Search

Mutations in oncogenes such as KRAS and EGFR cause a high proportion of lung cancers. Drugs targeting these proteins cause tumor regression but ultimately fail to elicit cures. As a result, there is an intense interest in how to best combine targeted therapies with other treatments, such as immunotherapies. However, preclinical systems for studying the interaction of lung tumors with the host immune system are inadequate, in part due to the low tumor mutational burden in genetically engineered mouse models. Here we set out to develop mouse models of mutant KRAS–driven lung cancer with an elevated tumor mutational burden by expressing the human DNA cytosine deaminase, APOBEC3B, to mimic the mutational signature seen in human lung cancer. This failed to substantially increase clonal tumor mutational burden and autochthonous tumors remained refractory to immunotherapy. However, establishing clonal cell lines from these tumors enabled the generation of an immunogenic syngeneic transplantation model of KRAS-mutant lung adenocarcinoma that was sensitive to immunotherapy. Unexpectedly, antitumor immune responses were not directed against neoantigens but instead targeted derepressed endogenous retroviral antigens. The ability of KRASG12C inhibitors to cause regression of KRASG12C -expressing tumors was markedly potentiated by the adaptive immune system, highlighting the importance of using immunocompetent models for evaluating targeted therapies. Overall, this model provides a unique opportunity for the study of combinations of targeted and immunotherapies in immune-hot lung cancer.Significance:This study develops a mouse model of immunogenic KRAS-mutant lung cancer to facilitate the investigation of optimal combinations of targeted therapies with immunotherapies.

PURPOSE: To decrease the financial burden on people with cancer, clinicians and patients increasingly use medication price comparison websites to seek pharmacies where medications may be cheaper. Shopping around at different pharmacies can add additional time and logistic burden to patients and care partners. We sought to determine whether a single pharmacy consistently offered the lowest price for symptom control medications. METHODS: We compiled medications/formulations used to manage two common cancer-associated symptoms: nausea/vomiting and anorexia/cachexia. We extracted discounted, lowest price with coupon prices for a typical fill of these medications at nine pharmacies in Minneapolis, MN, using GoodRx. We compared prices across formulations and pharmacies to assess whether a pharmacy consistently offered the lowest price. RESULTS: We included 24 formulations for nausea/vomiting (14 generic and 10 brand-name) and 19 for anorexia/cachexia (12 generic and seven brand-name). Prices for brand-name formulations were similar across pharmacies, but prices of generic formulations varied widely across pharmacies. For example, the prices of a seven-unit fill of generic 5-mg olanzapine tablets ranged from $4 to $57 US dollars. No single pharmacy consistently offered the lowest price across the formulations studied. For example, for the 12 generic formulations for anorexia/cachexia, one pharmacy had the highest price for four formulations and the lowest price for two others. CONCLUSION: In this study of discounted medication prices, we found that no single pharmacy in an urban zip code consistently offered the lowest price for medications used to manage two common cancer-associated symptoms. Well-intentioned efforts to pursue the cheapest source of each medication by visiting multiple pharmacies may add extra time and logistic toxicity to patients and care partners. This approach can increase redundant scripts and expose patients to medication-related adverse events.

OBJECTIVE. Physical activity is associated with improved cancer outcomes; however, it is unclear which patients may benefit most from increased physical activity. We evaluated whether associations between meeting the American Cancer Society (ACS) physical activity recommendations and psychosocial outcomes in gynecologic cancer survivors varied by type of treatments received. METHODS. We recruited English-speaking adult gynecologic cancer patients from an academic gynecologic oncology practice to participate in a prospective cohort study. Participants completed a survey at study entry regarding their psychosocial health—including distress, depression, anxiety, post-traumatic stress disorder, and quality of life (QoL)—and physical activity. Multivariate linear regression models for each psychosocial outcome tested for interactions between physical activity and each effect modifier (receipt of chemotherapy, radiation therapy, and/or minimally invasive surgery), adjusted for age, pain, body mass index, primary cancer diagnosis, cancer stage, time since diagnosis, and annual household income. RESULTS. Among a total of 362 participants, 213 (59%) met ACS physical activity recommendations. We found evidence of interactions between physical activity and receipt of chemotherapy for depression, anxiety, and QoL scores; those who had received chemotherapy had a stronger association between physical activity and these psychosocial outcomes, compared to those who had not. We found no evidence of interactions between physical activity and receipt of radiation therapy or minimally invasive surgery for any of the outcomes. CONCLUSIONS. Gynecologic cancer survivors who received chemotherapy had significant associations between psychosocial health and physical activity, suggesting they may derive greatest benefit from prescribed exercise.

BACKGROUND: Metastasis to the oral soft tissues and jawbones is rare and frequently associated with wide spread disease and dismal prognosis. Herein, we report the clinicopathologic characteristics of 40 intraoral metastatic neoplasms and perform a comprehensive review of the pertinent literature. METHODS: Criteria for inclusion included: (a) archived cases from the UMN Oral Pathology laboratory with available tissue blocks and/or H&E-stained preparations diagnosed between 2003 and 2021, (b) proper documentation of the clinico-radiographic characteristics of oral metastasis along with confirmed history of primary malignancy, or (c) microscopic findings consistent with metastatic disease with or without discovery of the primary site. RESULTS: Intraoral metastases comprised 0.03% of all accessioned cases; 22 (55%) occurred in men and 18 (45%) in women (median age = 66.5; range = 18–94 years). Eighteen cases (45%) involved the gingiva, 16 (40%) the gingiva and jawbones, 5 (12.5%) were exclusively intraosseous, and 1 affected (2.5%) the tongue. The lung was the two most frequent primary site in both men (n = 6, 27.3%) and women (n = 5, 27.7%), followed by the colon (n = 4, 18.2%) and kidney (n = 3, 13.7%) in men, and colon (n = 4, 22.2%) and breast (n = 3, 16.6%) in women. Analysis of 1,084 metastatic cases from the literature (male-to-female ratio = 1.2; mean = 52.3; range = 0.6–90 years) indicated strong preference for the jawbones (69.5%) and significant site-specific predilection of certain primary malignancies. CONCLUSIONS: Oral and gnathic metastases are rare but demonstrate a clear predilection for the gingiva and mandible. Clinicians should remain cognizant of such lesions since they frequently mimic inflammatory, reactive or benign neoplastic processes and, in certain cases, are the first indication of occult disease.

