Endocytosis Inhibition in Humans to Improve Responses to ADCC-Mediating Antibodies.

A safe and controlled manipulation of endocytosis in vivo may have disruptive therapeutic potential. Here, we demonstrate that the anti-emetic/anti-psychotic prochlorperazine can be repurposed to reversibly inhibit the in vivo endocytosis of membrane proteins targeted by therapeutic monoclonal antibodies, as directly demonstrated by our human tumor ex vivo assay. Temporary endocytosis inhibition results in enhanced target availability and improved efficiency of natural killer cell-mediated antibody-dependent cellular cytotoxicity (ADCC), a mediator of clinical responses induced by IgG1 antibodies, demonstrated here for cetuximab, trastuzumab, and avelumab. Extensive analysis of downstream signaling pathways ruled out on-target toxicities. By overcoming the heterogeneity of drug target availability that frequently characterizes poorly responsive or resistant tumors, clinical application of reversible endocytosis inhibition may considerably improve the clinical benefit of ADCC-mediating therapeutic antibodies.

Steroid Premedication and Monoclonal Antibody Therapy: Should We Reconsider?

OPINION STATEMENT: Monoclonal antibody (mAb) therapy is now considered a main component of cancer therapy in Australia. Although traditionally thought of as pure signalling inhibitors, a large proponent of these medications function through antibody-dependent cell-mediated cytotoxicity (ADCC). Currently, most protocols and institutional guidelines for ADCC-mediated mAbs promote the use of corticosteroids as premedication: this is implemented to reduce infusion-related reactions (IRRs) and antiemesis prophylaxis and combat concurrently administered chemotherapy-related syndromes. Concerningly, the inhibitory effects of ADCC by corticosteroids are well documented; henceforth, it is possible the current standard of care is misaligned to the literature surrounding ADCC. Subsequently, clinicians' decisions to act in contrast to this literature may be reducing the efficacy of mAbs. The literature suggests that the redundant use of corticosteroids should be cautioned against when used in conjunction with ADCC-mediated mAbs-this is due to the consequent reduction in anti-tumour activity. Owing to the fact IRRs typically occur upon initial infusion, the authors advocate for individual clinicians and institutional protocols to considering augmenting their practice to corticosteroid premedication at the first dose only, unless clinically indicated. Additionally, product information (PI) and consumer medicine information (CMI) documents distributed by Australian and international regulatory agencies should consider disclosing the risk of concurrent steroids with these medications. Moreover, the authors suggest considering alternative medications for the management of side effects.

Development of a key performance indicator for breast cancer in Queensland, Australia.

PURPOSE: Using population-based data for women diagnosed with stage I-III breast cancer, our aim was to examine the impact of time to treatment completion on survival and to identify factors associated with treatment delay. METHODS: This retrospective study used clinical and treatment data from the Queensland Oncology Repository. Time from diagnosis to completing surgery, chemotherapy and radiation therapy identified a cut-off of 37 weeks as the optimal threshold for completing treatment. Logistic regression was used to identify factors associated with the likelihood of completing treatment > 37 weeks. Overall (OS) and breast cancer-specific survival (BCSS) were examined using Cox proportional hazards models. RESULTS: Of 8279 women with stage I-III breast cancer, 31.9% completed treatment > 37 weeks. Apart from several clinical factors, being Indigenous (p = 0.002), living in a disadvantaged area (p = 0.003) and receiving ≥ two treatment modalities within the public sector (p < 0.001) were associated with an increased likelihood of completing treatment > 37 weeks. The risk of death from any cause was about 40% higher for women whose treatment went beyond 37 weeks (HR 1.37, 95%CI 1.16-1.61), a similar result was observed for BCSS. Using the surgery + chemotherapy + radiation pathway, a delay of > 6.9 weeks from surgery to starting chemotherapy was significantly associated with poorer survival (p = 0.001). CONCLUSIONS: Several sociodemographic and system-related factors were associated with a greater likelihood of treatment completion > 37 weeks. We are proposing a key performance indicator for the management of early breast cancer where a facility should have > 90% of patients with a time from surgery to adjuvant chemotherapy < 6.9 weeks.

High-dose chemotherapy for relapsed germ cell tumours: outcomes in low-volume specialized centres.

