Abstract 2512
Background
Activation of AXL receptor tyrosine kinase is a key mediator of epithelial to mesenchymal transition (EMT). AXL is overexpressed in several human cancers, including CRC.
Methods
AXL expression was assessed by immunohistochemistry in tumor samples from 346 mCRC pts treated at three Institutions and enrolled in different clinical trials (CAPRI, MACBETH, MOMA, TRIBE2). In silico data of AXL RNA levels were obtained from GSE5851 dataset, including 80 pts with advanced mCRC treated with cetuximab in a later line.
Results
AXL expression was found in 18% of cases within tumor cells, with no difference among RAS cohorts. In the RAS WT group, AXL positive pts had a worse mPFS whether treated with chemotherapy (CT) + anti-EGFR [6.2 m (CI95% 4.2- 8.2) vs 12.1 m (CI95% 10.6 – 13.6) p 0.012] or CT+anti-angiogenic agent [6.7 m (CI95% 8.9- 19.3) vs 14.1 m (CI95% 9.4– 13.0) p 0.007], whereas in RAS mutant pts no impact on PFS was observed. AXL expression correlated with worse mOS in both cohorts; notably, in RAS WT pts mOS was 19.9 m (CI95% 10.5- 29.2) vs 37.6 m (CI95% 31.1– 44.1) p 0.006]. In tumor stroma, assessable in 334 samples, AXL was expressed in 80% of cases, with no difference among RAS groups. AXL expression correlated with lower mOS in both cohorts. (Table) Intriguingly, AXL expression in tumor and stroma (+/+) correlated with shorter mOS; in particular, RAS WT pts (+/+) had a mOS of 19.9 m (CI95% 8.0- 31.7) vs (-/-) 50.1 m (CI95% 43.9- 56.2) p 0.004]. In silico analyses showed high AXL RNA levels in 50% of pts. Moreover, in this population treated with cetuximab, in the KRAS exon2 WT cohort (N = 43) AXL high pts had worse mPFS [1.9 m (CI95% 1.7 -2.0) vs 3.8 m (CI95% 0.7-6.7) p 0.59].Table: 121P
Cohort | AXL expression in tumor cells | AXL expression in stroma | ||||||||
---|---|---|---|---|---|---|---|---|---|---|
N | Negative <1% (%) | Positive ≥1% (%) | PFS months p value | OS months p value | N | Negative <1% (%) | Positive ≥1% (%) | PFS months p value | OS months p value | |
Overall population | 346 | 285 (82) | 61 (18) | 10.7 vs 8.0 0.008 | 32.4 vs 23.0 0.007 | 334 | 66 (20) | 268 (80) | 10.7 vs 8.0 0.11 | 41.1 vs 28.5 0.004 |
RAS WT (overall) | 175 | 147 (84) | 28 (16) | 12.3 vs 6.6 <0.000 | 37.6 vs 19.9 0.006 | 167 | 33 (20) | 134 (80) | 15.0 vs 10.7 0.034 | 49.8 vs 33.5 0.031 |
RAS WT CT + anti-EGFR | 136 | 114 (84) | 22 (16) | 12.1 vs 6.2 0.012 | 35.8 vs 23.0 0.087 | 129 | 18 (14) | 111 (86) | 14.3 vs 10.4 0.37 | 44.4 vs 33.5 0.11 |
RAS WT CT + anti-angiogenic | 39 | 33 (85) | 6 (15) | 14.1 vs 6.7 0.007 | 44.8 vs 13.2 0.004 | 38 | 15 (39) | 23 (61) | 15.0 vs 11.0 0.12 | 50.1 vs 40.6 0.17 |
RAS mut (overall) CT + anti-angiogenic | 171 | 138 (81) | 33 (19) | 9.6 vs 8.9 0.78 | 27.6 vs 23.7 0.33 | 167 | 33 (20) | 134 (80) | 9.7 vs 9.2 0.98 | 35.5 vs 24.7 0.056 |
Conclusions
AXL expression in tumor and stroma might have a negative prognostic relevance in mCRC. In RAS WT pts, AXL expression might represent a predictive biomarker of lack of efficacy for both anti-EGFR and anti-angiogenic agents.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Department of Precision Medicine, Università degli Studi della Campania "Luigi Vanvitelli".
Funding
AIRC MFAG-2015-ID: 7778.
Disclosure
F. Ciardiello: Advisory / Consultancy, Advisory Board: Merck KgA, Bayer, Amgen, Roche, Servier, Pfizer. E. Martinelli: Advisory / Consultancy: Merck KgA, Amgen, Bayer, Roche, Sanofi, Servier. All other authors have declared no conflicts of interest.
Resources from the same session
3349 - Interplay between miR-17-5p and MALAT-1 Shapes The Cytokine Storm in Triple Negative Breast Cancer (TNBC) Tumor Microenvironment
Presenter: Raghda Soliman
Session: Poster Display session 3
Resources:
Abstract
4014 - Clinical verification on the relationship between lipid metabolism and the immune microenvironment of breast cancer
Presenter: Wataru Goto
Session: Poster Display session 3
Resources:
Abstract
4158 - The clinical and transcriptional signatures of human CD204 reveal an applicable marker for tumor associated macrophage in breast cancer
Presenter: Yunjie He
Session: Poster Display session 3
Resources:
Abstract
5392 - Activated effector T cells co-expressing multiple inhibitory receptors (IRs) are enriched in the tumor immune microenvironment in high grade serous ovarian cancer (HGSOC)
Presenter: Alice Bergamini
Session: Poster Display session 3
Resources:
Abstract
2617 - Oncolytic reovirus as a new anti-tumor strategy in castration resistant prostate cancer
Presenter: Yunlim Kim
Session: Poster Display session 3
Resources:
Abstract
2995 - Dysregulation of helper T lymphocytes in esophageal squamous cell carcinoma (ESCC) patients is highly associated with aberrant production of miR-21
Presenter: Ali Memarian
Session: Poster Display session 3
Resources:
Abstract
3597 - Myeloid derived suppressor cells but not regulatory T cells are associated with adaptive immunity and clinical outcomes in anal squamous cell carcinoma
Presenter: Christophe Borg
Session: Poster Display session 3
Resources:
Abstract
3430 - Evaluation of immune responses among responders (R) and non-responders (non-R) in a humanized mouse model with colorectal cancer (CRC) xenografts treated with combination immunotherapy
Presenter: Juan Marín Jiménez
Session: Poster Display session 3
Resources:
Abstract
1995 - ¬¬Advanced melanoma patients with high CD16+ macrophages have better response and survival to anti-PD-1 based immunotherapy
Presenter: Hansol Lee
Session: Poster Display session 3
Resources:
Abstract
3988 - Basal NK activity and early Treg function inhibition predicts Nivolumab responsiveness in metastatic renal cancer patients (REVOLUTION) trial.
Presenter: Sara Santagata
Session: Poster Display session 3
Resources:
Abstract