bluuebunny/crossref_metadata_2025 huggingface dataset:
Genomic characterization of the GATA3 mutational landscape in breast cancer.
Authors: Mouabbi Jason A , Meric-Bernstam Funda , Turova Polina , Chernyshov Konstantin , Kushnarev Vladimir , Kotlov Nikita , Brown Jessica H. , Clayton Patrick , Nomie Krystle , Fowler Nathan , Tripathy Debu , Damodaran Senthil
Published: June 2023

1039

Background: GATA3 expression is broadly used as a biomarker for diagnosing cancer of breast origin and its expression is strongly associated with estrogen receptor (ER)-positive luminal phenotype. Although GATA3 mutations are observed in 12-18% of breast cancers (BC), they are poorly characterized. Recently, the pharmacological inhibition of MDM2 has been shown to significantly impair tumor growth in GATA3-deficient models in vitro, in vivo, and patient-derived xenograft harboring GATA3 somatic mutations. Therefore, given the potential targetability of GATA3-mutated BC cells, it is important to better understand and characterize the mutational landscape of GATA3 to help guide future prospective clinical studies. Methods: We accessed a cohort of BC samples profiled genomically and transcriptomically from two open-source datasets: TCGA (n=961) and METABRIC (n=1866). We used the chi-squared test to analyze the frequency of GATA3 mutations across PAM50 subtypes (Basal, HER2, Luminal A, Luminal B, Normal-like) and histological BC subtypes (invasive ductal carcinoma [IDC] and invasive lobular carcinoma [ILC]). Mutations affecting other genes in the GATA3-mutated samples and the GATA3 wild-type (WT) samples were compared using the chi-squared test. We analyzed the mutational landscape of the GATA3 gene and correlated different sites of mutations with GATA3 expression, MDM2 amplification, other co-occurring mutations, and clinical behavior. GATA3 expression levels were compared using the Mann-Whitney test. Results: Of the analyzed 2,827 BC samples, GATA3 mutations were unevenly distributed in the five PAM50 subtypes, as Luminal A and B subtypes had the highest frequency (16% and 17%, respectively) and the basal subtype had no observed GATA3 mutations (p <0.0001). Further analysis showed that GATA3 mutations were more common in luminal IDC than ILC (17% vs 8.7%; p <0.0001). While mutations in CBFB, AKT1, TBX3 and ARID1A were more frequently co-occurring with GATA3 mutations, mutations in TP53, CDH1 and PIK3CA were mutually exclusive with GATA3 mutations (adjusted p <0.0001 for all genes). Analysis of the GATA3 mutational landscape identified two types of mutations in GATA3: a group of truncating mutations occurring at the end of the GATA3 gene (after the 307 position including the splice site at 308) and a group occurring before the 307 position. The first group was associated with increased GATA3 expression, MDM2 amplification, and was mutually exclusive with TP53 mutations. The second group had little to no effect on GATA3 expression and behaved similarly to GATA3 WT. Conclusions: A subtype of GATA3 mutations are mutually exclusive with TP53 mutations and are associated with increased MDM2 amplification, making them an ideal target for clinical trials involving MDM2 inhibitors.
Updated results from a phase 2 study on dalpiciclib and pyrotinib, a dual-oral chemotherapy-free regimen in HER2-positive advanced breast cancer (DAP-HER-01).
Authors: Yan Min , Niu Limin , Lv Huimin , Zhang Mengwei , Liu Zhenzhen , Chen Xiuchun , Lu Zhenduo , Zhang Chongjian , Zeng Huiai , Zhao Shengnan , Feng Yajing , Wang Jing , Sun Huihui , Li Huajun
Published: June 2023

