Proteogenomic characterization of difficult-to-treat breast cancer with tumor cells enriched through laser microdissection.

BACKGROUND: Breast cancer (BC) is the most commonly diagnosed cancer and the leading cause of cancer death among women globally. Despite advances, there is considerable variation in clinical outcomes for patients with non-luminal A tumors, classified as difficult-to-treat breast cancers (DTBC). This study aims to delineate the proteogenomic landscape of DTBC tumors compared to luminal A (LumA) tumors. METHODS: We retrospectively collected a total of 117 untreated primary breast tumor specimens, focusing on DTBC subtypes. Breast tumors were processed by laser microdissection (LMD) to enrich tumor cells. DNA, RNA, and protein were simultaneously extracted from each tumor preparation, followed by whole genome sequencing, paired-end RNA sequencing, global proteomics and phosphoproteomics. Differential feature analysis, pathway analysis and survival analysis were performed to better understand DTBC and investigate biomarkers. RESULTS: We observed distinct variations in gene mutations, structural variations, and chromosomal alterations between DTBC and LumA breast tumors. DTBC tumors predominantly had more mutations in TP53, PLXNB3, Zinc finger genes, and fewer mutations in SDC2, CDH1, PIK3CA, SVIL, and PTEN. Notably, Cytoband 1q21, which contains numerous cell proliferation-related genes, was significantly amplified in the DTBC tumors. LMD successfully minimized stromal components and increased RNA-protein concordance, as evidenced by stromal score comparisons and proteomic analysis. Distinct DTBC and LumA-enriched clusters were observed by proteomic and phosphoproteomic clustering analysis, some with survival differences. Phosphoproteomics identified two distinct phosphoproteomic profiles for high relapse-risk and low relapse-risk basal-like tumors, involving several genes known to be associated with breast cancer oncogenesis and progression, including KIAA1522, DCK, FOXO3, MYO9B, ARID1A, EPRS, ZC3HAV1, and RBM14. Lastly, an integrated pathway analysis of multi-omics data highlighted a robust enrichment of proliferation pathways in DTBC tumors. CONCLUSIONS: This study provides an integrated proteogenomic characterization of DTBC vs LumA with tumor cells enriched through laser microdissection. We identified many common features of DTBC tumors and the phosphopeptides that could serve as potential biomarkers for high/low relapse-risk basal-like BC and possibly guide treatment selections.

Bone Sarcoma Survival in the US Military Health System: Comparison With the SEER Program.

BACKGROUND: Access to care is associated with cancer survival. The US Military Health System (MHS) provides universal health care to all beneficiaries. However, it is unknown whether survival among patients with bone sarcoma in a health system providing universal care is better than that in the general population. The aim of the study was to compare survival of patients with bone sarcoma in the US MHS with that of the US general population. METHODS: The MHS data were obtained from the Department of Defense Automated Central Tumor Registry (ACTUR). The US general population data were obtained from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) registry. Adult patients were defined as those aged 25 years or older with a histologically confirmed musculoskeletal bone sarcoma diagnosed from January 1, 1987, to December 31, 2013. Kaplan-Meier survival curves and multivariable Cox proportional hazards models were used to compare the overall survival of the two populations. RESULTS: The final analysis included 2,273 bone sarcoma cases from ACTUR and 9,092 bone sarcoma cases from SEER. ACTUR patients had significant lower 5-year all-cause death (hazard ratio = 0.72; 95% CI, 0.66 to 0.78) after adjustment for the potential confounders. ACTUR patients with bone sarcoma also exhibited significantly lower risk of all-cause death during the entire follow-up period than the SEER patients (hazard ratio = 0.75; 95% CI, 0.6 to 0.81). CONCLUSIONS: MHS beneficiaries with bone sarcoma may have longer survival than SEER patients. Our findings support the role of universal access to high-quality care in improving bone sarcoma outcomes.

Incidence rates of bladder and kidney cancers among US military servicemen: comparison with the rates in the general US population.

