UNLABELLED: Gastric cancer represents the third leading cause of global cancer mortality and an area of unmet clinical need. Drugs that target the DNA damage response, including ATR inhibitors (ATRi), have been proposed as novel targeted agents in gastric cancer. Here, we sought to evaluate the efficacy of ATRi in preclinical models of gastric cancer and to understand how ATRi resistance might emerge as a means to identify predictors of ATRi response. A positive selection genome-wide CRISPR-Cas9 screen identified candidate regulators of ATRi resistance in gastric cancer. Loss-of-function mutations in either SMG8 or SMG9 caused ATRi resistance by an SMG1-mediated mechanism. Although ATRi still impaired ATR/CHK1 signaling in SMG8/9-defective cells, other characteristic responses to ATRi exposure were not seen, such as changes in ATM/CHK2, γH2AX, phospho-RPA, or 53BP1 status or changes in the proportions of cells in S- or G2-M-phases of the cell cycle. Transcription/replication conflicts (TRC) elicited by ATRi exposure are a likely cause of ATRi sensitivity, and SMG8/9-defective cells exhibited a reduced level of ATRi-induced TRCs, which could contribute to ATRi resistance. These observations suggest ATRi elicits antitumor efficacy in gastric cancer but that drug resistance could emerge via alterations in the SMG8/9/1 pathway. SIGNIFICANCE: These findings reveal how cancer cells acquire resistance to ATRi and identify pathways that could be targeted to enhance the overall effectiveness of these inhibitors..

Oesophagogastric (OG) cancer is a highly lethal disease requiring novel treatment options. c-MYC and/or HER-2 amplified oesophageal cancer models have demonstrated sensitivity to BTK inhibition with ibrutinib. We evaluated the safety and efficacy of ibrutinib in patients with c-MYC and/or HER2 amplified pre-treated advanced OG cancer. c-MYC and HER2 amplification status were determined by FISH. The primary endpoint was overall response rate (ORR). Secondary endpoints were disease control rate (DC) at 8 weeks, safety, progression-free survival (PFS) and overall survival (OS). Eleven patients were enrolled. Eight patients had c-MYC amplified tumours, six were HER2 amplified and three were c-MYC and HER2 co-amplified. Grade ≥ 3 adverse events were fever, neutropenia, and vomiting. Grade ≥ 3 gastrointestinal haemorrhage occurred in three patients and was fatal in two cases. Among seven evaluable patients, three patients (43%) achieved a best response of SD at 8 weeks. No PR or CR was observed. Disease control was achieved for 32 weeks in one patient with a dual c-MYC and HER2 highly co-amplified tumour. The median PFS and OS were 1.5 (95% CI: 0.8-5.1) and 5.1 (95% CI: 0.8-14.5) months, respectively. Ibrutinib had limited clinical efficacy in patients with c-MYC and/or HER2 amplified OG cancer. Unexpected gastrointestinal bleeding was observed in 3 out of 8 treated patients which was considered a new safety finding for ibrutinib in this population..

1.Background The application of massively parallel sequencing has led to the identification of aberrant druggable pathways and somatic mutations within therapeutically relevant genes in gastro-oesophageal cancer. Given the widespread use of formalin-fixed paraffin-embedded (FFPE) samples in the study of this disease, it would be beneficial, especially for the purposes of biomarker evaluation, to assess the concordance between comprehensive exome-wide sequencing data from archival FFPE samples originating from a prospective clinical study and those derived from fresh-frozen material. 2.Methods We analysed whole-exome sequencing data to define the mutational concordance of 16 matched fresh-frozen and FFPE gastro-oesophageal tumours ( N = 32) from a prospective clinical study. We assessed DNA integrity prior to sequencing and then identified coding mutations in genes that have previously been implicated in other cancers. In addition, we calculated the mutant-allele heterogeneity (MATH) for these samples. 3.Results Although there was increased degradation of DNA in FFPE samples compared with frozen samples, sequencing data from only two FFPE samples failed to reach an adequate mapping quality threshold. Using a filtering threshold of mutant read counts of at least ten and a minimum of 5% variant allele frequency (VAF) we found that there was a high median mutational concordance of 97% (range 80.1-98.68%) between fresh-frozen and FFPE gastro-oesophageal tumour-derived exomes. However, the majority of FFPE tumours had higher mutant-allele heterogeneity (MATH) scores when compared with corresponding frozen tumours ( p < 0.001), suggesting that FFPE-based exome sequencing is likely to over-represent tumour heterogeneity in FFPE samples compared to fresh-frozen samples. Furthermore, we identified coding mutations in 120 cancer-related genes, including those associated with chromatin remodelling and Wnt/β-catenin and Receptor Tyrosine Kinase signalling. 4.Conclusions These data suggest that comprehensive genomic data can be generated from exome sequencing of selected DNA samples extracted from archival FFPE gastro-oesophageal tumour tissues within the context of prospective clinical trials..

