Cell-free circulating DNA (cfDNA) can be used for noninvasive profiling of tumor genomic aberrations. We hypothesized that molecular alterations may inform prognostication in advanced urothelial ...carcinoma (aUC). We evaluated 124 aUC patients who underwent cfDNA analysis using a 73-gene sequencing panel (Guardant360). The association of molecular alterations and clinical factors with overall survival (OS) and failure-free-survival (FFS) was evaluated using the Kaplan-Meier method and Cox proportional-hazards regression. The median age was 72yr, and 65 patients (52.4%) received prior therapy with platinum, 21 (17.1%) with a taxane, and ten (8.1%) with a PD-1/PD-L1 inhibitor. At least one genomic alteration was detected in 112 patients (90.3%). The median number of alterations per sample was four (range 0–80). Commonly altered genes included TP53 (54.8%), PIK3CA (24.2%), ARID1A (22.6%), ERBB2 (19.4%), EGFR (16.1%), NF1 (13.7%), RB1 (12.9%), FGFR3 (11.3%), BRAF (10.5%), BRCA1 (10.5%), and RAF1 (8.9%). BRCA1 and RAF1 alterations were associated with worse OS (hazard ratio HR 2.48; p=0.07; HR 4.87; p=0.007) and FFS (HR 2.35; p=0.016; HR 2.40; p=0.047). Poor Eastern Cooperative Oncology Group performance status and the presence of visceral metastasis were associated with shorter OS; genomic evolution was observed. In conclusion, cfDNA molecular alterations were detected in most aUC patients. BRCA1 and RAF1 alterations were negatively prognostic, supporting further evaluation of DNA damage response and RAF kinase inhibitors.
Noninvasive testing of cell-free circulating DNA in advanced urothelial carcinoma identifies clinically relevant molecular aberrations. Alterations in BRCA1 and RAF1 genes appear to be negatively associated with clinical outcomes, supporting further study of DNA damage response and RAF kinase inhibitors in selected patients.
Noninvasive testing of cell-free DNA in advanced urothelial carcinoma identifies clinically relevant molecular aberrations. Alterations in BRCA1 and RAF1 appear to be negatively associated with clinical outcomes, supporting further study of DNA damage response and RAF kinase inhibitors in selected patients.
Muscle mass is important for metastatic prostate cancer survival and quality of life (QoL). The backbone of treatment for men with metastatic castration sensitive prostate cancer (mCSPC) is androgen ...deprivation therapy (ADT) with an androgen signaling inhibitor. ADT is an effective cancer treatment, but it facilitates significant declines in muscle mass and adverse health outcomes important to mCSPC survivors, such as fatigue, and reductions in physical function, independence, insulin sensitivity, and QoL. In non-metastatic CSPC survivors, resistance training (RT) preserves muscle mass and improves these related health outcomes, but the biggest barrier to RT in CSPC survivors of all stages is fatigue. Creatine monohydrate supplementation coupled with RT (Cr + RT) may address this barrier since creatine plays a critical role in energy metabolism. Cr + RT in cancer-free older adults and other clinical populations improves muscle mass and related health outcomes. Evidence also suggests that creatine supplementation can complement cancer treatment. Thus, Cr + RT is a strategy that addresses gaps in survivorship needs of people with mCSPC. The purpose of this parallel, double-blind randomized controlled trial is to test the effects of 52-weeks of Cr + RT compared with placebo (PLA) and RT (PLA + RT) on muscle mass, other related health outcomes, and markers of cancer progression.
We will carry out this trial with our team's established, effective, home-based, telehealth RT program in 200 mCSPC survivors receiving ADT, and evaluate outcomes at baseline, 24-, and 52-weeks. RT will occur twice weekly with elastic resistance bands, and an established creatine supplementation protocol will be used for supplementation delivery. Our approach addresses a major facilitator to RT in mCSPC survivors, a home-based RT program, while utilizing a supervised model for safety.
Findings will improve delivery of comprehensive survivorship care by providing a multicomponent, patient-centered lifestyle strategy to preserve muscle mass, improve health outcomes, and complement cancer treatment (NCT06112990).
Objective
To review the genomic landscape of advanced urothelial carcinoma (UC) to assess the frequencies of EGFR and ERBB2 (HER2) alterations.
Materials and Methods
Tumour specimens from 3753 ...patients with advanced UC were assayed with hybrid capture‐based comprehensive genomic profiling of 180–395 genes. Tumour mutational burden (TMB) was assessed on 0.8 or 1.1 Mb of DNA, and is reported as mutations per megabase.
