Unraveling noncoding DNA variants and epimutations: a paradigm shift in hereditary cancer research.

Exhaustive efforts have been dedicated to uncovering genomic aberrations linked to cancer susceptibility. Noncoding sequence variants and epigenetic alterations significantly influence gene regulation and could contribute to cancer development. However, exploring noncoding regions in hereditary cancer susceptibility demands cutting-edge methodologies for functionally characterizing genomic discoveries. Additionally, comprehending the impact on cancer development of variants in noncoding DNA and the epigenome necessitates integrating diverse data through bioinformatic analyses. As novel technologies and analytical methods continue to advance, this realm of research is rapidly gaining traction. Within this mini-review, we delve into future research domains concerning aberrations in noncoding DNA regions, such as pseudoexons, promoter variants and cis-epimutations.

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Development of Novel Models of Aggressive Variants of Castration-resistant Prostate Cancer.

BACKGROUND: Genomic studies have identified new subsets of aggressive prostate cancer (PCa) with poor prognosis (eg, neuroendocrine prostate cancer [NEPC], PCa with DNA damage response [DDR] alterations, or PCa resistant to androgen receptor pathway inhibitors [ARPIs]). Development of novel therapies relies on the availability of relevant preclinical models. OBJECTIVE: To develop new preclinical models (patient-derived xenograft [PDX], PDX-derived organoid [PDXO], and patient-derived organoid [PDO]) representative of the most aggressive variants of PCa and to develop a new drug evaluation strategy. DESIGN, SETTING, AND PARTICIPANTS: NEPC (n = 5), DDR (n = 7), and microsatellite instability (MSI)-high (n = 1) PDXs were established from 51 patients with metastatic PCa; PDXOs (n = 16) and PDOs (n = 6) were developed to perform drug screening. Histopathology and treatment response were characterized. Molecular profiling was performed by whole-exome sequencing (WES; n = 13), RNA sequencing (RNA-seq; n = 13), and single-cell RNA-seq (n = 14). WES and RNA-seq data from patient tumors were compared with the models. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Relationships with outcome were analyzed using the multivariable chi-square test and the tumor growth inhibition test. RESULTS AND LIMITATIONS: Our PDXs captured both common and rare molecular phenotypes and their molecular drivers, including alterations of BRCA2, CDK12, MSI-high status, and NEPC. RNA-seq profiling demonstrated broad representation of PCa subtypes. Single-cell RNA-seq indicates that PDXs reproduce cellular and molecular intratumor heterogeneity. WES of matched patient tumors showed preservation of most genetic driver alterations. PDXOs and PDOs preserve drug sensitivity of the matched tissue and can be used to determine drug sensitivity. CONCLUSIONS: Our models reproduce the phenotypic and genomic features of both common and aggressive PCa variants and capture their molecular heterogeneity. Successfully developed aggressive-variant PCa preclinical models provide an important tool for predicting tumor response to anticancer therapy and studying resistance mechanisms. PATIENT SUMMARY: In this report, we looked at the outcomes of preclinical models from patients with metastatic prostate cancer enrolled in the MATCH-R trial (NCT02517892).

UGT1A1 Testing in Breast Cancer: should it become routine practice in patients treated with antibody-drug conjugates?

The use of genetic testing to personalize therapeutic strategies in cancer is rapidly evolving and thus changing the landscape of treatment of oncologic patients. The UGT1A1 gene is an important component for the metabolism and glucoronidation of certain drugs, including irinotecan and sacituzumab govitecan (SG); therefore, various UGT1A1 polymorphisms leading to decreased function of the UGT1A1 enzyme may lead to increased risk of treatment-related side effects. Testing for UGT1A1 polymorphism is not routinely adopted in clinical practice; that is due to the lack of concise studies and recommendations concerning the clinical relevance of this test and its impact on the quality of life of cancer patients. The knowledge regarding UGT1A1 polymorphism and its clinical relevance will be reviewed in this article, as well as the published literature on the association between UGT1A1 polymorphism and the toxicity risk of irinotecan as well as sacituzumab govitecan. The current recommendations and guidelines on UGT1A1 testing will be discussed in detail in the hopes of providing guidance to oncologists in their clinical practice.

A Comprehensive Review on the Role of Lurbinectedin in Soft Tissue Sarcomas.

OPINION STATEMENT: Soft tissue sarcoma (STS), a substantial group of aggressive and rare tumors with tissue heterogeneity, is infrequently represented in clinical trials with an urgent necessity for newer treatment options. Lurbinectedin, an analog of trabectedin, is currently approved, in various countries, as a single agent, for the treatment of patients with relapsed small cell lung cancer (SCLC). However, preclinical and phase I and phase II trials have demonstrated the efficacy of lurbinectedin in different tumor types, including STS. The better understanding of the pathophysiology and evolution of STS as well as the mechanism of action of lurbinectedin in addition to the available data regarding the activity of this drug in this subset of patients will pave the way to newer therapeutic options and strategies.