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Klotho was first discovered as an anti-ageing protein linked to a number of age-related disease processes, including cardiovascular, renal, musculoskeletal, and neurodegenerative conditions. Emerging research has also demonstrated a potential therapeutic role for Klotho in cancer biology, which is perhaps unsurprising given that cancer and ageing share similar molecular hallmarks. In addition to functioning as a tumour suppressor in numerous solid tumours and haematological malignancies, Klotho represents a candidate therapeutic target for patients with these diseases, the majority of whom have limited treatment options. Here, we examine contemporary evidence evaluating the anti-neoplastic effects of Klotho and describe the modulation of downstream oncogenic signalling pathways, including Wnt/β-catenin, FGF, IGF1, PIK3K/AKT, TGFβ, and the Unfolded Protein Response. We also discuss possible approaches to developing therapeutic Klotho and consider technological advances that may facilitate the delivery of Klotho through gene therapy..

Introduction The MYC proto-oncogene is among the most commonly dysregulated genes in human cancers. We report screening data from the iMYC trial, an ongoing phase II study assessing ibrutinib monotherapy in advanced pretreated MYC- and/or HER2-amplified oesophagogastric cancer, representing the first attempt to prospectively identify MYC amplifications in this tumour type for the purposes of therapeutic targeting.Methods Screening utilising a fluorescent in situ hybridisation (FISH) assay for assessment of tumour MYC amplification has been instituted. An experimental digital droplet polymerase chain reaction (ddPCR) assay to assess MYC amplification in both tumour and circulating-tumour (ct)DNA has been developed and investigated.Results One hundred thirty-five archival tumour specimens have undergone successful FISH analysis with 23% displaying evidence of MYC amplification. Intertumour heterogeneity was observed, with the percentage of cancer cells harbouring MYC amplification ranging widely between samples (median 51%, range 11-94%). Intratumoural clonal diversity of MYC amplification was also observed, with a significant degree of variance in amplification ratios (Bartlett's test for equal variance p < 0.001), and an association between greater variance in MYC amplification and improved outcome with prior first-line chemotherapy. ddPCR was most accurate in quantifying MYC amplification in tumour-derived DNA from cases with a high proportion (>70%) of amplified cells within the tumour specimen but was not reliable in samples containing a low proportion of amplified cells or in ctDNA.Conclusions Our results illustrate the utility of FISH to assess MYC amplification prospectively for a biomarker-selected trial by providing reliable and reproducible results in real time, with a high degree of heterogeneity of MYC amplification observed. We show that ddPCR can potentially detect high-level MYC amplifications in tumour tissue..

Accelerated vascular aging is a condition that occurs as a complication of several highly prevalent inflammatory conditions such as chronic kidney disease, cancer, HIV infection and diabetes. Age-associated vascular alterations underlie a continuum of expression toward clinically overt cardiovascular disease. This has contributed to the striking epidemiologic transition whereby such noncommunicable diseases have taken center stage as modern-day global epidemics and public health problems. The identification of α-Klotho, a remarkable protein that confers powerful anti-aging properties has stimulated significant interest. In fact, emerging data have provided fundamental rationale for Klotho-based therapeutic intervention for vascular diseases and multiple other potential indications. However, the application of such discoveries in Klotho research remains fragmented due to significant gaps in our molecular understanding of Klotho biology, as well as hurdles in clinical research and experimental barriers that must first be overcome. These advances will be critical to establish the scientific platform from which future Klotho-based interventional trials and therapeutic enterprises can be successfully launched..

