Search

The genomic era has significantly changed the practice of clinical oncology. The use of genomic-based molecular diagnostics including prognostic genomic signatures and new-generation sequencing has become routine for clinical decisions regarding cytotoxic chemotherapy, targeted agents and immunotherapy. In contrast, clinical decisions regarding radiation therapy (RT) remain uninformed about the genomic heterogeneity of tumors. In this review, we discuss the clinical opportunity to utilize genomics to optimize RT dose. Although from the technical perspective, RT has been moving towards a data-driven approach, RT prescription dose is still based on a one-size-fits all approach, with most RT dose based on cancer diagnosis and stage. This approach is in direct conflict with the realization that tumors are biologically heterogeneous, and that cancer is not a single disease. Here, we discuss how genomics can be integrated into RT prescription dose, the clinical potential for this approach and how genomic-optimization of RT dose could lead to new understanding of the clinical benefit of RT. [ABSTRACT FROM AUTHOR]

• Brachytherapy offers a superior 5-year local control and penile preservation rates compared to EBRT. • The primary late adverse events of brachytherapy, soft tissue necrosis (0–31%) and meatal stenosis (0–43%), are notably reduced with HDR brachytherapy. • Biopsy is recommended for poorly healing ulcers or raised lesions post-radiotherapy to exclude residual/recurrent disease. • Since brachytherapy remains underutilized, training for radiation oncologists in this area is welcome. In squamous cell carcinoma of the penis (PeCa), treatment options for primary tumors vary by disease stage and may include surgery, radiation, topical chemotherapy, or laser excision. This review aims to highlight the current evidence on the value of radiotherapy as an organ-preserving strategy in primary PeCa. Manuscripts on primary PeCa treatment with external beam radiotherapy (EBRT) and brachytherapy were evaluated via Scopus, PubMed/MEDLINE, and Web of ScienceTM (2013–2023) to assess their efficacy and safety. Animal studies, studies with <5 patients, and case reports were excluded. Radiotherapy offers the potential for organ preservation with tumor control rates comparable to radical surgery, while disease-specific survival rates up to 70 % were experienced with EBRT. Brachytherapy (BT) is the preferred method of irradiation for glans-limited tumors, whereas a higher relapse risk is expected for tumors >4 cm. BT shows 73 % amputation-free survival at 8–10 years and 81 % progression-free survival at 5–10 years. Compared with BT, total amputation significantly improves 5-year disease-free survival rate. BT offers a superior 5-year local control and penile preservation rates compared to EBRT. Common acute toxicities of brachytherapy include radiodermatitis, sterile urethritis, and urethral adhesions. The primary late adverse events of BT are soft tissue necrosis (0–31 %) and meatal stenosis (0–43 %). BT is a favorable radiation modality, offering an efficient and conservative approach. HDR BT is favored for its enhanced dose distribution and radiation protection. Collaboration between radiation oncologists and urologists is essential in order to provide an optimal patient selection and manage toxicities thus optimizing patient outcomes. [ABSTRACT FROM AUTHOR]

Purpose: Radiation therapy (RT) is a mainstay of cancer care, and accumulating evidence suggests the potential for synergism with components of the immune response. However, few data describe the tumor immune contexture in relation to RT sensitivity. To address this challenge, we used the radiation sensitivity index (RSI) gene signature to estimate the RT sensitivity of >10,000 primary tumors and characterized their immune microenvironments in relation to the RSI.Methods and Materials: We analyzed gene expression profiles of 10,469 primary tumors (31 types) within a prospective tissue collection protocol. The RT sensitivity of each tumor was estimated by the RSI and respective distributions were characterized. The tumor biology measured by the RSI was evaluated by differentially expressed genes combined with single sample gene set enrichment analysis. Differences in the expression of immune regulatory molecules were assessed and deconvolution algorithms were used to estimate immune cell infiltrates in relation to the RSI. A subset (n = 2368) of tumors underwent DNA sequencing for mutational frequency characterization.Results: We identified a wide range of RSI values within and across various tumor types, with several demonstrating nonunimodal distributions (eg, colon, renal, lung, prostate, esophagus, pancreas, and PAM50 breast subtypes; P < .05). Across all tumor types, stratifying RSI at a tumor type-specific median identified 7148 differentially expressed genes, of which 146 were coordinate in direction. Network topology analysis demonstrates RSI measures a coordinated STAT1, IRF1, and CCL4/MIP-1β transcriptional network. Tumors with an estimated high sensitivity to RT demonstrated distinct enrichment of interferon-associated signaling pathways and immune cell infiltrates (eg, CD8+ T cells, activated natural killer cells, M1-macrophages; q < 0.05), which was in the context of diverse expression patterns of various immunoregulatory molecules.Conclusions: This analysis describes the immune microenvironments of patient tumors in relation to the RSI gene expression signature. [ABSTRACT FROM AUTHOR]