1045

Background: Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have shown synergistic effect with anti-HER2 therapy on hormone receptor (HR)-positive and HER2-positive breast cancer from preclinical models and several clinical studies, while data of this combination in HR-negative and HER2-positive diseases are limited so far. DAP-HER-01 (NCT04293276) was aimed at evaluate the efficacy and safety of the novel dual-oral, chemotherapy-free regimen of CDK4/6 inhibitor dalpiciclib and pan-HER tyrosine kinase inhibitor pyrotinib in HER2-positive advanced breast cancer (ABC) regardless of HR status, and reported to meet the primary endpoints previously (overall ORR 70%), in which HR-negative patients achieved a higher ORR (81.8%, vs 55.6% in HR-positive patients; Min Yan, et al. ESMO 2021, Poster 276P). Here we reported the updated results of this trial. Methods: DAP-HER-01 was a single-arm, phase 2 study conducted in HER2-positive ABC patients with no more than one prior systemic treatment at advanced setting. Enrolled patients received dalpiciclib and pyrotinib until progression, unaccepted toxicity, or no further benefit. The primary endpoint was ORR as per RECIST 1.1, and secondary endpoints included progression-free survival (PFS), overall survival and safety. Results: Between April 9, 2020, and May 19, 2021, 41 patients were enrolled and received study treatment, and 40 of them were assessable for efficacy. With a median follow-up of 19.2 months, the median progression-free survival (PFS) was 11.0 months (95% CI 7.3-19.3). Considering HR status, the PFS in HR-negative patients was not matured (estimated median: 16.6 months; 95% CI: 7.3- NA), but still showed a tendency to be longer than that in HR-positive patients (median: 9.1 months; 95% CI: 5.4-11.0). Patients with brain metastases at baseline could also benefit from this treatment (median PFS: 11.0; 95% CI: 5.4-NA). Consistent with the safety data reported before, the most common grade 3 or 4 treatment-related adverse events were leukopenia (68.3%), neutropenia (65.9%) and diarrhea (19.5%). Most adverse events were tolerable, and no study-related death reported. Conclusions: Combined with previous reports, our findings suggest dalpiciclib combined with pyrotinib achieved promising efficacy and manageable toxicity in the treatment of HER2-positive ABC, including patients with HR-negative disease or brain metastases. This combination could be considered as a completely oral, chemo-free regimen for patients with HER2-positive ABC and is worthy of further study. Clinical trial information: NCT04293276 .
Secondary primary malignancy risk by ER, PR, and HER-2 status in post-menopausal women with breast cancer: A population-based analysis.
Authors: Khan Muhammad Hammad , Fatima Maurish , Akbar Usman Ali , Rehman Mohammad Ebad Ur , Basit Jawad , Aman Aleena , Taj Sobaan , Ali Fatima , Vikash Sindhu , Yousuf Saira , Khaliq Waseem , Ahmad Nabeel
Published: June 2023

1050

Background: Breast cancer is the most commonly diagnosed cancer and second leading cause of death due to cancer in women in the United States. We aimed to determine site specific incidence of SPMs in post-menopausal women with primary BC using data from the US Surveillance, Epidemiology, and End Results (SEER-17) cancer registries. Methods: We retrospectively analyzed post-menopausal women aged 45 or older with a first primary breast cancer diagnosis between 2000 and 2019, excluding those aged 45 or younger or with non-breast cancers as their first malignancy. We defined SPMs as second malignancies occurring at least 6 months after the initial breast cancer diagnosis and calculated standardized incidence ratios (SIRs) and absolute excess risk (AER) using SEER*Stat. Statistical significance was determined using p-values <0.05 and a 95% CI assuming a Poisson distribution of SPM incidence. Results: Among 774,965 post-menopausal women ≥45 years old with primary breast cancer, 10.8% developed SPMs, with significantly increased risk compared to the general population (SIR=1.14, 95% CI=1.13-1.15, p<0.05), particularly for solid tumors (SIR=1.16, 95% CI=1.15-1.16, p<0.05) and certain malignancies including salivary gland (SIR=1.77), thyroid (SIR=1.56), endocrine system (SIR=1.56), and hematological malignancies such as ALL, ANLL, and AML (SIR>1.70). Women aged 45-59 and Black women had the highest risk for all malignancies. PR receptor-positive women had higher risk for thyroid SPMs, while PR-negative women had higher risk for SPMs in female genitalia, bones and joints, and hematological malignancies. HER-positive and triple-positive (HER ER PR) women had higher risk for thyroid and hematological SPMs, while triple-negative women had higher risk for ALL, ANLL, and AML. Conclusions: This study found that 11% of post-menopausal women with primary BC develop SPMs, with thyroid cancer being the most common. Black and older women (45-59 years) had a higher risk of developing SPMs. [Table: see text]
Polygenic risk score calibration and association with breast cancer in diverse ancestries.
Authors: Kucera Matthew , Hughes Elisha , Mabey Brent , Hullinger Brooke , Pederson Holly Jane , Pal Tuya , Domchek Susan M. , Eng Charis , Garber Judy Ellen , Gordon Ora , Klemp Jennifer R. , Mukherjee Semanti , Vijai Joseph , Pruthi Sandhya , Kurian Allison W. , Whitworth Pat W. , Lanchbury Jerry , Slavin Thomas Paul , Gutin Alexander , Olopade Olufunmilayo I.
Published: June 2023