Results
In 3753 cases of UC, EGFR alterations were detected in 4.1% (154) and were most commonly amplifications (64%; 99/154), while exon 20 insertions (EGFRexon20ins) were the second most common alteration (18%; 27/154). Alterations in ERBB2 were observed in 15% (552/3753) of cases and, similarly, ERBB2 amplification was the most commonly observed alteration (278/552; 50%); ERBB2exon20ins occurred in 3.6% (20/552) of cases. EGFRexon20ins and ERBB2exon20ins occurred in younger patients (median age 62 vs 69 years, P = 2.6E‐2 and 60 vs 68 years, P = 7.8E‐4), and these cases had significantly lower TMB (median 3.6 vs 7.2, P = 2.7E‐4 and 2.5 vs 10, P = 1.2E‐7) and less frequent TP53 alterations (3.7% vs 83%, P = 4.3E‐14 and 20% vs 68%, P = 9.8E‐4) compared to cases with other EGFR or ERBB2 alterations.
Conclusion
EGFR and ERBB2 alterations occur in 4% and 15% of UC, respectively. EGFRexon20ins and ERBB2exon20ins were present in 0.7% and 0.5% of UC overall and collectively define a small, but distinct, subset of UC with infrequent co‐occurrence of other drivers and low TMB. Given recent promising clinical studies of inhibitors with activity against exon 20 insertions in non‐small cell lung cancer, consideration should be given to developing a trial inclusive of patients with UC harbouring these alterations.
Tumor tissue and circulating tumor DNA (ctDNA) next-generation sequencing (NGS) testing are frequently performed to detect genomic alterations (GAs) to help guide treatment in metastatic renal cell ...carcinoma (mRCC), especially after progression on standard systemic therapy. Our objective was to assess if GAs detected by ctDNA NGS are different from those detected by tumor tissue NGS, specifically in patients with mRCC, and if these platforms are interchangeable or complimentary.
When controlling for genes tested by both platforms, the median mutation rate for ctDNA was similar to tissue (median 3.0 vs. 1.0, p = 0.14). However, the concordance rate between the two platforms was only 8.6%. When comparing GAs by molecular pathway, GAs in tumor tissue were more common for the DNA repair and epigenetic pathways.
Results of NGS testing from tumor tissue and ctDNA from 19 sequential mRCC patients were compared. GAs in each were statistically evaluated using the Wilcoxon signed-rank test. The Fischer's exact test was used to compare the incidence of mutations in selected molecular pathways.
When controlling for genes tested by both platforms, similar number of GAs were detected by both tissue and ctDNA based NGS. However, there was discordance in the type of GAs detected suggesting that ctDNA NGS may be more reflective of dynamic tumor genomic heterogeneity. Hence, these two platforms may be considered complementary to each other, rather than interchangeable, for assessment of tumor GAs to guide selection of targeted clinical trial therapies.
Histone deacetylase (HDAC) inhibition has sporadic clinical efficacy in urothelial carcinoma; the genomic basis for clinical response is not known. In two separate phase I clinical trials testing ...pharmacokinetic aspects of HDAC inhibitors in advanced solid tumors, we identified one patient with advanced urothelial carcinoma who had a complete response to belinostat, and one patient with advanced urothelial carcinoma who had a partial response to panobinostat. The archived tumors of the responders were genomically characterized in comparison to others with urothelial carcinoma on the trials. Urothelial carcinoma cell lines treated with panobinostat and belinostat were studied to elucidate the mechanisms of benefit. Notably, the urothelial carcinoma tumors that responded to HDAC inhibition had
mutations.
mutations were also noted in the tumors of three patients who had stable disease as their best response to HDAC inhibition. Corroborating the basis of sensitivity, transcriptional profiling of platinum-resistant
-mutated HT1197 cells treated with panobinostat reveals negative enrichment for both cyto-proliferative (MYC and E2F targets) and DNA repair gene sets, and positive enrichment for TP53 and inflammatory gene sets. Our study identifies
loss as a basis for clinical response to pan HDAC inhibition and offers avenues for potential rational therapeutic combinations with HDAC inhibitors in advanced urothelial carcinoma.
Compared to the urban population, patients in rural areas face healthcare disparities and experience inferior healthcare-related outcomes. To compare the healthcare quality metrics and outcomes ...between patients with advanced genitourinary cancers from rural versus urban areas treated at a tertiary cancer hospital, in this retrospective study, eligible patients with advanced genitourinary cancers were treated at Huntsman Cancer Institute, an NCI-Designated Comprehensive Cancer Center in Utah. Rural–urban commuting area codes were used to classify the patients’ residences as being in urban (1–3) or rural (4–10) areas. The straight line distances of the patients’ residences from the cancer center were also calculated and included in the analysis. The median household income data were obtained and calculated from “The Michigan Population Studies Center”, based on individual zip codes. In this study, 2312 patients were screened, and 1025 eligible patients were included for further analysis (metastatic prostate cancer (n = 679), metastatic bladder cancer (n = 184), and metastatic renal cell carcinoma (n = 162). Most patients (83.9%) came from urban areas, while the remainder were from rural areas. Both groups had comparable demographic profiles and tumor characteristics at baseline. The annual median household income of urban patients was $8604 higher than that of rural patients (p < 0.001). There were fewer urban patients with Medicare (44.9% vs. 50.9%) and more urban patients with private insurance (40.4% vs. 35.1%). There was no difference between the urban and rural patients regarding receiving systemic therapies, enrollment in clinical trials, or tumor genomic profiling. The overall survival rate was not significantly different between the two populations in metastatic prostate, bladder, and kidney cancer, respectively. As available in a tertiary cancer hospital, access to care can mitigate the difference in the quality of healthcare and clinical outcomes in urban versus rural patients.