Our objective was to assess gynecologic cancer survivor preferences for telehealth cancer care. Gynecologic cancer survivors participating in a prospective cohort study were invited to complete a cross-sectional survey regarding their experience with and preferences for telehealth. Of 188 participants, 48.9% had undergone a telehealth visit since March 2020, and 53.7% reported a preference for exclusively in-person visits for their cancer care and surveillance. Furthermore, 80.5% of participants were satisfied with the telehealth care they received and 54.8% would recommend telehealth services to patients with similar conditions. Most participants thought a physical examination was critical to detecting recurrence, and concern that their provider may miss something during telehealth visits was greater among those who preferred in-person visits. With many gynecologic cancer survivors preferring in-person care, building a future care model that includes telehealth elements will require adaptations, careful evaluation of patient concerns, as well as patient education on telehealth.

PDF - 828K, Interrogation of an HNC Affymetrix U-133a microarray database for s50-TBG-RNAi-CK2-related proteins in human HNC tumor vs. normal oral mucosa.

PDF - 53K, Legends for Supplemental Figures 1 and 2.

PDF - 1588K, Weight change in mice for SCC-15, UM-11b and FaDu xenograft flank tumor models of HNSCC following treatment with s50-TBG-RNAi-CK2.

PDF - 53K, Hematological profile in FaDu metastatic spleen study mice 3 days post-treatment.

PDF - 48K, Serum chemistry in FaDu metastatic spleen study mice 3 days post-treatment.

Background Aromatase inhibitors (AIs) are recommended as adjuvant treatment for estrogen-receptor positive breast carcinoma in postmenopausal women. Studies demonstrate mixed results as to the impact of AIs on cardiovascular (CV) events and overall survival. With the increasing number of pre- and postmenopausal women on AIs for five to ten years, understanding the long-term impact of AIs on blood vessels and CV risk in cancer survivors is vital. Methods A single arm longitudinal study of 14 postmenopausal women with ER+ breast cancer prescribed adjuvant AIs at the University of Minnesota. Subjects with a history of tobacco use, hypertension, or hyperlipidemia were excluded. Participants underwent routine labs, blood pressure assessments, and vascular testing at baseline (prior to starting AIs) and at six months. Vascular assessment was performed using the EndoPAT 2000 and HDI/PulseWave CR-2000 Cardiovascular Profiling System and pulse contour analysis on two occasions as previously described. Vascular measurements were conducted by one trained vascular technician. Assessments were performed in triplicate, and the mean indices were used for analyses. All subjects were on an AI at the follow-up visit. The protocol was approved by the UMN Institutional Review Board and all participants were provided written informed consent. Baseline and follow-up characteristics were compared using Wilcoxon signed-rank tests. Analyses were performed using R version 3.6.1 (R Foundation for Statistical Computing, Vienna, Austria). Results After six months of AI treatment, EndoPAT® ratio declined to a median 1.12 (Q1: 0.85, Q3: 1.86; p=0.045) and median estradiol levels decreased to 2 pg/mL (Q1: 2, Q3: 3; p=0.052). There was no evidence of association between change in EndoPAT® and change in estradiol level (p=0.91). There were no statistically significant changes in small or large arterial elasticity. Conclusion Endovascular dysfunction is an early sign for atherosclerosis and vascular impairment. This study suggests that postmenopausal breast cancer survivors on aromatase inhibitor therapy develop endothelial dysfunction as early as six months which is a predictor of adverse CV disease. We hypothesize that long-term use of AIs can lead to persistent endothelial dysfunction. It is unclear if these changes are reversible once AI use is discontinued and further investigation is necessary.

PDF - 46K, Origin and characteristics of tumor cell lines used in HNSCC survival studies.

Improved survival for patients with head and neck cancers (HNC) with recurrent and metastatic disease warrants that cancer therapy is specific, with protected delivery of the therapeutic agent to primary and metastatic cancer cells. A further objective should be that downregulation of the intracellular therapy target leads to cell death without compensation by an alternate pathway. To address these goals, we report the utilization of a sub–50-nm tenfibgen (s50-TBG) nanocapsule that delivers RNAi oligonucleotides directed against the essential survival signal protein kinase CK2 (RNAi-CK2) in a cancer cell–specific manner. We have evaluated mechanism and efficacy of using s50-TBG-RNAi-CK2 nanocapsules for therapy of primary and metastatic head and neck squamous cell carcinoma (HNSCC). s50-TBG nanocapsules enter cancer cells via the lipid raft/caveolar pathway and deliver their cargo (RNAi-CK2) preferentially to malignant but not normal tissues in mice. Our data suggest that RNAi-CK2, a unique single-stranded oligonucleotide, co-opts the argonaute 2/RNA-induced silencing complex pathway to target the CK2αα′ mRNAs. s50-TBG-RNAi-CK2 inhibited cell growth corresponding with reduced CK2 expression in targeted tumor cells. Treatment of three xenograft HNSCC models showed that primary tumors and metastases responded to s50-TBG-RNAi-CK2 therapy, with tumor shrinkage and 6-month host survival that was achieved at relatively low doses of the therapeutic agent without any adverse toxic effect in normal tissues in the mice. We suggest that our nanocapsule technology and anti-CK2 targeting combine into a therapeutic modality with a potential of significant translational promise. Mol Cancer Ther; 13(8); 2018–29. ©2014 AACR.