OBJECTIVE: To report treatment patterns and survival outcomes of patients with relapsed and refractory metastatic germ cell tumours (GCTs) treated with high-dose chemotherapy (HDCT) and autologous stem-cell transplantation in low-volume specialized centres within the widely dispersed populations of Australia and New Zealand between 1999 and 2019. PATIENTS AND METHODS: We conducted a retrospective analysis of 111 patients across 13 institutions. Patients were identified from the Australasian Bone Marrow Transplant Recipient Registry. We reviewed treatment regimens, survival outcomes, deliverability and toxicities. Primary endpoints included overall (OS) and progression-free survival (PFS). Cox proportional hazards models were used to test the association of survival outcomes with patient and treatment factors. RESULTS: The median (range) age was 30 (14-68) years and GCT histology was non-seminomatous in 84% of patients. International Prognostic Factors Study Group (IPFSG) prognostic risk category was very low/low, intermediate, high and very high in 18%, 36%, 25% and 21% of patients, respectively. Salvage conventional-dose chemotherapy (CDCT) was administered prior to HDCT in 59% of patients. Regimens included paclitaxel, ifosfamide, carboplatin and etoposide (50%), carboplatin and etoposide (CE; 28%), carboplatin, etoposide and ifosfamide (CEI; 6%), carboplatin, etoposide and cyclophosphamide (CEC; 5%), CEC-paclitaxel (6%) and other (5%). With a median follow-up of 4.4 years, the 1-, 2- and 5-year PFS rates were 62%, 57% and 52%, respectively, and OS rates were 73%, 65% and 61%, respectively. There were five treatment-related deaths. Progression on treatment occurred in 17%. In a univariable analysis, worse International Germ Cell Cancer Collaborative Group (IGCCCG) and IPFSG prognostic groups were associated with inferior survival outcomes. An association of inferior survival was not found with the number of high-dose cycles received nor when HDCT was delivered after salvage CDCT. CONCLUSION: This large dual-national registry-based study reinforces the efficacy and deliverability of HDCT for relapsed and refractory metastatic GCT in low-volume specialized centres in Australia and New Zealand, with survival outcomes comparable to those found in international practice.

End-of-life intravenous chemotherapy administration patterns in the treatment of Queensland lung and pancreas cancer patients: a 10-year retrospective analysis.

BACKGROUND: End-of-life (EOL) chemotherapy administration rates for solid tumours are 12-20% and are associated with a reduced quality of life, increased hospitalisation and incidence of death within an acute care facility. AIM: We sought to determine the rate of EOL chemotherapy in government and private hospitals and determine the impact on hospitalisations and location of death in lung and pancreatic cancer patients. METHODS: Data were obtained from the Queensland Oncology Repository between 2005 and 2014. Lung (n = 16 501) and pancreatic cancer (n = 4144) deaths were analysed. EOL chemotherapy was determined to be within 30 days of death. Demographics, location of treatment and death are reported. RESULTS: Chemotherapy was administered to 6518 (40%) lung cancer and 1694 (41%) pancreatic cancer patients. A total of 1474 (9%) and 477 (12%) patients, respectively, received EOL chemotherapy. EOL chemotherapy was more common in males and those with distant metastatic disease, while less likely in the elderly and those with a lower socioeconomic status. EOL chemotherapy was more prevalent in large hospitals and was more common in private compared with government hospitals for pancreatic cancer (30 vs 26%; P < 0.001), while it was similar for lung cancer (24 vs 22%; P = 0.115). Death after EOL chemotherapy compared with all cancer deaths was more common in an acute care facility (lung cancer: 60 vs 37%; P < 0.001; pancreatic cancer: 53 vs 36%; P < 0.001). CONCLUSIONS: EOL chemotherapy rates were similar to Australian yet marginally lower than international rates, with variation dependent on the size and type of facility and increased the rate of deaths within an acute care facility.

Survival of advanced melanoma patients treated with immunotherapy and targeted therapy: A real-world study.