Synergic prognostic value of 3D CT scan subcutaneous fat and muscle masses for immunotherapy-treated cancer.

BACKGROUND: Our aim was to explore the prognostic value of anthropometric parameters in a large population of patients treated with immunotherapy. METHODS: We retrospectively included 623 patients with advanced non-small cell lung cancer (NSCLC) (n=318) or melanoma (n=305) treated by an immune-checkpoint-inhibitor having a pretreatment (thorax-)abdomen-pelvis CT scan. An external validation cohort of 55 patients with NSCLC was used. Anthropometric parameters were measured three-dimensionally (3D) by a deep learning software (Anthropometer3DNet) allowing an automatic multislice measurement of lean body mass, fat body mass (FBM), muscle body mass (MBM), visceral fat mass (VFM) and sub-cutaneous fat mass (SFM). Body mass index (BMI) and weight loss (WL) were also retrieved. Receiver operator characteristic (ROC) curve analysis was performed and overall survival was calculated using Kaplan-Meier (KM) curve and Cox regression analysis. RESULTS: In the overall cohort, 1-year mortality rate was 0.496 (95% CI: 0.457 to 0.537) for 309 events and 5-year mortality rate was 0.196 (95% CI: 0.165 to 0.233) for 477 events. In the univariate Kaplan-Meier analysis, prognosis was worse (p<0.001) for patients with low SFM (<3.95 kg/m2), low FBM (<3.26 kg/m2), low VFM (<0.91 kg/m2), low MBM (<5.85 kg/m2) and low BMI (<24.97 kg/m2). The same parameters were significant in the Cox univariate analysis (p<0.001) and, in the multivariate stepwise Cox analysis, the significant parameters were MBM (p<0.0001), SFM (0.013) and WL (0.0003). In subanalyses according to the type of cancer, all body composition parameters were statistically significant for NSCLC in ROC, KM and Cox univariate analysis while, for melanoma, none of them, except MBM, was statistically significant. In multivariate Cox analysis, the significant parameters for NSCLC were MBM (HR=0.81, p=0.0002), SFM (HR=0.94, p=0.02) and WL (HR=1.06, p=0.004). For NSCLC, a KM analysis combining SFM and MBM was able to separate the population in three categories with the worse prognostic for the patients with both low SFM (<5.22 kg/m2) and MBM (<6.86 kg/m2) (p<0001). On the external validation cohort, combination of low SFM and low MBM was pejorative with 63% of mortality at 1 year versus 25% (p=0.0029). CONCLUSIONS: 3D measured low SFM and MBM are significant prognosis factors of NSCLC treated by immune checkpoint inhibitors and can be combined to improve the prognostic value.

Overview of the role of liquid biopsy in cancer management.

With the emergence of novel targeted therapeutic options in early-stage and advanced-stage malignancies, researchers have shifted their focus on developing personalized treatment plans through molecular profiling. Circulating tumor DNA (ctDNA) is a cell-free DNA (ctDNA) fragment, originating from tumor cells, and circulating in the bloodstream as well as biological fluids. Over the past decade, many techniques were developed for liquid biopsies through next-generation sequencing. This alternative non-invasive biopsy offers several advantages in various types of tumors over traditional tissue biopsy. The process of liquid biopsy is considered minimally invasive and therefore easily repeatable when needed, providing a more dynamic analysis of the tumor cells. Moreover, it has an advantage in patients with tumors that are not candidates for tissue sampling. Besides, it offers a deeper understanding of tumor burden as well as treatment response, thereby enhancing the detection of minimal residual disease and therapeutic guidance for personalized medicine. Despite its many advantages, ctDNA and liquid biopsy do have some limitations. This paper discusses the basis of ctDNA and the current data available on the subject, as well as its clinical utility. We also reflect on the limitations of using ctDNA in addition to its future perspectives in clinical oncology and precision medicine.

Genomic Profiling of Metastatic Castration-Resistant Prostate Cancer Samples Resistant to Androgen Receptor Pathway Inhibitors.

