Kathryn Demanelis

Inorganic arsenic, a naturally occurring metalloid found in groundwater, is a well‐established human carcinogen. Epidemiological studies from highly contaminated regions link chronic arsenic exposure to increased risks of skin, lung, bladder, and kidney cancer. However, studies investigating the mechanisms driving arsenic‐related mutagenicity in human tumors remain limited. To improve our understanding, we analyzed whole‐exome sequencing (WES) data from tumor samples of 17 cancer patients treated in Dhaka, Bangladesh, with known or suspected exposure based on toenail arsenic concentrations. These patients included bladder ( n = 9), kidney ( n = 6), and lung ( n = 2) cancers. The mutational burden (mutations per megabase) across all exomes ranged from 23 to 117 for single‐base substitutions (SBS) and 2 to 13 for small insertions and deletions (indel). We showed that SBS and indel signatures, including SBS5, SBS6, ID6, and ID19 contributed the highest mutation load across all exomes. However, we did not observe associations between arsenic exposure levels and any mutational signature. We additionally analyzed WES data from two cell line models of chronic arsenic exposure, HaCaT skin epithelial and BEAS‐2B lung epithelial cells exposed to low‐dose of arsenite (100 nM) for 28 weeks. Consistent with the patient‐derived results, we observed no exposure‐related mutational burden or signature. Taken together, our findings suggest that arsenic alone may have limited independent mutagenic effects and instead may act through co‐carcinogenic mechanisms. However, limited sensitivity to detect low‐frequency mutations and small sample sizes potentially reduced our ability to capture mutational processes that may be associated with chronic arsenic exposure.

PURPOSE: Based on improved invasive disease-free survival in the monarchE trial, the US Food and Drug Administration (FDA) approved abemaciclib for adjuvant treatment of high-risk, estrogen receptor–positive (ER+), human epidermal growth factor receptor 2 (HER2)–negative breast cancer (BC) in combination with endocrine therapy. This study examines real-world prescribing patterns and clinical experiences with adjuvant abemaciclib at an academic cancer center in the United States. METHODS: This is a retrospective single-institution cohort study that included patients diagnosed between January 2021 and August 2023 with lymph node–positive, stage II-III ER+/HER2– BC at the University of Pittsburgh Medical Center who would have met eligibility criteria for the monarchE trial. We assessed tumor, provider, and patient factors associated with abemaciclib prescribing using multivariable logistic regression. RESULTS: Four hundred sixty-eight patients met monarchE eligibility criteria: 271 (58%) were eligible for abemaciclib under the 2021 FDA approval indications, 324 (69%) met monarchE cohort 1, and 144 (31%) met cohort 2 eligibility criteria only. In the entire cohort, 162 (35%) received a prescription, which was higher in patients meeting FDA approval indications (44%) and lower in those meeting only cohort 2 eligibility (20%). Prescribing increased from 28% in 2021 to 42% in 2022 ( P = .0097). Younger age at diagnosis, higher nodal burden, and higher tumor size were significantly associated with abemaciclib prescribing. Patient refusal was the primary reason for nonprescription (55%). Among those prescribed abemaciclib, 81% experienced toxicities, 47% required dose modifications, and 20% discontinued treatment before completion, primarily due to diarrhea. Abemaciclib prescription was associated with a 66% lower risk of recurrence after adjustment for age, BMI, nodal status, and other variables. CONCLUSION: Adjuvant abemaciclib prescribing was low despite its proven benefits. Further research is needed to address prescribing barriers and understand decision-making factors.

Cytokine Biomarkers of the 54-Plex Immunoassay (Meso Scale Discovery) during Phase I of the study.

Median (minimum, maximum) values of PBMC composition measurements in lung adenocarcinoma and squamous cell carcinoma cases.

Background:There are currently no blood-based biomarkers for early detection of lung cancer. We explored cellular and soluble mediators of immune dysregulation as potential biomarkers of lung cancer risk and development. We conducted a prospective nested case–control study of incident lung cancer cases and individually matched healthy controls from the Pittsburgh Lung Screening Study cohort of current and former smokers at high risk for developing lung cancer.Methods:Peripheral blood mononuclear cells were analyzed by flow cytometry, and Meso Scale Discovery multiplex platform immunoassay was used for detection of serum cytokines and chemokines at a distal (∼7 years prior) and a proximal (∼9 months prior) time point prior to cancer diagnosis. A linear mixed model was used to assess differences of analytes between cases and controls. Conditional logistic regression models were used to evaluate associations between levels of analytes and lung cancer risk.Results:No significant peripheral blood mononuclear cell differences were found between cases and controls. Serum IL-6, IL-12/IL-23p40, IL-17A, and TNF-α were significantly higher in cases than in controls (P < 0.05) at the proximal time point. Cases had higher levels of the angiogenic protein placental growth factor in sera from both distal and proximal time points (P < 0.05). Doubling concentrations of these analytes were associated with a 40% to 300% increase in lung cancer risk (P < 0.05).Conclusions:These circulating candidate biomarkers warrant further validation for early detection of lung cancer and identification of elevated risk.Impact:If validated in larger studies, these biomarkers could have clinical relevance.

Levels of Myeloid-Derived Suppressor Cells (MDSCs) and T Cells and Risk of Lung Cancer.

Geometric mean (95% CI) of peripheral blood mononuclear cells (PBMCs) composition measurements in lung cancer cases and controls.

Levels of cytokine biomarkers in distal and proximal sera and risk of lung adenocarcinoma and squamous cell carcinoma.

Geometric means (95% CI) of five serum cytokine biomarkers associated with lung cancer risk in both distal and proximal sera among lung cancer cases with and without nodules at time of sample collection.