Background:In patients presenting with peripheral lymphadenopathy, it is critical to effectively identify those with underlying cancer who require urgent specialist care. Methods:We analyzed a large dataset of 1000 consecutive patients with unexplained lymphadenopathy referred between 2001 and 2009 to the Royal Marsden Hospital (RMH) rapid access lymph node diagnostic clinic (LNDC). Results:Cancer was diagnosed in 14% of patients. Factors predictive for malignant disease were male sex, age, supraclavicular and multiple site involvement. Cancer-associated symptoms were present for a median of 8 weeks. The median time from referral to start of cancer therapy was 53 days. Fine needle aspiration (FNA) was performed in 83% of patients with malignancies. Sensitivity and specificity of FNA were limited (50 and 87%, respectively for any malignancy; 30 and 79%, respectively for lymphoma). The vast majority of cancer patients received diagnostic biopsies on the basis of suspicious clinical and ultrasound findings; the FNA result contributed to establishing the diagnosis in only 4 cases. Conclusions:In conclusion, we demonstrate that Oncologist-led rapid access clinics are successful concepts to assess patients with unexplained lymphadenopathy. Our data suggest that a routine use of FNA should be reconsidered in this setting..

The cell adhesion glycoprotein E-cadherin (CDH1) is commonly inactivated in breast tumors. Precision medicine approaches that exploit this characteristic are not available. Using perturbation screens in breast tumor cells with CRISPR/Cas9-engineered CDH1 mutations, we identified synthetic lethality between E-cadherin deficiency and inhibition of the tyrosine kinase ROS1. Data from large-scale genetic screens in molecularly diverse breast tumor cell lines established that the E-cadherin/ROS1 synthetic lethality was not only robust in the face of considerable molecular heterogeneity but was also elicited with clinical ROS1 inhibitors, including foretinib and crizotinib. ROS1 inhibitors induced mitotic abnormalities and multinucleation in E-cadherin-defective cells, phenotypes associated with a defect in cytokinesis and aberrant p120 catenin phosphorylation and localization. In vivo , ROS1 inhibitors produced profound antitumor effects in multiple models of E-cadherin-defective breast cancer. These data therefore provide the preclinical rationale for assessing ROS1 inhibitors, such as the licensed drug crizotinib, in appropriately stratified patients. Significance: E-cadherin defects are common in breast cancer but are currently not targeted with a precision medicine approach. Our preclinical data indicate that licensed ROS1 inhibitors, including crizotinib, should be repurposed to target E-cadherin-defective breast cancers, thus providing the rationale for the assessment of these agents in molecularly stratified phase II clinical trials. Cancer Discov; 8(4); 498-515. ©2018 AACR. This article is highlighted in the In This Issue feature, p. 371 ..

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Objective Oesophageal cancer is the seventh most common cause of cancer-related death worldwide. Disease relapse is frequent and treatment options are limited.Design To identify new biomarker-defined therapeutic approaches for patients with oesophageal cancer, we integrated the genomic profiles of 17 oesophageal tumour-derived cell lines with drug sensitivity data from small molecule inhibitor profiling, identifying drug sensitivity effects associated with cancer driver gene alterations. We also interrogated recently described RNA interference screen data for these tumour cell lines to identify candidate genetic dependencies or vulnerabilities that could be exploited as therapeutic targets.Results By integrating the genomic features of oesophageal tumour cell lines with siRNA and drug screening data, we identified a series of candidate targets in oesophageal cancer, including a sensitivity to inhibition of the kinase BTK in MYC amplified oesophageal tumour cell lines. We found that this genetic dependency could be elicited with the clinical BTK/ERBB2 kinase inhibitor, ibrutinib. In both MYC and ERBB2 amplified tumour cells, ibrutinib downregulated ERK-mediated signal transduction, cMYC Ser-62 phosphorylation and levels of MYC protein, and elicited G 1 cell cycle arrest and apoptosis, suggesting that this drug could be used to treat biomarker-selected groups of patients with oesophageal cancer.Conclusions BTK represents a novel candidate therapeutic target in oesophageal cancer that can be targeted with ibrutinib. On the basis of this work, a proof-of-concept phase II clinical trial evaluating the efficacy of ibrutinib in patients with MYC and/or ERBB2 amplified advanced oesophageal cancer is currently underway (NCT02884453).Trial registration number NCT02884453; Pre-results..

