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At the ESMO Congress 2025 in Berlin, Dr. Martina Carullo (Pisa, Italy) presented groundbreaking findings from the translational program of AtezoTRIBE and AVETRIC, two clinical trials exploring immunotherapy in proficient mismatch repair (pMMR) metastatic colorectal cancer (mCRC). Using the Lunit SCOPE IO artificial intelligence (AI) platform, the investigators developed and validated a digital biomarker capable of predicting which pMMR tumors benefit from immune checkpoint inhibition—an area long considered resistant to immunotherapy.

Background

Immune checkpoint inhibitors (ICIs) have transformed treatment outcomes for patients with deficient mismatch repair (dMMR/MSI-H) mCRC, but have shown minimal activity in pMMR tumors, which constitute the vast majority of metastatic cases. Identifying predictive markers within this refractory group remains one of the central challenges in gastrointestinal oncology.

Recent advances in AI-driven pathology have enabled quantitative analysis of the tumor microenvironment on digitized hematoxylin and eosin (H&E) slides. By mapping immune, stromal, and tumor cell populations, AI models can capture subtle biological patterns invisible to traditional pathology. The present study used this approach to generate an AI-derived biomarker that could distinguish responders from non-responders to ICI-based regimens in pMMR mCRC.

Methods

The analysis incorporated pre-treatment tumor slides from patients enrolled in AtezoTRIBE (NCT03721653) and AVETRIC (NCT04513951). In AtezoTRIBE, patients received FOLFOXIRI/bevacizumab with or without atezolizumab, while in AVETRIC, the regimen was FOLFOXIRI/cetuximab/avelumab.

Using the Lunit SCOPE IO platform, the research team quantified the density of lymphocytes, fibroblasts, macrophages, endothelial, mitotic, and tumor cells within both cancer areas and surrounding stroma. A multivariate Cox regression model was trained on the atezolizumab-treated arm of AtezoTRIBE to identify cellular features most predictive of progression-free survival (PFS). A cut-off optimized for PFS was then applied to classify tumors as biomarker-high or biomarker-low, with AVETRIC serving as an external validation set.

Results from AtezoTRIBE

The AI-based analysis was conducted on whole-slide images from 161 patients. The resulting biomarker integrated densities of tumor and mitotic cells in the cancer area, lymphocytes in the tumor core, and fibroblasts, macrophages, and endothelial cells in the stroma. Of the evaluated patients, 113 (70%) were classified as biomarker-high, a group characterized by older age (p = 0.030) and a higher frequency of liver metastases (p = 0.023).

In the atezolizumab arm, biomarker-high patients achieved significantly superior outcomes compared with biomarker-low ones, with PFS p = 0.036 and overall survival (OS) p = 0.024. No such association was observed in the control arm (PFS p = 0.564; OS p = 0.186).

A formal treatment–biomarker interaction analysis showed a stronger benefit from atezolizumab among biomarker-high patients (HR for PFS 0.69; 95% CI 0.45–1.04 and HR for OS 0.54; 95% CI 0.33–0.88), while biomarker-low tumors did not derive advantage (HR for PFS 1.34; 95% CI 0.66–2.72 and HR for OS 1.70; 95% CI 0.69–4.20).

Validation in AVETRIC

The model was independently tested on 48 patients from the AVETRIC trial. Thirty-six (75%) were classified as biomarker-high and displayed numerically improved outcomes compared with biomarker-low cases, with PFS p = 0.043and OS p = 0.053. The validation confirmed the reproducibility of the AI-generated signature across different ICI-based regimens and patient populations.

Interpretation

This dual-trial analysis demonstrates that an AI-defined histologic signature reflecting immune–stromal interactions can predict the benefit of immunotherapy even in microsatellite-stable disease. The biomarker captures a complex interplay between immune infiltration and stromal architecture—features often underestimated by genomic profiling alone.

By transforming standard H&E slides into predictive, quantifiable datasets, this work illustrates how digital pathology and AI can refine patient selection for immunotherapy and accelerate the transition toward precision oncology in pMMR mCRC.

You can read the full abstract here.