Radiotherapy efficacy is the result of radiation-mediated cytotoxicity coupled with stimulation of antitumor immune responses. We develop an in silico 3-dimensional agent-based model of diverse tumor-immune ecosystems (TIES) represented as anti- or pro-tumor immune phenotypes. We validate the model in 10,469 patients across 31 tumor types by demonstrating that clinically detected tumors have pro-tumor TIES. We then quantify the likelihood radiation induces antitumor TIES shifts toward immune-mediated tumor elimination by developing the individual Radiation Immune Score (iRIS). We show iRIS distribution across 31 tumor types is consistent with the clinical effectiveness of radiotherapy, and in combination with a molecular radiosensitivity index (RSI) combines to predict pan-cancer radiocurability. We show that iRIS correlates with local control and survival in a separate cohort of 59 lung cancer patients treated with radiation. In combination, iRIS and RSI predict radiation-induced TIES shifts in individual patients and identify candidates for radiation de-escalation and treatment escalation. This is the first clinically and biologically validated computational model to simulate and predict pan-cancer response and outcomes via the perturbation of the TIES by radiotherapy. [ABSTRACT FROM AUTHOR]

Purpose: To assess the effectiveness and safety of prostatic artery embolization (PAE) on lower urinary tract symptoms (LUTS) in the setting of localized prostate cancer (PCa).Materials and Methods: This was a retrospective, single-center, institutional review board-approved study from December 2016 to June 2020 of 21 patients (median age, 72; range, 63-83 years) with moderate LUTS and localized PCa. Clinical effectiveness was evaluated at 6 and 12 weeks using International Prostate Symptom Score (IPSS) and quality of life (QoL) improvement. Seventeen patients were scheduled to receive definitive radiotherapy (RT) after PAE; 13 patients completed RT. Short-term imaging signs of oncologic progression were evaluated at 6 and 12 weeks defined by at least one of the following on magnetic resonance imaging: increased Prostate Imaging-Reporting and Data System score of index lesion(s) to at least 4, new extracapsular extension, seminal vesicle involvement, or pelvic lymphadenopathy. Nonparametric Wilcoxon signed-rank test was used for analysis.Results: IPSS improved by a median of 12 (n = 19, P < .0001) and 14 (n = 14, P < .0001) at 6 and 12 weeks, respectively. QoL improved by a median of 2 (n = 19, P < .0001) and 3 (n = 3, P < .0001) at 6 and 12 weeks. Prostate volume decreased by a median of 24% (n = 19, P < .0001) and 36% (n = 12, P = .015) at 6 and 12 weeks. No patients demonstrated disease progression at 6 (n = 16) or 12 (n = 8) weeks by imaging. No patients experienced increased prostate-specific antigen after RT, grade ≥3 adverse events, or greater genitourinary toxicity.Conclusions: PAE is effective and safe for the treatment of men with LUTS from benign prostatic hyperplasia in the setting of concomitant, localized, non-obstructive PCa. [ABSTRACT FROM AUTHOR]