Osteosarcoma (OS) is an aggressive sarcoma, where novel treatment approaches are required. Genomic studies suggest that a subset of OS, including OS tumour cell lines (TCLs), exhibit genomic loss of heterozygosity (LOH) patterns reminiscent of BRCA1 or BRCA2 mutant tumours. This raises the possibility that PARP inhibitors (PARPi), used to treat BRCA1/2 mutant cancers, could be used to target OS. Using high-throughput drug sensitivity screening we generated chemosensitivity profiles for 79 small molecule inhibitors, including three clinical PARPi. Drug screening was performed in 88 tumour cell lines, including 18 OS TCLs. This identified known sensitivity effects in OS TCLs, such as sensitivity to FGFR inhibitors. When compared to BRCA1/2 mutant TCLs, OS TCLs, with the exception of LM7, were PARPi resistant, including those with previously determined BRCAness LoH profiles. Post-screen validation experiments confirmed PARPi sensitivity in LM7 cells as well as a defect in the ability to form nuclear RAD51 foci in response to DNA damage. LM7 provides one OS model for the study of PARPi sensitivity through a potential defect in RAD51-mediated DNA repair. The drug sensitivity dataset we generated in 88 TCLs could also serve as a resource for the study of drug sensitivity effects in OS..

Purpose The Cancer Esophagus Gefitinib trial demonstrated improved progression-free survival with the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor gefitinib relative to placebo in patients with advanced esophageal cancer who had disease progression after chemotherapy. Rapid and durable responses were observed in a minority of patients. We hypothesized that genetic aberration of the EGFR pathway would identify patients benefitting from gefitinib. Methods A prespecified, blinded molecular analysis of Cancer Esophagus Gefitinib trial tumors was conducted to compare efficacy of gefitinib with that of placebo according to EGFR copy number gain (CNG) and EGFR, KRAS, BRAF, and PIK3CA mutation status. EGFR CNG was determined by fluorescent in situ hybridization (FISH) using prespecified criteria and EGFR FISH-positive status was defined as high polysomy or amplification. Results Biomarker data were available for 340 patients. In EGFR FISH-positive tumors (20.2%), overall survival was improved with gefitinib compared with placebo (hazard ratio [HR] for death, 0.59; 95% CI, 0.35 to 1.00; P = .05). In EGFR FISH-negative tumors, there was no difference in overall survival with gefitinib compared with placebo (HR for death, 0.90; 95% CI, 0.69 to 1.18; P = .46). Patients with EGFR amplification (7.2%) gained greatest benefit from gefitinib (HR for death, 0.21; 95% CI, 0.07 to 0.64; P = .006). There was no difference in overall survival for gefitinib versus placebo for patients with EGFR, KRAS, BRAF, and PIK3CA mutations, or for any mutation versus none. Conclusion EGFR CNG assessed by FISH appears to identify a subgroup of patients with esophageal cancer who may benefit from gefitinib as a second-line treatment. Results of this study suggest that anti-EGFR therapies should be investigated in prospective clinical trials in different settings in EGFR FISH-positive and, in particular, EGFR-amplified esophageal cancer..

Background Pre-operative chemoradiotherapy (CRT) for MRI-defined, locally advanced rectal cancer is primarily intended to reduce local recurrence rates by downstaging tumours, enabling an improved likelihood of curative resection. However, in a subset of patients complete tumour regression occurs implying that no viable tumour is present within the surgical specimen. This raises the possibility that surgery may have been avoided. It is also recognised that response to CRT is a key determinant of prognosis. Recent radiological advances enable this response to be assessed pre-operatively using the MRI tumour regression grade (mrTRG). Potentially, this allows modification of the baseline MRI-derived treatment strategy. Hence, in a 'good' mrTRG responder, with little or no evidence of tumour, surgery may be deferred. Conversely, a 'poor response' identifies an adverse prognostic group which may benefit from additional pre-operative therapy.Methods/design TRIGGER is a multicentre, open, interventional, randomised control feasibility study with an embedded phase III design. Patients with MRI-defined, locally advanced rectal adenocarcinoma deemed to require CRT will be eligible for recruitment. During CRT, patients will be randomised (1:2) between conventional management, according to baseline MRI, versus mrTRG-directed management. The primary endpoint of the feasibility phase is to assess the rate of patient recruitment and randomisation. Secondary endpoints include the rate of unit recruitment, acute drug toxicity, reproducibility of mrTRG reporting, surgical morbidity, pathological circumferential resection margin involvement, pathology regression grade, residual tumour cell density and surgical/specimen quality rates. The phase III trial will focus on long-term safety, regrowth rates, oncological survival analysis, quality of life and health economics analysis.Discussion The TRIGGER trial aims to determine whether patients with locally advanced rectal cancer can be recruited and subsequently randomised into a control trial that offers MRI-directed patient management according to radiological response to CRT (mrTRG). The feasibility study will inform a phase III trial design investigating stratified treatment of good and poor responders according to 3-year disease-free survival, colostomy-free survival as well as an increase in cases managed without a major resection.Trial registration ClinicalTrials.gov, ID: NCT02704520 . Registered on 5 February 2016..

