micropapillary, sarcomatoid, nested variant). Of note, 31 patients in the non-pT0 group had variant histologic features in different combinations (squamous differentiation in 16, adeno/glandular differentiation in 7, nested variant in 11, micropapillary in 8, small cell in 3, plasmacytoid in 1, sarcomatoid in 1, and lymphoepithelioma in 1). The inclusion of these different histologic variants might have contributed to the decreased pT0 response in the patients with mixed histologic features. Multiple observational and retrospective studies have identified the variant histologic subtypes of BC as poor prognostic indicators, associated with decreased disease-specific survival. Culp et al31 retrospectively analyzed the data from patients who had undergone cystectomy without NAC for MIBC and reported that the 5year disease-specific survival was low in those with a micropapillary variant histologic type. Wasco et al32 retrospectively identified that patients with nested variant BC had unfavorable outcomes

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pT0 Predictors in Muscle-Invasive Bladder Carcinoma compared with those with PUC. Wang et al33 used a populationbased registry to identify 221 patients with sarcomatoid BC and reported very low 5-year cancer-specific survival in these patients. This led many cancer centers to recommend NAC for those with mixed tumors with these additional variant histologic types. However, no prospective studies have demonstrated that NAC is beneficial for mixed histologic variants. It must also be recognized that certain histologic variants, especially squamous and micropapillary,34,35 are not chemotherapy sensitive. In addition, Kamat et al,35 from MD Anderson Cancer Center, reported in a retrospective analysis that patients with micropapillary variant BC have better 5-year overall survival rates with upfront cystectomy compared with those who received NAC. Also, Wasco et al32 reported a poor response to NAC in a small series of 15 patients with nested variant BC. The present study had certain limitations. A single-institution cohort can possibly generate an increased risk of bias. The sample size in our study was small, and the follow-up duration was not yet sufficient to show survival data. The retrospective nature of the study and the absence of a comparative arm with upfront cystectomy and no NAC must also be acknowledged as a limitation. In addition, a discrepancy was found between the TURBT and cystectomy histologic features in the non-pT0 group. One third of the patients in the non-pT0 group with PUC at TURBT were found to have additional variant histologic variants at cystectomy. This could be partly explained by the staging accuracy difficulties with TURBT and the successful elimination of the pure urothelial component by the NAC. It is also rarely possible that the PUC found at TURBT in the non-pT0 group might have evolved into variant urothelial histologic types in response to NAC. Furthermore, incomplete or less-extensive TURBT might have resulted in variant urothelial histologic features not being recognized in the pT0 group, and this subset of patients might have responded to NAC, resulting in pT0 at cystectomy. Thus, a meticulous and thorough TURBT is crucial to accurately identify the histopathologic predictors of pT0 to NAC in MIBC. Detailed data on the extent and sufficiency of TURBT were not available in our study.

Conclusion Our study showed that the presence of urothelial variant histologic features (eg, squamous, glandular differentiation, small cell, micropapillary, sarcomatoid, nested component, lymphoepithelioma-like, and plasmacytoid variants) confers a decreased chance of a pT0 to NAC. These results from our series of patients were statistically significant and suggest the need for further prospective evaluations. With more urothelial histologic variants being identified, larger randomized prospective studies are needed to better understand the role of NAC in these aggressive phenotypes. In the era of precision medicine, the future should aim at determining potential sophisticated biomarkers based on gene arrays and gene expression profiles, which might surpass the morphologic designations in predicting the response to chemotherapy.

Clinical Practice Points  The current standard of care for MIBC is to administer 3 to 4

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cycles of cisplatin-based NAC (after confirmation of muscle invasiveness on biopsy) and then perform cystectomy.

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 However, only 30% to 40% of patients receiving NAC have the

survival advantage by attaining pT0 (complete pathologic response), and no clinicopathologic factors to predict this response to NAC have been established. Also, pivotal trials have reported higher (approximately 36%) grade 3 and 4 toxicities with cisplatin-based chemotherapy, including mucositis and neutropenia. The unpredictable response, absence of substantial survival benefit, higher morbidity related to chemotherapy, and delay to definitive surgery led to dramatic underusage of NAC, with < 20% of patients receiving the recommended standard of care.  Our retrospective analysis found that the odds of pT0 for PUC were approximately 11 times greater relative to cancers with additional urothelial variant histologic features (mixed tumors), suggesting that patients with mixed tumors might potentially benefit from upfront definitive cystectomy and avoid the morbidity of cisplatin-based NAC.  The role of urothelial/transitional cell variant histologic types (eg, squamous, glandular differentiation, small cell, micropapillary, sarcomatoid, nested component, lymphoepithelioma-like, and plasmacytoid variants) as negative predictors of pT0 to NAC needs further prospective evaluation, which might help in the ideal selection of patients with MIBC for NAC.

Disclosure Dr. George has received research funding (including funds paid to his institution) from Bristol-Myers Squibb, Novartis, Pfizer, Bayer, Acceleron, Merck, and Agensis and is a consultant or advisory board member for Sanofi, Bayer, Astellas, Novartis, and Bristol-Myers Squibb. The remaining authors have declared that they have no competing interests.

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