Supplementary Data from An Immunogenic Model of KRAS-Mutant Lung Cancer Enables Evaluation of Targeted Therapy and Immunotherapy Combinations

Supplementary Table from An Immunogenic Model of KRAS-Mutant Lung Cancer Enables Evaluation of Targeted Therapy and Immunotherapy Combinations

Supplementary Methods, Tables, and Figures

Purpose:Clear cell ovarian carcinoma (CCOC) is an aggressive disease that often demonstrates resistance to standard chemotherapies. Approximately 25% of patients with CCOC show a strong APOBEC mutation signature. Here, we determine which APOBEC3 enzymes are expressed in CCOC, establish clinical correlates, and identify a new biomarker for detection and intervention.Experimental Designs:APOBEC3 expression was analyzed by IHC and qRT-PCR in a pilot set of CCOC specimens (n = 9 tumors). The IHC analysis of APOBEC3B was extended to a larger cohort to identify clinical correlates (n = 48). Dose-response experiments with platinum-based drugs in CCOC cell lines and carboplatin treatment of patient-derived xenografts (PDXs) were done to address mechanistic linkages.Results:One DNA deaminase, APOBEC3B, is overexpressed in a formidable subset of CCOC tumors and is low or absent in normal ovarian and fallopian tube epithelial tissues. High APOBEC3B expression associates with improved progression-free survival (P = 0.026) and moderately with overall survival (P = 0.057). Cell-based studies link APOBEC3B activity and subsequent uracil processing to sensitivity to cisplatin and carboplatin. PDX studies extend this mechanistic relationship to CCOC tissues.Conclusions:These studies demonstrate that APOBEC3B is overexpressed in a subset of CCOC and, contrary to initial expectations, associated with improved (not worse) clinical outcomes. A likely molecular explanation is that APOBEC3B-induced DNA damage sensitizes cells to additional genotoxic stress by cisplatin. Thus, APOBEC3B is a molecular determinant and a candidate predictive biomarker of the therapeutic response to platinum-based chemotherapy. These findings may have broader translational relevance, as APOBEC3B is overexpressed in many different cancer types.

PDF file - 481K, Table S1: Cell line information Table S2: Quantitative PCR primer and probe sequences. Table S3: Non-malignant tissues tested Table S4: Early stage serous ovarian tumors used in sequence analyses Table S5: Additional ovarian tumor specimens analyzed Table S6: Microarray analysis of APOBEC3 and select control gene probe sets in ovarian TCGA data Figure S1: Polynucleotide cytosine deaminase expression in ovarian cell lines. Figure S2: Endogenous DNA deaminase activity in APOBEC3B high and low cell lines. Figure S3: Endogenous APOBEC3B activity on alternate dinucleotide substrates. Figure S4: Polynucleotide cytosine deaminase expression in ovarian primary samples. Figure S5: Polynucleotide cytosine deaminase expression in ovarian TCGA samples by RNAseq.

Physical activity has been associated with improved outcomes among cancer survivors of various malignancies; however, this topic is understudied among melanoma survivors. Our objective was to determine whether long-term melanoma survivors are less likely to meet American Cancer Society physical activity guidelines than non-melanoma population controls. We conducted a cross-sectional survey in 2015 to follow up participants from a case-control study of melanoma and population controls in Minnesota. The primary outcome was meeting American Cancer Society recommendations for healthy physical activity levels. Physical activity, sun protection practices and time spent outside were compared between survivors and controls using generalized linear regression models. Melanoma survivors (N = 724) and controls (N = 639) were similar with the exceptions of daily hours spent outside, sun protection scores, skin tone, and smoking status. Half (50.8%) of melanoma survivors reported meeting the physical activity guidelines, compared to 39.7% of controls (p 0.0001), with an 11% (95% CI 0.05-0.17) difference after adjusting for potential confounders. While long-term melanoma survivors were more likely to meet American Cancer Society physical activity guidelines than population controls, nearly 50% did not meet recommendations. This finding is concerning given the known improvements in quality of life and survival among physically active cancer survivors. Opportunities remain to promote physical activity among melanoma survivors. Health communications that promote outdoor exercise, in particular, should include advice about sun protection.