INTRODUCTION: We aimed to examine the survival outcomes plus patient and treatment characteristics of advanced melanoma patients treated with first-line immunotherapy (IT), targeted therapy (TT), and chemotherapy (CTH) and compare findings with information from pivotal trials for each therapy. MATERIALS AND METHODS: We retrospectively reviewed the use of systematic IT, TT and CTH therapies in melanoma patients in four Queensland public hospitals. We estimated median duration of overall survival (OS) and survival rates (6 months, 1, and 2 years) using Kaplan-Meier methods. We compared our findings to those of clinical trials. RESULTS: Five hundred three patients who met the inclusion criteria were divided into three groups based on the first-line treatment: IT 232; TT 157; and CTH 114. OS was 18 months with IT (95% CI 13, 22); 12 months with TT (95% CI 8, 15); and 5 months with CTH (95% CI 5, 6). The demographic characteristics, treatment protocols, and durations for IT and TT were generally consistent with trials but fewer patients in our study had subsequent therapy than in the trials. The OS in our study was slightly lower than the OS reported in trials. CONCLUSION: The OS of novel cancer therapy in the real world was lower than seen in trials but is expected given these are patients who have a poorer prognosis. A future study could investigate the impact of prognostic factors on survival in the longer term. This study provides evidence that we can use routinely collected real-world data to evaluate the effectiveness of checkpoint and kinase inhibitors in patients with advanced melanoma.

Nonbreast cancer incidence, treatment received and outcomes: Are there differences in breast screening attendees versus nonattendees?

While reductions in breast cancer mortality have been evident since the introduction of population-based breast screening in women aged 50-74 years, participation in cancer screening programs can be influenced by several factors, including health system and those related to the individual. In our study, we compared cancer incidence and mortality for several cancer types other than breast cancer, noncancer mortality and patterns of treatment amongst women who did and did not participate in mammography screening. All women aged 50-65 years enrolled on the Queensland Electoral Roll in 2000 were included. The study population was then linked to records from the population-based breast screening program and private fee-for-service screening options to establish screened and unscreened cohorts. Diagnostic details for selected cancers and cause of death were obtained from the Queensland Oncology Repository. We calculated incidence rate ratios and hazard ratios comparing screened and unscreened cohorts. Among screened compared to unscreened women, we found a lower incidence of cancers of the lung, cervix, head and neck and esophagus and an increase in colorectal cancers. Cancer mortality (excluding breast cancer) was 35% lower among screened compared to unscreened women and they were also about 23% less likely to be diagnosed with distant disease. Screened compared to unscreened women were more likely to receive surgery and less likely to receive no treatment. Our study adds further to the population data examining outcomes among women participating in mammography screening.

Patterns of primary health care service use of Indigenous Australians diagnosed with cancer.

PURPOSE: The role of general practitioners in cancer care has expanded in recent years. However, little is known about utilization of primary health care (PHC) services by patients with cancer, particularly among socio-economically disadvantaged groups. We describe utilization of PHC services by patients with cancer, and the nature of the care provided. The study focuses on a disadvantaged group in Australia, namely Indigenous Australians. METHODS: A retrospective audit of clinical records in ten PHC services in Queensland, Australia. Demographic and clinical data of Indigenous Australians diagnosed with cancer during 2010-2016 were abstracted from patient's medical records at the PHC services. The rates of cancer-related visits were calculated using person years at risk as a denominator. RESULTS: A total of 138 patients' records were audited. During 12 months following the cancer diagnosis, patients visited the PHC service on average 5.95 times per year. Frequency of visits were relatively high in remote areas and among socioeconomic disadvantaged patients (IRR = 1.87, 95%CI 1.61-2.17; IRR = 1.79, 95%CI 1.45-2.21, respectively). Over 80% of visits were for seeking attention for symptoms, wound care, and emotional or social support. Patients who did not undergo surgery, had greater comorbidity, received chemotherapy and/or radiotherapy, and male gender had significantly greater rate of visits than their counterparts. CONCLUSION: The frequency of utilization of PHC services, especially by patients with comorbidities, and the range of reasons for attendance highlights the important role of PHC services in providing cancer care. The reliance on PHC services, particularly by patients in remote and disadvantaged communities, has important implications for appropriate resourcing and support for services in these locations.

Bortezomib use and outcomes for the treatment of multiple myeloma.

