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MICROSCOPIC PATTERNS OF RESIDUAL TUMOUR AFTER NEOADJUVANT CHEMOTHERAPY IN LOCALLY ADVANCED OESOPHAGEAL ADENOCARCINOMA
Sulaiman Sajjad
*1, Yasmin Dorudi
1, Najeed Khan
1, Vasiliki Michalarea
3, Neel Bhuva
3, Mark Harrison
3, Edward W. Park
2, Farhan Rashid
4, Robert Goldin
1,2, Stefan Antonowicz
1,21Surgery and Cancer, Imperial College London, London, United Kingdom; 2Imperial College Healthcare NHS Trust, London, United Kingdom; 3Mount Vernon Cancer Centre, London, Middlesex, United Kingdom; 4Bedfordshire Hospitals NHS Foundation Trust, Luton, England, United Kingdom
BackgroundOesophageal adenocarcinoma (OAC) primary tumours typically have an incomplete response to neoadjuvant chemotherapy (NAC). Clinically adopted methods to assess NAC response are quantitative and ignore spatial dimension. In breast, rectal, and oesophageal squamous cancer, the spatial patterns of residual disease can be prognostic and provide insight into treatment resistance. We aimed to characterise the morphological and anatomical patterns of regression in OAC after NAC and evaluate their clinical and prognostic impact.
MethodsIn this single-centre retrospective observational study, patients treated curatively for OAC who had an incomplete response to NAC (Mandard 2-4) in the resected specimen were eligible. OAC-containing replicate slides (3-5) were obtained from consecutive patients between 2011–2023. Residual tumour was categorised into
morphological ("shrinkage" and "fragmentation") and
anatomical ("shallow," "central," "deep," and "diffuse") regression patterns. Associated clinical factors such as survival were assessed using data from a prospectively maintained database.
ResultsA total of 107 patients were included in the analysis. Morphologically, fragmented patterns (69%) were more common than shrinkage (31%). Typically, residual tumour cells were embedded within the oesophagus as islands, distributed across the submucosa and/or muscle, and throughout the body of the original tumour. Residual tumour was absent from the epithelium in 48% of patients. In 35% of patients clinically staged as T2, residual tumour lay beyond the muscularis propria. Patients with fragmented disease patterns had a poorer disease-specific survival than those with shrinkage patterns (p=0.036). A diffuse distribution was the most frequently seen anatomical pattern (59%). Patients with focused anatomical regression (shallow/central/deep) did not show a better prognosis than those with a diffuse pattern (p=0.098). The patterns of residual cancer were not associated with demographics, tumour characteristics, NAC choice or incomplete NAC provision (e.g. dose reduction or less-than-intended cycles).
ConclusionThe widely used Mandard score originally assessed chemoradiotherapy response – the present data suggests there may be value beyond quantifying tumour-fibrosis ratio after chemotherapy. The spatial patterns of residual OAC after NAC fell into distinct groups that are agnostic to the chemotherapy regime. Given the pervasive nature of fragmented residual disease, it suggests structural effects like therapeutic biodistribution could be more relevant as a resistance mechanism compared to genetic evolution. Around half had a normal overlying epithelium, highlighting the challenge of confirming residual disease endoscopically. Further studies are needed to evaluate other structural relationships with these patterns, in particular vascular and immune microenvironments.
Kaplan-Meir Plot comparing disease-specific survival in patients with two distinct morphological regression patterns, "shrinkage" or "fragmentation". Fragmented patterns showed a pooer 5 year survival (p=0.036)
Kaplan-Meir Plot comparing disease-specific survival in patients with focused anatomical regression patterns (shallow, central and deep), with a diffuse pattern. There was no significant difference between the two groups (p=0.167).
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