Background A cancer diagnosis may lead to existential despair but potentially also to perceived inner growth. This growth may be fostered through meaningful connections with others. We sought to describe existential and related psychosocial outcomes and their association with a sense of connection with others in individuals with gynecological and breast cancers. Methods We used cross-sectional data from two ongoing cohort studies of gynecologic (N = 236) and breast (N = 62) cancer survivors at the University of Minnesota. We summarized self-reported post-traumatic growth (PTG), sense of meaning, peace, spirituality, hopelessness, loneliness, and three exploratory measures of sense of connections with others, and used multivariate linear regression models to describe the associations between them. Results Hope, sense of meaning, peace, and spirituality were generally high among participants, but PTG and loneliness scores varied more. Sense of connection with others was consistently associated with greater PTG and decreased loneliness with medium effect sizes: for example having positive interactions with most/all versus nobody on one’s medical team, PTG (coefficient 10.49, 95% CI: 4.10, 16.87, Cohen’s D 0.44); loneliness (coefficient − 0.85, 95% CI: − 1.36, − 0.34, Cohen’s D 0.43). Those who knew someone in a similar life situation felt a strong sense of connection with such a person; however, 28% of participants had not met anyone in a similar situation. Conclusions There may be untapped opportunities to nurture beneficial existential outcomes in cancer survivors. Potential interventions include connecting survivors with one another and creating opportunities for more authentic patient-provider relationships, for example, within palliative care. Supplementary Information The online version contains supplementary material available at 10.1007/s00520-021-06784-8.

SUMMARYThe antiviral DNA cytosine deaminase APOBEC3B has been implicated as a source of mutation in many different cancers. Despite over 10 years of work, a causal relationship has yet to be established between APOBEC3B and any stage of carcinogenesis. Here we report a murine model that expresses tumor-like levels of human APOBEC3B after Cre-mediated recombination. Animals appear to develop normally with full-body expression of APOBEC3B. However, adult males manifest infertility and older animals of both sexes show accelerated rates of tumorigenesis (mostly lymphomas or hepatocellular carcinomas). Interestingly, primary tumors also show overt heterogeneity, and a subset spreads to secondary sites. Both primary and metastatic tumors exhibit increased frequencies of C-to-T mutations in TC dinucleotide motifs consistent with the established biochemical activity of APOBEC3B. Elevated levels of structural variation and insertion-deletion mutations also accumulate in these tumors. Together, these studies provide the first cause-and-effect demonstration that human APOBEC3B is an oncoprotein capable of causing a wide range of genetic changes and driving tumor formationin vivo.

Intercellular communication is critical for the development of invasive cancers. Multiple forms of intercellular communication have been well characterized, involving diffusible soluble factors or contact-dependent channels for immediately adjacent cells. Over the past 1-2 decades, the emergence of a unique form of F-actin-based cellular protrusion known as tunneling nanotubes (TNTs) has filled the niche of long-range cell-contact dependent intercellular communication that facilitates cell growth, differentiation, and in the case of invasive cancer phenotypes, a more chemoresistant phenotype. The cellular machinery of TNT-mediated transport is an area of active investigation, and microtubules have been implicated in this process as they are in other membranous protrusions. Tumor-Treating Fields (TTFields) therapy is a novel therapeutic strategy in clinical use for patients with advanced cancers, based on the principle of using low-intensity alternating electric fields to disrupt microtubules in cancer cells undergoing mitosis. Other mechanisms of action have also been demonstrated. In this study, we investigated the effects of TTFields on TNTs in malignant pleural mesothelioma (MPM)in vitroand also on the spatial transcriptomic landscapein vivo. We found that applying TTFields at 1.0 V/cm significantly suppressed TNT formation in a biphasic MPM cell line (MSTO-211H), but not in sarcomatoid MPM (VAMT). At these parameters, TTFields significantly reduced cell count in MSTO-211H, but did not significantly alter intercellular transport of mitochondria via intact TNTs. To understand how TTFields may impact expression of genes with known involvement to TNT formation and overall tumor growth, we performed spatial genomic assessment of TTFields-treated tumors from anin vivoanimal model of MPM, and detected upregulation of immuno-oncologic biomarkers with simultaneous downregulation of pathways associated with cell hyperproliferation, invasion, and other critical regulators of oncogenic growth. Several molecular classes and pathways coincide with markers that we and others have found to be differentially expressed in cancer cell TNTs, including MPM specifically. In this study, we report novel cellular and molecular effects of TTFields in relation to tumor communication networks enabled by TNTs and related molecular pathways. These results position TNTs as potential therapeutic targets for TTFields-directed cancer treatment strategies; and also identify the ability of TTFields to potentially remodel the tumor microenvironment, thus enhancing response to immunotherapeutic drugs.

To describe fear of cancer recurrence in a cohort of women with gynecologic cancers and to identify psychosocial predictors of elevated fear of recurrence.Survey data from an ongoing cohort study of gynecologic cancer survivors were used (n = 154). Relationships between fear of cancer recurrence measured by the 6-item Cancer Worry Scale in the most recent survey and psychosocial factors (cancer-related distress, depression, anxiety, hopelessness, and posttraumatic growth) assessed 6-18 months prior were examined using univariate and multivariate linear regression models, adjusting for age, cancer stage, cancer type, and time since diagnosis.Most participants were ≥60 years old, diagnosed with early-stage cancer, and 2-5 years post-diagnosis. The mean score on the Cancer Worry Scale was 10.31 (SD = 3.01), and 46 individuals (30.0%) scored ≥12, indicating high fear of recurrence. In univariate analyses, greater distress (p = 0.007), anxiety (p = 0.006), hopelessness (p = 0.007), and posttraumatic growth (p = 0.0006) were significantly associated with higher scores on the Cancer Worry Scale. The associations of hopelessness and posttraumatic growth with higher Cancer Worry Scale scores remained significant after adjustment for covariates.Fear of recurrence is frequent among gynecologic cancer survivors. Women who reported more distress, hopelessness, anxiety and, surprisingly, more post-traumatic growth reported more fear. These results contribute to our understanding of which cancer survivors are most at risk of elevated fear of recurrence and highlight the importance of continued focus on psychosocial well-being among cancer survivors.

