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Clinical Trial
. 2023 Jun;128(12):2318-2325.
doi: 10.1038/s41416-023-02257-3. Epub 2023 Apr 7.

Tumour infiltrating lymphocytes and survival after adjuvant chemotherapy in patients with gastric cancer: post-hoc analysis of the CLASSIC trial

Drolaiz H W Liu #  1   2 , Young-Woo Kim #  3 , Nina Sefcovicova  1 , Jon P Laye  4 , Lindsay C Hewitt  1   5 , Andrew F Irvine  4 , Vincent Vromen  1   6 , Yannick Janssen  1 , Naser Davarzani  1 , Gregorio E Fazzi  1 , Shahab Jolani  7 , Veerle Melotte  1   8 , Derek R Magee  9   10 , Myeong-Cherl Kook  11 , Hyunki Kim  12 , Rupert Langer  2 , Jae-Ho Cheong  13   14   15 , Heike I Grabsch  16   17
Affiliations
Clinical Trial

Tumour infiltrating lymphocytes and survival after adjuvant chemotherapy in patients with gastric cancer: post-hoc analysis of the CLASSIC trial

Drolaiz H W Liu et al. Br J Cancer. 2023 Jun.

Abstract

Background: Only a subset of gastric cancer (GC) patients with stage II-III benefits from chemotherapy after surgery. Tumour infiltrating lymphocytes per area (TIL density) has been suggested as a potential predictive biomarker of chemotherapy benefit.

Methods: We quantified TIL density in digital images of haematoxylin-eosin (HE) stained tissue using deep learning in 307 GC patients of the Yonsei Cancer Center (YCC) (193 surgery+adjuvant chemotherapy [S + C], 114 surgery alone [S]) and 629 CLASSIC trial GC patients (325 S + C and 304 S). The relationship between TIL density, disease-free survival (DFS) and clinicopathological variables was analysed.

Results: YCC S patients and CLASSIC S patients with high TIL density had longer DFS than S patients with low TIL density (P = 0.007 and P = 0.013, respectively). Furthermore, CLASSIC patients with low TIL density had longer DFS if treated with S + C compared to S (P = 0.003). No significant relationship of TIL density with other clinicopathological variables was found.

Conclusion: This is the first study to suggest TIL density automatically quantified in routine HE stained tissue sections as a novel, clinically useful biomarker to identify stage II-III GC patients deriving benefit from adjuvant chemotherapy. Validation of our results in a prospective study is warranted.

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Conflict of interest statement

DRM is director of HeteroGenius Limited. RL received consulting fees from Astellas, Janssen, Roche, MSD not related to the current study. HIG received consulting fees from AstraZeneca and BMS not related to the current study. The remaining authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Example of image analysis-based tumour infiltrating lymphocyte detection in haematoxylin-eosin (HE) stained gastric cancer tissue.
a Original HE stained tissue. b HE stained tissue with segmentation mask (green circles) around the lymphocytes.
Fig. 2
Fig. 2. Disease-free survival (DFS) and tumour infiltrating lymphocyte (TIL) density in the Yonsei Cancer Center cohort.
a Patients with low TIL density (≤1290 TILs/mm2) gastric cancer have similar survival when treated by surgery or surgery followed by adjuvant chemotherapy (HR 1.038, 95% CI: 0.662–1.628, P = 0.870). b Patients with high TIL density (>1290 TILs/mm2) gastric cancer have similar survival when treated by surgery or surgery followed by adjuvant chemotherapy (HR 0.775, 95% CI: 0.398–1.510, P = 0.454). c Patients treated with surgery alone with high TIL density gastric cancer have significantly longer DFS compared to patients treated with surgery alone with low TIL density (HR 2.496, 95% CI: 1.288–4.837, P = 0.007). d Patients treated with surgery plus adjuvant chemotherapy with high TIL density have significantly longer DFS compared to patients treated with surgery plus adjuvant chemotherapy with low TIL density (HR 1.792, 95% CI: 1.134–2.833, P = 0.012).
Fig. 3
Fig. 3. Disease-free survival (DFS) and tumour infiltrating lymphocyte (TIL) density in the CLASSIC trial cohort.
a Patients with low TIL density (≤1360 TILs/mm2) gastric cancer have a significant longer DFS when treated by surgery followed by adjuvant chemotherapy (HR 1.760, 95% CI: 1.213–2.553, P = 0.003). b Patients with high TIL density (>1360 TILs/mm2) gastric cancer have similar survival when treated by surgery alone or surgery followed by adjuvant chemotherapy (HR 1.248, 95% CI: 0.830–1.876, P = 0.287). c Patients treated with surgery alone with high TIL density gastric cancer have significantly longer DFS compared to patients treated with surgery alone with low TIL density gastric cancer (HR 1.591, 95% CI: 1.104–2.292, P = 0.013). d Patients treated with surgery followed by adjuvant chemotherapy have similar survival irrespective of TIL density high or low gastric cancer (HR 1.128, 95% CI: 0.746–1.706, P = 0.567).
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