Radiation therapy (RT) is a cornerstone in oncologic management and is employed in various curative and palliative scenarios for local-regional control. RT is thought to locally control tumor cells by direct physical DNA damage or indirect insults from reactive oxygen species. Therapeutic effects apart from those observed at the treatment target, that is, abscopal effect, have been observed for several decades, though the underlying mechanisms regulating this phenomenon have been unclear. Accumulating evidence now suggests that the immune system is a major determinant in regulating the abscopal effect. It is now evident that RT may also enhance immunologic responses to tumors by creating an in situ vaccine by eliciting antigen release from dying tumor cells. Harnessing the specificity and dynamic nature of the immune system to target tumors in conjunction with RT is an emerging field with much promise. To optimize this approach, it is important to systematically evaluate the intricacies of the host immune system, the new generation of immunotherapeutics and the RT approach. Here we will discuss the current biologic mechanisms thought to regulate the RT-induced abscopal effect and how these may be translated to the clinical setting. [ABSTRACT FROM AUTHOR]

The immunoglobulin superfamily glycoprotein CD147 (emmprin; basigin) is associated with an invasive phenotype in various types of cancers, including malignant breast cancer. We showed recently that up-regulation of CD147 in non-transformed, non-invasive breast epithelial cells is sufficient to induce an invasive phenotype characterized by membrane type-1 matrix metalloproteinase (MT1-MMP)-dependent invadopodia activity (Grass, G. D., Bratoeva, M., and Toole, B. P. (2012) Regulation of invadopodia formation and activity by CD147. J. Cell Sci. 125, 777-788). Here we found that CD147 induces breast epithelial cell invasiveness by promoting epidermal growth factor receptor (EGFR)-Ras-ERK signaling in a manner dependent on hyaluronan-CD44 interaction. Furthermore, CD147 promotes assembly of signaling complexes containing CD147, CD44, and EGFR in lipid raftlike domains. We also found that oncogenic Ras regulates CD147 expression, hyaluronan synthesis, and formation of CD147-CD44-EGFR complexes, thus forming a positive feedback loop that may amplify invasiveness. Last, we showed that malignant breast cancer cells are heterogeneous in their expression of surface-associated CD147 and that high levels of membrane CD147 correlate with cell surface EGFR and CD44 levels, activated EGFR and ERK1, and activated invadopodia. Future studies should evaluate CD147 as a potential therapeutic target and disease stratification marker in breast cancer. [ABSTRACT FROM AUTHOR]

Sphingosine 1-phosphate (S1P) is a blood-borne lysosphingo-lipid that acts to promote endothelial cell (EC) barrier function. In plasma, S1P is associated with both high density lipoproteins (HDL) and albumin, but it is not known whether the carriers impart different effects on S1P signaling. Here we establish that HDL-S1P sustains EC barrier longer than albumin-S1P. We showed that the sustained barrier effects of HDL-S1P are dependent on signaling by the S1P receptor, S1P1, and involve persistent activation of Akt and endothelial NOS(eNOS), as well as activity of the downstream NO target, soluble guanylate cyclase (sGC). Total S1P1 protein levels were found to be higher in response to HDL-S1P treatment as compared with albumin-S1P, and this effect was not associated with increased S1P1 mRNA or dependent on de novo protein synthesis. Several pieces of evidence indicate that long term EC barrier enhancement activity of HDL-S1P is due to specific effects on S1P1 trafficking. First, the rate of S1P1 degradation, which is proteasome mediated, was slower in HDL-S1P-treated cells as compared with cells treated with albumin-S1P. Second, the long term barrier-promoting effects of HDL-S1P were abrogated by treatment with the recycling blocker, monensin. Finally, cell surface levels of S1P1 and levels of S1P1 in caveolin-enriched microdomains were higher after treatment with HDL-S1P as compared with albumin-S1P. Together, the findings reveal S1P carrier-specific effects on S1P1 and point to HDL as the physiological mediator of sustained S1P1- PI3K-Akt-eNOS-sGC-dependent EC barrier function. [ABSTRACT FROM AUTHOR]