BACKGROUND: The public subsidy in Australia of bortezomib (Velcade) for untreated non-transplant multiple myeloma patients was based on the VISTA trial. AIMS: To ascertain the health outcomes of bortezomib in 'real world' transplant-ineligible elderly patients, compared to trial data. METHODS: Patient and treatment data were extracted from an oncology information system, laboratory information system and medical chart audits for three Queensland public hospitals. RESULTS: We identified 74 patients; the median age was 75 years. Our cohort comprised 47% patients who were International Staging System stage III, 45% at stage II and 8% at stage I. Patients who had comorbidities, such as cardiac disease (41%), pulmonary disease (14%), diabetes (22%), peripheral neuropathy (14%) and other comorbidities (41%) at baseline were included. The common regimens prescribed were VMP, CVD and VD, and most patients (n = 73) received bortezomib on a once-weekly or twice-a-week basis. The overall response rate was 81%. Half (53%) of the patients did not complete their planned therapy due to toxicity (30%), suboptimal response or disease progression (15%), or death on treatment (8%). Overall survival was 40.7 months and progression free survival was 17.7 months. CONCLUSIONS: Our patients were older, had worse disease characteristics and more comorbidities than patients in the VISTA trial. While response rates were similar, survival outcomes appeared worse. Bortezomib-based treatment in the real world setting still carries a high risk of toxicity in the elderly population.

Are general practitioners getting the information they need from hospitals and specialists to provide quality cancer care for Indigenous Australians?

BACKGROUND: Cancer care involves many different healthcare providers. Delayed or inaccurate communication between specialists and general practitioners (GP) may negatively affect care. AIM: To describe the pattern and variation of communication between primary healthcare (PHC) services and hospitals and specialists in relation to the patient's cancer care. METHODS: A retrospective audit of clinical records of Indigenous Australians diagnosed with cancer during 2010-2016 identified through 10 PHC services in Queensland is described. Poisson regression was used to model the dichotomous outcome availability of hospital discharge summary versus not. RESULTS: A total of 138 patient records was audited; 115 of those patients visited the PHC service for cancer-related care after cancer diagnosis; 40.0% visited the service before a discharge summary was available, and 36.5% of the patients had no discharge summary in their medical notes. While most discharge summaries noted important information about the patient's cancer, 42.4% lacked details regarding the discharge medications regimen. CONCLUSIONS: Deficits in communication and information transfer between specialists and GP may adversely affect patient care. Indigenous Australians are a relatively disadvantaged group that experience poor health outcomes and relatively poor access to care. The low proportion of discharge summaries noting discharge medication regimen is of concern among Indigenous Australians with cancer who have high comorbidity burden and low health literacy. Our findings provide an insight into some of the factors associated with quality of cancer care, and may provide guidance for focus areas for further research and improvement efforts.

Antitumour activity of pembrolizumab in advanced mucosal melanoma: a post-hoc analysis of KEYNOTE-001, 002, 006.

BACKGROUND: Mucosal melanoma is an aggressive melanoma with poor prognosis. We assessed efficacy of pembrolizumab in patients with advanced mucosal melanoma in KEYNOTE-001 (NCT01295827), -002 (NCT01704287), and -006 (NCT01866319). METHODS: Patients received pembrolizumab 2 mg/kg every 3 weeks (Q3W) or 10 mg/kg Q2W or Q3W. Response was assessed by independent central review per RECIST v1.1. RESULTS: 1567 patients were treated and 84 (5%) had mucosal melanoma. Fifty-one of 84 were ipilimumab-naive. In patients with mucosal melanoma, the objective response rate (ORR) was 19% (95% CI 11-29%), with median duration of response (DOR) of 27.6 months (range 1.1 + to 27.6). Median progression-free survival (PFS) was 2.8 months (95% CI 2.7-2.8), with median overall survival (OS) of 11.3 months (7.7-16.6). ORR was 22% (95% CI 11-35%) and 15% (95% CI 5-32%) in ipilimumab-naive and ipilimumab-treated patients. CONCLUSION: Pembrolizumab provides durable antitumour activity in patients with advanced mucosal melanoma regardless of prior ipilimumab.

Survival outcomes in patients with non-small-cell lung cancer treated with erlotinib.