OBJECTIVE: The military population may differ from the general population in factors related to bladder and kidney cancers. However, incidence rates of these cancers have not been systematically compared between the two populations. This study compared incidence rates of bladder and kidney cancers between active-duty servicemen and men in the general US population. METHODS: Data were obtained from the Department of Defense's Automated Central Tumor Registry (ACTUR) and the National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) database. Included were 18-59-year-old active-duty servicemen in ACTUR and men in SEER who were diagnosed with malignant bladder and kidney cancers from 1990 to 2013. Age-adjusted rates, incidence rate ratios (IRR) and their 95% confidence intervals (95% CI) were compared between the two populations by age, race, and cancer stage. RESULTS: Incidence rates were lower in ACTUR than SEER for bladder cancer overall (IRR = 0.55, 95% CI, 0.48-0.62) and by age (except ages 50-59), race, and tumor stage. For ages 50-59, rates did not differ between the populations. Kidney cancer incidence rates were lower in the military for younger groups and Black men, but higher for ages 50-59. CONCLUSION: Lower bladder and kidney cancer incidence in ACTUR, notably in younger men, may be primarily associated with better health and healthcare access. The lack of differences in bladder or kidney cancer incidence among 50-59-year-old men between the populations might result from multifactorial effects, such as the possible effects of cumulative military-related exposures offset by healthier status and better medical care.

Proteogenomic analysis of enriched HGSOC tumor epithelium identifies prognostic signatures and therapeutic vulnerabilities.

We performed a deep proteogenomic analysis of bulk tumor and laser microdissection enriched tumor cell populations from high-grade serous ovarian cancer (HGSOC) tissue specimens spanning a broad spectrum of purity. We identified patients with longer progression-free survival had increased immune-related signatures and validated proteins correlating with tumor-infiltrating lymphocytes in 65 tumors from an independent cohort of HGSOC patients, as well as with overall survival in an additional 126 HGSOC patient cohort. We identified that homologous recombination deficient (HRD) tumors are enriched in pathways associated with metabolism and oxidative phosphorylation that we validated in independent patient cohorts. We further identified that polycomb complex protein BMI-1 is elevated in HR proficient (HRP) tumors, that elevated BMI-1 correlates with poor overall survival in HRP but not HRD HGSOC patients, and that HRP HGSOC cells are uniquely sensitive to BMI-1 inhibition.

Immuno-Molecular Targeted Therapy Use and Survival Benefit in Patients with Stage IVB Cervical Carcinoma in Commission on Cancer®-Accredited Facilities in the United States.

PURPOSE: To investigate IMT use and survival in real-world stage IVB cervical cancer patients outside randomized clinical trials. METHODS: Patients diagnosed with stage IVB cervical cancer during 2013-2019 in the National Cancer Database and treated with chemotherapy (CT) ± external beam radiation (EBRT) ± intracavitary brachytherapy (ICBT) ± IMT were studied. The adjusted hazard ratio (AHR) and 95% confidence interval (CI) for risk of death were estimated in patients treated with vs. without IMT after applying propensity score analysis to balance the clinical covariates. RESULTS: There were 3164 evaluable patients, including 969 (31%) who were treated with IMT. The use of IMT increased from 11% in 2013 to 46% in 2019. Age, insurance, facility type, sites of distant metastasis, and type of first-line treatment were independently associated with using IMT. In propensity-score-balanced patients, the median survival was 18.6 vs. 13.1 months for with vs. without IMT (p < 0.001). The AHR was 0.72 (95% CI = 0.64-0.80) for adding IMT overall, 0.72 for IMT + CT, 0.66 for IMT + CT + EBRT, and 0.69 for IMT + CT + EBRT + ICBT. IMT-associated survival improvements were suggested in all subgroups by age, race/ethnicity, comorbidity score, facility type, tumor grade, tumor size, and site of metastasis. CONCLUSIONS: IMT was associated with a consistent survival benefit in real-world patients with stage IVB cervical cancer.

Survival disparities in non-Hispanic Black and White cervical cancer patients vary by histology and are largely explained by modifiable factors.

