Importance Therapies for individual keratinocyte carcinomas (KCs) do not prevent the onset of new KCs in a field of sun damage, and therefore the KC burden remains unchanged. Objective To investigate the association of immune checkpoint inhibitors (ICIs) with changes in field cancerization evaluated by the number of actinic keratoses (AKs) and KCs at baseline compared with 12 months after starting ICI therapy. Design, Setting, and Participants This prospective cohort study was performed at the outpatient oncology clinic of a single tertiary public hospital in Brisbane, Australia, from April 1, 2022, to November 30, 2023. Consecutive immunocompetent adults starting therapy with an inhibitor for programmed cell death 1 (PD-1) or programmed cell death ligand 1 (PDL-1) for any active cancer, with a planned treatment duration of at least 6 months, and who exhibited clinical AKs on their forearms were eligible. Those with immunosuppression, concurrent chemotherapy or radiotherapy, or recent topical fluorouracil use were excluded. Exposures Intravenous ICI therapy, either PD-1 or PDL-1 inhibitors with or without a cytotoxic T-lymphocyte–associated protein 4 inhibitor, with therapy duration determined by the treating oncologist. Main Outcomes and Measures Clinical AKs were counted and photographed before and 3, 6, and 12 months after starting ICI therapy. KC numbers were evaluated based on histopathology reports of all skin lesions excised 12 months before and after starting ICI therapy. Participants’ medical history, primary cancer tumor response using Response Evaluation Criteria in Solid Tumors, and adverse events were recorded. Results A total of 23 participants were recruited, of whom 17 (73.9%) were male, with a mean (SD) age of 69.7 (9.6) years. No participants withdrew; however, 4 died during the study due to disease progression. The mean (SD) AK number significantly decreased from 47.2 (33.8) at baseline to 14.3 (12.0) at 12 months ( P < .001). Younger patients (8 of 12 [66.7%] vs 4 of 12 [33.3%]; P = .007) and those with a history of blistering sunburn (12 of 12 [100%] vs 0; P = .005) were more likely to reduce their AK numbers by 65% or greater. KC total numbers decreased from 42 in the 12 months before starting ICI therapy to 17 in the 12 months after. The number of cutaneous squamous cell carcinomas decreased from 16 to 5 in the same period. Conclusions and Relevance This pilot cohort study found that ICIs used for any cancer were associated with a significant reduction of AKs, suggesting potential as an immunopreventive strategy for high-risk individuals. Given the known effects of other chemopreventive agents on KCs, further investigation into ICIs managing field cancerization is required, especially considering toxicity and cost.

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.

TPS524 Background: Bleomycin, etoposide, and cisplatin (BEP) given 3-weekly x 4 remains standard first-line chemotherapy for intermediate and poor-risk metastatic GCT. Accelerating standard chemotherapy regimens by shortening the cycle length to 2-weekly improved cure rates in other cancers. P3BEP is the first international, randomized trial of chemotherapy for intermediate and poor-risk metastatic GCT to include adults and children of both sexes. It aims to determine the superiority of accelerated BEP versus standard BEP in this setting. Methods: This open label, randomized, phase 3 trial is conducted seamlessly in 2 stages. The primary endpoint for stage 1 (n = 150) was favourable response; and for stage 2 (n = 500) is progression free survival at 2 years (PFS2y). These sample sizes provide > 80% power with a two-sided type I error rate of 5% to detect an absolute improvement of 21% in the favourable response rate (stage 1) and of 7% in the PFS2y (stage 2). The target population is males and females aged 11 to 45 with intermediate or poor-risk metastatic GCT of the testis, ovary, retroperitoneum, or mediastinum. Participants are randomized (1:1) to 4 cycles of standard BEP (q3w) or accelerated BEP (q2w) with cisplatin 20mg/m2 D1-5, etoposide 100mg/m2 D1-5, bleomycin 30 KIU weekly x 12, and pegylated G-CSF 6mg D6 or filgrastim daily. Study assessments occur at 30 days after completing chemotherapy, 6 months from randomization, and after completion of all post-chemotherapy treatments (e.g. surgery). Tumour tissue and baseline blood samples are collected for translational substudies. As of 24 August 2023, 274 participants have been recruited from 23 ANZ sites, 17 UK sites (led by Cambridge Clinical Trials Unit), and 150 USA sites (led by Children’s Oncology Group). The first planned interim analysis for safety (n = 76) identified no safety concerns. The stage 1 analysis of safety and activity (response rate) for the 1st 150 patients was reviewed by the IDSMC, which recommended continuation of the trial as per protocol. Clinical trial information: NCT02582697 .