PURPOSE: The androgen receptor axis inhibitors (ARPI; e.g., enzalutamide, abiraterone acetate) are administered in daily practice for men with metastatic castration-resistant prostate cancer (mCRPC). However, not all patients respond, and mechanisms of both primary and acquired resistance remain largely unknown. EXPERIMENTAL DESIGN: In the prospective trial MATCH-R (NCT02517892), 59 patients with mCRPC underwent whole-exome sequencing (WES) and/or RNA sequencing (RNA-seq) of samples collected before starting ARPI. Also, 18 patients with mCRPC underwent biopsy at time of resistance. The objectives were to identify genomic alterations associated with resistance to ARPIs as well as to describe clonal evolution. Associations of genomic and transcriptomic alterations with primary resistance were determined using Wilcoxon and Fisher exact tests. RESULTS: WES analysis indicated that no single-gene genomic alterations were strongly associated with primary resistance. RNA-seq analysis showed that androgen receptor (AR) gene alterations and expression levels were similar between responders and nonresponders. RNA-based pathway analysis found that patients with primary resistance had a higher Hedgehog pathway score, a lower AR pathway score and a lower NOTCH pathway score than patients with a response. Subclonal evolution and acquisition of new alterations in AR-related genes or neuroendocrine differentiation are associated with acquired resistance. ARPIs do not induce significant changes in the tumor transcriptome of most patients; however, programs associated with cell proliferation are enriched in resistant samples. CONCLUSIONS: Low AR activity, activation of stemness programs, and Hedgehog pathway were associated with primary ARPIs' resistance, whereas most acquired resistance was associated with subclonal evolution, AR-related events, and neuroendocrine differentiation. See related commentary by Slovin, p. 4323.

Experience with second-line trabectedin in daily clinical practice: case studies.

As a recommended second-line option for advanced soft tissue sarcoma, trabectedin can provide the necessary balance between long-term tumor control and preserved quality of life. Three case studies illustrate the long-lasting responses that patients can achieve with second-line trabectedin. A female patient with metastatic leiomyosarcoma maintained disease control for 2 years with trabectedin (× 41 cycles) with excellent tolerability and no relevant adverse events. At the time of writing, a male patient with a metastatic solitary fibrous tumor was asymptomatic after 30 cycles of trabectedin and treatment was ongoing. A young male patient with a recurrent, nonresectable, retroperitoneal myxoid/round cell liposarcoma was able to continue his sporting activities (triathlons) over 2 years with trabectedin (× 14 cycles) plus watchful waiting.

Perioperative risk factors associated with delayed graft function following deceased donor kidney transplantation: A retrospective, single center study.

BACKGROUND: There is an abundant need to increase the availability of deceased donor kidney transplantation (DDKT) to address the high incidence of kidney failure. Challenges exist in the utilization of higher risk donor organs into what appears to be increasingly complex recipients; thus the identification of modifiable risk factors associated with poor outcomes is paramount. AIM: To identify risk factors associated with delayed graft function (DGF). METHODS: Consecutive adults undergoing DDKT between January 2016 and July 2017 were identified with a study population of 294 patients. The primary outcome was the occurrence of DGF. RESULTS: The incidence of DGF was 27%. Under logistic regression, eight independent risk factors for DGF were identified including recipient body mass index ≥ 30 kg/m2, baseline mean arterial pressure < 110 mmHg, intraoperative phenylephrine administration, cold storage time ≥ 16 h, donation after cardiac death, donor history of coronary artery disease, donor terminal creatinine ≥ 1.9 mg/dL, and a hypothermic machine perfusion (HMP) pump resistance ≥ 0.23 mmHg/mL/min. CONCLUSION: We delineate the association between DGF and recipient characteristics of pre-induction mean arterial pressure below 110 mmHg, metabolic syndrome, donor-specific risk factors, HMP pump parameters, and intraoperative use of phenylephrine.

Role of microRNAs in the predisposition to gastrointestinal malignancies.

MicroRNAs (miRNAs) are highly deregulated in cancer and play a role in the initiation of tumorigenesis. Recently, miRNAs have attracted attention in gastrointestinal (GI) cancers. Single nucleotide polymorphisms (SNPs) could affect the genes involved in each step of miRNA biosynthesis. Several meta-analyses of case-control studies have assessed the association between miRNA "pathway" gene-SNPs (including biosynthesis regulators and binding sites) and susceptibility to GI cancers. We present in this mini-review the current knowledge on the association between miRNAs "pathway" genes and GI cancer predisposition. The interaction between miRNA/regulators/binding site-SNPs and environmental as well as genomic factors is an interesting field that should be exploited in future studies.

Comprehensive tumor profiling-guided therapy in rare or refractory solid cancer: A feasibility study in daily clinical practice.

