Brenda Hernandez

BACKGROUND/AIMS: Inflammation-based scores, such as the neutrophil-to-lymphocyte ratio (NLR), have been associated with prognosis in hepatocellular carcinoma (HCC); but variable cut-off values and potential lack of specificity have limited the utility of NLR. This study evaluates NLR in a large cohort of HCC patients. METHODS: We retrospectively reviewed 789 HCC cases (1993-2017) for demographics, tumor characteristics, treatment, and survival. NLR was stratified into NLR ≥1.5 and NLR ≥3 and analyzed for correlation with American Joint Committee on Cancer (AJCC) and Barcelona Clinic Liver Cancer (BCLC) stages. In 235 patients who underwent liver resection, survival and recurrence were evaluated by NLR. RESULTS: In 789 HCC cases, mean NLR was increased with advanced AJCC and BCLC stages. Hepatitis C patients were less likely to have NLR ≥1.5 and ≥3. Non-alcoholic steatohepatitis patients were more likely to have NLR ≥3. Patients with tumor size >5 cm, rupture, or macrovascular invasion were more likely to have NLR ≥3. In patients treated with resection, NLR ≥3 predicted early recurrence (odds ratio [OR] 4.14, P<0.01) and overall recurrence (OR 4.05, P<0.01). Mean NLR was 4.30 in those with recurrence and 2.75 in those without recurrence. Patients with NLR ≥3 showed significantly worse survival compared to those with NLR <3 (P<0.01 by log-rank test). CONCLUSION: Elevated NLR is associated with advanced cancer stage and aggressive tumor characteristics, such as large size, rupture, and invasion. NLR ≥3 was associated with early and overall recurrence after resection but varied with etiology. NLR may be a useful biomarker in predicting recurrence for HCC patients undergoing curative resection, but further studies are required to elucidate the effect of disease etiology.

BACKGROUND: Ductal carcinoma in situ (DCIS) is a precursor of invasive breast cancer; however, the majority of DCIS tumors do not progress to invasive breast cancer. Elucidating shared and distinct risk factors for DCIS and invasive breast cancer may provide novel insights into the pathogenesis of breast cancer. METHODS: The Multiethnic Cohort Study was used to examine whether known risk factors for invasive breast cancer are associated with DCIS among a racially and ethnically diverse U.S. population of women. RESULTS: African American (HR 1.49, 95% CI 1.24-1.78), Native Hawaiian (HR 1.50, 95% CI 1.19-1.88), and Japanese American (HR 1.66, 95% CI 1.43-1.94) women were found to have a significantly higher risk of DCIS compared to White women, with Latino women having a non-significant increased risk (HR 1.19, 95% CI 0.97-1.48). Of the risk factors we investigated, increased risk of DCIS was associated with family history of breast cancer (HR 1.55, 95% CI 1.34-1.79), Type 2 diabetes (HR 1.27, 95% CI 1.09-1.48), nulliparity (HR 1.36, 95% CI 1.15-1.62), older age (> 30 yrs) at first live birth (p-trend 0.001), and current use of estrogen hormone therapy with or without progesterone (HR 1.19, 95% CI 1.04-1.35; HR 1.18, 95% CI 1.02-1.38, respectively). Decreased risk of DCIS was associated with parity, with a p-trend = 0.0001 for increasing number of children, and non-U.S. birthplace (HR 0.78, 95% CI 0.66-0.93). Risk factor associations did not differ significantly across racial and ethnic groups, with the exception of smoking status (p-het = 0.05), where an increased risk was found only for Native Hawaiians. CONCLUSION: The identification of both shared and distinct risk factors of DCIS and invasive breast cancer underscores the need for other methods for risk stratification to differentiate indolent DCIS tumors from aggressive precursor lesions.

