Inflammation Gene Variant May Shape Survival After Rectal Cancer Therapy Choice

A single gene variant that shapes how much inflammatory signaling a patient’s cells produce may determine which neoadjuvant treatment strategy gives them the best chance of surviving rectal cancer, according to an exploratory analysis published in BMC Cancer. The study, led by Rita Ambraziene of the Lithuanian University of Health Sciences in Kaunas, examined patients enrolled in a prospective randomized noninferiority trial that compared intensified chemotherapy with standard chemoradiotherapy before surgery for locally advanced rectal cancer. The genetic finding is tantalizing precisely because it emerged from a randomized design, yet the authors are careful to stress that it does not survive correction for multiple testing and rests on a small number of cancer-specific deaths.

The trial, registered as NCT05378919, enrolled 150 patients with stage II to III rectal cancer at a single center and randomized them equally to one of two preoperative strategies. One group received intensified neoadjuvant chemotherapy, consisting of eight cycles of the FOLFOX4 regimen, which combines folinic acid, fluorouracil, and oxaliplatin. The other group received the standard approach of chemoradiotherapy, delivering 50 Gy in 25 fractions with concurrent fluoropyrimidine chemotherapy. The primary endpoint was five-year disease-free survival, with a noninferiority margin set at a hazard ratio of up to 1.29 for the chemotherapy arm relative to the chemoradiotherapy arm. The idea behind the trial was to test whether chemotherapy alone could spare patients the toxicities of pelvic radiation while achieving comparable disease control.

On the primary question, the answer was negative. In the intention-to-treat population, five-year disease-free survival was 49.3 percent in the intensified chemotherapy arm versus 64.1 percent in the chemoradiotherapy arm, corresponding to a hazard ratio of 1.52 with a 95 percent confidence interval of 0.90 to 2.56. Because the upper bound of that confidence interval exceeded the prespecified noninferiority margin of 1.29, noninferiority was not demonstrated. In the per-protocol analysis, which included only patients who completed their assigned treatment as planned, the chemotherapy arm was significantly inferior, with five-year disease-free survival of 57.9 percent versus 79.2 percent and a hazard ratio of 2.26. Overall survival and cancer-specific survival did not differ significantly between the two arms in the unselected population, but the trial was underpowered for these endpoints, a limitation the authors acknowledge openly.

Against this backdrop of a failed noninferiority test, the genetic analysis offers a different kind of insight. The researchers genotyped two polymorphisms in the gene encoding interleukin-1 beta, a potent proinflammatory cytokine involved in tissue remodeling, immune cell recruitment, and tumor microenvironment dynamics. The variants, rs1143634 and rs16944, were analyzed using TaqMan assays on blood samples collected prospectively and stored in an institutional biobank. Interleukin-1 beta polymorphisms are known to modulate cytokine expression levels, and the researchers hypothesized that this could influence how tumors respond differently to radiation-based versus chemotherapy-based neoadjuvant treatment by altering inflammatory signaling within the tumor microenvironment.

The key finding concerned rs1143634 and cancer-specific survival. Using Cox regression models with multiplicative interaction terms, the researchers identified a nominally significant treatment-by-genotype interaction for this variant in cancer-specific survival, with a Wald test interaction p-value of 0.041 and a likelihood-ratio test p-value of 0.028. When patients were stratified by treatment arm, the pattern was striking. In the intensified chemotherapy arm, carriage of the T allele, meaning patients with either CT or TT genotypes, was associated with inferior cancer-specific survival, with a hazard ratio of 4.84 and a 95 percent confidence interval of 1.04 to 22.43. In the chemoradiotherapy arm, the same T-allele carriage showed no prognostic effect at all, with a hazard ratio of 0.69 and a p-value of 0.494. No such interaction was detected for disease-free survival, and the second variant, rs16944, showed no interaction with either treatment arm for any survival endpoint.

The biological logic behind this differential effect is worth unpacking. Interleukin-1 beta is a central mediator of the inflammatory response, and elevated levels have been linked to tumor progression, angiogenesis, and resistance to cell death in multiple cancer types. The rs1143634 variant, located in the coding region of the IL1B gene, is associated with altered production of the cytokine. One plausible mechanism is that patients carrying the T allele produce different amounts of interleukin-1 beta in response to the cellular stress induced by chemotherapy, and this altered inflammatory milieu could either promote survival of residual tumor cells or fail to support the immune-mediated clearance of micrometastatic disease. Radiation therapy, by contrast, kills cells through a different mechanism involving DNA double-strand breaks and generates a distinct inflammatory signature in the treated tissue, which could explain why the same variant has no effect in that arm.

