Systematic review of the efficacy of stereotactic ablative radiotherapy for oligoprogressive disease in metastatic cancer.

BACKGROUND: Stereotactic Ablative Radiotherapy (SABR) for the treatment of oligometastatic disease can improve survival and delay the requirement for systemic therapy. The benefits of SABR in oligoprogressive disease are less well-defined. Here, we evaluate the available evidence investigating the efficacy of SABR in the treatment of oligoprogressive disease. METHODS: A systematic review was carried out following PRISMA guidelines. Medline and Embase databases were searched using the terms "stereotactic radiotherapy" OR "SABR" OR "Stereotactic Ablative Body Radiotherapy" OR "SBRT" OR "SRT" AND "oligoprogression" in May 2022, June 2023, and February 2024. Studies were excluded where: SABR was used as a radical treatment, a specific oligoprogressive cohort could not be identified, publication was as a conference abstract or where fewer than 10 patients were recruited. Studies treating only brain metastases were also excluded. The site of primary tumour, oligoprogressive sites, rates of overall survival (OS), progression free survival (PFS), local control (LC) and time to next systemic therapy were collected. RESULTS: Thirty-three full text studies were included. These consisted of single centre and multi-institutional observational studies, case series and phase II trials. Twenty-two studies were related to a specific tumour type: 12 urological cancer (9 prostate, 3 renal cancer), 6 non-small cell lung cancer, 2 colorectal cancer, 2 breast cancer and 11 were studies covering multiple tumour sites (5 studies involving SABR to a single organ and 6 studies involving SABR to multi-organ). Median PFS was >6 months in patients with oligoprogressive prostate, non-small cell lung cancer and renal cancer patients. CONCLUSIONS: SABR appears to have clinical benefit in oligoprogresssive prostate, lung, and renal patients. However, the optimal management of patients with oligoprogressive disease is still somewhat uncertain due to lack of prospective data. This will hopefully become clearer in the near future with the publication of further randomised trials.

Prognostic value of the Scottish Inflammatory prognostic Score in patients with NSCLC expressing PD-L1 ≥ 50 % progressing on first-line pembrolizumab.

BACKGROUND: Most patients with advanced non-small cell lung cancer (NSCLC) treated with first-line pembrolizumab monotherapy will experience progressive disease (PD). Only a minority will go on to receive subsequent systemic anticancer therapy for which outcomes are guarded. We investigated the prognostic significance of biomarkers of systemic inflammation following failure of first-line pembrolizumab for NSCLC to aid subsequent management decisions. METHODS: Patients with radiological and/or clinical evidence of PD on first-line pembrolizumab for advanced NSCLC at a regional Scottish cancer centre were identified. Inflammatory biomarkers at the time of PD, including serum albumin, neutrophil count and the Scottish Inflammatory Prognostic Score (SIPS; combing albumin and neutrophils), and clinicopathological factors, including age, sex, histology, PDL1 expression and time to PD were recorded. The relationship between these and post-progression overall survival (ppOS) were examined. RESULTS: Data were available for 211 patients. Median ppOS was 2.1 months. Only SIPS was predictive of ppOS on multivariate analysis (HR2.54 (95 %CI 1.81-3.56) (<0.001)), stratifying ppOS from 0.8 months (SIPS2), to 1.8 months (SIPS1), to 8.1 months (SIPS0) (p < 0.001). Thirty (14 %) patients received second-line systemic anticancer therapy with median ppOS 8.7 months. These patients had lower levels of systemic inflammation, as defined by albumin (p < 0.001), neutrophil count (p = 0.002), and SIPS (p = 0.004)), than all other patients. CONCLUSIONS: SIPS, a simple biomarker of systemic inflammation, predicts ppOS after first-line pembrolizumab and may be useful alongside routine assessments of patient fitness to inform individualised discussions about subsequent treatment. We highlight poor outcomes in this patient group and a role for SIPS in signposting transition to best supportive care and early referral to palliative care. It may also help identify a small group of patients most likely to benefit from further lines of therapy.

Know when to fold 'em: Polycomb complexes in oncogenic 3D genome regulation.

Chromatin is spatially and temporally regulated through a series of orchestrated processes resulting in the formation of 3D chromatin structures such as topologically associating domains (TADs), loops and Polycomb Bodies. These structures are closely linked to transcriptional regulation, with loss of control of these processes a frequent feature of cancer and developmental syndromes. One such oncogenic disruption of the 3D genome is through recurrent dysregulation of Polycomb Group Complex (PcG) functions either through genetic mutations, amplification or deletion of genes that encode for PcG proteins. PcG complexes are evolutionarily conserved epigenetic complexes. They are key for early development and are essential transcriptional repressors. PcG complexes include PRC1, PRC2 and PR-DUB which are responsible for the control of the histone modifications H2AK119ub1 and H3K27me3. The spatial distribution of the complexes within the nuclear environment, and their associated modifications have profound effects on the regulation of gene transcription and the 3D genome. Nevertheless, how PcG complexes regulate 3D chromatin organization is still poorly understood. Here we glean insights into the role of PcG complexes in 3D genome regulation and compaction, how these processes go awry during tumorigenesis and the therapeutic implications that result from our insights into these mechanisms.

Urothelial cancer: a narrative review of the role of novel immunotherapeutic agents with particular reference to the management of non-muscle-invasive disease.

