Immune microenvironment modulation following neoadjuvant therapy for oesophageal adenocarcinoma: a translational analysis of the DEBIOC clinical trial.

BACKGROUND: The Dual Erb B Inhibition in Oesophago-gastric Cancer (DEBIOC) trial reported an acceptable safety profile for neoadjuvant oxaliplatin and capecitabine (Xelox) ± AZD8931 in oesophageal adenocarcinoma (OAC) but limited efficacy. We evaluated the impact of neoadjuvant Xelox ± AZD8931, a novel small-molecule inhibitor with equipotent activity against epidermal growth factor receptor (EGFR), human epidermal growth factor receptor (HER)2 and HER3, on biological pathways using a unique software-driven solution. PATIENTS AND METHODS: Transcriptomic profiles from 25 pre-treatment formalin-fixed paraffin-embedded OAC biopsies and 18 matched resection specimens, treated with Xelox + AZD8931 (n = 16) and Xelox alone (n = 9), were analysed using the Almac claraT total mRNA report analysing 92 gene signatures, 100 unique single-gene drug targets and 7337 single genes across 10 hallmarks of cancer. Gene-set enrichment analysis (GSEA) was utilised to investigate pathways governing pathological response. Tumour-infiltrating lymphocytes (TILs) were assessed digitally using the QuPath software. RESULTS: Hierarchical clustering identified three molecular subgroups classified by activation of innate immune signalling. The immune-high subgroup was associated with HER2 positivity, increased pathological response and a marked reduction in immune signalling and TILs following neoadjuvant therapy. The immune-low cluster was predominantly HER2/EGFR-negative, and EGFR positivity was associated with the immune-mixed subgroup. Treatment with neoadjuvant therapy induced common resistance mechanisms, such as angiogenesis and epithelial-mesenchymal transition signalling, and a reduction in DNA repair signatures. Addition of AZD8931 was associated with reduction of expression of EGFR, HER2 and AKT pathways and also promoted an immunosuppressive microenvironment. GSEA showed that patients with a pathological response to treatment had increased immune signalling, whereas non-responders to neoadjuvant therapy were enriched for nucleotide repair and cellular growth through the action of E2F transcription factors. CONCLUSION: OAC may be subdivided into three immune-related subgroups which undergo modulation in response to neoadjuvant therapy with marked suppression of the immune microenvironment in HER2-positive/immune-high tumours.

A Prospective Study of Diffusion-weighted Magnetic Resonance Imaging as an Early Prognostic Biomarker in Chemoradiotherapy in Squamous Cell Carcinomas of the Anus.

AIMS: The use of diffusion-weighted magnetic resonance imaging (DW-MRI) as a prognostic marker of treatment response would enable early individualisation of treatment. We aimed to quantify the changes in mean apparent diffusion coefficient (ΔADCmean) between a DW-MRI at diagnosis and on fraction 8-10 of chemoradiotherapy (CRT) as a biomarker for cellularity, and correlate these with anal squamous cell carcinoma recurrence. MATERIALS AND METHODS: This prospective study recruited patients with localised anal cancer between October 2014 and November 2017. DW-MRI was carried out at diagnosis and after fraction 8-10 of radical CRT. A region of interest was delineated for all primary tumours and any lymph nodes >2 cm on high-resolution T2-weighted images and propagated to the ADC map. Routine clinical follow-up was collected from Nation Health Service electronic systems. RESULTS: Twenty-three of 29 recruited patients underwent paired DW-MRI scans. Twenty-six regions of interest were delineated among the 23 evaluable patients. The median (range) tumour volume was 13.6 cm3 (2.8-84.9 cm3). Ten of 23 patients had lesions with ΔADCmean ≤ 20%. With a median follow-up of 41.2 months, four patients either failed to have a complete response to CRT or subsequently relapsed. Three of four patients with disease relapse had lesions demonstrating ΔADCmean <20%, the other patient with persistent disease had ΔADCmean of 20.3%. CONCLUSIONS: We demonstrated a potential correlation between patients with ΔADCmean <20% and disease relapse. Further investigation of the prognostic merit of DW-MRI change is needed in larger, prospective cohorts.

Is There a Role for an 18F-fluorodeoxyglucose-derived Biological Boost in Squamous Cell Anal Cancer?

AIMS: To investigate the potential role for a biological boost in anal cancer by assessing whether subvolumes of high 18F-fluorodeoxyglucose (FDG) avidity, identified at outset, are spatially consistent during a course of chemoradiotherapy (CRT). MATERIALS AND METHODS: FDG-positron emission tomography (FDG-PET) scans from 21 patients enrolled into the ART study (NCT02145416) were retrospectively analysed. In total, 29 volumes including both primary tumours and involved nodes >2 cm were identified. FDG-PET scans were carried out before treatment and on day 8 or 9 of CRT. FDG subvolumes were created using a percentage of maximum FDG avidity at thresholds of 34%, 40%, 50%, on the pre-treatment scans, and 70% and 80% on the subsequent scans. Both FDG-PET scans were deformably registered to the planning computed tomography scan. The overlap fraction and the vector distance were calculated to assess spatial consistency. FDG subvolumes for further investigation had an overlap fraction >0.7, as this has been defined in previous publications as a 'good' correlation. RESULTS: The median overlap fractions between the diagnostic FDG-PET subvolumes 34%, 40% and 50% of maximum standardised uptake value (SUVmax) and subsequent FDG-PET subvolumes of 70% of SUVmax were 0.97, 0.92 and 0.81. The median overlap fraction between the diagnostic FDG-PET subvolumes 34%, 40% and 50% and subsequent FDG-PET subvolumes of 80% were 1.00, 1.00 and 0.92. The median (range) vector distance values between diagnostic FDG-PET subvolumes 34%, 40% and 50% and subsequent FDG-PET subvolumes of 80% were 0.74 mm (0.19-2.94) 0.74 mm (0.19-3.39) and 0.71 mm (0.2-3.29), respectively. Twenty of 29 volumes (69.0%) achieved a threshold > 0.7 between the FDG 50% subvolume on the diagnostic scan and the FDG 80% subvolume on the subsequent scan. CONCLUSION: FDG-avid subvolumes identified at baseline were spatially consistent during a course of CRT treatment. The subvolume of 50% of SUVmax on the pre-treatment scan could be considered as a potential target for dose escalation.