Metastatic urinary tract cancer (mUTC) is challenging to treat in older adults due to comorbidities. We compared the clinical courses of younger and older (≥70 years) adults with mUTC receiving ...first-line (1L) systemic therapy in a tertiary cancer center. Baseline clinical characteristics, treatments received, tolerability, and survival outcomes were analyzed. Among 212 patients (103 older vs. 109 younger), the older patients had lower hemoglobin at baseline (84% vs. 71%, p = 0.03), the majority were cisplatin-ineligible (74% vs. 45%, p < 0.001), received more immunotherapy-based treatments in the 1L (52% vs. 36%, p = 0.01), received fewer subsequent lines of treatment (median 0 vs. 1, p = 0.003), and had lower clinical trial participation (30% vs. 18%, p = 0.05) compared to the younger patients. When treated with 1L chemotherapy, older patients required more dose adjustments (53.4% vs. 23%, p = 0.001) and received fewer cycles of chemotherapy (median 4 vs. 5, p= 0.01). Older patients had similar OS (11.2 months vs. 14 months, p = 0.06) and similar rates of treatment-related severe toxicity and healthcare visits, independent of the type of systemic treatment received, compared to younger patients. We conclude that select older adults with mUTC can be safely treated with immunotherapy and risk-adjusted regimens of chemotherapy with tangible survival benefits.
Urothelial carcinoma (UC) has significant morbidity, mortality, and remains the most financially costly carcinoma to manage and treat. This review will cover special morphologic features of UC that ...may be noted by the pathologist and any subsequent significance in terms of clinical management or treatment considerations as mentioned or recommended in the latest WHO 2022 classification of GU tumors. Many important potentially therapy altering morphologic findings can be consistently identified and reported on routine microscopic examination of hematoxylin and eosin (H&E) stained slides. Furthermore, there has been a rapid advancement of molecular diagnostics and tailored therapies throughout oncology, and we will briefly highlight some of these as they relate to the management of UC. We will actively attempt to limit the discussion of histologic descriptions or pathologic diagnostic criteria of these entities and focus rather on the recognition of their importance/implication for clinicians who must make clinical management decisions based upon these findings. Finally, the importance of open lines of communication with the pathologists who review clinical specimens as well as their practice and reporting methods cannot be overstated.
Poly (ADP-ribose) polymerase (PARP) inhibitors have demonstrated clinical benefit for patients with solid tumors bearing germline or somatic alterations in DNA damage response (DDR) genes. Somatic ...alterations in DDR genes are common in advanced urothelial cancer, raising the possibility that PARP inhibition may confer therapeutic benefit in a molecularly selected subgroup of patients with metastatic urothelial cancer (mUC).
This single-arm, open-label, multi-institutional, investigator-initiated phase II study evaluated the antitumor activity of olaparib 300 mg twice a day in participants with mUC harboring somatic DDR alterations. Patients had progressed despite previous platinum-based chemotherapy, or were cisplatin-ineligible, and harbored somatic alterations in at least one of a prespecified list of DDR genes. The primary end point was objective response rate; secondary end points were safety, progression-free survival (PFS), and overall survival (OS).
Overall, 19 patients with mUC were enrolled and received olaparib; the trial closed early before slow accrual. The median age was 66 years (range, 45-82). Nine patients (47.4%) had received previous cisplatin chemotherapy. Ten patients (52.6%) had alterations in homologous recombination (HR) genes: eight patients (42.1%) had pathogenic
mutations and two patients carried alterations in other HR genes. No patients achieved a partial response although six patients achieved stable disease lasting 2.13-16.1 months (median, 7.69). The median PFS was 1.9 months (range, 0.8-16.1), and the median OS was 9.5 months (range, 1.5-22.1).
Single-agent olaparib showed limited antitumor activity in patients with mUC and DDR alterations, which may be related to poorly characterized functional implications of particular DDR alterations and/or cross-resistance with platinum-based chemotherapy in a disease where such therapy represents standard first-line treatment.
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