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Tumor associated fibroblasts (TAFs) are essential contributors of the progression of non-small cell lung cancer (NSCLC). Most lung TAFs exhibit an activated phenotype characterized by the expression of α-SMA and fibrillar collagens. However, the prognostic value of these activation markers in NSCLC remains unclear. To address this question we conducted a retrospective multicentric study of the prognostic value of the standard markers of activated fibroblasts. For this purpose, we conducted a quantitative image analysis of α-SMA immunostaining and picrosirius red staining of fibrillar collagens imaged by bright-field and polarized microscopy, respectively, using tissue microarrays with samples from 220 surgical patients, which elicited a percentage of positive staining area for each marker and patient. Kaplan-Meier curves showed that all TAF activation markers were significantly associated with poor survival, and their prognostic value was independent of TNM staging as revealed by multivariate analysis, which elicited an adjusted increased risk of death after 3 years of 129% and 94% for fibrillar collagens imaged with bright-field (p = 0.004) and polarized light (p = 0.003), respectively, and of 89% for α-SMA (p = 0.009). We also found a significant association between all TAF activation markers and tumor necrosis, which is often indicative of hypoxia, supporting a pathologic link between tumor desmoplasia and necrosis/hypoxia. Our findings identify patients with large histologic coverage of fibrillar collagens and α-SMA+ TAFs to be at higher risk of recurrence and death, supporting that they could be considered for adjuvant therapy. Moreover it supports that antifibrotic drugs aiming to target tumor fibrosis may be an effective therapeutic approach to improve survival in NSCLC. Citation Format: Jordi Alcaraz, Josep-Lluís Carrasco, Laura Millares, Iuliana-Cristiana Benchea, Francisco-Javier Fernández, Anabel Martínez, María José Pajares, Julio Sánchez de Cos, Ramon Rami-Porta, Luis Seijo, Josep Ramírez, Noemí Reguart, Esther Barreiro, Eduard Monsó. Stromal markers of activated tumor associated fibroblasts predict poor survival and are associated with necrosis in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3160.

A major hallmark of non-small cell lung cancer (NSCLC) and other solid tumors is a desmoplastic tumor stroma rich in activated fibroblasts and fibrillar collagens. Previous studies have revealed that these tumor-associated fibroblasts contribute to virtually all steps of tumor progression and even therapy resistance. However, our knowledge of the prognostic value of markers of activated fibroblasts in NSCLC is very scarce. To fill this gap of knowledge we conducted a retrospective multicentric study of the prognostic value of the standard markers of activated fibroblasts α-SMA and fibrillar collagens by quantitative image analysis of α-SMA immunostaining and picrosirius red (PSR) staining, respectively. For this purpose tissue microarrays from a cohort of 222 patients with early-stage (I-IIp) NSCLC recruited in Spain for the International Association for the Study of Lung Cancer TNM-16 staging project were analyzed. A percentage of positive staining area/image was obtained for each marker and patient. Kaplan-Meier analysis revealed that PSR was associated with poor survival when using data obtained from both bright-field (p = 0.04) and polarized microscopy (p = 0.002), whereas α-SMA was not (p = 0.7). Remarkably, the prognostic value of PSR was independent of TNM stage, and patients with PSR above the cut-offs exhibited a 55% (for bright-field; HR=1.55, 95%CI (1.0-2.4)) and 109% (for polarized microscopy; HR=2.09, 95%CI (1.3-3.2)) increased risk of 3 year mortality. These results reveal that the content of stromal fibrillar collagens, assessed from image analysis of picrosirius red staining (particularly using polarized microscopy) is associated with adverse prognosis independently of the tumor stage. This new prognostic biomarker may help predict which patients subject to therapeutic surgery are at higher risk of progression and death. Moreover it supports that antifibrotic drugs aiming to target stromal fibrillar collagens may be an effective therapeutic approach to improve survival in NSCLC. Citation Format: Jordi Alcaraz, Laura Millares, Josep-Lluís Carrasco, Iuliana-Cristiana Benchea, Francisco-Javier Fernández, Esther Barreiro, Anabel Martínez, Julio Sánchez, María Ángeles González-Castro, Ana Blanco, Rosa Sánchez-Gil, Mireia Serra, Ramon Rami-Porta, Jaume Sauleda, Esther Fernández, Rosario Melchor, Luis Seijo, Leonardo de Esteban, Eduard Monsó. High stromal fibrillar collagen predicts poor survival in surgical non-small cell lung cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1554.