The authors are appropriately cautious about what this means. The interaction p-value of 0.041 did not survive correction for multiple testing, which is the statistical standard required when researchers examine several variants and several endpoints simultaneously. The finding is also based on a small number of cancer-specific events, meaning the hazard ratio of 4.84 carries a wide confidence interval that reflects substantial uncertainty. The authors explicitly state that this exploratory finding does not establish rs1143634 as a predictive biomarker and that prospective validation in an adequately powered, biomarker-stratified trial is warranted before any clinical application could be considered.

What makes this study noteworthy in the broader landscape of cancer pharmacogenomics is the randomized design. Most biomarker studies in oncology are retrospective, drawing on tissue or blood samples from patients treated in heterogeneous ways across different eras and institutions. Because patients in this trial were prospectively randomized to two distinct neoadjuvant strategies, the treatment-genotype interaction is less susceptible to the selection biases that plague observational biomarker research. The randomization ensures that, within each genotype group, patients were equally likely to receive either treatment, which strengthens the causal interpretation of the differential survival pattern. This is the same methodological logic that underpins the landmark biomarker-stratified trials in breast and lung cancer, where treatment effects were shown to differ by genetic or molecular subtype.

The failed noninferiority result for the primary endpoint also carries clinical weight. Intensified neoadjuvant chemotherapy with FOLFOX4 has been explored as a radiation-sparing alternative for rectal cancer, motivated by the desire to avoid the long-term toxicities of pelvic radiotherapy, including bowel dysfunction, sexual dysfunction, and increased fracture risk. The finding that chemotherapy alone did not achieve noninferiority in disease-free survival, and was significantly inferior in the per-protocol population, suggests that radiation remains an essential component of neoadjuvant therapy for unselected patients with locally advanced rectal cancer. The trial was underpowered for the primary endpoint, which the authors note, but the direction of the effect and the per-protocol result both point away from a strategy of replacing radiotherapy with chemotherapy in this population.

The intersection of these two results, a negative primary endpoint and a positive exploratory genetic interaction, illustrates a recurring theme in modern oncology. Population-level trials can fail to show benefit for a new strategy even when a molecularly defined subgroup might respond differently. The rs1143634 finding, if validated, could eventually allow clinicians to identify which patients with locally advanced rectal cancer are more or less likely to benefit from intensified chemotherapy versus chemoradiotherapy, moving the field closer to personalized neoadjuvant treatment selection. Until such validation is completed in adequately powered prospective studies, the standard of care for unselected patients remains chemoradiotherapy followed by surgery, and the IL1B variant remains a hypothesis-generating signal rather than a clinical decision tool.

Subject of Research: IL1B rs1143634 genotype and differential cancer-specific survival by neoadjuvant strategy in locally advanced rectal cancer: an exploratory analysis of a prospective randomized noninferiority trial

Article Title: IL1B rs1143634 genotype and differential cancer-specific survival by neoadjuvant strategy in locally advanced rectal cancer: an exploratory analysis of a prospective randomized noninferiority trial

Article References: Ambraziene, R., Malonyte, R., Muduraite, R., Chlebopaseviene, G., Grinkevicius, R., Tamelis, A., Latkauskas, T., Pauzas, H., Lizdenis, P., Svagzdys, S., Pikuniene, I., Rudzianskas, V., Janciauskas, D., Bartnykaite, A., Ugenskiene, R., & Janciauskiene, R. (2026). IL1B rs1143634 genotype and differential cancer-specific survival by neoadjuvant strategy in locally advanced rectal cancer: an exploratory analysis of a prospective randomized noninferiority trial. BMC Cancer. https://doi.org/10.1186/s12885-026-17139-z

Image Credits: AI Generated

DOI: 10.1186/s12885-026-17139-z

Keywords: rectal cancer, IL1B, rs1143634, neoadjuvant chemotherapy, chemoradiotherapy, noninferiority trial, cancer-specific survival, biomarker, pharmacogenomics, tumor microenvironment, interleukin-1 beta, FOLFOX4