Breast cancer is the most prevalent cancer in women worldwide and a leading cause of cancer-related mortality. In 2021, more than 2.1 million women were diagnosed globally, and the disease claimed over 674,000 lives. Iran presents a particularly worrying picture. Despite global advances in early detection and treatment, the age-standardized breast cancer mortality rate there rose by 16.5 percent between 1990 and 2019, and national health insurance data show mortality climbing from 0.68 to 0.86 per 100,000 individuals between 2021 and 2022. Iranian women are also typically diagnosed about a decade earlier than women in Western countries, and often at more advanced stages, making modifiable risk factors such as diet an urgent target for prevention research.

Chronic inflammation has long been suspected as a plausible contributor to cancer development. Inflammatory pathways may promote carcinogenesis through the release of cytokines, the generation of reactive oxygen species, DNA damage, and sustained signaling that supports tumor initiation and progression. Diet is one of the most powerful modulators of systemic inflammation, capable of either amplifying or dampening these processes. To capture this effect quantitatively, researchers developed the Dietary Inflammatory Index, or DII, and its energy-adjusted counterpart, the E-DII. These tools have been validated through associations with inflammatory biomarkers in 63 studies and examined across hundreds of cancer studies, but results on breast cancer have been inconsistent, with some reporting elevated risk and others finding no association at all.

The Isfahan study was designed to test whether that inconsistency might be resolved by accounting for total energy intake. Cases were identified from the Isfahan Breast Cancer Registry and recruited if they had histologically confirmed, newly diagnosed breast cancer with no previous cancer history; 92 percent of the 653 newly identified cases agreed to participate. Controls were drawn from the same source population of roughly 780,000 women using random digit dialing across all 15 municipal districts of Isfahan, yielding 600 participants and a response rate of 70.4 percent. Five trained female interviewers conducted structured telephone interviews, with recordings randomly reviewed to minimize interviewer bias, and the study was approved by the Ethics Committee of Isfahan University of Medical Sciences.

Dietary intake was assessed using a validated 168-item food frequency questionnaire adapted to Iranian foods, with portion sizes converted to grams per day using standard household measures. The DII score was calculated from 35 of the 45 original food parameters, including macronutrients, fatty acids, cholesterol, fiber, and selected vitamins and minerals. Each participant’s intakes were standardized against a global reference database to generate z-scores, converted to centered percentiles, and multiplied by literature-derived inflammatory effect scores before being summed, with higher scores indicating a more pro-inflammatory diet. The E-DII applied the same algorithm but expressed nutrient intakes per 1,000 kilocalories, isolating the inflammatory potential of the diet from overall caloric consumption.

The results revealed a striking divergence between the two indices. The mean E-DII score was higher among cases, 1.77, than controls, 1.63, and while the unadjusted association was not significant, adjustment for confounders changed the picture dramatically. Each one-unit increase in E-DII was associated with 14 percent higher odds of breast cancer, and women in the highest quartile had 63 percent greater odds of diagnosis than those in the lowest quartile, with a statistically significant linear trend across quartiles. In contrast, the DII showed no significant association with breast cancer in either continuous or quartile analysis, suggesting that energy adjustment may enhance the predictive capacity of dietary inflammatory potential.

The biological plausibility of these findings rests on well-characterized mechanisms. Pro-inflammatory cytokines such as IL-6, TNF-α, and IL-1β are elevated in breast cancer patients and associated with poorer prognosis. IL-6 in particular promotes tumor progression through activation of the STAT3 signaling pathway, enhancing cancer cell migration and invasiveness. Saturated fats and refined carbohydrates promote inflammation, whereas fiber and other bioactive compounds exert anti-inflammatory effects. Natural compounds characteristic of the Mediterranean diet, particularly polyphenols from extra-virgin olive oil, fruits, vegetables, and nuts, may help protect against breast cancer through antioxidant, anti-inflammatory, antiproliferative, and pro-apoptotic mechanisms.

The divergence between DII and E-DII associations has been reported before. DII scores are influenced by total food intake, and energy consumption generally declines with age, which can distort the inflammatory signal when calories are not accounted for. Consistent evidence linking higher DII scores with lower energy intake led to the development of the E-DII, and the Isfahan findings support that approach, as the E-DII better captures inflammatory nutrient density independent of total caloric intake. Previous studies in northwestern Iran found an 87 percent higher breast cancer risk with elevated E-DII scores, while research in Spanish women found no significant link, and one study found E-DII associated only with triple-negative breast cancer, highlighting the potential relevance of subtype-specific effects.

The study’s strengths include random sampling of population-based controls, a relatively large sample size, and high response rates among newly diagnosed cases. But the authors caution that the case-control design cannot establish cause and effect, and retrospective dietary assessment may have introduced recall bias and measurement error. Only 35 of the 45 original DII components were available, potentially reducing precision, and residual confounding from genetic influences, parity, breastfeeding history, and smoking cannot be ruled out. Recruitment through random digit dialing also limited participation to households with residential landlines, potentially underrepresenting some segments of the population, though high response rates likely minimized such bias.

The findings provide hypothesis-generating evidence that anti-inflammatory dietary patterns rich in fruits, vegetables, and whole grains may help reduce breast cancer risk, and they underscore the importance of energy adjustment in nutritional epidemiology. The authors emphasize that prospective and intervention studies are needed to confirm causality and evaluate preventive potential before specific public health recommendations can be made. For now, the message emerging from Isfahan is that the inflammatory character of a diet, measured carefully and independently of how much a woman eats, may be a meaningful and modifiable piece of the breast cancer puzzle.

Subject of Research: Association between the energy-adjusted Dietary Inflammatory Index and breast cancer risk in a population-based case-control study of Iranian women

Article Title: Inflammatory Potential of Diet and Breast Cancer Risk: A Population‐Based Case–Control Study

Article References: Amani‐Beni, R., Price, S., Darouei, B., Abdollahpour, I., Javanmard, S. H., Zendehdel, K., & Hebert, J. R. (2026). Inflammatory Potential of Diet and Breast Cancer Risk: A Population‐Based Case–Control Study. Food Science & Nutrition, 14(10), Article e72473. https://doi.org/10.1002/fsn3.72473

Image Credits: AI Generated

DOI: 10.1002/fsn3.72473

Keywords: breast cancer, dietary inflammatory index, E-DII, DII, chronic inflammation, nutrition epidemiology, case-control study, Iran, energy adjustment, cytokines, STAT3 pathway, dietary patterns