Background Exposure to conflicting health information can produce negative affective and cognitive responses, including confusion and backlash, and the effects of this exposure can even “carry over” and reduce people’s receptivity to subsequent messages about health behaviors for which there is scientific consensus. What is not known is whether certain population subgroups are more vulnerable to such carryover effects. Aims This study investigates whether carryover effects of exposure to conflicting information are moderated by two factors, trust in news media and research literacy, testing the hypothesis that lower trust and higher literacy could protect against such effects. Method The analysis draws on data from a longitudinal population-based experiment ( N = 2,716), in which participants were randomly assigned to view health news stories and social media posts that either did or did not feature conflicting information, and subsequently exposed to ads from existing health campaigns about behaviors for which there is scientific consensus. Structural equation modeling was used to test study hypotheses. Results Neither lower trust in news media nor higher research literacy protected against carryover effects, as effects were observed across levels of both trust and literacy. Although level of research literacy did not affect whether carryover effects were observed, it did shape how those effects emerged. Conclusion The public, regardless of their level of trust in news media or research literacy, is vulnerable to the downstream effects of exposure to conflicting health information. Targeted health communication interventions are needed to improve messaging about evolving science and, in turn, increase receptivity to public health recommendations.

No single pharmacy in an urban zip code is consistently the least expensive across medications. If medication prices change differently across pharmacies, patients and clinicians will face challenges accessing affordable medications when refilling medications. This is especially pertinent to people with cancer with multiple fills of supportive care medications over time. We evaluated if the lowest-priced pharmacy for a formulation remains the lowest-priced over time.We compiled generic medications used to manage nausea/vomiting (14 formulations) and anorexia/cachexia (12 formulations). We extracted discounted prices in October 2021 and again in March 2022 for a typical fill at 8 pharmacies in Minneapolis, Minnesota, USA (zip code 55,414) using GoodRx.com. We examined how prices changed across formulations and pharmacies over time.Data were available for all 208 possible pharmacy-formulation combinations (8 pharmacies × 26 formulations). For 172 (83%) of the 208 pharmacy-formulation combinations, the March 2022 price was within 20% of the October 2021 price. Across pharmacy-formulation combinations, the price change over time ranged from - 76 to + 292%. For 12 (46%) of the 26 formulations, at least one pharmacy with the lowest price in October 2021 no longer was the least costly in March 2022. For one formulation (dronabinol tablets), the least expensive pharmacy became the most expensive, with an absolute and relative price increase of a fill of $22 and 85%.For almost half of formulations studied, at least one pharmacy with the lowest price was no longer the least costly a few months later. The lowest price for a formulation (across pharmacies) could also change considerably. Thus, even if a patient accesses the least expensive pharmacy for a medication, they may need to re-check prices across all pharmacies with each subsequent fill to access the lowest prices. In addition to safety concerns, directing medications to and accessing medications at multiple pharmacies can add time and logistic toxicity to patients with cancer, their care partners, prescribers, and pharmacy teams.

Although the APOBEC3 family of single-stranded DNA cytosine deaminases is well-known for its antiviral factors, these enzymes are rapidly gaining attention as prominent sources of mutation in cancer. APOBEC3′s signature single-base substitutions, C-to-T and C-to-G in TCA and TCT motifs, are evident in over 70% of human malignancies and dominate the mutational landscape of numerous individual tumors. Recent murine studies have established cause-and-effect relationships, with both human APOBEC3A and APOBEC3B proving capable of promoting tumor formation in vivo. Here, we investigate the molecular mechanism of APOBEC3A-driven tumor development using the murine Fah liver complementation and regeneration system. First, we show that APOBEC3A alone is capable of driving tumor development (without Tp53 knockdown as utilized in prior studies). Second, we show that the catalytic glutamic acid residue of APOBEC3A (E72) is required for tumor formation. Third, we show that an APOBEC3A separation-of-function mutant with compromised DNA deamination activity and wildtype RNA-editing activity is defective in promoting tumor formation. Collectively, these results demonstrate that APOBEC3A is a “master driver” that fuels tumor formation through a DNA deamination-dependent mechanism.

Introduction: Skin cancer is the most common cancer in the United States (US) and is associated with notable morbidity and mortality. There has been mixed evidence regarding whether rural vs. urban residence is an independent risk factor for skin cancer, and it is not clear to what degree these differences are driven by demographic or behavioral factors. We investigated if there are differences in skin cancer sun protection behaviors between urban and rural residents. Methods: We used data from three (2013-2018) National Health and Nutrition Examination Survey (NHANES) cycles. Sunburns and sun exposure and behavior measures were dichotomized: 2+ hours outside during work days or non-work days, at least one sunburn in the past year (yes/no); sunscreen use, wearing long sleeves, staying in the shade (never, rarely, sometimes/most of the time, always). Urban/rural residence was measured as a 2-level indicator. We compared sunburn and sun behavior measures by rural-urban status using adjusted survey-weighted logistic regression models. Because of distribution difference by rural-urban status, we stratified by non-Hispanic (NH) white identity vs. identifying as a person of color. Odds ratios and 95% confidence intervals presented were adjusted for age, sex, income, education, body mass index, and smoking. Results: When comparing urban vs. rural residents, both NH white individuals (42.9 vs. 29.1%, OR: 1.60 [1.27, 2.01]) and people of color (48.9 vs. 36.5%, OR: 1.54 [1.08, 2.19]) in rural communities had greater odds of spending 2+ hours outside on work days. Rural NH white residents had greater odds of spending 2+ hours outside on non-work days (64.8 vs. 72.2%, OR: 1.45 [1.12, 1.88]). Both rural NH white individuals (26.7 vs. 21.6%, OR: 0.72 [0.57, 0.89]) and rural people of color (41.1 vs. 35.5%, OR: 0.81 [0.68, 0.97]) had lower odds of staying in the shade. Rural NH white residents reported lower sunscreen use (35.1 vs. 26.0%, OR: 0.74 [0.59, 0.93]). Among people of color, rural residency was associated with greater odds of at least one sunburn in the past year (34.5 vs. 24.7%, OR: 1.60 [1.23, 2.09]). Sunburns were more frequent overall (59-61%) in NH white individuals; however, no significant differences by rural-urban residence were observed. Conclusions: Rural residents report engaging in skin cancer preventative sun behaviors less often than urban residents. Greater sunburn frequency among rural and urban NH white individuals compared with individuals of color is consistent with higher skin cancer rates in NH white individuals. However, over 25% of people of color reported a sunburn in the past year, highlighting the importance of intervention on skin cancer risk beyond NH white individuals. Consistently less sun protection behavior across rural populations even after adjustment for demographics emphasizes that rurality should be recognized as an independent risk factor for sun risk behaviors. Citation Format: Allison C. Dona, Patricia Jewett, Rehana L. Ahmed, DeAnn Lazovich, Rachel I. Vogel. Not just demographics: Urban and rural differences in skin cancer sun protection behaviors in the United States [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1929.