Conclusion

The AtezoTRIBE and AVETRIC translational analyses show that AI-derived tumor microenvironment biomarkerscan identify subsets of pMMR colorectal cancer patients who benefit from ICI-based therapy. In AtezoTRIBE, biomarker-high status correlated with significantly longer PFS (p = 0.036) and OS (p = 0.024) under atezolizumab, and these findings were validated in AVETRIC (PFS p = 0.043; OS p = 0.053).

These results mark an important advance in AI-assisted immuno-oncology, suggesting that digital pathology could soon complement molecular testing in guiding treatment for colorectal cancer beyond MSI status.

20 October 2025

• Current account recorded €12 billion surplus in August 2025, down from €30 billion in previous month
• Current account surplus amounted to €303 billion (2.0% of euro area GDP) in the 12 months to August 2025, down from €404 billion (2.7%) one year earlier
• In financial account, euro area residents’ net acquisitions of non-euro area portfolio investment securities totalled €848 billion and non-residents’ net acquisitions of euro area portfolio investment securities totalled €745 billion in the 12 months to August 2025

The current account of the euro area recorded a surplus of €12 billion in August 2025, a decrease of €18 billion from the previous month (Chart 1 and Table 1). Surpluses were recorded for goods (€15 billion) and services (€14 billion). Deficits were recorded for secondary income (€16 billion) and primary income (€1 billion).

Data for the current account of the euro area

In the 12 months to August 2025, the current account recorded a surplus of €303 billion (2.0% of euro area GDP), compared with a surplus of €404 billion (2.7% of euro area GDP) one year earlier. This decrease was explained by a deterioration of all the accounts, particularly by a switch from a surplus (€41 billion) to a deficit (€11 billion) for primary income, but also by a larger deficit for secondary income (up from €167 billion to €186 billion), and reductions in the surplus for services (down from €169 billion to €154 billion) and goods (down from €360 billion to €347 billion).

In direct investment, euro area residents made net investments of €123 billion in non-euro area assets in the 12 months to August 2025, following net disinvestments of €191 billion one year earlier (Chart 2 and Table 2). Non-residents invested €57 billion in net terms in euro area assets in the 12 months to August 2025, following net disinvestments of €472 billion one year earlier.

In portfolio investment, euro area residents’ net purchases of non-euro area equity increased to €226 billion in the 12 months to August 2025, up from €139 billion one year earlier. Over the same period, net purchases of non-euro area debt securities by euro area residents increased to €623 billion, up from €420 billion. Non-residents’ net purchases of euro area equity increased to €387 billion in the 12 months to August 2025, up from €370 billion one year earlier. Over the same period, non-residents made net purchases of euro area debt securities amounting to €359 billion, following net purchases of €415 billion.

Data for the financial account of the euro area

In other investment, euro area residents recorded net acquisitions of non-euro area assets amounting to €489 billion in the 12 months to August 2025 (following net acquisitions of €202 billion one year earlier), while their net incurrence of liabilities was €367 billion (following net disposals of €209 billion one year earlier).

The monetary presentation of the balance of payments (Chart 3) shows that the net external assets (enhanced) of euro area MFIs increased by €245 billion in the 12 months to August 2025. This increase was driven by the current and capital accounts surplus and euro area non-MFIs’ net inflows in other investment and portfolio investment equity. These developments were partly offset by euro area non-MFIs’ net outflows in other flows, direct investment and portfolio investment debt.

In August 2025 the Eurosystem’s stock of reserve assets increased to €1,507.8 billion up from €1,499 billion in the previous month (Table 3). This increase was driven by positive price changes (€13.8 billion), mostly due to an increase in the price of gold, and, to a lesser extent, by net acquisitions of assets (€1.2 billion) which were partly offset by negative exchange rate changes (€6.2 billion).

Data for the reserve assets of the euro area

Data revisions

This press release incorporates revisions to the data for July 2025. These revisions did not significantly alter the figures previously published.

Next releases:

• Monthly balance of payments: 19 November 2025 (reference data up to September 2025)
• Quarterly balance of payments: 13 January 2026 (reference data up to the third quarter of 2025)^[1]

For media queries, please contact Benoît Deeg, tel.: +49 172 1683704.

Notes

• Current account data are always seasonally and working day-adjusted, unless otherwise indicated, whereas capital and financial account data are neither seasonally nor working day-adjusted.
• Hyperlinks in this press release lead to data that may change with subsequent releases as a result of revisions.