BACKGROUND: Breast tumor immune infiltration is clearly associated with improved treatment response and outcomes in breast cancer. However, modifiable patient factors associated with breast cancer immune infiltrates are poorly understood. The Nurses' Health Study (NHS) offers a unique cohort to study immune gene expression in tumor and adjacent normal breast tissue, immune cell-specific immunohistochemistry (IHC), and patient exposures. We evaluated the association of body mass index (BMI) change since age 18, physical activity, and the empirical dietary inflammatory pattern (EDIP) score, all implicated in systemic inflammation, with immune cell-specific expression scores.

METHODS: This population-based, prospective observational study evaluated 882 NHS and NHSII participants diagnosed with invasive breast cancer with detailed exposure and gene expression data. Of these, 262 women (training cohort) had breast tumor IHC for four classic immune cell markers (CD8, CD4, CD20, and CD163). Four immune cell-specific scores were derived via lasso regression using 105 published immune expression signatures' association with IHC. In the remaining 620 patient evaluation cohort, we evaluated association of each immune cell-specific score as outcomes, with BMI change since age 18, physical activity, and EDIP score as predictors, using multivariable-adjusted linear regression.

RESULTS: Among women with paired expression/IHC data from breast tumor tissue, we identified robust correlation between novel immune cell-specific expression scores and IHC. BMI change since age 18 was positively associated with CD4+ (β = 0.16; p = 0.009), and CD163 novel immune scores (β = 0.14; p = 0.04) in multivariable analyses. In other words, for each 10 unit (kg/m2) increase in BMI, the percentage of cells positive for CD4 and CD163 increased 1.6% and 1.4%, respectively. Neither physical activity nor EDIP was significantly associated with any immune cell-specific expression score in multivariable analyses.

CONCLUSIONS: BMI change since age 18 was positively associated with novel CD4+ and CD163+ cell scores in breast cancer, supporting further study of the effect of modifiable factors like weight gain on the immune microenvironment.

Background. The link between Epstein-Barr Virus (EBV) and breast cancer (BC) remains unclear. Infectious mononucleosis (IM) is a clinical manifestation of delayed onset of EBV infection in early adulthood. We utilized the Health of Women (HOW) Study to understand the association between IM and BC risk.

Subjects and methods. The HOW Study was a web-based survey of BC risk factors with >40,000 participants who answered seven modules between 2012 and 2015; 3,654 women had IM between the ages of 10 and 22 years (16.8%) and 17,026 never developed IM (78.5%). Of these 20,680 women, 1,997 (9.7%) had Stages I-III BC and 13,515 (65.4%) were cancer-free. Multivariable binary logistic regression ascertained the association between IM and BC risk by controlling for ethnicity, family history, age at menarche, oral contraceptive use, tobacco use, birthplace, parity, age at first birth, body mass index, and breast biopsy. Secondary analyses stratified cancer cases into those who had BC at <50 or >=50 years old and by estrogen receptor (ER) subtype.

Results. Participants were mostly white, middle-aged women born in the United States or Canada. Women who had IM were less likely to develop BC than those who did not develop IM (adjusted odds ratio (OR)=0.83, 95% confidence interval (CI) 0.71-0.96). Findings were similar when stratifying women into <50 or >=50 years old at BC diagnosis (<50 years old, adjusted OR=0.82, 95% CI 0.67-0.998; >=50 years old, adjusted OR=0.83, 95% CI 0.69-1.00). Women who had IM were less likely to develop ER positive BC (adjusted OR=0.84, 95% CI 0.71-0.997); there was no association between IM and ER negative BC (adjusted OR=0.88, 95% CI 0.65-1.16).

Conclusion. In the HOW Study, women diagnosed with IM between the ages of 10 and 22 had lower breast cancer risk compared to women who never developed IM.