Improving biomarkers of metastasis in colorectal and breast cancer patients through perioperative blockade of inflammatory-stress responses in two phase-II clinical trials

Introduction: Excess release of prostaglandins and/or catecholamines was suggested to mediate pro-metastatic effects of stress and surgery. In our previous work in six tumor models we showed that a perioperative combined blockade of prostaglandins and catecholamines improves postoperative resistance to tumor metastasis and/or overall long-term survival rates.

Material and method: Here, in two recent biomarker clinical trials (randomized and placebo-controlled) in colorectal (CRC, n=34) and in breast cancer patients (BC, n=38), we tested the combined perioperative use of the COX2-inhibitor, etodolac, and the β-blocker, propranolol, scheduled for 20 perioperative days, starting 5 days before surgery. Excised tumor tissue was subjected to histological analyses, whole genome mRNA profiling, and transcriptional control pathways analyses. In BC patients, repeated blood samples were assessed for cytokine levels and immune indices.

Results and discussion: In both studies, (i) drugs were well tolerated and (ii) whole genome mRNA profiling of excised tumors showed decreased epithelial-to-mesenchymal transition (EMT); down-regulation of the transcriptional activity of CREB, NFkB, GATA family, and STAT3; reduced presence of tumor-associated monocytes; and increased presence of NK cells (CRC) and B cells (BC). In blood samples of BC patients, treatment reduced serum IL-6 and CRP levels (starting before surgery) without affecting anti-inflammatory soluble factors (cortisol and IL-10), improved cytotoxicity markers in NK cells, and enhanced induced production of IFNγ and IL-12. The tumor proliferation marker Ki67 was tested and significantly reduced by drug treatment in BC patients; and in CRC patients three-year follow-up showed large but statistically insignificant improvement in disease free survival (DFS) (1/15 vs 5/19, treated vs placebo groups), suggesting the long-term safety and efficacy of the paradigm. Overall, these findings suggest a metastatic-reducing impact of this novel treatment, which should be tested in larger clinical trials.

Conclusion: Such an inflammatory-stress-reducing approach may enable us to exploit the critical perioperative period to reduce cancer recurrence, potentially leading to improved long-term survival rates.