PURPOSE: We investigated racial disparities in survival by histology in cervical cancer and examined the factors contributing to these disparities. METHODS: Non-Hispanic Black and non-Hispanic White (hereafter known as Black and White) patients with stage I-IV cervical carcinoma diagnosed between 2004 and 2017 in the National Cancer Database were studied. Survival differences were compared using Cox modeling to estimate hazard ratio (HR) or adjusted HR (AHR) and 95% confidence interval (CI). The contribution of demographic, socioeconomic and clinical factors to the Black vs White differences in survival was estimated after applying propensity score weighting in patients with squamous cell carcinoma (SCC) or adenocarcinoma (AC). RESULTS: This study included 10,111 Black and 43,252 White patients with cervical cancer. Black patients had worse survival than White cervical cancer patients (HR = 1.40, 95% CI = 1.35-1.45). Survival disparities between Black and White patients varied significantly by histology (HR = 1.20, 95% CI = 1.15-1.24 for SCC; HR = 2.32, 95% CI = 2.12-2.54 for AC, interaction p < 0.0001). After balancing the selected demographic, socioeconomic and clinical factors, survival in Black vs. White patients was no longer different in those with SCC (AHR = 1.01, 95% CI 0.97-1.06) or AC (AHR = 1.09, 95% CI = 0.96-1.24). In SCC, the largest contributors to survival disparities were neighborhood income and insurance. In AC, age was the most significant contributor followed by neighborhood income, insurance, and stage. Diagnosis of AC (but not SCC) at ≥65 years old was more common in Black vs. White patients (26% vs. 13%, respectively). CONCLUSIONS: Histology matters in survival disparities and diagnosis at ≥65 years old between Black and White cervical cancer patients. These disparities were largely explained by modifiable factors.

Incidence of papillary thyroid cancer: Comparison of the military and the general population by race and tumor stage/size.

BACKGROUND: A previous study found higher papillary thyroid cancer incidence in the US military than the general population with larger differences among Black than White individuals. This study compared the two populations in the incidence by sex, race, tumor stage, and size to assess possible factors related to identified differences. METHODS: Subjects were aged 18-59 in the military and general populations. Papillary thyroid cancer patients diagnosed during 1990-2013 were identified from the Department of Defense's Automated Central Tumor Registry (ACTUR) and the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program. Age-adjusted rates and incidence rate ratios (IRR) comparing ACTUR to SEER were calculated. RESULTS: Higher incidence rates in ACTUR than SEER were more obvious for Black (IRR=2.07, 95%CI=1.56-2.70) than White men (IRR=1.17, 95%CI=1.07-1.26) and for Black (IRR=2.30, 95%CI=1.91-2.71) than White women (IRR=1.50, 95%CI=1.38-1.64). Population differences by race were observed for localized tumors among both men and women and were larger for Black individuals. Differences were observed regardless of tumor size among Black men and White women, and in smaller tumors among Black women. CONCLUSION: Higher incidence in the military than general population primarily in localized tumors suggests universal healthcare in the military may lead to earlier detection. The differences were larger among Blacks than Whites, suggesting universal access in the military may be more impactful among Black persons, who are less likely to have timely care than White persons in the general population. Nevertheless, observed differences for tumors > 2 cm suggest other factors may also play a role.

Treatment of pancreatic adenocarcinoma in relation to survival in the U.S. Military Health System.