Erlotinib is used to treat non-small-cell lung cancer (NSCLC). Erlotinib was subsidized on the Pharmaceutical Benefits Schedule in Australia for the treatment of advanced stage (IIIB or IV) NSCLC (August 2008). In the pivotal trial supporting initial subsidy, erlotinib increased overall survival (OS) by 2 months compared with placebo (adjusted hazard ratio, 0.70; 95% confidence interval: 0.58-0.85). We examined the effectiveness of erlotinib in a 'real-world' setting by measuring survival outcomes in NSCLC patients treated in two tertiary metropolitan public hospitals in Queensland. We extracted data from the electronic oncology prescribing system (CHARM) for NSCLC patients prescribed erlotinib (1 September 2009 to 1 February 2015). Survival estimates and analyses were generated using Kaplan-Meier curves. 134 patients received at least one dose of erlotinib during the study period. At the date of data extraction 113 patients had died. The median patient age was 64 years and 55% were men. The median duration of treatment was 2.0 months. The median OS was 5.8 months. The median progression-free survival (time from start of erlotinib to disease progression or death from any cause) was 3.6 months. The use of erlotinib in the two Queensland sites was consistent with the pivotal trial used to support subsidy. The median OS was somewhat less than the trial (5.8 vs. 6.7 months), which could be because of the hospital cohort including frailer patients who were unsuitable for parenteral chemotherapy, and the mixed epidermal growth factor receptor mutation status of the hospital cohort.

Neoadjuvant chemotherapy or chemoradiotherapy for adenocarcinoma of the esophagus.

BACKGROUND: The optimal treatment strategy for patients with esophageal adenocarcinoma (EAC) remains undetermined. This study compared outcomes in patients undergoing neoadjuvant chemotherapy (nCT) and neoadjuvant chemoradiotherapy (nCRT) for EAC. METHODS: Patients who underwent nCT or nCRT followed by surgery for EAC were identified from a prospective database (2000-2017) and included. After propensity score matching, the impact of the treatments on postoperative complications, in-hospital mortality, pathological outcomes, and survival rates were compared. RESULTS: Of the 396 eligible patients, 262 patients were analysed following matching with 131 patients in both groups. There were no significant differences between the nCT and nCRT groups for overall complications (59% vs 57%, P = 0.802) or in-hospital mortality (2% vs 0%, P = 0.156). Patients who had nCRT had more R0 resections (93% vs 83%, P = 0.013), and higher pathological complete response rates (15% vs 5%, P < 0.001). No differences in 5-year overall survival rates (nCT vs nCRT; 44% vs 33%, P = 0.645) were found. CONCLUSION: In this study no differences between nCT and nCRT were seen in postoperative complications and in-hospital mortality in patients treated for EAC. Inspite of improved complete resection and pathological response there was no difference in the overall survival between the treatment modalities.

Community-identified recommendations to enhance cancer survivorship for Aboriginal and Torres Strait Islander people.

Indigenous Australians diagnosed with cancer experience higher mortality and lower survival rates compared to non-Indigenous Australians. Reasons are multifaceted and complex. Knowledge about Indigenous cancer survivors' perspectives of positive cancer survivorship is a gap in research evidence. The study explored cancer survivorship perspectives of Indigenous cancer survivors, their support people and healthcare workers with a view to developing recommendations for cancer survivorship. Indigenous Australians who completed cancer treatment in the previous 6 months to 5 years, their support people and primary healthcare workers were recruited from primary healthcare centres and a large tertiary Queensland hospital. Semi-structured interviews and focus groups were conducted with written and informed consent obtained prior. Participants emphasised key action areas and recommendations to enhance cancer survivorship, namely: establishing a community cancer advocate and peer support program, availability and use of a cancer-specific Indigenous primary healthcare worker and hospital-based Indigenous patient navigator, as well as adoption of question prompt lists and cancer survivorship care plans. Existing research suggests significant benefits from implementing the key recommendations identified in this study. Greater support and commitment across health sectors and funding bodies is needed to promote institutional change and health system development.

Temporal changes in loss of life expectancy due to cancer in Australia: a flexible parametric approach.