Cervical cancer screening is recommended for those with a cervix who are 21 to 65 years old, with specific timelines being dependent on individual risk. This study compared rates of ever undergoing Papanicolaou (Pap) testing at the intersection of self-reported sexual minority (SM) status and race/ethnicity.Data from the National Health Interview Survey (2015 and 2018) were used to examine cervical cancer screening disparities. Natal females without a history of hysterectomy who were 21 to 65 years old and had reported their sexual orientation and Pap testing history were included. Demographic and health characteristics were summarized with descriptive statistics. To adjust for differences in confounding variables between groups, propensity score-based inverse probability of treatment weighting (IPTW) was performed. IPTW-adjusted multivariable logistic regression models estimated odds of ever undergoing a Pap test by sexual orientation alone and with race/ethnicity (non-Hispanic White, non-Hispanic Black, and Hispanic).SM persons (n = 877) had significantly reduced odds of ever undergoing Pap testing (odds ratio, 0.54; 95% confidence interval, 0.42-0.70) in comparison with heterosexual persons (n = 17,760). When the intersection of sexual orientation and race/ethnicity was considered, non-Hispanic White SM participants and Hispanic SM participants had reduced odds of ever undergoing Pap testing in comparison with non-Hispanic White heterosexual participants. No significant differences were observed between non-Hispanic White heterosexual participants and participants of non-Hispanic Black SM or Hispanic heterosexual identities.SM participants were significantly less likely to have ever undergone a Pap test in comparison with heterosexual participants, with Hispanic SM participants having the lowest uptake. Future studies should further examine the roles of systemic discrimination and other key drivers of these disparities.

COVID-19 has illuminated health inequity in the United States. The burdens of disease are much higher among Black and Indigenous people and other people of color. Disparities by income are also profound, as lower-wage workers were less able to adopt mitigating behaviors compared to higher-income counterparts. These disparities became part of public health discourse in 2020, with commentators frequently highlighting the connection between racism, socioeconomic position, and COVID-19. But what proportion of the public-and among key subgroups-recognized these social group disparities, relative to disparities associated with age and chronic illness, and did public recognition change over the first year of the pandemic? To address these questions, we analyzed data from three nationally-representative cross-sectional public opinion surveys, collected using the NORC AmeriSpeak panel in April 2020 (N = 1007), August 2020 (N = 2716), and April 2021 (N = 1020). The key outcomes were respondents' agreement with statements about disparities in COVID-19 mortality by age, chronic illness, income, and race. We found little change from 2020 to 2021 in Americans' recognition of disparities. At all three time points, most respondents acknowledged age and chronic illness disparities, while no more than half at any time point recognized income- and race-based disparities. Political party affiliation was not statistically associated with agreement with age or illness-related disparities, but was strongly associated with views about income- and race-based disparities. Efforts to promote recognition of racial and socioeconomic health disparities in the United States need to be mindful of the ways in which public understanding of health inequities is linked to partisanship.

Recent reports in both cervical and endometrial cancer suggest that minimally invasive surgery (MIS) had an unanticipated negative impact on long-term clinical outcomes, including recurrence and death. Given increasing use of robotic surgery since the LAP2 trial, we sought to compare the intermediate and long-term outcomes between those who underwent robotic surgery or laparoscopy for Stage I endometrial cancer.We performed a retrospective review of patients from a single, large, academic, urban practice who underwent either laparoscopic or robot-assisted MIS (RA-MIS) for the treatment of endometrial carcinoma between 2006 and 2016, ensuring at least 5 years of potential follow-up. To adjust for differences in confounding variables between groups, propensity score-based inverse probability of treatment weighting (IPTW) was performed. Overall and recurrence-free survival were compared using Cox proportional hazards regression models adjusting for confounding weights.1027 patients were included; 461 received laparoscopy and 566 received RA-MIS. RA-MIS use increased steadily during the study window, which resulted in longer mean surveillance in laparoscopy group (median 8.7 years versus 6.3 years, p0.001). RA-MIS was associated poorer recurrence-free (HR: 1.41, 95% CI: 1.12, 1.77) and overall survival (HR: 1.39, 95% CI: 1.06, 1.83). Disease-specific survival was also poorer in the RA-MIS group (HR: 3.51, 95% CI: 2.19, 5.63). Among those who recurred, median time to first recurrence was shorter in the RA-MIS group than the laparoscopy group (16.3 vs. 28.7 months, p = 0.07).RA-MIS was associated with poorer long-term patient outcomes. Our data in this lower-risk population indicate relevant clinical endpoints may be occurring during intermediate and long-term follow-up windows. These findings support a prospective evaluation of the long-term outcomes of RA-MIS.