BACKGROUND: Pancreatic cancer has a high case fatality and relatively short survival after diagnosis. Treatment is paramount to improving survival, but studies on the effects of standard treatment by surgery or chemotherapy on survival in U.S. healthcare settings is limited. Further, variability in access to care may impact treatment and outcomes for patients. We aimed to assess the relationship between standard treatment(s) and survival of pancreatic adenocarcinoma in a population with access to comprehensive healthcare. METHODS: We used the Military Cancer Epidemiology (MilCanEpi) database, which includes data from the Department of Defense cancer registry and medical encounter data from the Military Health System (MHS), to study a cohort of 1408 men and women who were diagnosed with pancreatic adenocarcinoma between 1998 and 2014. Treatment with surgery or chemotherapy in relation to overall survival was examined in multivariable time-dependent Cox regression models. RESULTS: Overall, 75 % of 441 patients with early-stage and 51 % of 967 patients with late-stage pancreatic adenocarcinoma received treatment. In early-stage disease, surgery alone or surgery with chemotherapy were both associated with statistically significant 52 % reduced risks of death, but chemotherapy alone was not. In late-stage disease, surgery alone, chemotherapy alone, or both surgery and chemotherapy significantly reduced the risk of death by 42 %, 25 %, and 52 %, respectively. CONCLUSIONS: Our findings from the MHS demonstrate improved survival after treatment with surgery or surgery with chemotherapy for early- or late-stage pancreatic cancer and after chemotherapy for late-stage pancreatic cancer. In the era of immunotherapy and personalized medicine, further research on treatment and survival of pancreatic cancer in observational settings is needed.

Racial, ethnic and country of origin disparities in aggressive endometrial cancer histologic subtypes.

OBJECTIVE: This study investigated the risk of an aggressive endometrial cancer (EC) diagnosis by race, ethnicity, and country of origin to further elucidate histologic disparities in non-Hispanic Black (NHB), Hispanic, Asian/Pacific Islander (API), American Indian/Alaskan Native (AIAN) vs. non-Hispanic White (NHW) patients, particularly in Hispanic or API subgroups. METHODS: Patient diagnosed between 2004 and 2020 with low grade (LG)-endometrioid endometrial cancer (ECC) or an aggressive EC including grade 3 EEC, serous carcinoma, clear cell carcinoma, mixed epithelial carcinoma, or carcinosarcoma in the National Cancer Database were studied. The odds ratio (OR) and 95% confidence interval (CI) for diagnosis of an aggressive EC histology was estimated using logistic modeling. RESULTS: There were 343,868 NHW, 48,897 NHB, 30,013 Hispanic, 15,015 API and 1646 AIAN patients. The OR (95% CI) for an aggressive EC diagnosis was 3.07 (3.01-3.13) for NHB, 1.08 (1.06-1.11) for Hispanic, 1.17 (1.13-1.21) for API and 1.07 (0.96-1.19) for AIAN, relative to NHW patients. Subset analyses by country of origin illustrated the diversity in the OR for an aggressive EC diagnosis among Hispanic (1.18 for Mexican to 1.87 for Dominican), Asian (1.14 Asian Indian-Pakistani to 1.48 Korean) and Pacific Islander (1.00 for Hawaiian to 1.33 for Samoan) descendants. Hispanic, API and AIAN patients were diagnosed 5-years younger that NHW patients, and the risk for an aggressive EC histology were all significantly higher than NHW patients after correcting for age. Insurance status was another independent risk factor for aggressive histology. CONCLUSIONS: Risk of an aggressive EC diagnosis varied by race, ethnicity, and country of origin. NHB patients had the highest risk, followed by Dominican, South/Central American, Cuban, Korean, Thai, Vietnamese, and Filipino descendants.

Characteristics Associated With Survival in Surgically Nonresected Pancreatic Adenocarcinoma in the Military Health System.

OBJECTIVES: Pancreatic cancer is often diagnosed at advanced stages with high-case fatality. Many tumors are not surgically resectable. We aimed to identify features associated with survival in patients with surgically nonresected pancreatic cancer in the Military Health System. METHODS: We used the Military Cancer Epidemiology database to identify the Department of Defense beneficiaries aged 18 and older diagnosed with a primary pancreatic adenocarcinoma between January 1998 and December 2014 who did not receive oncologic surgery as treatment. We used Cox Proportional Hazard regression with stepwise procedures to select the sociodemographic and clinical characteristics related to 2-year overall survival, expressed as adjusted hazard ratios (aHR) and 95% CIs. RESULTS: Among 1148 patients with surgically nonresected pancreatic cancer, sex, race-ethnicity, marital status, and socioeconomic indicators were not selected in association with survival. A higher comorbidity count (aHR 1.30, 95% CI: 1.06-1.59 for 5 vs. 0), jaundice at diagnosis (aHR 1.57, 95% CI: 1.33-1.85 vs. no), tumor grade G3 or G4 (aHR 1.32, 95% CI: 1.05-1.67 vs. G1/G2), tumor location in pancreas tail (aHR 1.49, 95% CI: 1.22-1.83 vs. head) or body (aHR 1.30, 95% CI: 1.04-1.62 vs. head), and metastases were associated with survival. Patients receiving chemotherapy (aHR 0.66, 95% CI: 0.57-0.76) had better survival compared with no treatment. CONCLUSIONS: In a comprehensive health system, sociodemographic characteristics were not related to survival in surgically nonresected pancreatic cancer. This implicates access to care in reducing survival disparities in advanced pancreatic cancer and emphasizes the importance of treating patients based on clinical features.