Current guidelines recommend surgery as standard of care for primary lung neuroendocrine tumor (LNET). Given that LNET is a rare clinical entity, there is a lack of literature regarding treatment of LNET with stereotactic body radiation therapy (SBRT). We hypothesized that SBRT could lead to effective locoregional tumor control and long-term outcomes. We retrospectively reviewed 48 tumors in 46 patients from 11 institutions with a histologically confirmed diagnosis of LNET, treated with primary radiation therapy. Data were collected for patients treated nonoperatively with primary radiation therapy between 2006 and 2020. Patient records were reviewed for lesion characteristics and clinical risk factors. Kaplan-Meier analysis, log-rank tests, and Cox multivariate models were used to compare outcomes. Median age at treatment was 71 years and mean tumor size was 2 cm. Thirty-two lesions were typical carcinoid histology, 7 were atypical, and 9 were indeterminate. The most common SBRT fractionation schedule was 50 to 60 Gy in 5 daily fractions. Overall survival at 3, 6, and 9 years was 64%, 43%, and 26%, respectively. Progression-free survival at 3, 6, and 9 years was 88%, 78%, and 78%, respectively. Local control at 3, 6, and 9 years was 97%, 91%, and 91%, respectively. There was 1 regional recurrence in a paraesophageal lymph node. No grade 3 or higher toxicity was identified. This is the largest series evaluating outcomes in patients with LNET treated with SBRT. This treatment is well tolerated, provides excellent locoregional control, and should be offered as an alternative to surgical resection for patients with early-stage LNET, particularly those who may not be ideal surgical candidates. [ABSTRACT FROM AUTHOR]

Purpose: Consolidative thoracic radiation therapy (TRT) has been shown to improve outcomes for patients with extensive stage small cell lung cancer. We hypothesized that the addition of ipilimumab (IPI) and nivolumab (NIVO) after TRT would improve outcomes for patients with extensive stage small cell lung cancer.Methods and Materials: Eligibility required stable disease or better after platinum doublet chemotherapy. Study therapy included consolidative TRT to 30 Gy in 10 fractions, targeting residual primary tumor and initially involved regional lymph nodes. Two weeks after TRT, patients received concurrent IPI (3 mg/kg) and NIVO (1 mg/kg) every 3 weeks for 4 doses followed by NIVO monotherapy (480 mg) every 4 weeks until progression or up to 1 year.Results: The study enrolled 21 patients, with 6-month progression-free survival (PFS) of 24% (90% confidence interval [CI], 11%-40%) and a median PFS of 4.5 months (95% CI, 2.7%-4.6%). The 12-month overall survival (OS) was 48% (95% CI, 29%-64%) with a median OS of 11.7 months (95% CI, 4.7%-16.0%). Fifty-two percent of patients had ≥1 possibly related grade 3 to 4 immune-related adverse event. Grade 3 pulmonary and gastrointestinal immune-related adverse events were recorded in 19% and 24% of patients, respectively. Exploratory analysis showed increased cytotoxic T cell (CD3+CD8+) tumor infiltration was associated with favorable PFS (P = .01) and OS (P = .02). Reduction in peripheral blood CD3+CD8+ from baseline to after first dose of IPI/NIVO was associated with improved PFS (P = .02) and OS (P = .02).Conclusions: Consolidative IPI and NIVO after platinum-based chemotherapy and TRT demonstrated a toxicity profile consistent with the known adverse events attributable to IPI and NIVO. Although the study regimen did not significantly improve PFS, the OS was higher than historic expectations. CD3+CD8+ tumor infiltration and migration may identify patients most likely to have improved outcomes in small cell lung cancer. [ABSTRACT FROM AUTHOR]