Tumor profiling has been shown to benefit patients with rare or refractory metastatic cancer, but several limitations hamper its use in daily clinical practice. We aim to assess the added benefit of a comprehensive tumor profiling, including factors predictive of response to targeted and cytotoxic therapy, in the treatment of refractory or rare solid tumors outside of a formal clinical trial. Patients were included between 2013 and 2017. Multiplatform comprehensive tumor profiling (CTP) was performed on FFPE specimens. Tumor response was evaluated by imaging using the RECIST criteria version 1.1. The PFS ratio was defined as PFS under CTP-guided therapy (PFS2)/PFS under previous standard therapy (PFS1). A clinical benefit was identified if the PFS ratio exceeded the 1.3 threshold value. In total, 184 patients were enrolled among whom 104 were evaluable for the PFS ratio. Objective response rates (ORR) were equal to 25% (CI95: 16.6-33.4%) and 36.5% (CI95: 27.2-45.8%) on the last therapy before CTP and on the CTP-guided therapy respectively (P-value=0.058 on paired proportion comparison test). The proportion of patients achieving a PFS2/PFS1 ratio≥1.3 was equal to 50%. The median PFS1 was statistically lower than PFS2 (120 days compared to 184 days respectively, P-value log rank 0.01). These results confirm the feasibility and the added benefit of a CTP in patients with refractory tumors in daily clinical practice especially in patients not able to enter a clinical trial.

Non-branched microcysts of the pancreas on MR imaging of patients with pancreatic tumors who had pancreatectomy may predict the presence of pancreatic intraepithelial neoplasia (PanIN): a preliminary study.

PURPOSE: To evaluate whether pancreatic parenchymal abnormalities on magnetic resonance imaging (MRI) are associated with pancreatic intraepithelial neoplasia (PanIN) on histology. MATERIALS AND METHODS: Retrospective study approved by institutional review board. One hundred patients (48 men, 52 women; mean age, 53.2 ± 16.29 [SD]) underwent MRI before pancreatectomy for pancreatic tumors analyzed by two independent observers blinded to histopathological results for the presence of non-communicating microcysts and pancreatic atrophy (global or focal) beside tumors. MRI findings were compared to histopathological findings of resected specimens. Interobserver agreement was calculated. The association between parenchymal abnormalities and presence of PanIN was assessed by uni- and multivariate analyses. RESULTS: PanIN was present in 65/100 patients (65%). The presence of microcysts on MRI had a sensitivity of 52.3% (34/65 [95%CI, 51.92-52.70%]), a specificity of 77.1% (27/35 [95%CI, 76.70-77.59]), and accuracy of 61% (61/100 95%CI [50.7-70.6]) for the diagnosis of PanIN while global atrophy had a sensitivity of 24.6% (16/6 [95%CI, 24.28-24.95]) and a specificity of 97.1% (34/35 [95%CI, 96.97-97.32%]). In multivariate analysis, the presence of microcysts (OR, 3.37 [95%CI, 1.3-8.76]) (p = 0.0127) and global atrophy (OR, 9.79 [95%CI, 1.21-79.129]) (p = 0.0324) were identified as independent predictors of the presence of PanIN. The combination of these two findings was observed in 10/65 PanIN patients and not in patients without PanIN (p = 0.013 with an OR of infinity [95%CI, 1.3-infinity]) and was not discriminant for PanIN-3 and lower grade (p = 0.22). Interobserver agreement for the presence of microcysts was excellent (kappa = 0.92), and for the presence of global atrophy, it was good (kappa = 0.73). CONCLUSION: The presence of non-communicating microcysts on pre-operative MRI can be a significant predictor of PanIN in patients with pancreatic tumors. KEY POINTS: • In patients with pancreatic tumors who had partial pancreatectomy, MR non-communicating pancreatic microcysts have a 52.3% sensitivity, a 77.1% specificity, and a 61% accuracy for the presence of PanIN with univariate and with an odds ratio of 3.37 with multivariate analyses. • The association of global atrophy and non-communicating microcysts increases the predictive risk of PanIN.

Post-shingles granulomatous dermatosis related to anti-programmed cell death 1.

The most recent progress in the oncology field has led to a paradigm shift in the management of cancer with the tsunami of immune checkpoint inhibitors that are associated with a particular pattern of immunological adverse events. This is a case of a 54-year-old woman that demonstrated a granulomatous reaction in the same dermatomal distribution of a previously treated shingles infection during treatment with an anti-programmed death 1 agent (pembrolizumab) for a newly diagnosed stage IV Hodgkin lymphoma. The purpose of this case is to increase the awareness of oncologists dealing with a new pattern of side effects taking into account the patient's background and recent exposures to latent viruses such as herpes zoster to prevent unnecessary diagnostic and therapeutic measures.