10505

Background: Polygenic risk scores (PRS) have been shown to substantially improve breast cancer (BC) risk prediction when incorporated into traditional risk assessment models. However, PRS developed primarily in women of European ancestry have shown poor performance when applied to non-European populations. We previously described development and validation of a multiple-ancestry PRS (MA-PRS) that is based on individual ancestral genetic composition. MA-PRS has been incorporated into the Tyrer-Cuzick model for use in clinical practice and has been shown to provide independent value to the model. Here, we describe performance of the MA-PRS in a large cohort of women from diverse ancestral backgrounds. Methods: The study cohort included 203,586 patients who were referred for hereditary cancer testing and negative for pathogenic variants in genes associated with BC. MA-PRS was calculated as previously described based on 149 SNPs (93 BC and 56 ancestry-informative). Association of MA-PRS with invasive BC status (affected vs unaffected) was analyzed using logistic regression adjusted for personal and family cancer history, age, and ancestry. Calibration was assessed by examining the MA-PRS distribution within unaffected patients, and through goodness-of-fit tests. All analyses were conducted within the full cohort and within ancestral subpopulations. Odds ratios (ORs) are reported per standard deviation. Results: One-fifth (43,782/203,586, 21.5%) of patients were diagnosed with invasive BC, and 60,657 (29.8%) of patients reported BC in a first degree relative. The MA-PRS distribution was centered around zero among unaffected patients overall and within each subpopulation. MA-PRS significantly improved BC risk prediction over clinical factors in the full cohort (OR = 1.43, 95% CI:1.41-1.44) and within each ancestral subpopulation (Table). The strongest associations were observed in Ashkenazi Jewish (OR = 1.56, 95% CI:1.39-1.76) and South Asian (OR = 1.49,95% CI: 1.23-1.81) populations. The top decile of the MA-PRS consistently identified patients with two-fold increased risk of developing BC. Goodness-of-fit tests showed that the MA-PRS was well calibrated and predicted BC risk accurately in the tails of the distribution for both European and non-European women. Conclusions: The breast cancer MA-PRS based on genetic ancestral composition is well-calibrated and strongly associated with BC in all tested ancestral populations. Incorporation of PRS adds independent information to risk models and supports equitable access to personalized BC risk management. [Table: see text]
Whole exome sequencing and machine learning germline analysis of individuals presenting with phenotypes of extreme high and low risk of developing tobacco-induced lung adenocarcinoma.
Authors: Perez-Gracia Jose Luis , Guruceaga Elisabet , Andueza Maria Pilar , Ocon Marimar , de VIllalonga Zornoza Nicolas , Fodop Sokoudjou Jafait Junior , Alkorta-Aranburu Gorka , Camps Carlos , Jantus-Lewintre Eloisa , Navamuel Andueza Maria , Sanmamed Miguel F. , Gurpide Alfonso , Melero Bermejo Ignacio , Elgendy Mohamed , Perez Valencia Juan Alberto , Hernaez Mikel , Pio Oses Ruben , Montuenga Luis M. , Ochoa Idoia , Patiño-García Ana
Published: June 2023