BACKGROUND:Frailty is an indicator of individual vulnerability and differentiates health status among people of the same chronological age. OBJECTIVES:This study aimed to determine whether baseline frailty index (FI) was associated with systemic anticancer therapy treatment outcomes in older adults with solid cancers. DESIGN:Retrospective cohort study. SETTING:Major metropolitan outpatient oncology service. PARTICIPANTS:Adults aged over 65 years with a solid malignancy who had been referred for consideration of systemic therapy, and had completed a baseline frailty assessment between January 2019 and July 2021. MEASUREMENTS:Frailty had been prospectively assessed with a 58-item FI derived from a geriatric oncology nurse assessment prior to initial oncologist appointments. Primary outcome was treatment completion, and secondary outcomes included incidence of high-grade treatment-related toxicity or unplanned hospital admissions, and survival outcomes. Univariate and multivariable regression analyses were conducted to test the association between treatment outcomes and baseline FI. Co-variates included age, sex, performance status, treatment intent, and stage. Kaplan-Meier and cox proportional hazard analysis were conducted for survival analysis. RESULTS:The median FI (IQR) was 0.24 (0.15-0.31) and 43% were frail (FI>0.25). FI was positively correlated with ECOG, however 28% of ECOG 0-1 were frail. In multivariable regression analyses, each 0.10 increase in FI was associated with an increased likelihood of not completing or not receiving treatment (OR 1.37, 95% CI 1.02-1.84; p=.04), treatment-related toxicity (OR 1.60, 95% CI 1.14-2.23; p<.01) and unplanned hospital admissions (OR 1.61; 95% CI 1.16-2.25; p<.01). Frail patients had increased mortality (adjusted HR 2.81, 95% CI 1.42-5.56; p<.01). Age did not predict treatment completion, toxicities, or survival. CONCLUSION:Baseline FI is a granular measure that can help to identify frailer older patients who are more likely to require tailored therapy and support, and less frail older patients who are more likely to tolerate treatment.

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.

HER2Pro: A Phase 1b dose de-escalation study of high dose prochlorperazine added to paclitaxel, trastuzumab and pertuzumab in patients with previously untreated HER2-positive metastatic breast cancer Authors Teesha Downton1,2, Emma Karlsen1, Katharine Cuff3,4, Euan Walpole3,4, Fiona Simpson3,4, Elgene Lim1,2. Affiliations 1Garvan Institute of Medical Research, Darlinghurst NSW, Australia; 2School of Clinical Medicine, St Vincent’s Healthcare Clinical Campus, Faculty of Medicine and Health, University of New South Wales Sydney, Australia; 3Diamantina Institute, University of Queensland, Woolloongabba QLD, Australia; 4Princess Alexandra Hospital, Brisbane QLD, Australia Disclosures T. Downton: None. E. Karlsen: None. K. Cuff: None. E. Walpole: None. F. Simpson: None. E. Lim. Advisory Board for Pfizer, Astra Zeneca, Lilly, Roche, Novartis, Gilead Australia. Research Funding from Pfizer, Novartis, Bayer. Abstract Background: The anti-emetic prochlorperazine reversibly inhibits dynamin-mediated endocytosis. Preclinical studies have demonstrated that through this mechanism, high dose prochlorperazine can temporarily increase tumor cell antigen presentation, enhance interaction of tumor antigens with therapeutic monoclonal antibodies, and improve antibody-dependent cellular cytotoxicity (Chew H et al. Cell 2020). High dose prochlorperazine has been well tolerated and proof of mechanism demonstrated in a pilot study (ACTRN12619001051134), and in a phase Ib trial (ACTRN12619001527156) of prochlorperazine with cetuximab in patients with EGFR-expressing advanced head and neck squamous cell carcinoma or breast cancer. Prochlorperazine potentially offers a novel approach to improve the efficacy of a range of therapeutic antibodies. This study HER2Pro (ACTRN12622000016730) aims to evaluate the feasibility and safety of high dose prochlorperazine in combination with paclitaxel, trastuzumab, and pertuzumab in patients with HER2-positive metastatic breast cancer. Trial Design: In this phase Ib single-arm trial, patients receive standard of care trastuzumab and pertuzumab 3-weekly and paclitaxel weekly. From cycle 2, patients in addition receive de-escalating doses of prochlorperazine weekly for 6 weeks, though an additional 6 weeks may be given if there are no treatment associated serious adverse events. Dose de-escalation will be evaluated using a 3+3 design, commencing at a prochlorperazine intravenous dose of 0.8mg/kg weekly. Eligibility: Eligible patients must have previously untreated HER2-positive metastatic breast cancer, Eastern Cooperative Oncology Group performance status 0-1, and baseline left ventricular ejection fraction 50%. Key exclusion criteria include current daily treatment with corticosteroids at a dose >10mg prednisolone or equivalent, blood pressure < 90/50 mmHg, prolonged QT interval, and Parkinson’s disease. Objectives: The primary objective is to determine the recommended phase 2 dose. Secondary objectives include determining the frequency and severity of adverse events, rates of cardiotoxicity, objective response rate, duration of response and progression free survival. Tertiary objectives include analysis of receptor trafficking and immune system activation on paired tumor biopsies obtained before and after first prochlorperazine dose. Accrual: 6-12 patients will be enrolled across 2 Australian sites. Enrollment for this trial is expected to commence late 2022. Citation Format: Teesha Downton, Emma Karlsen, Katharine Cuff, Euan Walpole, Fiona Simpson, Elgene Lim. HER2Pro: A Phase 1b dose de-escalation study of high dose prochlorperazine added to paclitaxel, trastuzumab and pertuzumab in patients with previously untreated HER2-positive metastatic breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT2-10-05.

