HER2 overexpression in urothelial carcinoma with GATA3 and PPARG copy number gains.

HER2, encoded by the ERBB2 gene, is an important druggable driver of human cancer gaining increasing importance as a therapeutic target in urothelial carcinoma (UC). The genomic underpinnings of HER2 overexpression in ERBB2 nonamplified UC are poorly defined. To address this knowledge gap, we investigated 172 UC tumors from patients treated at the University of California San Francisco, using immunohistochemistry and next-generation sequencing. We found that GATA3 and PPARG copy number gains individually predicted HER2 protein expression independently of ERBB2 amplification. To validate these findings, we interrogated the Memorial Sloan Kettering/The Cancer Genome Atlas (MSK/TCGA) dataset and found that GATA3 and PPARG copy number gains individually predicted ERBB2 mRNA expression independently of ERBB2 amplification. Our findings reveal a potential link between the luminal marker HER2 and the key transcription factors GATA3 and PPARG in UC and highlight the utility of examining GATA3 and PPARG copy number states to identify UC tumors that overexpress HER2 in the absence of ERBB2 amplification. In summary, we found that an increase in copy number of GATA3 and PPARG was independently associated with higher ERBB2 expression in patient samples of UC. This finding provides a potential explanation for HER2 overexpression in UC tumors without ERBB2 amplification and a way to identify these tumors for HER2-targeted therapies.

Natural History and Genomic Landscape of Chemotherapy-Resistant Muscle-Invasive Bladder Cancer.

PURPOSE: Patients with residual invasive bladder cancer after neoadjuvant chemotherapy (NAC) and radical cystectomy have a poor prognosis. Data on adjuvant therapy for these patients are conflicting. We sought to evaluate the natural history and genomic landscape of chemotherapy-resistant bladder cancer to inform patient management and clinical trials. METHODS: Data were collected on patients with clinically localized muscle-invasive urothelial bladder cancer treated with NAC and cystectomy at our institution between May 15, 2001, and August 15, 2019, and completed four cycles of gemcitabine and cisplatin NAC, excluding those treated with adjuvant therapies. Survival was estimated using the Kaplan-Meier method, and multivariable Cox proportional hazards models were used to identify predictors of recurrence-free survival (RFS). Genomic alterations were identified in targeted exome sequencing (Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets) data from post-NAC specimens from a subset of patients. RESULTS: Lymphovascular invasion (LVI) was the strongest predictor of RFS (hazard ratio, 2.15 [95% CI, 1.37 to 3.39]) on multivariable analysis. Patients with ypT2N0 disease without LVI had a significantly prolonged RFS compared with those with LVI (70% RFS at 5 years). Lymph node yield did not affect RFS. Among patients with sequencing data (n = 101), chemotherapy-resistant tumors had fewer alterations in DNA damage response genes compared with tumors from a publicly available chemotherapy-naïve cohort (15% v 29%; P = .021). Alterations in CDKN2A/B were associated with shorter RFS. PIK3CA alterations were associated with LVI. Potentially actionable alterations were identified in more than 75% of tumors. CONCLUSION: Although chemotherapy-resistant bladder cancer generally portends a poor prognosis, patients with organ-confined disease without LVI may be candidates for close observation without adjuvant therapy. The genomic landscape of chemotherapy-resistant tumors is similar to chemotherapy-naïve tumors. Therapeutic opportunities exist for targeted therapies as adjuvant treatment in chemotherapy-resistant disease.

"I think my vagina is still there?": Women's perspectives on sexual function and dysfunction following radical cystectomy for bladder cancer, a qualitative study.

BACKGROUND: Women's sexual health after radical cystectomy is an important but poorly understood aspect of bladder cancer survivorship. Dedicated investigation is needed to elucidate patient perceptions on sexual function and dysfunction in this setting. AIMS: In this study we sought to qualitatively examine women's perceptions and experiences of sexual health following radical cystectomy for bladder cancer. METHODS: We conducted one-on-one qualitative telephone interviews with 40 women who underwent radical cystectomy in the past 6 months to 5 years and signed a research consent form to be contacted for future studies. We examined women's experiences of engaging in sexual activity after surgery and their attitudes toward sex and body image. We audio recorded, transcribed, and coded the interviews using ATLAS.ti software and applied grounded theory methods for analysis. OUTCOMES: For data that emerged during the qualitative interviews that was related to lack of knowledge about how physical and psychological sexual health would be affected after surgery, we reviewed and discussed transcripts that enabled coding of the data into emerging topic areas. RESULTS: Our analysis yielded 4 main themes. (1) Women reported receiving little to no information from providers about female sexual dysfunction prior to or after radical cystectomy. Women wished they had been provided more information about female sexual dysfunction from their clinicians, including strategies for postoperative self-pleasure and nonintercourse methods of sexual pleasure with partners. (2) Women shared that they were not sexually active following surgery due to physical and mental barriers. (3) When women did try to engage in sex, they described feeling disappointed that it did not feel the same as prior to surgery. (4) Some women found that physical therapy helped them to physically and mentally recover their strength to engage in sexual activity again. CLINICAL IMPLICATIONS: Clinicians must directly address sexual health concerns with patients who undergo radical cystectomy. STRENGTHS AND LIMITATIONS: This study has several key strengths. Investigation into women's sexual function and dysfunction addresses a gap in understanding of this component of women's health-related quality of life after radical cystectomy, which represents an unmet need. The large number of interviews conducted as well as the in-depth information obtained through one-on-one interviews are additional strengths. This study also has limitations, including possible shortcomings of telephone interviews compared with in-person interviews. However, telephone interviews were beneficial because the interviews took place during the COVID-19 pandemic and spared patients from extra visits or from having to travel long distances to the respective medical centers. Other possible limitations were that patients may have been reluctant to share all of their experiences and that patients who underwent urostomies, also termed ileal conduits, were overrepresented in this study compared with women who underwent continent urine diversions, which allow greater control over urine output. CONCLUSION: Broadening the understanding of sexual health beyond sexual intercourse to encompass sexuality and self-pleasure can provide clinicians, patients, and their families with more effective preparation and strategies to care for an essential aspect of their wellbeing.