Cancer incidence in the US military: An updated analysis.

BACKGROUND: Military and general populations differ in factors related to cancer occurrence and diagnosis. This study compared incidence of colorectal, lung, prostate, testicular, breast, and cervical cancers between the US military and general US populations. METHODS: Data from the US Department of Defense's Automated Central Tumor Registry (ACTUR) and the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program were analyzed. Persons in ACTUR were active-duty members 20-59 years old during 1990-013. The same criteria applied to persons in SEER. Age-adjusted incidence rates, incidence rate ratios, and 95% confidence intervals were calculated by sex, race, age, and cancer stage. Temporal trends were analyzed. RESULTS: ACTUR had higher rates of prostate and breast cancers, particularly in 40- to 59-year-olds. Further analyses by tumor stage showed this was primarily confined to localized stage. Incidence rates of colorectal, lung, testicular, and cervical cancers were significantly lower in ACTUR than in SEER, primarily for regional and distant tumors in men. Temporal incidence trends were generally similar overall and by stage between the populations, although distant colorectal cancer incidence tended to decrease starting in 2006 in ACTUR whereas it increased during the same period in SEER. CONCLUSION: Higher rates of breast and prostate cancers in servicemembers 40-59 years of age than in the general population may result from greater cancer screening utilization or cumulative military exposures. Lower incidence of other cancers in servicemembers may be associated with better health status.

Survival among lung cancer patients: comparison of the U.S. military health system and the surveillance, epidemiology, and end results (SEER) program by health insurance status.

PURPOSE: The U.S. military health system (MHS) provides beneficiaries with universal health care while health care access varies in the U.S. general population by insurance status/type. We divided the patients from the U.S. general population by insurance status/type and compared them to the MHS patients in survival. METHODS: The MHS patients were identified from the Department of Defense's Automated Central Tumor Registry (ACTUR). Patients from the U.S. general population were identified from the Surveillance, Epidemiology, and End Results (SEER) program. Multivariable Cox regression analysis was conducted to compare different insurance status/type in SEER to ACTUR in overall survival. RESULTS: Compared to ACTUR patients with non-small cell lung cancer (NSCLC), SEER patients showed significant worse survival. The adjusted hazard ratios (HRs) were 1.08 [95% Confidence Interval (CI) = 1.03-1.13], 1.22 (95% CI = 1.16-1.28), 1.40 (95% CI = 1.33-1.47), 1.50 (95% CI = 1.41-1.59), for insured, insured/no specifics, Medicaid, and uninsured patients, respectively. The pattern was consistently observed in subgroup analysis by race, gender, age, or tumor stage. Results were similar for small cell lung cancer (SCLC), although they were only borderline significant in some subgroups. CONCLUSION: The survival advantage of patients receiving care from a universal health care system over the patients from the general population was not restricted to uninsured or Medicaid as expected, but was present cross all insurance types, including patients with private insurance. Our findings highlight the survival benefits of universal health care system to lung cancer patients.

Association of clinicopathologic and molecular factors with the occurrence of positive margins in breast cancer.