TPS431 Background: Bleomycin, etoposide, and cisplatin (BEP) given 3-weekly x 4 remains standard 1st line chemotherapy for intermediate or poor risk metastatic GCT. Accelerating standard regimens by shortening the cycle length to 2-weekly improved cure rates in other cancers. P3BEP will determine effects of accelerated versus standard BEP in this setting. This is a first international, randomized trial of chemotherapy for intermediate and poor-risk metastatic GCT to include adults and children of both sexes. Methods: This open label, randomized, phase 3 trial is conducted seamlessly in 2-stages. The primary endpoint for stage I (n=150) was complete response (CR); and for stage 2 (n=500) is progression free survival at 2 years (PFS2y). These sample sizes provide >80% power with a two-sided type I error rate of 5% to detect an absolute improvement of 25% in the CR rate (stage 1) and of 7% in the PFS2y (stage 2). The target population is males and females aged 11 to 45 with intermediate-or poor-risk metastatic GCT of the testis, ovary, retroperitoneum, or mediastinum. Participants are randomized (1:1) to 4 cycles of standard BEP (q3w) or accelerated-BEP (q2w) with cisplatin 20mg/m 2 D1-5, etoposide 100mg/m 2 D1-5, bleomycin 30 KIU weekly x 12, and pegylated G-CSF D6 or filgrastim daily. Study assessments occur at 30 days after completing chemotherapy, 6 months from randomization, and after completion of all post-chemotherapy treatments (e.g. surgery). Tumour and baseline blood samples are collected for translational substudies. Progress: As of Sept 2022, 226 participants have been recruited from 24 ANZ sites, 17 UK sites (led by Cambridge Clinical Trials Unit), and 149 USA sites (led by Children’s Oncology Group). The first planned interim analysis for safety (n=76) identified no safety concerns. Stage I analysis (n=150) showed sufficiently favorable results with no futility concerns, supporting ongoing trial recruitment. Clinical trial information: NCT02582697 .

The cancer genomics field has embraced the advent of precision oncology, and vast volumes of data have been mined for biomarkers of drug actionability. While some cancers have detailed panels of actionable genomic biomarkers, such as lung cancer, breast cancer has been less well-placed to apply standard sequencing panels given its large number of cancer driver genes mutated at a relatively low frequency. Furthermore, mutation signatures have potential to play an important role in the targeting of homologous recommendation deficiency-driven tumours to PARP inhibitor therapy. To investigate whether whole genome sequencing could benefit breast cancer patients we initiated the Q-IMPROvE (Queensland-IMplementation of PRecision Oncology in brEast cancer) pilot study. We report the analysis of matched tumour and normal genomes of 28 high-risk breast cancer patients, and demonstrate that there are detectable, actionable events that would otherwise have not been identified.

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.

Abstract Oesophageal adenocarcinoma (OAC) is a deadly disease with an increasing incidence globally. Treatment outcomes with traditional therapy have largely plateaued and responses to immunotherapy are modest at best, necessitating the need for better biomarker driven selection. We aimed to unravel the tumour neoantigen landscape and immune microenvironment in OAC patients to aid improved patient selection and inform novel immunotherapy trials. To characterise the tumour immune microenvironment and neoantigen landscape of OACs, we performed DNA sequencing (n = 117) and RNA sequencing (n = 115) on biopsies taken at pre-treatment endoscopy. Using expression-based computational methods we analysed transcriptomic data to profile infiltration levels of 28 immune cell populations and their functional orientation, as well as stromal signatures and immune checkpoint molecules. TCGA data was used for as a validation cohort. Tumour neoantigens were predicted using the pVAC-Seq pipeline. Using an immune based classification based on the tumour microenvironment composition, we identified three distinct phenotypes; immune-enriched (IE), heterogeneously-infiltrated (HI), and immune-cold (IC). The IE group showed improved survival compared to both HI and IC, with HI showing the worst survival. The HI-group showed no difference in stromal scores to the IE group, but showed significantly decreased adaptive-immune cell infiltration, indicating that an immunosuppressive stromal compartment may be driving outcomes for these patients. No difference was seen in total or quality neoantigen load between groups, but high correlation with antigen processing machinery is seen. Our analysis expands the knowledge of the relatively unknown tumour immune microenvironment of OAC. We have identified three immune TME-phenotypes with prognostic utility with current standard of care therapies; which may also act as potential immunotherapy biomarkers. This is being explored further in ongoing immune microenvironment research and will guide future translational studies.

ObjectiveTo 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 MethodsWe 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.ResultsThe 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.ConclusionThis 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.

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. 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. Of 8279 women with stage I-III breast cancer, 31.9