PURPOSE: To evaluate changes in cancer mortality burden over time by assessing temporal trends in life expectation for Australian residents diagnosed with cancer. METHODS: The study cohort consisted of all people diagnosed with cancer in the period 1990-2000 and aged 15-89 years (n = 1,275,978), with mortality follow-up to 31 December 2010. Flexible parametric survival models incorporating background age-sex-year-specific population mortality rates were applied to generate the observed survival curves for all cancers combined and selected major cancer types. Predicted values of loss of life expectancy (LOLE) in years were generated and then averaged across calendar year and age group (15-49, 50-69 and 70-89 years) or spread of disease (localized, regional, distant, unknown). RESULTS: The greatest LOLE burden was for lung cancer (14.3 years per diagnosis) and lowest for melanoma (2.5 years). There was a significant decrease in LOLE over time (-0.13 LOLE per year) for all cancers combined. Decreases were also observed for female breast cancer (-0.21), prostate cancer (-0.17), colorectal cancer (-0.08), melanoma (-0.07) and stomach cancer (-0.02), with slight increases for lung cancer (+0.04). When restricted to the sub-cohort from New South Wales with spread of disease information, these decreases in LOLE were primarily among cancers categorized as localized or regional spread at diagnosis. CONCLUSIONS: In Australia, persons diagnosed with cancer have a steadily improving outlook that exceeds that expected by general improvement in population life expectancy. The overall improvement is observed in persons with localized or regional cancers but not in those with advanced cancers, findings which encourage earlier diagnosis.

Perioperative FOLFOX4 chemotherapy and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC 40983): long-term results of a randomised, controlled, phase 3 trial.

BACKGROUND: Previous results of the EORTC intergroup trial 40983 showed that perioperative chemotherapy with FOLFOX4 (folinic acid, fluorouracil, and oxaliplatin) increases progression-free survival (PFS) compared with surgery alone for patients with initially resectable liver metastases from colorectal cancer. Here we present overall survival data after long-term follow-up. METHODS: This randomised, controlled, parallel-group, phase 3 study recruited patients from 78 hospitals across Europe, Australia, and Hong Kong. Eligible patients aged 18-80 years who had histologically proven colorectal cancer and up to four liver metastases were randomly assigned (1:1) to either perioperative FOLFOX4 or surgery alone. Perioperative FOLFOX4 consisted of six 14-day cycles of oxaliplatin 85mg/m(2), folinic acid 200 mg/m(2) (DL form) or 100 mg/m(2) (L form) on days 1-2 plus bolus, and fluorouracil 400 mg/m(2) (bolus) and 600 mg/m(2) (continuous 22 h infusion), before and after surgery. Patients were centrally randomised by minimisation, adjusting for centre and risk score and previous adjuvant chemotherapy to primary surgery for colorectal cancer, and the trial was open label. Analysis of overall survival was by intention to treat in all randomly assigned patients. FINDINGS: Between Oct 10, 2000, and July 5, 2004, 364 patients were randomly assigned to a treatment group (182 patients in each group, of which 171 per group were eligible and 152 per group underwent resection). At a median follow-up of 8·5 years (IQR 7·6-9·5), 107 (59%) patients in the perioperative chemotherapy group had died versus 114 (63%) in the surgery-only group (HR 0·88, 95% CI 0·68-1·14; p=0·34). In all randomly assigned patients, median overall survival was 61·3 months (95% CI 51·0-83·4) in the perioperative chemotherapy group and 54·3 months (41·9-79·4) in the surgery alone group. 5-year overall survival was 51·2% (95% CI 43·6-58·3) in the perioperative chemotherapy group versus 47·8% (40·3-55·0) in the surgery-only group. Two patients in the perioperative chemotherapy group and three in the surgery-only group died from complications of protocol surgery, and one patient in the perioperative chemotherapy group died possibly as a result of toxicity of protocol treatment. INTERPRETATION: We found no difference in overall survival with the addition of perioperative chemotherapy with FOLFOX4 compared with surgery alone for patients with resectable liver metastases from colorectal cancer. However, the previously observed benefit in PFS means that perioperative chemotherapy with FOLFOX4 should remain the reference treatment for this population of patients. FUNDING: Norwegian and Swedish Cancer Societies, Cancer Research UK, Ligue Nationale Contre Cancer, US National Cancer Institute, Sanofi-Aventis.

HPV status represents dominant trait driving delineation of survival-associated gene co-expression networks in head and neck cancer.