PURPOSE: To explore the association of clinicopathologic and molecular factors with the occurrence of positive margins after first surgery in breast cancer. METHODS: The clinical and RNA-Seq data for 951 (75 positive and 876 negative margins) primary breast cancer patients from The Cancer Genome Atlas (TCGA) were used. The role of each clinicopathologic factor for margin prediction and also their impact on survival were evaluated using logistic regression, Fisher's exact test, and Cox proportional hazards regression models. In addition, differential expression analysis on a matched dataset (71 positive and 71 negative margins) was performed using Deseq2 and LASSO regression. RESULTS: Association studies showed that higher stage, larger tumor size (T), positive lymph nodes (N), and presence of distant metastasis (M) significantly contributed (p ≤ 0.05) to positive surgical margins. In case of surgery, lumpectomy was significantly associated with positive margin compared to mastectomy. Moreover, PAM50 Luminal A subtype had higher chance of positive margin resection compared to Basal-like subtype. Survival models demonstrated that positive margin status along with higher stage, higher TNM, and negative hormone receptor status was significant for disease progression. We also found that margin status might be a surrogate of tumor stage. In addition, 29 genes that could be potential positive margin predictors and 8 pathways were identified from molecular data analysis. CONCLUSION: The occurrence of positive margins after surgery was associated with various clinical factors, similar to the findings reported in earlier studies. In addition, we found that the PAM50 intrinsic subtype Luminal A has more chance of obtaining positive margins compared to Basal type. As the first effort to pursue molecular understanding of the margin status, a gene panel of 29 genes including 17 protein-coding genes was also identified for potential prediction of the margin status which needs to be validated using a larger sample set.

Differences in Survival between Black and White Patients with Head and Neck Squamous Cell Carcinoma: Comparison of Data from the DOD Central Cancer Registry and SEER.

BACKGROUND: Barriers to health care access may contribute to the poorer survival of Black patients with head and neck squamous cell carcinoma (HNSCC) than their White counterparts in the U.S. general population. The Department of Defense's (DOD) Military Health System (MHS) provides universal health care access to all beneficiaries with various racial backgrounds. METHODS: We compared overall survival of patients with HNSCC by race in the MHS and the general population, respectively, to assess whether there were differences in racial disparity between the two populations. The MHS patients were identified from the DOD's Central Cancer Registry (CCR) and the patients from the U.S. general population were identified from the NCI's Surveillance, Epidemiology and End Results (SEER) program. For each cohort, a retrospective study was conducted comparing survival by race. RESULTS: Black and White patients in the CCR cohort had similar survival in multivariable Cox regression models with a HR of 1.04 and 95% confidence interval (95% CI) of 0.81 to 1.33 after adjustment for the potential confounders. In contrast, Black patients in the SEER cohort exhibited significantly worse survival than White patients with an adjusted HR of 1.47 (95% CI = 1.43-1.51). These results remained similar in the subgroup analyses for oropharyngeal and non-oropharyngeal sites, respectively. CONCLUSIONS: There was no racial difference in survival among patients with HNSCC in the MHS system, while Black patients had significantly poorer survival than White patients in the general population. IMPACT: Equal access to health care could reduce racial disparity in overall survival among patients with HNSCC.

Cancer stage at diagnosis: Comparison of insurance status in SEER to the Department of Defense Cancer Registry.

BACKGROUND: Military individuals, retirees, and their families have free care or minimal out-of-pocket costs in the US military health system (MHS). In contrast, out-of-pocket costs in the US general population vary substantially. This study compared cancer patients with various insurance types in the general population to those in the MHS in cancer stage at diagnosis. METHODS: Patients were identified from the US Department of Defense's (DoD) Automated Central Tumor Registry (ACTUR) and the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program. Tumor stage at diagnosis of breast, prostate, lung, and colon cancers during 2007-2013 was compared between ACTUR and SEER insurance categories of "insured," "insured-no specifics," "any Medicaid," and "uninsured," A multivariable logistic regression analysis estimated the odds ratio (OR) of late stage (Stages III and IV) versus early stage (Stages I and II) cancers comparing SEER insurance status to ACTUR. RESULTS: There were 18,440 eligible patients identified from ACTUR and 831,959 patients identified from SEER. For all cancer types, patients in the SEER-insured/no specifics, Medicaid, and uninsured groups had significantly greater likelihood of late stage diagnosis compared to ACTUR patients. The adjusted ORs were greatest among uninsured and Medicaid patients. The SEER-insured group also had a significantly higher odds of advanced stage disease than ACTUR patients for prostate cancer and lung cancer. CONCLUSION: Patients in the MHS with universal access to healthcare were diagnosed at an earlier stage than those in the general population. This difference was most evident compared to Medicaid and uninsured groups.