Repeat transurethral resection of bladder tumor (reTURBT) is recommended for high-risk non-muscle invasive bladder cancer (NMIBC) given the prevalence of residual disease as well as the potential for pathologic upstaging. However, upwards of 50% of patients lack disease on reTURBT. Urinary cell-free DNA (ucfDNA) based assays may help identify the presence of disease following index TURBT and identify optimal candidates for reTURBT. Given the higher sensitivity afforded by tumor informed approaches, we sought to explore the genomic concordance of index and reTURBT specimens. In addition, we evaluated the utility of low-pass whole genome sequencing (LPWGS) to predict residual disease at reTURBT, which is less resource-intensive when compared to whole exome sequencing. Fifty-one patients undergoing repeat TURBT within 12 weeks of an initial diagnosis of high-risk NMIBC were prospectively enrolled at Moffitt Cancer Center. Tumor tissue was collected from index and repeat TURBT. Peripheral blood for germline analysis and urine was obtained prior to reTURBT. Tumor tissue and blood buffy coat were subject to whole-exome sequencing at ∼20,000X with PredicineWES+ and ucfDNA underwent LPWGS (PredicineSCORE 1-3X). Non-synonymous mutations and significant gene copy-number variation (CNVs) were identified and compared between index and reTURBT specimens with matched germline control. Bespoke urinary tumor fraction (TF) based on tumor variants was calculated using Predicine DeepSea pipeline algorithm. Thirty patients had residual disease on reTURBT and 21 did not. Overall average variant concordance between index and repeat tumors was 74%. 29 out of 30 patients with disease detected at reTURBT had novel tumor variants in the reTUR tissue. Index tumors had a median 161.5 mutations (range 1-1384) and 9 CNVs (range 1-73). ReTUR tissue had a median of 43 mutations (range 2-1113) and 3 CNVs (range 1-21). Mean urinary TF from LPWGS was significantly higher in patients that were disease positivie at reTURBT (12.2% vs. 4.9% Wilcoxon, p=0.002). At a threshold TF of 2.2%, we had 81% sensitivity at 71% specificity to predict residual disease at reTUR in this cohort (AUC: 0.76). Index and reTURBT tumor tissue have high variant concordance, demonstrating the rationale in utilizing tumor informed ucfDNA assays to identify residual disease prior to repeat transurethral resection. Novel mutations also arise in almost all patients highlighting the potential utility of personalized MRD tracking prior to reTURBT. We demonstrate that urinary TF derived from LPWGS of ucfDNA currently provides moderate sensitivity to detect disease prior to reTURBT. With further development, these two methodologies have strong potential to select optimal candidates for reTURBT in high risk NMIBC. [ABSTRACT FROM AUTHOR]

Plasmacytoid urothelial cancer (PUC) is notorious for its discohesive spread along fascial planes. Its presence is thought to induce worse clinicopathologic features such as higher stage, rate of positive margin, and lymph node involvement. However, given PUC often co-exists with conventional urothelial carcinoma (CUC), it is unclear which histology is truly driving these pathologic findings. We performed a retrospective review of patients with PUC who underwent cystectomy at Moffitt Cancer Center between 2012-2022. Repeat histological review of all specimens by specialty trained genitourinary pathologists (ED, AV) was performed and plasmacytoid percentage assigned. Positive margins and lymph nodes were re-examined and classified by histological subtype. For pT3 cases, the ratio of tissue sections with peri-vesical fat invasion to total number of slides with peri-vesical fat was calculated (fat invasion ratio, FIR) and compared to the standard pT3 sub-staging definition. Pearson's correlation coefficient was used to measure strength and direction of relationship between variables. Kaplan-Meier (KM) analysis was performed for overall survival (OS). Sixty-eight patients were included of which 55.4% had ≥cT3 disease and 59% received neoadjuvant chemotherapy. Median percentage of PUC was 25% (IQR 3-90%) with 8 (12%), 5 (7.4%), 7 (10%), 25 (37%), 23 (34%) being pT0, pT1, pT2, pT3, pT4, respectively. In pT3 subgroup, 13 were pT3a with median 75% (IQR 11-82%) FIR, which was higher than pT3b (N=12) stage at 56% (43-66%). FIR did not correlate with pT3 sub-staging (p=0.597). In those with positive soft tissue and/or ureteral margins, PUC was the driver histology in 82% and 84% of patients, respectively. 187 of 1,413 lymph nodes were positive for malignancy with 68.6% containing PUC histology. Histologic subtype did not drive differences in OS (Figure 1). Univariate analysis confirmed an increasing percentage of PUC histology portended a worse OS (HR 3.17, 95% CI 1.47-6.82, p=0.003) and correlated with worse pT Stage, lymph node density and FIR (Figure 2). Plasmacytoid urothelial carcinoma was the driver histology for the majority of positive lymph nodes, soft tissue and ureteral margins. However, survival outcomes did not depend on which histology was responsible for these pathologic features. Additionally, pT3 sub-staging does not adequately capture the extent of disease involving the peri-vesical fat in PUC and may warrant further evaluation. [ABSTRACT FROM AUTHOR]