Integration of high-dimensional tumor gene expression data with clinicopathological data can increase our understanding of disease diversity, enable retrospective patient stratification, and identify new potential biomarkers and therapeutic targets. Using a systems biology approach, we provide a holistic overview of gene co-expression networks in head and neck squamous cell carcinomas (HNSCC). Weighted gene co-expression network analysis of HNSCC RNA sequencing data from 519 patients from The Cancer Genome Atlas (TCGA) was used to determine correlates of 5-year survival, using regression tree-based optimal threshold calculations. Survival-associated gene sets were transformed to gene set scores that were assessed for correlation with clinicopathological data. We identified 8 gene co-expression modules for HNSCC tumors, each of which contained co-expressed genes associated significantly with 5-year survival. Survival-associated co-expression gene signatures correlated dominantly with tumor HPV and p16 status. Network analysis identified that survival was associated with signaling networks of infection, immunity, epithelial-mesenchymal transition (EMT), hypoxia, glycolysis, focal adhesion, extracellular matrix, MYC signaling, autophagy and transcriptional regulation. EMT-associated gene signatures were expressed dominantly in fibroblasts, and cancer-associated fibroblasts were inversely correlated with immune activity. Interestingly, a high Immune Suppression Score based on expression of 21 genes associated with immune inhibition and including immune checkpoints, cytokines and regulatory T cell factors, was also associated with increased survival probability, and was significantly higher in HPV+ HNSCC. Networks associated with HNSCC survival were further associated with survival in cervical cancer, melanoma and lung cancer. This study defines 5129 genes associated with HNSCC survival, organized into co-expressed networks, their correlation with clinicopathological data, and with gene expression data from other malignant diseases, and provides a source for the discovery of biomarkers and novel therapies for HNSCC.

Multi-omic features of oesophageal adenocarcinoma in patients treated with preoperative neoadjuvant therapy.

Oesophageal adenocarcinoma is a poor prognosis cancer and the molecular features underpinning response to treatment remain unclear. We investigate whole genome, transcriptomic and methylation data from 115 oesophageal adenocarcinoma patients mostly from the DOCTOR phase II clinical trial (Australian New Zealand Clinical Trials Registry-ACTRN12609000665235), with exploratory analysis pre-specified in the study protocol of the trial. We report genomic features associated with poorer overall survival, such as the APOBEC mutational and RS3-like rearrangement signatures. We also show that positron emission tomography non-responders have more sub-clonal genomic copy number alterations. Transcriptomic analysis categorises patients into four immune clusters correlated with survival. The immune suppressed cluster is associated with worse survival, enriched with myeloid-derived cells, and an epithelial-mesenchymal transition signature. The immune hot cluster is associated with better survival, enriched with lymphocytes, myeloid-derived cells, and an immune signature including CCL5, CD8A, and NKG7. The immune clusters highlight patients who may respond to immunotherapy and thus may guide future clinical trials.

Predictive factors for the benefit of perioperative FOLFOX for resectable liver metastasis in colorectal cancer patients (EORTC Intergroup Trial 40983).

OBJECTIVE: In EORTC study 40983, perioperative FOLFOX increased progression-free survival (PFS) compared with surgery alone for patients with initially 1 to 4 resectable liver metastases from colorectal cancer (CRC). We conducted an exploratory retrospective analysis to identify baseline factors possibly predictive for a benefit of perioperative FOLFOX on PFS. METHODS: The analysis was based on 237 events from 342 eligible patients. Cox proportional hazards regression models with a significance level of 0.1 were used to build up univariate and multivariate models. RESULTS: After adjustment for identified prognostic factors, moderately (5.1-30 ng/mL) and highly (>30 ng/mL) elevated carcinoembryonic antigen (CEA) serum levels were both predictive for the benefit of perioperative chemotherapy (interaction P = 0.07; hazard ratio [HR] = 0.58 and HR = 0.52 for treatment benefit). For patients with moderately or highly elevated CEA (>5 ng/mL), the 3-year PFS was 35% with perioperative chemotherapy compared to 20% with surgery alone. Performance status (PS) 0 and BMI lower than 30 were also predictive for the benefit of perioperative chemotherapy (interaction P = 0.04 and P = 0.02). However, the number of patients with PS 1 and BMI 30 or higher were limited. The benefit of perioperative therapy was not influenced by the number of metastatic lesions (1 vs 2-4, interaction HR = 0.98). CONCLUSIONS: Perioperative FOLFOX seems to benefit in particular patients with resectable liver metastases from CRC when CEA is elevated and when PS is unaffected, regardless of the number of metastatic lesions.ClinicalTrials.gov number NCT00006479.