Colorectal cancer and brain metastases: An aggressive disease with a different response to treatment.

INTRODUCTION: Brain metastases (BM) are rare in colorectal cancer (CRC) and are associated with a dismal prognosis. This work aims to report the rate of BM in CRC patients treated in a single institution, along with survival and prognostic factors. METHODS: Medical charts for patients with histologically proven CRC were retrospectively reviewed. RESULTS: A total of 538 patients were identified, of whom 33% developed any metastatic disease and 4.4% presented BM. Lung was the most frequently associated metastatic site (in 68% of the cases). The only factor independently associated with BM development was the presence of metastatic disease at the time of initial presentation. The median duration from initial diagnosis to BM development was 38.6 months (SD 29.1 months). Median survival after BM development was 62 days (95% confidence interval [CI] 56-68). Patients diagnosed with BM within 1 year of cancer diagnosis responded significantly better to treatment than those who acquired BM later, with a median survival after BM diagnosis of 261 days versus 61 days, respectively (p = .002). Patients with BM who received antiangiogenic therapy had an improved median survival compared to those who did not (151 days vs 59 days, p = 0.02; hazard ratio for death 0.29 [95% CI 0.09-0.94]). CONCLUSION: CRC with BM is an aggressive disease resistant to standard treatment and is associated with poor outcomes. Adding antiangiogenic therapy might be of value for those patients. Patients with BM developing early in the disease course might respond better to treatment.

Preserving quality of life as a key treatment goal in advanced soft tissue sarcomas.

INTRODUCTION: Health-related quality of life (HRQoL) is a patient-reported outcome that addresses patients' perceptions of symptoms across physical, emotional, cognitive and social domains. As HRQoL is currently rarely measured outside clinical trials in oncology, it must be inferred from patients' everyday performance during treatment. To gain insight into the HRQoL of advanced STS patients receiving palliative treatment in clinical practice, three case studies of patients treated with trabectedin are examined. Areas covered: The patient in Case 1 has maintained complete remission for more than 8 years after receiving nine cycles of second-line trabectedin followed by secondary surgery for recurrent myxoid liposarcoma, and was able to resume normal activities during trabectedin treatment. Case 2 describes 10 years' follow-up of a patient with myxoid liposarcoma who remains well after many lines of chemotherapy including extended use of trabectedin in the second line. The third case illustrates the feasibility of extending survival time in an elderly patient with metastatic leiomyosarcoma who was able to maintain a busy and active lifestyle while receiving second-line trabectedin. Expert commentary: Owing to its relatively benign safety profile, trabectedin frequently permits prolonged therapy and is generally well tolerated, often allowing patients to carry on with normal daily activities.

Molecular characteristics of colorectal cancer in a Middle Eastern population in a single institution.

BACKGROUND: The few studies of the molecular biology of colorectal cancer (CRC) in Middle Eastern populations have included only small samples of patients. OBJECTIVE: Evaluate the frequency and prognostic effect of RAS, BRAF, PIK3CA, PTEN, and EGFR somatic mutations as well as mismatch repair (MMR) deficiency in Lebanese Middle Eastern patients. DESIGN: Retrospective single-center descriptive study. SETTING: Lebanese Middle Eastern patients in a tertiary medical cen.ter. METHODS: We included all patients diagnosed with CRC between January 2010 and December 2015, in whom RAS mutational status and the expression of MLH1 and MSH2 proteins were available. MAIN OUTCOME MEASURES: Genetic mutations detected by direct sequencing while MMR protein expression was evaluated by immunohistochemistry. SAMPLE SIZE: 645 patients. RESULTS: RAS, BRAF, EGFR, PI3KCA, and PTEN mutation rates were 38.5%,12.9%, 0%, 11.1% and 0% respectively. The MMR deficiency rate was 20.6%. No factor was associated with RAS mutation whereas MMR-deficient tumors were less likely to be metastatic at diagnosis. Among patients with wild-type RAS females fared better than males (median overall survival [OS]=1734 vs 1079 days respectively, P=.015) even after adjustment for confounding factors by Cox regression analy.sis. This finding was not reproduced in the RAS-mutated group. The median OS of patients with MMR-deficient tumors was not reached, while the median OS was 2475 days in patients who had maintained expression of both MLH1 and MSH2. CONCLUSION: The RAS mutation rate was similar to Western and East Asian countries, but not for the BRAF mutation and MMR deficiency. We also found a prognostic effect for sex in the RAS wild-type group, a finding worthy of further exploration. LIMITATIONS: Retrospective, single center and small sample size. Expression of MSH6 and PMS2 not analyzed. CONFLICT OF INTEREST: None.