Introduction: Increasing our understanding of drivers of mutagenesis in lung cancer is critical in our efforts to prevent tumor reoccurrence and resistance. Results: Using the multi-region TRACERx lung cancer study, we uncovered that APOBEC3B is significantly upregulated when compared with other APOBEC family members in EGFR driven lung cancer and identified subclonal enrichment of APOBEC mutational signatures. To model APOBEC mutagenesis in lung cancer, several novel EGFR mutant mouse models containing a human APOBEC3B transgene were generated. Using these models, it was uncovered that APOBEC3B expression is detrimental at tumor initiation when expressed continuously in a p53 wildtype background. This detrimental effect is likely due to elevated chromosomal instability, which was observed to increase significantly with APOBEC3B expression in an EGFR mutant TP53 deficient mouse model. Induction of subclonal expression of APOBEC3B in an EGFR mutant mouse model with tyrosine kinase inhibitor (TKI) therapy resulted in a significant increase in resistant tumor development. Significant downregulation of the base excision repair gene uracil-DNA glycosylase (UNG) was also observed in APOBEC3B expressing mice, which paralleled findings in patient tumors and cell lines treated with TKI therapy. Finally, a mouse mutational signature was identified in APOBEC3B expressing cell lines, reinforcing the idea that APOBEC driven mutagenesis contributes to TKI resistance. Conclusion: This study demonstrates a unique principle by which targeted therapy induces changes within tumors ideal for APOBEC driven tumor evolution, fueling therapy resistance. Citation Format: Manasi Mayekar, Deborah Caswell, Natalie Vokes, Emily K. Law, Wei Wu, William Hill, Eva Gronroos, Andrew Rowan, Maise Al Bakir, Clare Weeden, Caroline E. McCoach, Collin M. Blakely, Nuri Alpay Temiz, Ai Nagano, Daniel L. Kerr, Julia K. Rotow, Oriol Pich, Franziska Haderk, Michelle Dietzen, Carlos Martinez Ruiz, Bruna Almeida, Lauren Cech, Beatrice Gini, Joanna Przewrocka, Chris Moore, Miguel Murillo, Bjorn Bakker, Brandon Rule, Cameron Durfee, Shigeki Nanj, Lisa Tan, Lindsay K. Larson, Prokopios P. Argyris, William L. Brown, Johnny Yu, Carlos Gomez, Philippe Gui, Rachel I. Vogel, Elizabeth A. Yu, Nicholas J. Thomas, Subramanian Venkatesan, Sebastijan Hobor, Su Kit Chew, Nicholas McGranahan, Nnennaya Kanu, Eliezer M. Van Allen, Julian Downward, Reuben S. Harris, Trever Bivona, Charles Swanton. Targeted cancer therapy induces APOBEC fueling the evolution of drug resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2197.

Introduction: Cancer screening disparities have been documented among LGBTQ+ individuals. Our objective was to examine how LGBTQ+-based discriminatory experiences in the clinical setting were associated with current cancer screening practices. Methods: Participants were recruited via social media. Those who self-reported identifying within the LGBTQ+ community, being 40+ years of age, and residing in the US were eligible to participate. Participants completed a survey which collected data on health behaviors, medical history, cancer screening and preventive health resource uptake, experiences in the clinical setting, desired changes in the clinical setting, and interests in community outreach initiatives. Descriptive statistics were used to examine distributions of demographic characteristics. Chi-squared, Fisher’s exact, and Student’s t-tests were used to compare differences in cancer screening and by discriminatory clinical experiences. Results: A total of 339 participants completed the survey. Participants were on average 54.4±9.0 years old and primarily white (92.9%). Approximately half (52.5%) of the participants were assigned female sex at birth, 46.9% male at birth, and 0.6% reported intersex characteristics. Currently, 16.8% identified as transgender and gender diverse (TGD; gender neutral, non-binary, or similar). Most participants identified as lesbian (36.9%) or gay (41.9%). Of those eligible for each cancer screening modality, most had undergone and were up to date with cancer screening via Pap testing (99.1%), mammography (93.8%), and colonoscopy (75.3%). Nearly half (44.9%) reported experiencing discrimination in the medical setting relating to LGBTQ+ identities. As compared to those without these experiences, participants who reported discrimination rated their providers as less competent in the clinical care of LGBQ and TGD patients, were less likely to have a personal provider, were less likely to have engaged in primary care in the last 12 months, were more likely to have delayed care due to costs, were less likely to disclose their sexual orientation, and were more likely to feel excluded because of gendered language (p Conclusions: We noted disparities among our participants with respect to cancer screening associated with past discriminatory experiences in the clinical setting. Future studies should continue to examine systemic discrimination as a key driver of LGBTQ+ disparities in cancer-screening. Citation Format: Ashley E. Stenzel, G. Nic Rider, Olivia S. Wicker, Deanna Teoh, B.R. Simon Rosser, Rachel I. Vogel. Experienced discrimination in the medical setting relating to LGBTQ+ identities and subsequent cancer screening [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6237.

