<div>AbstractPurpose:<p>Erdafitinib is the only FDA-approved targeted therapy for FGFR2/3-altered metastatic urothelial cancer. We characterized the genetic landscape of FGFR-altered urothelial carcinoma and real-world clinical outcomes with erdafitinib, including on-treatment genomic evolution.</p>Experimental Design:<p>Prospectively collected clinical data were integrated with institutional genomic data to define the landscape of FGFR2/3-altered urothelial carcinoma. To identify mechanisms of erdafitinib resistance, a subset of patients underwent prospective cell-free (cf) DNA assessment.</p>Results:<p>FGFR3 alterations predictive of erdafitinib sensitivity were identified in 39% (199/504) of patients with non-muscle invasive, 14% (75/526) with muscle-invasive, 43% (81/187) with localized upper tract, and 26% (59/228) with metastatic specimens. One patient had a potentially sensitizing FGFR2 fusion. Among 27 FGFR3-altered cases with a primary tumor and metachronous metastasis, 7 paired specimens (26%) displayed discordant FGFR3 status. Erdafitinib achieved a response rate of 40% but median progression-free and overall survival of only 2.8 and 6.6 months, respectively (<i>n</i> = 32). Dose reductions (38%, 12/32) and interruptions (50%, 16/32) were common. Putative resistance mutations detected in cfDNA involved TP53 (<i>n</i> = 5), AKT1 (<i>n</i> = 1), and second-site FGFR3 mutations (<i>n</i> = 2).</p>Conclusions:<p>FGFR3 mutations are common in urothelial carcinoma, whereas FGFR2 alterations are rare. Discordance of FGFR3 mutational status between primary and metastatic tumors occurs frequently and raises concern over sequencing archival primary tumors to guide patient selection for erdafitinib therapy. Erdafitinib responses were typically brief and dosing was limited by toxicity. FGFR3, AKT1, and TP53 mutations detected in cfDNA represent putative mechanisms of acquired erdafitinib resistance.</p></div>
498 Background: Cisplatin-based neoadjuvant chemotherapy followed by radical cystectomy (RC) confers survival benefit but a substantial subset of MIBC pts are cisplatin-ineligible. We conducted a phase II trial of N±I neoadjuvant therapy for cisplatin-ineligible MIBC. Methods: Cisplatin-ineligible pts with MIBC (cT2-T4aN0M0) were enrolled into 2 consecutive cohorts of 15 pts each (C1: N 3 mg/kg q 2 weeks (wk) x 5; C2: I (3mg/kg) + N (1mg/kg) wk 0 and 6, with N (3mg/kg) wk 3 and 9). A 3rd cohort was planned (C3: I (3mg/kg) + N (1mg/kg) q 3 wk x 3). Primary endpoint (EP) was eligibility for planned RC within 60 days without delay from treatment-related adverse events (TRAEs) or progressive disease (PD). Secondary EPs included pathologic downstaging (PaDo, <ypT2pN0) and complete response (pCR, ypT0pN0) rates, recurrence-free survival (RFS), and safety. Exploratory EP was event-free survival (EFS). Results: From 8/2018-5/2021, 15 pts were enrolled onto C1 and C2 (N = 30). Median age 76 (range 53-87), 80% male, with median Charlson comorbidity score of 1 (range 0-5). In C1 and C2, 14/15 and 6/15 pts received all planned treatment, respectively. In C2, 7/15 received ≤ 50% of planned doses. In C1, 11 pts underwent RC, 2 had PD before RC, 1 did not undergo RC due to TRAE, and 1 declined RC. Overall, 12/15 met the primary EP. For C2, 9 pts underwent RC, 3 had PD before RC, 2 did not undergo RC due to AE (1 of which was TRAE), and 1 opted for radiation, with 8/15 meeting the primary EP. C3 was dropped due to C2’s failure to meet the primary EP. In C1, 4 pts had PaDo (26%), with 2 pCRs (13%). In C2, 3 pts had PaDo (20%), with 1 pCR (7%). In C1, 1 pt who did not undergo RC due to TRAE had clinical CR of 13.2 months (mos) but died of sepsis at 16.1 mos; 2 pts in C2 who did not undergo RC have ongoing clinical CR at 16.1 and 10.8 mos follow-up (f/u). For time-to-event EPs, see Table. In C1, the only observed grade 3-4 TRAE was myocarditis (n=1, 7%). In C2, 4 pts (27%) had grade 3-4 TRAE, including elevated lipase (20%), pneumonitis (13%), fatigue (13%), and elevated AST + ALT(13%). Median tumor mutation burden was 8.8/megabase; DNA damage response genes were altered in 31% of pts and FGFR3 in 14%, with no genomic correlation with PaDo. For C1, 4/10 had baseline PD-L1 expression on ≥1% of tumor cells; 1 had PD-L1 ≥5%. Conclusions: In this cohort of cisplatin-ineligible pts with MIBC and comorbidities, neoadjuvant N was well tolerated. N+I was associated with greater toxicity resulting in RC delays. Pathologic response rates were low in both cohorts, raising questions about utility of treatment intensification in cisplatin-ineligible patients. Some pts who did not undergo RC due to TRAEs had sustained clinical CR. Clinical trial information: NCT03520491. Clinical trial information: NCT03520491. [Table: see text]