Clinical and Genomic Landscape of FGFR3-Altered Urothelial Carcinoma and Treatment Outcomes with Erdafitinib: A Real-World Experience.

PURPOSE: 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. EXPERIMENTAL DESIGN: 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. RESULTS: 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 (n = 32). Dose reductions (38%, 12/32) and interruptions (50%, 16/32) were common. Putative resistance mutations detected in cfDNA involved TP53 (n = 5), AKT1 (n = 1), and second-site FGFR3 mutations (n = 2). CONCLUSIONS: 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.

Cxbladder Monitor testing to reduce cystoscopy frequency in patients with bladder cancer.

PURPOSE: Bladder cancer surveillance is associated with high costs and patient burden. CxMonitor (CxM), a home urine test, allows patients to skip their scheduled surveillance cystoscopy if CxM-negative indicating a low probability of cancer presence. We present outcomes from a prospective multi-institutional study of CxM to reduce surveillance frequency during the coronavirus pandemic. MATERIALS AND METHODS: Eligible patients due for cystoscopy from March-June 2020 were offered CxM and skipped their scheduled cystoscopy if CxM-negative. CxM-positive patients came for immediate cystoscopy. The primary outcome was safety of CxM-based management, assessed by frequency of skipped cystoscopies and detection of cancer at immediate or next cystoscopy. Patients were surveyed on satisfaction and costs. RESULTS: During the study period, 92 patients received CxM and did not differ in demographics nor history of smoking/radiation between sites. 9 of 24 (37.5%) CxM-positive patients had 1 T0, 2 Ta, 2 Tis, 2 T2, and 1 Upper tract urothelial carcinoma (UTUC) on immediate cystoscopy and subsequent evaluation. 66 CxM-negative patients skipped cystoscopy, and none had findings on follow-up cystoscopy requiring biopsy. Six of these patients did not attend follow-up, 4 elected to undergo additional CxM instead of cystoscopy, 2 stopped surveillance, and 2 died of unrelated causes. CxM-negative and positive patients did not differ in demographics, cancer history, initial tumor grade/stage, AUA risk group, or number of prior recurrences. Median satisfaction (5/5, IQR 4-5) and costs (26/33, 78.8% no out-of-pocket costs) were favorable. CONCLUSIONS: CxM safely reduces frequency of surveillance cystoscopy in real-world settings and appears acceptable to patients as an at-home test.

Scratching the Surface: NECTIN-4 as a Surrogate for Enfortumab Vedotin Resistance.

Clinical data with enfortumab vedotin (EV) suggest that most bladder cancers overexpress NECTIN-4. A recent article shows that NECTIN-4 membranous expression changes with progression to metastatic disease and that low NECTIN-4 expression in metastatic biopsies is potentially associated with EV resistance. These data argue for incorporation of NECTIN-4 expression into future biomarker strategies. See related article by Klümper et al., p. 1496.

Prostate cancer disparities among American Indians and Alaskan Natives in the United States.

