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.

Racial-Ethnic Comparison of Treatment for Papillary Thyroid Cancer in the Military Health System.

PURPOSE: We aimed to compare Asian or Pacific Islander, Black, Hispanic, and non-Hispanic White patients in treatment for papillary thyroid cancer (PTC) in the equal access Military Health System to better understand racial-ethnic cancer health disparities observed in the United States. METHODS: We used the MilCanEpi database to identify a cohort of men and women aged 18 or older who were diagnosed with PTC between 1998 and 2014. Low- or high-risk status was assigned using tumor size and lymph node involvement. Treatment with surgery (e.g., thyroidectomy) overall and treatment by risk status [active surveillance (low-risk) or adjuvant radioactive iodine (RAI) (high-risk)] was compared between racial-ethnic groups using multivariable logistic regression and expressed as adjusted odds ratios (AOR) with 95% confidence intervals (CIs). RESULTS: The study included 598 Asian, 553 Black, 340 Hispanic, and 2958 non-Hispanic White patients with PTC. Asian (AOR = 1.21, 95% CI 0.98, 1.49), Black (AOR = 1.07, 95% CI 0.87, 1.32), and Hispanic (AOR = 0.92, 95% CI 0.71, 1.19) patients were as likely as White patients to receive surgery. By risk status, there were no significant racial-ethnic differences in receipt of active surveillance or thyroidectomy for low-risk PTC or in thyroidectomy or total thyroidectomy with adjuvant RAI for high-risk PTC. CONCLUSIONS: In the Military Health System, where patients have equal access to care, there were no overall racial-ethnic differences in surgical treatment for PTC. As American Thyroid Association guidelines evolve to include more conservative treatment, further research is warranted to understand potential disparities in active surveillance and surgical management in U.S. healthcare settings.

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.

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.

Dual use of cigarettes and smokeless tobacco among active duty service members in the US military.

The high prevalence of dual use of cigarettes and smokeless tobacco is a unique tobacco use behavior in the US military population. However, dual tobacco use has rarely been addressed in active duty populations. We aimed to identify factors contributing to dual tobacco use among active duty service members from Army and Air Force. We also compared age at initiation, duration of use, and amount of use between dual users and exclusive users. The study included 168 exclusive cigarette smokers, 171 exclusive smokeless tobacco users, and 110 dual users. In stepwise logistic regression, smokeless tobacco use among family members (OR = 4.78, 95% CI = 2.05-11.13 for father use vs. no use, OR = 3.39, 95% CI = 1.56-7.37 for other relatives use vs. no use), and deployment history (serving combat unit vs. combat support unit: OR = 4.12, 95% CI = 1.59-10.66; never deployed vs. combat support unit: OR = 3.32, 95% CI = 1.45-7.61) were factors identified to be associated with dual use relative to exclusive cigarette smoking. Cigarette smoking among family members (OR = 1.96, 95% CI = 1.07-3.60 for sibling smoking), high perception of harm using smokeless tobacco (OR = 2.34, 95% CI = 1.29-4.26), secondhand smoke exposure (OR = 4.83, 95% CI = 2.73-8.55), and lower education (associated degree or some college: OR = 2.76, 95% CI = 1.01-7.51; high school of lower: OR = 4.10, 95% CI = 1.45-11.61) were factors associated with dual use relative to exclusive smokeless tobacco use. Compared to exclusive cigarette smokers, dual users started smoking at younger age, smoked cigarettes for longer period, and smoked more cigarettes per day. Our study addressed dual tobacco use behavior in military population and has implications to tobacco control programs in the military.

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.

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.

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.

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.

Comparative Trends in the Distribution of Prostate Cancer Stage at Diagnosis in the Department of Defense Cancer Registry and the Surveillance, Epidemiology, and End Results Data, 2004-2014.

INTRODUCTION: It has been demonstrated that there was an increase in later-stage prostate cancer (PCa) at diagnosis after the U.S. Preventive Services Task Force recommended against prostate-specific antigen screening for prostate cancer. However, the cancer characteristics at diagnosis within the equal-access Military Health System (MHS) during the period have not been described. In this study, we compared PCa stage at diagnosis and its trends between the military health care system and the general public and further compared the trends in tumor stage by race. MATERIALS AND METHODS: This study was based on nonidentifiable data from the U.S. Department of Defense's Central Cancer Registry (CCR) and the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute. Patients diagnosed between 2004 and 2014 were included. The distributions of PCa stage at diagnosis over time were compared between the 2 populations. Comparisons were further conducted for White and Black patients, respectively. RESULTS: Among the 11,895 patients in the CCR and 544,142 patients in SEER, the majority of patients were diagnosed with stage I or II prostate cancer. However, the CCR had a larger proportion of early-stage tumors (stages I and II combined) with 84.3% vs. 80.0% of SEER patients. The proportion of late-stage tumors (stages III and IV combined) increased over time from 2008 for both populations and the proportion of early-stage tumors decreased for the general population. In terms of temporal distributions by race, the trends were the same between White and Black groups in the general population. In the MHS, the trends in the White patients were similar to those in the general population, but in the Black patients, the percentages of stages I and II at diagnosis continued to increase and those of stages III and IV decreased, differing from those in the general population. CONCLUSIONS: The MHS consistently diagnosed PCa at an earlier stage than the U.S. general population across all time periods evaluated in this study. Although similar trends were observed for White patients between both populations, the proportion of stages I and II at diagnosis increased from 2012 among Black patients in the MHS, which stands in sharp contrast to trends in the U.S. general population. Although the differences between the two populations may be associated with various factors, differences in accessibility to care and thus the use of prostate-specific antigen testing might play an important role.

Pulmonary Hypertension and Survival among Non-Small Cell Lung Cancer Patients: A Retrospective Cohort Study in the U.S. Military Health System.

Background: Lung cancer is one of the most lethal cancers with survival being closely related to stage and influenced by comorbid illness. The survival implications of pulmonary hypertension (PH) on patients with non-small cell lung cancer (NSCLC) have only been evaluated in small cohorts, with limited long-term follow-up. Methods: We conducted a retrospective cohort study of 7946 patients with NSCLC diagnosed in the MHS. This study evaluated the survival impact of PH in patients diagnosed with NSCLC in the MHS. Patients were classified as having and not having PH. We stratified PH into those diagnosed before the diagnosis of NSCLC and those diagnosed after NSCLC diagnosis. Results: Relative to patients without PH, patients with PH diagnosed before NSCLC had an increased risk of death (HR = 1.15 [95% CI, 1.02-1.29]). The increased risk of death was more obvious for patients with PH diagnosed after NSCLC compared with those without PH (HR = 2.74 [95% CI, 2.51-2.99]). The results were similar when stratified by patient demographics. Conclusions: In the MHS, PH is associated with worsened NSCLC survival, regardless of when it is diagnosed. When PH is diagnosed after NSCLC, it is associated with a marked reduction in survival, and this finding may suggest a potential role for monitoring pulmonary pressures in NSCLC patients. Furthermore, as specific PH therapy exists, some NSCLC patients with PH may be candidates for therapy.

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.

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.

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.

Something to Dye For: Toward Better Breast Lumpectomy Margins.

The development of fluorescence imaging in oncology led to the possibility of using intraoperative devices to improve the precision of surgical techniques.1 In this issue of NEJM Evidence, Smith et al.2 report results from a prospective multicenter trial evaluating the ability of intravenous pegulicianine with an optical head device and software to intraoperatively identify lumpectomy margins with residual cancer and excise them immediately. Identifying these margins intraoperatively avoids the need for a second surgery, which is required when margins are positive on the final pathology.