MilCanEpi: Increased Capability for Cancer Care Research in the Department of Defense.

The Military Health System (MHS) of the US Department of Defense (DoD) provides comprehensive medical care to over nine million beneficiaries, including active-duty members, reservists, activated National Guard, military retirees, and their family members. The MHS generates an extensive database containing administrative claims and medical encounter data, while the DoD also maintains a cancer registry that collects information about the occurrence of cancer among its beneficiaries who receive care at military treatment facilities. Collating data from the two sources diminishes the limitations of using registry or medical claims data alone for cancer research and extends their usage. To facilitate cancer research using the unique military health resources, a computer interface linking the two databases has been developed, called Military Cancer Epidemiology, or MilCanEpi. The intent of this article is to provide an overview of the MilCanEpi data system, describing its components, structure, potential uses, and limitations.

Selection of optimal quantile protein biomarkers based on cell-level immunohistochemistry data.

BACKGROUND: Protein biomarkers of cancer progression and response to therapy are increasingly important for improving personalized medicine. Advanced quantitative pathology platforms enable measurement of protein expression in tissues at the single-cell level. However, this rich quantitative cell-by-cell biomarker information is most often not exploited. Instead, it is reduced to a single mean across the cells of interest or converted into a simple proportion of binary biomarker-positive or -negative cells. RESULTS: We investigated the utility of retaining all quantitative information at the single-cell level by considering the values of the quantile function (inverse of the cumulative distribution function) estimated from a sample of cell signal intensity levels in a tumor tissue. An algorithm was developed for selecting optimal cutoffs for dichotomizing cell signal intensity distribution quantiles as predictors of continuous, categorical or survival outcomes. The proposed algorithm was used to select optimal quantile biomarkers of breast cancer progression based on cancer cells' cell signal intensity levels of nuclear protein Ki-67, Proliferating cell nuclear antigen, Programmed cell death 1 ligand 2, and Progesterone receptor. The performance of the resulting optimal quantile biomarkers was validated and compared to the standard cancer compartment mean signal intensity markers using an independent external validation cohort. For Ki-67, the optimal quantile biomarker was also compared to established biomarkers based on percentages of Ki67-positive cells. For proteins significantly associated with PFS in the external validation cohort, the optimal quantile biomarkers yielded either larger or similar effect size (hazard ratio for progression-free survival) as compared to cancer compartment mean signal intensity biomarkers. CONCLUSION: The optimal quantile protein biomarkers yield generally improved prognostic value as compared to the standard protein expression markers. The proposed methodology has a broad application to single-cell data from genomics, transcriptomics, proteomics, or metabolomics studies at the single cell level.

Chemotherapy Treatment Costs and Clinical Outcomes of Colon Cancer in the U.S. Military Health System's Direct and Private Sector Care Settings.

