Systemic release of osteoprotegerin during oxaliplatin-containing induction chemotherapy and favorable systemic outcome of sequential radiotherapy in rectal cancer

Sebastian Meltzer, Erta Kalanxhi, Helga Helseth Hektoen, Svein Dueland, Kjersti Flatmark, Kathrine Røe Redalen, Anne Hansen Ree, Sebastian Meltzer, Erta Kalanxhi, Helga Helseth Hektoen, Svein Dueland, Kjersti Flatmark, Kathrine Røe Redalen, Anne Hansen Ree

Abstract

In colorectal cancer, immune effectors may be determinative for disease outcome. Following curatively intended combined-modality therapy in locally advanced rectal cancer metastatic disease still remains a dominant cause of failure. Here, we investigated whether circulating immune factors might correlate with outcome. An antibody array was applied to assay changes of approximately 500 proteins in serial serum samples collected from patients during oxaliplatin-containing induction chemotherapy and sequential chemoradiotherapy before final pelvic surgery. Array data was analyzed by the Significance Analysis of Microarrays software and indicated significant alterations in serum osteoprotegerin (TNFRSF11B) during the treatment course, which were confirmed by osteoprotegerin measures using a single-parameter immunoassay. Patients experiencing increase in circulating osteoprotegerin during the chemotherapy had significantly better 5-year progression-free survival than those without increase (78% versus 48%; P = 0.009 by log-rank test). Hence, systemic release of this soluble tumor necrosis factor decoy receptor following the induction phase of neoadjuvant therapy was associated with favorable long-term outcome in patients given curatively intended chemoradiotherapy and surgery but with metastatic disease as the main adverse event. This finding suggests that osteoprotegerin may mediate or reflect systemic anti-tumor immunity invoked by combined-modality therapy in locally advanced rectal cancer.

Keywords: metastasis; osteoprotegerin; oxaliplatin; radiotherapy; rectal cancer.

Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1. Serum OPG levels during neoadjuvant…
Figure 1. Serum OPG levels during neoadjuvant therapy
Using the single-parameter immunoassay, OPG was measured in serum sampled from patients at baseline (n = 74), post-NACT (n = 64), post-CRT (n = 61), and at evaluation of the neoadjuvant treatment (n = 57). For each sample group, where mean value is indicated by a line, distribution of values was different from baseline (* P < 0.01, ** P < 0.0001; calculated by unpaired one-way analysis of variance).
Figure 2. Serum OPG levels and PFS
Figure 2. Serum OPG levels and PFS
Patients were separated into cases with (solid line) or without (dashed line) increase in circulating OPG levels from baseline to completion of induction neoadjuvant chemotherapy, as measured by the single-parameter immunoassay. The difference between the two groups was significant (log-rank test; P = 0.009).

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