One approach to identifying cancer-specific vulnerabilities and therapeutic targets is to profile genetic dependencies in cancer cell lines. Here, we describe data from a series of siRNA screens that identify the kinase genetic dependencies in 117 cancer cell lines from ten cancer types. By integrating the siRNA screen data with molecular profiling data, including exome sequencing data, we show how vulnerabilities/genetic dependencies that are associated with mutations in specific cancer driver genes can be identified. By integrating additional data sets into this analysis, including protein-protein interaction data, we also demonstrate that the genetic dependencies associated with many cancer driver genes form dense connections on functional interaction networks. We demonstrate the utility of this resource by using it to predict the drug sensitivity of genetically or histologically defined subsets of tumor cell lines, including an increased sensitivity of osteosarcoma cell lines to FGFR inhibitors and SMAD4 mutant tumor cells to mitotic inhibitors..

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Abstract The HER2 gene ERBB2 is amplified and/ or overexpressed in up to 15% of all invasive breast cancers. These cancers are characterised by an aggressive phenotype and poor clinical outcome. HER2 positive tumours often display multiple high level amplifications of genes in addition to HER2. Although targeted therapies to HER2 have proven clinical benefit, a substantial number of patients have tumours that are either de novo resistant or acquire resistance over time to these agents. Reasons for this are still largely unknown. By using a high throughput siRNA screen we sought to determine whether genes recurrently amplified and overexpressed in HER2-amplified breast cancer mediate resistance to HER2-targeting agents. We profiled 45 HER2-amplified primary breast cancers and 13 HER2-amplified cell lines with high resolution microarray-based comparative genomic hybridisation (aCGH) and Illumina WG6 v2 arrays. Overlaying of aCGH and gene expression data led to the identification of 369 genes recurrently amplified and overexpressed when amplified. Lapatinib-resistant HER2-amplified breast cancer cell lines were treated with lapatinib, a HER2 small molecule inhibitor, and screened with an RNA interference (RNAi) library targeting these 369 genes and controls. This RNAi screen and subsequent validation screens identified eight genes that when silenced lead to a significant sensitization to lapatinib. The mechanisms of resistance conferred by the identified genes were further investigated and pointed to the involvement of NF-kappaB-signalling, Wnt-signalling and reactive oxygen species scavenging. Our results indicate that specific amplified and overexpressed genes found in HER2 positive breast cancers mediate resistance to anti-HER2 agents. These findings might be used to identify patients likely to be de novo resistant to lapatinib and provide new targets for combined targeted therapies to overcome resistance to anti-HER2 therapies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4987. doi:10.1158/1538-7445.AM2011-4987.