AIM: This narrative review describes current guidelines for treating NMIBC, provides an overview of the principle behind immune checkpoint inhibition, and summarizes current evidence for checkpoint inhibitors in urothelial malignancy. Further, we discuss potential strategies for immune checkpoint inhibition in the management of NMIBC. BACKGROUND: Adjuvant intravesical BCG immunotherapy has been the mainstay of treatment for high-risk non-muscle-invasive bladder cancer (NMIBC) for decades but is associated with both a significant side effect profile and failure rate. Recently, a substantial body of trial data has been published demonstrating the successful use of systemic immunotherapy in the treatment of advanced urothelial malignancy and, in particular, a class of drugs known as 'immune checkpoint inhibitors'. This has led to the approval of a number of these drugs by the UK National Institute of Health and Care Excellence and the US Food and Drug Administration, and ongoing trials are examining use in the management of NMIBC. METHODS: To identify relevant published data, using the PubMed/ Medline search engine, an online search of the Pubmed/ Medline archives was conducted using the terms bladder cancer' in combination with 'checkpoint inhibitors', and limited to articles in English published between 1966 and September 2017.To identify ongoing trials of interest but not yet published, a further search of the clinical trials.gov search engine was conducted using the term 'non-muscle-invasive bladder cancer'. CONCLUSION: There has been little advance in available adjuvant therapy for NMIBC treated with TURBT. Current intravesical therapies are associated with a high recurrence rate and significant side effect profile. The impending publication of the wealth of ongoing trials, both into the delivery and efficacy of checkpoint inhibition will direct the future treatment of NMIBC.

Spindle assembly checkpoint protein expression correlates with cellular proliferation and shorter time to recurrence in ovarian cancer.

Ovarian carcinoma (OC) is the most lethal of the gynecological malignancies, often presenting at an advanced stage. Treatment is hampered by high levels of drug resistance. The taxanes are microtubule stabilizing agents, used as first-line agents in the treatment of OC that exert their apoptotic effects through the spindle assembly checkpoint. BUB1-related protein kinase (BUBR1) and mitotic arrest deficient 2 (MAD2), essential spindle assembly checkpoint components, play a key role in response to taxanes. BUBR1, MAD2, and Ki-67 were assessed on an OC tissue microarray platform representing 72 OC tumors of varying histologic subtypes. Sixty-one of these patients received paclitaxel and platinum agents combined; 11 received platinum alone. Overall survival was available for all 72 patients, whereas recurrence-free survival (RFS) was available for 66 patients. Increased BUBR1 expression was seen in serous carcinomas, compared with other histologies (P = .03). Increased BUBR1 was significantly associated with tumors of advanced stage (P = .05). Increased MAD2 and BUBR1 expression also correlated with increased cellular proliferation (P < .0002 and P = .02, respectively). Reduced MAD2 nuclear intensity was associated with a shorter RFS (P = .03), in ovarian tumors of differing histologic subtype (n = 66). In this subgroup, for those women who received paclitaxel and platinum agents combined (n = 57), reduced MAD2 intensity also identified women with a shorter RFS (P < .007). For the entire cohort of patients, irrespective of histologic subtype or treatment, MAD2 nuclear intensity retained independent significance in a multivariate model, with tumors showing reduced nuclear MAD2 intensity identifying patients with a poorer RFS (P = .05).

JAM-A expression positively correlates with poor prognosis in breast cancer patients.

The cell-cell adhesion protein junctional adhesion molecule-A (JAM-A) influences epithelial cell morphology and migration. As migration is required for tumor cell invasion and metastasis, we sought to elucidate the role of JAM-A in invasive breast cancer. A breast cancer tissue microarray was analyzed for JAM-A protein expression, in parallel with analysis of JAM-A gene expression data from a breast cancer clinical dataset. Our data demonstrate a novel association between JAM-A gene and protein upregulation and poor prognosis in breast cancer. To mechanistically dissect this process, we used lentiviral technology to stably knock down JAM-A gene expression by shRNA in MCF7 breast cancer cells, which express high-endogenous levels of JAM-A. We also antagonized JAM-A function in wild-type MCF7 cells using an inhibitory antibody that blocks JAM-A dimerization. Knockdown or functional antagonism of JAM-A decreased breast cancer cell migration in scratch-wound assays. Reductions in beta1-integrin protein levels were observed after JAM-A-knockdown in MCF7 cells, suggesting a mechanism for reduced motility after loss of JAM-A. Consistent with this hypothesis, tissue microarray analysis of beta1-integrin protein expression in invasive breast cancer tissues revealed a trend toward high beta1-integrin protein levels being indicative of poor prognosis. Twenty-two percent of patients were observed to coexpress high levels of JAM-A and beta1-integrin protein, and MDA-MB-231 breast cells stably overexpressing JAM-A showed an increase in beta1-integrin protein expression. Our results are consistent with a previously unreported role for JAM-A overexpression as a possible mechanism contributing to progression in primary breast cancer; and a potential therapeutic target.

The transcription factor Sox11 is a prognostic factor for improved recurrence-free survival in epithelial ovarian cancer.

BACKGROUND: Current prognostic molecular markers for epithelial ovarian cancer (EOC) are insufficient. The aim of the current study was to investigate the role of Sox11 in EOC. METHODS: Using an in silico transcriptomic screen, Sox11 was identified as a potential EOC biomarker. Sox11 protein expression was evaluated using immunohistochemistry (IHC) in 76 EOC cases, which were analysed using automated algorithms to develop a quantitative scoring model. RESULTS: Sox11 mRNA expression was upregulated in EOC compared to normal tissues. Automated analysis of Sox11 in the EOC cohort revealed high expression of Sox11, in 40% of tumours, who had an improved recurrence-free survival (RFS) (p=0.002). Multivariate analysis confirmed that Sox11 was an independent predictor of improved RFS after controlling for stage and grade. CONCLUSIONS: These data suggest that Sox11 is a new prognostic marker in EOC. Loss of Sox11 is associated with a decreased RFS and a more aggressive phenotype.