4526 Background: LNEC is a rare, poorly characterized entity morphologically resembling small cell NEC of the urothelial tract (SNEC). Methods: Pure and partial LNEC and SNEC cases were identified by histopathologic re-review; clinical outcomes were compared. A subset was sequenced with MSK-IMPACT (279-505 genes). Results: Between 1992-2020, 43 patients (pts) with LNEC were identified (42 bladder, 1 upper tract); 19 (44%) had concomitant SNEC. LNEC cases were compared to 192 SNEC without LNEC (SNEC-only) (Table 1). Compared to SNEC-only pts, LNEC pts experienced longer overall survival (OS), adjusting for age and M0 vs M1 (median OS not reached vs 22.4 months [mos]; HR 0.34, 95% CI 0.16-0.74, p =.006). Neoadjuvant chemo (NAC) use increased over time. Pathologic response rate (<ypT2N0) after NAC was 25% for LNEC and 50% for SNEC-only (p =.13); the ypT0N0 rate was 25% for LNEC and 40% for SNEC-only (p =.52). Perioperative chemo did not improve OS compared to surgery alone in LNEC, adjusting for age and concurrent SNEC (HR 1.46, 95% CI 0.12-17.5, p =.76), but was associated with longer OS among SNEC-only pts (n = 98; HR 0.39, 95% CI 0.22-0.69, p =.001). Two M1 LNEC pts received immunotherapy (IO) in the first-line: 1 atezolizumab, 1 atezolizumab + chemo. Both remained free of progression on IO at a follow-up of 20 and 12 mos, respectively. Of 18 sequenced LNEC tumors, 89% had TERT promoter alterations (alts), similar to 85% seen in 52 SNEC tumors. All LNEC tumors had alts of TP53 or RB1, and 10 (56%) had both. Median tumor mutational burden (TMB) was 14 (IQR 8-38) in LNEC and 30 (IQR 15-55) in SNEC. Epigenetic modifiers were altered in 78% LNEC and 79% SNEC. Two LNEC pts had ERCC2 alts and received platinum chemo; both were alive at last follow-up from NEC diagnosis of 30.7-39.1 mos. Conclusions: LNEC pts experienced longer OS compared to pts with SNEC-only in this cohort, but did not appear more chemo-sensitive. Genomic profiles of LNEC and SNEC-only tumors were similar; TERT promoter mutations suggest a potential urothelial precursor. Further investigation of IO for LNEC is warranted.[Table: see text]
4598 Background: The gut microbiome is an emerging modifiable predictor of ICB efficacy. Diet impacts the gut microbiome and fiber intake is associated with longer progression-free survival (PFS) in advanced melanoma treated with ICB. Whether diet impacts ICB benefit in mUC or mRCC remains unknown. Methods: Using a prospective cohort design, baseline dietary data were collected from pts with mUC or mRCC initiating ICB at Memorial Sloan Kettering Cancer Center using the extensively validated Harvard Willett Food Frequency Questionnaire. Tumor mutational burden (TMB) was estimated by next generation sequencing (MSK-IMPACT). The primary endpoint was radiologist assessed PFS, with secondary endpoint of overall survival (OS). Fiber intake was stratified as high or low using the median intake in our cohort. Associations between fiber intake and clinical outcomes were assessed using Kaplan-Meier curves plus univariable (UV) and multivariable (MV) Cox proportional hazards regression. Models were adjusted for prior ICB exposure. Models for mUC controlled for TMB and Bellmunt risk factors. Models for mRCC controlled for histology (clear vs non-clear cell) and IMDC risk score. Results: From 2/2021-6/2022, 88 pts eligible for analysis were enrolled with median follow-up of 10.1 months (mo) (mUC n = 40; mRCC n = 48). Median fiber intake was 17.5 g/day (interquartile range 12.5-24.5). Among pts with mUC, high fiber intake (≥17.5 g/day) was associated with longer PFS (UV hazard ratio [HR] 0.56, 95% CI 0.26-1.19, p = .13; MV HR 0.39, 95% CI 0.16-0.93, p = .03). Similar trends were observed for mRCC. In subgroup analyses, PFS was numerically longer with high fiber intake among mUC pts on maintenance avelumab (median PFS 6.1 vs 3.0 mo, n = 14) and in pts with mRCC treated with first-line (1L) ipilimumab + nivolumab (median PFS 18.0 vs 5.7 mo, n = 14) and 1L ICB + tyrosine kinase inhibitor (median PFS not reached vs 5.1 mo, n = 21). Among pts with mUC on non-maintenance ICB, pts with high fiber intake had numerically higher PFS at 6 mo (38% vs 14%, n = 26). Conclusions: This pilot study indicates that high fiber intake is associated with longer PFS among pts with mUC on ICB. Trends towards longer PFS and OS with high fiber intake were observed among pts with mRCC. Analyses of the gut microbiome are underway to investigate mechanisms of action. [Table: see text]