Abstract HER2 is amplified and/or overexpressed in 15% and 20% of breast and oesophagogastric (OG) cancers, respectively. Results from the recently published ToGA trial reveal that trastuzumab plus standard chemotherapy improves survival in patients with advanced HER2-positive OG cancer compared with chemotherapy alone, which mirrors the survival benefit shown with trastuzumab plus chemotherapy in metastatic breast cancer. The clinical value of lapatinib, already confirmed in advanced trastuzumab-resistant breast cancer, is currently being evaluated in prospective phase III trials for HER2-positive OG cancer in the metastatic setting. Despite improvements in outcome with anti-HER2 therapy, less than half of patients respond to treatment, and predictive biomarkers to lapatinib for breast and OG cancer have not yet been identified. We sought to identify predictive biomarkers of resistance to lapatinib treatment, common to both breast and OG cancer, by using a siRNA screen of genes identified in a primary siRNA screen to sensitise lapatinib-resistant breast cancer cell lines to lapatinib. These genes are found recurrently amplified and overexpressed in 45 HER2-amplified primary breast cancers and 13 HER2-amplified breast cancer cell lines. OG junction cell lines were treated with lapatinib and screened using the siRNA library. We found that silencing of TP53INP1, a gene target of TP53 which is known to be a reactive oxygen species scavenger, resulted in significant sensitisation to lapatinib in two of the most lapatinib-resistant HER2-positive cell lines derived from the OG junction. TP53INP1 was over-expressed, but not amplified, in the sensitised OG junction cell lines. Our results suggest that genes which mediate resistance to anti-HER2 therapy in breast cancer may be relevant to OG cancer. We are currently developing assays for TP53INP1 in tumours for validation within the context of prospective randomised controlled clinical trials for OG cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3039. doi:10.1158/1538-7445.AM2011-3039.

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Aims: The role of concomitant chemotherapy with radiotherapy (CRT) in locally advanced pancreatic cancer (LAPC) is controversial. The aim of this study was to report the outcomes of patients with LAPC treated with CRT over a 10-year period within a single institution and to identify those patients who derived the most benefit. Methods: Patients with LAPC who received radical radiotherapy (> 45Gy) between January 2004 – October 2014 were identified. The Electronic Patient Record was reviewed to collect data regarding staging, treatment, response and outcome. The Kaplan-Meier and Cox regression methods were used to analyse survival outcomes and compare survival rates between groups. Results: 138 patients were identified. Patients who had a response on imaging after induction chemotherapy had a median OS of 17.4 months compared to 10.3 months in non-responders (HR 0.55, 95% CI 0.35–0.87, p=0.01). At three months post-radiotherapy, patients who had achieved a response on CT had a median OS of 56 months compared to 10.7 months (HR 0.28, 95% CI 0.12–0.65, p=0.003). However, a reduction in CA19-9 prior to radiotherapy was not significantly associated with progression free survival (PFS) or Overall survival (OS). Patients with a response in CA19-9 levels at 3-months post-radiotherapy compared to baseline had an OS of 19.1 months compared to 10.5 months in non-responders (HR 0.42, 95% CI 0.26–0.68, pless than 0.001). Conclusion: Patients with LAPC who responded to chemotherapy on imaging prior to radiotherapy had improved PFS and OS than non-responders and therefore appeared to benefit the most from CRT. A decrease in CA19-9 prior to radiotherapy was not associated with improved survival and proved less useful for patient selection for CRT. .

Background Anal squamous cell carcinoma (ASCC) is an uncommon cancer associated with human immunodeficiency virus (HIV) infection. There has been increasing interest in providing organ-sparing treatment in small node-negative ASCC's, however, there is a paucity of evidence about the use of local excision alone in people living with HIV (PLWH). The aim of this study was to evaluate the efficacy of local excision alone in this patient population.Methods We present a case series of stage 1 and stage 2 ASCC in PLWH and HIV negative patients. Data were extracted from a 20-year retrospective cohort study analysing the treatment and outcomes of patients with primary ASCC in a cohort with a high prevalence of HIV.Results Ninety-four patients were included in the analysis. Fifty-seven (61%) were PLWH. Thirty-five (37%) patients received local excision alone as treatment for ASCC, they were more likely to be younger (p = 0.037, ANOVA) and have either foci of malignancy or well-differentiated tumours on histology (p = 0.002, Fisher's exact test). There was no statistically significant difference in 5-year disease-free survival and recurrence between treatment groups, however, patients who had local excision alone and PLWH were both more likely to recur later compared to patients who received other treatments for ASCC. (72.3 months vs 27.3 months, p = 0.06, ANOVA, and 72.3 months vs 31.8 months, p = 0.035, ANOVA, respectively).Conclusions We recommend that local excision be considered the sole treatment for stage 1 node-negative tumours that have clear margins and advantageous histology regardless of HIV status. However, PLWH who have local excision alone must have access to an expert long-term surveillance programme after treatment to identify late recurrences..