BACKGROUND: Americans Indians and Alaska Natives face disparities in cancer care with lower rates of screening, limited treatment access, and worse survival. Prostate cancer treatment access and patterns of care remain unknown. METHODS: We used Surveillance, Epidemiology, and End Results data to compare incidence, primary treatment, and cancer-specific mortality across American Indian and Alaska Native, Asian and Pacific Islander, Black, and White patients. Baseline characteristics included prostate-specific antigen (PSA), Gleason score (GS), tumor stage, 9-level Cancer of the Prostate Risk Assessment risk score, county characteristics, and health-care provider density. Primary outcomes were first definitive treatment and prostate cancer-specific mortality (PCSM). RESULTS: American Indian and Alaska Native patients were more frequently diagnosed with higher PSA, GS greater than or equal or 8, stage greater than or equal to cT3, high-risk disease overall (Cancer of the Prostate Risk Assessment risk score ≥ 6), and metastases at diagnosis than any other group. Adjusting for age, PSA, GS, and clinical stage, American Indian or Alaska Native patients with localized prostate cancer were more likely to undergo external beam radiation than radical prostatectomy and had the highest rates of no documented treatment. Five-year PCSM was higher among American Indian and Alaska Natives than any other racial group. However, after multivariable adjustment accounting for clinical and pathologic factors, county-level demographics, and provider density, American Indian and Alaska Native patient PCSM hazards were no different than those of White patients. CONCLUSIONS: American Indian or Alaska Native patients have more advanced prostate cancer, lower rates of definitive treatment, higher mortality, and reside in areas of less specialty care. Disparities in access appear to account for excess risks of PCSM. Focused health policy interventions are needed to address these disparities.

Immune mechanisms and molecular therapeutic strategies to enhance immunotherapy in non-muscle invasive bladder cancer: Invited review for special issue "Seminar: Treatment Advances and Molecular Biology Insights in Urothelial Carcinoma".

Intravesical immunotherapy with Bacillus Calmette-Guérin (BCG) has been the standard of care for patients with high-risk non non-muscle invasive bladder cancer (NMIBC) for over four decades. Despite its success as a cancer immunotherapy, disease recurrence and progression remain common. Current efforts are focused on developing effective and well-tolerated alternatives to BCG and salvage bladder preservation therapies after BCG has failed. The focus of this review is to synthesize our current understanding of the molecular biology and tumor immune microenvironment of NMIBC to provide rationale for existing and emerging therapeutic targets. We highlight recent and ongoing clinical trials and define the current treatment landscape, challenges, and future directions of salvage treatment. Combination regimens that are rationally designed will be needed to make meaningful therapeutic advancements. Investigations into the molecular underpinnings of NMIBC are leading to the emergence of predictive molecular biomarkers that provide greater insight into the clinical heterogeneity of NMIBC and enable us to identify drivers of treatment resistance and new therapeutic targets.

Genomic heterogeneity as a barrier to precision oncology in urothelial cancer.

Precision oncology relies on the accurate molecular characterization of individual patients with cancer at the time of treatment initiation. However, tumor molecular profiles are not static, and cancers continually evolve because of ongoing mutagenesis and clonal selection. Here, we performed genomic analyses of primary tumors, metastases, and plasma collected from individual patients to define the concordance of actionable genomic alterations and to identify drivers of metastatic disease progression. We observed a high degree of discordance of actionable genomic alterations, with 23% discordant between primary and metastatic disease sites. Among chromatin-modifying genes, ARID1A mutations, when discordant, were exclusive to the metastatic tumor samples. Our findings indicate that the high degree of lesion-to-lesion genomic heterogeneity may be a barrier to precision oncology approaches for bladder cancer and that circulating tumor DNA profiling may be preferred to tumor sequencing for a subset of patients.

TROP2 Expression Across Molecular Subtypes of Urothelial Carcinoma and Enfortumab Vedotin-resistant Cells.

Sacituzumab govitecan (SG) is an antibody-drug conjugate (ADC) targeting TROP2, which has recently been approved for treatment-refractory metastatic urothelial cancer (UC). However, the variability of TROP2 expression across different bladder cancer (BC) subtypes, as well as after enfortumab vedotin (EV) exposure, remains unknown. Using gene expression data from four clinical cohorts with >1400 patient samples of muscle-invasive BC and a BC tissue microarray, we found that TROP2 mRNA and protein are highly expressed across basal, luminal, and stroma-rich subtypes, but depleted in the neuroendocrine subtype. In addition, TROP2 mRNA levels are correlated with NECTIN4 mRNA but are more highly expressed than NECTIN4 mRNA in patient cohorts and BC cell lines. Moreover, CRISPR/Cas9-mediated knockdown of TROP2 demonstrates that its expression is one factor governing SG sensitivity. After prolonged EV exposure, cells can downregulate NECTIN4, leading to EV resistance, but retain TROP2 expression and remain sensitive to SG, suggesting nonoverlapping resistance mechanisms to these ADCs. While our findings warrant further validation, they have significant implications for biomarker development, patient selection, and treatment sequencing in the clinic as well as clinical trial design and stratification for metastatic BC patients. PATIENT SUMMARY: In this report, we investigated the expression levels of the drug target TROP2 across different molecular subtypes of bladder cancer in multiple patient cohorts and cell lines. We found high levels of TROP2 in most subtypes except in the neuroendocrine subtype. Overall, TROP2 gene expression is higher than NECTIN4 gene expression, and cells resistant to enfortumab vedotin (EV), a NECTIN4-targeting antibody-drug conjugate, remain sensitive to sacituzumab govitecan (SG). Our findings suggest that SG may be effective across most bladder cancer subtypes, including the bladder cancers previously treated with EV.