Current US cervical cancer screening guidelines do not differ by human papillomavirus (HPV) vaccination status. However, as the positive predictive value (PPV) of a screening test decreases, the risk of a false-positive result increases.To evaluate whether HPV vaccination is associated with decreased PPV for abnormal cervical cytology.This retrospective cohort study conducted via electronic medical record review included eligible patients aged 21 to 35 years who had at least 1 cervical cytology result within a single health system between January 2015 and December 2018. The health system comprises a partnership between an academic health center and a private not-for-profit health center. Patients with abnormal screening cytology and no diagnostic test results were omitted from analysis. Data were analyzed from December 2019 to November 2021.HPV vaccination, defined as receiving at least 1 dose of HPV vaccine. Subgroup analyses were performed for those completing all vaccination doses per Advisory Committee on Immunization Practices guidelines and by age at vaccination initiation, dichotomized as younger than 21 years vs 21 years or older.PPV of abnormal cervical cytology for risk of cervical intraepithelial neoplasia (CIN) 2 or more severe diagnosis.A total of 46 988 patients (mean [SD] age, 28.7 [4.5] years; 3058 [6.5%] Asian; 4159 [8.9%] Black or African American; 35 446 [75.4%] White) were included; 15 494 (33.0%) were at least partially vaccinated, and 4289 (9.1%) had abnormal cytology results during the study period. Among the individuals with abnormal cytology, the PPV for CIN 2 or more severe diagnosis was lower among vaccinated individuals (17.4%; 95% CI, 16.4%-18.4%) than unvaccinated individuals (21.3%; 95% CI, 20.4%-22.3%). Among vaccinated individuals, PPV was significantly lower among those completing vaccination (15.9%; 95% CI, 14.9%-17.0%) than those with incomplete vaccination (22.4%; 95% CI, 20.0%-25.0%), especially among those initiating vaccination when younger than 21 years (11.9%; 95% CI, 10.9%-12.9%) vs those initiating at age 21 years or older (30.7%; 95% CI, 27.3%-34.4%).Among a population with relatively low HPV vaccine coverage, the PPV of cervical cytology for CIN 2 or more severe diagnosis was significantly lower among vaccinated individuals. PPV will likely further decrease in the future as a population with higher HPV vaccination coverage ages into screening. Confirmation of these results will call for changes in screening strategies, particularly for completely vaccinated individuals who initiated vaccination when younger than 21 years.

Objectives: Cervical cancer screening is recommended for those with a cervix aged 21-65, with specific timelines dependent on individual risk. Persons belonging to sexual minority (SM) groups may experience greater risk factors for cancer while also being less likely to participate in cancer screening. We compared cervical cancer screening rates by sexual orientation, as well as intersectional analyses with race/ethnicity. Methods: Data from the NHIS years 2015 and 2018, were used to examine cervical cancer screening disparities. Biologic females without history of hysterectomy, ages 21-65 years, who reported sexual orientation and Pap testing history were included. Demographic, health, and cervical cancer screening characteristics were examined using descriptive statistics. Multivariable logistic regression models explored Pap testing rates by sexual orientation alone and with race/ethnicity (non-Hispanic (NH) white, NH Black, Hispanic), adjusting for age, partner status, education, health insurance, and poverty status. Results: SM participants (N=874) were younger, less likely to be living with a partner, had lower income, were less likely to have a medical clinic they go to for regular care, and more likely to delay their medical care due to costs, when compared to heterosexual counterparts (N=17,733). SM persons had significantly reduced odds of ever undergoing Pap testing (OR: 0.57, CI: 0.44-0.74) when compared to heterosexual persons. When considering the intersection of sexual orientation and race/ethnicity, heterosexual Hispanic, SM NH white, and SM Hispanic participants all had reduced odds of ever undergoing Pap testing when compared to NH white heterosexual participants. There were no significant differences observed between heterosexual and SM participants of NH Black or white identities. Conclusions: Participants identifying as SM were significantly less likely to have ever undergone a Pap test when compared to heterosexual participants. When stratifying by race/ethnicity, disparities remained for most participants identifying as SM. These results demonstrate a need for continued effort to increase Pap testing among the SM community. Further research is needed to further examine roles of systemic discrimination and other key drivers of these disparities. Citation Format: Ashley E. Stenzel, Gabriela Bustamante, Courtney Sarkin, Katherine Harripersaud, Patricia Jewett, Deanna Teoh, Rachel I. Vogel. The intersection of sexual orientation with race and ethnicity in cervical cancer screening: Results from the National Health Interview Survey [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PO-265.

CK2 is a master regulator protein kinase which demonstrates heightened expression in diverse cancer types and is considered a promising target for therapy. Given its ubiquitous expression and potent influence on cell survival, cancer cell-directed targeting of the CK2 signal is an important factor for development of an anti-CK2 therapeutic. We previously reported on the malignant cell specificity and effect on CK2 signaling of a tenfibgen (TBG) based nanocapsule for delivery of the CK2 small molecule inhibitor 2-dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole (DMAT) in cultured prostate cancer cells. Here we tested the ability of TBG-DMAT to affect the growth of prostate xenograft tumors in mice. Our results show that treatment of PC3-LN4 xenograft tumors with TBG-DMAT caused loss of proliferative Ki-67 signal as well as Nuclear Factor-kappa B (NF-κB) expression in the tumors. Further, the TBG-DMAT nanocapsule was detected in tumors and not in liver or testis. In conclusion, TBG-based nanocapsule delivery of anti-CK2 small molecule drugs holds significant promise for treatment of prostate cancer.