Abstract Background: Obesity is a major modifiable risk factor for postmenopausal breast cancer prognosis. Mechanisms underlying the association between obesity and post-menopausal breast cancer include higher levels of estradiol, cholesterol, and inflammation. Circulating cholesterol is metabolized into 27-hydroxychlolesterol (27HC) by the sterol 27-hydroxylase enzyme (CYP27A1). 27HC is catabolized by the oxysterol 7α-hydroxylase enzyme (CYP7B1). 27HC can regulate breast cancer pathobiology by functioning as an endogenous selective estrogen receptor modulator in breast tumors. In this study, we examined the associations of expression levels of CYP27A1 and CYP7B1 in tumor tissue with clinicopathological characteristics of breast cancer in a multiethnic population. Methods: Invasive breast tumor tissue from 510 postmenopausal females (62 African American, 114 Japanese American, 93 Latino, 135 Native Hawaiian, and 106 White) in the Multiethnic Cohort Study were used for targeted profiling of gene expression using the NanoString nCounter Breast Cancer 360™ (BC360) Panel, including 51 additional custom genes. Generalized odds logistic regression analysis was conducted to examine associations of gene expression levels for CYP27A1 and CYP7B1 with clinicopathological characteristics -- stage, PAM50 molecular subtype (Luminal A, B, HER2-enriched, Basal-like) and NanoString Risk of Recurrence (ROR) score. Results: CYP27A1 expression was associated with a lower likelihood of advanced versus localized stage at diagnosis (OR=0.87; 95% CI 0.74, 1.02). No association was observed for CYP7B1 with stage. CYP27A1 expression was associated with a lower likelihood of HER2-enciched (OR=0.71; 95% CI 0.55, 0.92) and Luminal B (OR=0.71; 95% CI 0.58, 0.89) subtypes in comparison to Luminal A subtypes. CYP7B1 expression was associated with Basal-like (OR=1.23; 95% CI 1.02, 1.49), HER2-enriched (OR=0.59; 95% CI 0.43, 0.80), and Luminal B (OR=0.43; 95% CI 0.32, 0.58) subtypes in comparison to Luminal A. No significant association was observed for CYP27A1 and ROR categories (low, intermediate, and high). In contrast, CYP7B1 expression was associated with lower risk of recurrence score (ROR intermediate vs. low: OR=0.77; 95% CI 0.62, 0.96; ROR high vs. low: OR=0.56; 95% CI 0.40, 0.79). Conclusion: This study identified that gene expression levels of 27HC metabolizing enzymes, CYP27A1 and CYP7B1, in breast tumors were associated stage, breast cancer subtype, and risk of recurrence among a multiethnic population of women. Citation Format: Lenora W. M. Loo, Yuqing Li, Kami K. White, Jose A. Aparicio, Veronica Wendy Setiawan, Brenda Y. Hernandez, Anna H. Wu, Christopher Haiman, Loic Le Marchand, Lynne R. Wilkens, Iona Cheng. Expression of 27-hydroxycholesterol metabolizing enzymes and breast cancer clinicopathological characteristics: The Multiethnic Cohort Study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2321.

BRCA-associated homologous recombination deficiency (HRD) is present in ~50% of high-grade serous carcinomas (HGSC) and predicts sensitivity to platinum-based therapy. However, there is little understanding of why some patients with BRCA-deficient tumors experience poor outcomes. In a large HGSC cohort (n = 1389) including 282 individuals with pathogenic germline BRCA variants (gBRCApv), residual disease after primary surgery has limited prognostic effect in gBRCApv-carriers compared to non-carriers, and prognostic outcomes differ based on the mutation location within functional domains of the BRCA genes. Multi-omic profiling is performed on 154 tumors, enriched for patients with BRCA-deficient tumors that experienced short overall survival ( ≤ 3 years, n = 42). Patients with BRCA2-deficient HGSC and loss of NF1 survive twice as long as those without NF1 loss, whereas PIK3CA, RAD21 and MYC amplification define BRCA2-deficient HGSC with exceptionally short survival. Patients with BRCA1-deficient HGSC and a more elevated HRD score survive significantly longer. BRCA1-deficient tumors in short survivors have evidence of immunosuppressive c-kit signaling and EMT. Our findings confirm that outcome is not determined by BRCA status alone, but rather a combination of co-occurring genomic alterations, the extent of DNA repair deficiency, and the tumor-immune microenvironment.