INTRODUCTION: Identifying low-value cancer care may be an important step in containing costs associated with treatment. Low-value care occurs when the medical services, tests, or treatments rendered do not result in clinical benefit. These may be impacted by care setting and patients' access to care and health insurance. We aimed to study chemotherapy treatment and the cost paid by the Department of Defense (DoD) for treatment in relation to clinical outcomes among patients with colon cancer treated within the U.S. Military Health System's direct and private sector care settings to better understand the value of cancer care. MATERIALS AND METHODS: A cohort of patients aged 18 to 64 years with primary colon cancer diagnosed between January 1, 1999, and December 31, 2014, were identified in the Military Cancer Epidemiology database. Multivariable time-dependent Cox proportional hazards regression models were used to assess the relationship between chemotherapy treatment and the cost paid by the DoD (in quartiles, Q) and the outcomes of cancer progression, cancer recurrence, and all-cause death modeled as adjusted hazard ratios (aHRs) and 95% confidence intervals (95% CIs). The Military Cancer Epidemiology data were approved for research by the Uniformed Services University of the Health Sciences' Institutional Review Board. RESULTS: The study included 673 patients using direct care and 431 patients using private sector care. The median per patient chemotherapy costs in direct care ($111,202) were lower than in private sector care ($350,283). In direct care, higher chemotherapy costs were associated with an increased risk of any outcome but not with all-cause death. In private sector care, higher chemotherapy costs were associated with a higher risk of any outcome and with all-cause death (aHR, 2.67; 95% CI, 1.20-5.92 for Q4 vs. Q1). CONCLUSIONS: The findings in the private sector may indicate low-value care in terms of the cost paid by the DoD for chemotherapy treatment and achieving desirable survival outcomes for patients with colon cancer in civilian health care. Comprehensive evaluations of value-based care among patients treated for other tumor types may be warranted.

Factors Associated With Survival Disparities Between Non-Hispanic Black and White Patients With Uterine Cancer.

Importance: Disparities in survival exist between non-Hispanic Black (hereafter, Black) and non-Hispanic White (hereafter, White) patients with uterine cancer. Objective: To investigate factors associated with racial disparities in survival between Black and White patients with uterine cancer. Design, Setting, and Patients: This cohort study used data from the National Cancer Database on 274 838 Black and White patients who received a diagnosis of uterine cancer from January 1, 2004, to December 31, 2017, with follow-up through December 2020. Statistical analysis was performed in July 2022. Main Outcomes and Measures: Overall survival by self-reported race and evaluation of explanatory study factors associated with hazard ratio (HR) reduction for Black vs White patients. A propensity scoring approach was applied sequentially to balance racial differences in demographic characteristics, comorbidity score, neighborhood income, insurance status, histologic subtype, disease stage, and treatment. Results: The study included 32 230 Black female patients (mean [SD] age at diagnosis, 63.8 [10.0] years) and 242 608 White female patients (mean [SD] age at diagnosis, 63.5 [10.5] years) and had a median follow-up of 74.0 months (range, 43.5-113.8 months). Black patients were more likely than White patients to have low income (44.1% vs 14.0%), be uninsured (5.7% vs 2.6%), present with nonendometrioid histologic characteristics (46.1% vs 21.6%), have an advanced disease stage (34.1% vs 19.8%), receive first-line chemotherapy (33.8% vs 18.2%), and have worse 5-year survival (58.6% vs 78.5%). Among patients who received a diagnosis at younger than 65 years of age, the HR for death for Black vs White patients was 2.43 (95% CI, 2.34-2.52) in a baseline demographic-adjusted model and 1.29 (95% CI, 1.23-1.35) after balancing other factors. Comorbidity score, neighborhood income, insurance status, histologic subtype, disease stage, treatment, and unexplained factors accounted for 0.8%, 7.2%, 11.5%, 53.1%, 5.8%, 1.2%, and 20.4%, respectively, of the excess relative risk (ERR) among the younger Black vs White patients. Among patients 65 years or older, the HR for death for Black vs White patients was 1.87 (95% CI, 1.81-1.93) in the baseline model and 1.14 (95% CI, 1.09-1.19) after balancing other factors. Comorbidity score, neighborhood income, insurance status, histologic subtype, disease stage, treatment, and unexplained factors accounted for 3.0%, 7.5%, 0.0%, 56.2%, 10.6%, 6.9%, and 15.8%, respectively, of the ERR among Black vs White patients aged 65 years or older. Conclusions and Relevance: This study suggests that histologic subtype was the dominant factor associated with racial survival disparity among patients with uterine cancer, while insurance status represented the main modifiable factor for women younger than 65 years. Additional studies of interactions between biology and social determinants of health are merited.