A combination of a cyclooxygenase-2 (COX-2) inhibitor and a β-blocker given perioperatively has been shown to inhibit a range of tumor and circulating biomarkers associated with disease progression and metastases in early-stage breast cancer in the first clinical trial of its kind. The researchers hope that this will translate clinically to fewer metastases and cancer recurrences.
"The intervention is based on empirical findings," senior author, Shamgar Ben-Eliyahu, PhD, Tel Aviv University, Israel, explained to Medscape Medical News. The first is that "the perioperative period is really disproportionately significant in determining long-term cancer outcomes," and second, "during this period, there are strong stress and inflammatory responses that suppress immunity and directly impact the malignant tissue and its microenvironment, making them more prometastatic and inviting disease progression."
"So we treated patients with the combination of etodolac and propranolol beginning 5 days before surgery (and continued for 6 further days), and we found that treatment reduced the metastatic potential of the tissue and of the host," he said.
"Our hope is that, when we have a large enough sample, we will see more patients who don't develop metastatic disease down the line and who live without cancer recurrence," Dr Ben-Eliyahu added.
The research was published in the August issue of Clinical Cancer Research.
Important Trial
Asked by Medscape Medical News to comment on the study, Jonathan Hiller, MD, a clinical and research anesthetist at the Peter MacCallum Cancer Centre in Victoria, Australia, said he felt that this study is an important trial and, excitingly, translates experimental findings in animals to measurable benefits in patients with breast cancer.
"In the trial, researchers used 2 commonly available and safe drugs together to achieve 2 important outcomes — reducing the metastatic potential of a breast cancer and reducing the inflammatory and immunosuppressive stress response of surgery," Dr Hiller said in an email.
"So this trial contributes to increasing research into the effects of inflammatory and immune changes occurring at the time of surgery and their effect on residual or dormant cancer cells," he added.
"And it suggests that a week of pre-operative dosing — 'a cancer pre-med' — may very well translate to a cancer benefit for patients," Dr Hiller concluded.
Study Details
The randomized, placebo-controlled biomarker trial involved 38 patients with stage I to III breast cancer. Patients received the two-drug combination or placebo for 11 consecutive days, starting 5 days before their primary tumor was resected.
Etodolac was given at a dose of 400 mg twice a day, while extended-release propranolol was given at a dose of 20 mg twice a day during the 5 days preceding surgery and at a dose of 80 mg on the morning and the evening of the surgery itself, as well as the morning after surgery. Thereafter, propranolol was given at a dose of 20 mg twice a day for 5 days after the operation.
Blood samples were taken at multiple time points, and both blood samples and the primary tumor were tested and profiled for a range of biological markers predictive of metastases, Dr Ben-Eliyahu noted.
Given the physiologic and psychologic stresses leading up to surgery, the placebo group showed an increase in certain cytokines: Serum levels of interleukin (IL)-6 increased by 24% and C-reactive protein (CRP) increased by 41.5% in the 5 days before surgery (measured from the morning of the fifth day before surgery [when participants started taking drug or placebo] to the morning before surgery).
"This pattern was significantly reversed in the drug-treated group," investigators report, declining by 11.3% for IL-6 (P = .0009) and by 10% for CRP (P = .034).
The morning after surgery, both IL-6 and CRP increased dramatically in both groups relative to presurgical levels, they note.
But there was still a significant reduction in IL-6 levels between pretreatment and study endpoint (P = .011) among patients who received the perioperative regimen compared with placebo controls.
Changes in CRP were minimal in the perioperative regimen group.
As the researchers explain, IL-6 and CRP are both associated with tumor progression and poor prognosis in many solid tumors, including those of the breast, prostate, and lung.
Investigators also observed that the two-drug regimen reversed epithelial-to-mesenchymal transition — the process by which tumor cells escape from the primary tumor and metastasize to other organs.
Favorable influences from the same perioperative treatment strategy were also noted in the gene expression profiles of the primary tumor; circulating immune parameters (including increased levels of natural killer-cell activation markers), and reduced monocyte influx. All of these have been linked to a reduced risk for tumor progression in both animal models and human clinical studies, the researchers point out.
In a related study involving roughly the same numbers of patients with colorectal cancer, Dr Ben-Eliyahu and colleagues observed very similar changes in blood and tumor biomarkers when patients were treated with the same perioperative regimen.
"[C]ombined perioperative β-blockade and COX-2 inhibition may inhibit stress-induced inflammatory and metastatic processes through multiple cellular and molecular pathways," the researchers conclude.
In addition, they suggest that "the favorable safety profile and favorable impacts on tumor transcriptome profiles and immune parameters provide a rationale for future clinical trials."
The work was supported by the National Cancer Institute Network on Biobehavioral Pathways in Cancer, the Israel Science Foundation, and the National Institutes of Health/National Institute on Aging. The authors and Dr Hiller have disclosed no relevant financial relationships.
Clin Cancer Res. 2017;23:4651-4661. Abstract
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