Background: Apathy is a common neuropsychiatric symptom in Alzheimer's disease (AD) dementia and mild cognitive impairment (MCI). Detecting apathy accurately may facilitate earlier diagnosis of AD. The Apathy Evaluation Scale (AES) is a promising tool for measurement of apathy in prodromal and pos sibly preclinical AD. Objective: To compare the three AES sub-scales— subject-reported (AES-S), informant-reported (AES-I), and clinician-reported (AES-C)— over time in individuals at risk for AD due to MCI and advanced age (cognitively normal [CN] elderly). Methods: Mixed effects longitudinal models were used to assess predictors of score for each AES sub-scale. Cox proportional hazards models were used to assess which AES sub-scales predict progression from MCI to AD dementia. Results: Fifty-seven MCI and 18 CN subjects (ages 53–86) were followed for 1.4 ± 1.2 years and 0.7 ± 0.7 years, respectively. Across the three mixed effects longitudinal models, the common findings were associations between greater apathy and greater years in study, a baseline diagnosis of MCI (compared to CN), and male gender. CN elderly self-reported greater apathy compared to that reported by informants and clinicians, while individuals with MCI under-reported their apathy compared to informants and clinicians. Of the three sub-scales, the AES-C best predicted transition from MCI to AD dementia. Conclusion: In a sample of CN elderly and elderly with MCI, apathy increased over time, particularly in men and those with MCI. AES-S scores may be more sensitive than AES-I and AES-C scores in CN elderly, but less reliable if subjects have MCI. Moreover, the AES-C sub-scale predicted progression from MCI to AD dementia.
Purpose Observational studies have demonstrated increased colon cancer recurrence in states of relative hyperinsulinemia, including sedentary lifestyle, obesity, and increased dietary glycemic load. Greater coffee consumption has been associated with decreased risk of type 2 diabetes and increased insulin sensitivity. The effect of coffee on colon cancer recurrence and survival is unknown. Patients and Methods During and 6 months after adjuvant chemotherapy, 953 patients with stage III colon cancer prospectively reported dietary intake of caffeinated coffee, decaffeinated coffee, and nonherbal tea, as well as 128 other items. We examined the influence of coffee, nonherbal tea, and caffeine on cancer recurrence and mortality using Cox proportional hazards regression. Results Patients consuming 4 cups/d or more of total coffee experienced an adjusted hazard ratio (HR) for colon cancer recurrence or mortality of 0.58 (95% CI, 0.34 to 0.99), compared with never drinkers (P trend = .002). Patients consuming 4 cups/d or more of caffeinated coffee experienced significantly reduced cancer recurrence or mortality risk compared with abstainers (HR, 0.48; 95% CI, 0.25 to 0.91; P trend = .002), and increasing caffeine intake also conferred a significant reduction in cancer recurrence or mortality (HR, 0.66 across extreme quintiles; 95% CI, 0.47 to 0.93; P trend = .006). Nonherbal tea and decaffeinated coffee were not associated with patient outcome. The association of total coffee intake with improved outcomes seemed consistent across other predictors of cancer recurrence and mortality. Conclusion Higher coffee intake may be associated with significantly reduced cancer recurrence and death in patients with stage III colon cancer.
Abstract Bladder cancer remains a leading cause of cancer death worldwide and is associated with substantial impacts on patient quality of life, morbidity, mortality, and cost to the healthcare system. Gross hematuria frequently precedes the diagnosis of bladder cancer. Non-muscle-invasive bladder cancer (NMIBC) is managed initially with transurethral resection of a bladder tumor (TURBT), followed by a risk stratified approach to adjuvant intravesical therapy (IVe), and is associated with an overall survival of 90%. However, cure rates remain lower for muscle invasive bladder cancer (MIBC) owing to a variety of factors. NMIBC and MIBC groupings are heterogeneous and have unique pathological and molecular characteristics. Indeed, The Cancer Genome Atlas project identified genetic drivers and luminal and basal molecular subtypes of MIBC with distinct treatment responses. For NMIBC, IVe immunotherapy (primarily BCG) is the gold standard treatment for high grade and high risk NMIBC to reduce or prevent both recurrence and progression after initial TURBT; novel trials incorporate immune checkpoint inhibitors. IVe gene therapy and combination IVe chemotherapy have recently been completed, with promising results. For localized MIBC, essential goals are improving care and reducing morbidity following cystectomy or bladder preserving strategies. In metastatic disease, advances in understanding of the genomic landscape and tumor microenvironment have led to the implementation of immune checkpoint inhibitors, targeted treatments, and antibody-drug conjugates. Defining better selection criteria to identify the patients most likely to benefit from a specific treatment is an urgent need.