10507

Background: Tobacco is the main risk factor for developing lung cancer. Yet, while some heavy smokers develop lung cancer at young age others never develop it, even at advanced age. This suggests a remarkable variability in the individual susceptibility to the carcinogenic effects of tobacco. We characterized the germline profile of subjects presenting these extreme phenotypes with Whole Exome Sequencing (WES) and Machine Learning (ML). Methods: We sequenced germline DNA from heavy smokers who either developed lung adenocarcinoma at early age ( extreme cases) or did not develop it at advanced age ( extreme controls). The discovery and validation cohorts included respectively 50 and 66 extreme cases and 50 and 83 extreme controls, selected from databases including > 6,000 subjects. We selected individual coding variants and variant-rich genes showing a significantly different distribution between extreme cases and controls. We trained ML models (Logistic Regression, Random Forest, Support Vector machine Classifier (SVC)) on the discovery cohort to classify subjects into their respective phenotypes and tested them on the validation cohort. Results: Mean age for extreme cases and controls in both cohorts was 50.2 and 78.4 years. Mean tobacco consumption was 38.1 and 59.1 pack-years. We validated 16 significant individual variants. The most significant variants were in ADAMTS7 (2 variants) in cases and TMEM191B (1) in controls. We validated 33 genes enriched with significant variants. The genes harboring more variants were HLA-A (4 variants) and ADAMTS7 (2) in cases; and PLIN4 (2) in controls (Table). We trained several ML models on the discovery cohort using as input the 16 significant individual variants and the number of variants in the 33 enriched genes. We tested them in the validation cohort obtaining accuracy of 72% and AUC-ROC of 87.4% with the best model (SVC), using 16 variants as input, confirming their association with the phenotypes. Functions of validated genes included oncogenes, tumor-suppressors, DNA repair, maintenance of genomic stability, HLA mediated antigen presentation and regulation of proliferation, migration, apoptosis and inflammatory pathways. Conclusions: Individuals presenting phenotypes of extreme high and low risk of developing tobacco-induced lung adenocarcinoma have different germline profiles. Our strategy may allow to identify high-risk subjects and to develop new therapeutic approaches. [Table: see text]
Clinical evaluation of cancer signal origin prediction and diagnostic resolution following multi-cancer early detection testing.
Authors: Klein Eric A. , McDonnell Charles H. , Nadauld Lincoln , Dilaveri Christina A. , Reid Robert Lawrence , Marinac Catherine R. , Chung Karen C. , Lopatin Margarita , Fung Eric T. , Schrag Deborah , Shaknovich Rita
Published: June 2023

10520

Background: PATHFINDER (NCT04241796) was a prospective, interventional return of results study that enrolled 6,662 participants (pts) from 7 US institutions to assess clinical implementation of a blood-based multi-cancer early detection (MCED) test. Test results for those with a cancer signal detected also included a cancer signal origin prediction designed to help guide diagnostic evaluations. We analyzed whether the diagnostic evaluations in PATHFINDER were appropriately directed by cancer signal origin predictions, assessed the residual risk of cancer after negative initial evaluation, and examined the role of whole-body imaging (WBI, defined as PET/CT or CT chest/abdomen/pelvis) in diagnostic evaluation. Methods: Analysis included pts with a cancer signal detected result from the two different versions of an MCED test evaluated in PATHFINDER. Prespecified criteria blinded to study results were used to define expected diagnostic evaluations by cancer signal origin prediction. These criteria were then used to judge concordance between cancer signal origin predictions and the diagnostic evaluation actually performed. Definitive cancer or no cancer diagnosis (cancer status at end of study [EOS]) was assessed at 12 months after enrollment (EOS). Results: 39 pts had cancer signal detected results by both test versions. Diagnostic evaluations were consistent with cancer signal origin in 30/39 (77%) cases. Diagnostic resolution was achieved in 32/39 (82%) pts after initial evaluation, while 7/39 (18%) required additional workup. 25 of the 32 (78%) pts who achieved diagnostic resolution after initial evaluation had a cancer signal origin-guided workup. Additional evaluation of the 7 pts not achieving initial diagnostic resolution was based on persistent clinical suspicion of cancer due to prior cancer history (n = 1) or abnormal/equivocal findings on initial evaluation (n = 6). Additional workup led to diagnostic resolution in all 7 cases (3 with cancer and 4 with no cancer confirmed at EOS). WBI was ordered in 27 cases, of whom 9 had a prior cancer history, 10 had non-localizing cancer signal origin (hematologic or indeterminate), and 1 had both. WBI was equivocal or had no impact on diagnostic resolution in 8/27 (30%) cases. Conclusions: Most cases resulted in diagnostic resolution after cancer signal origin-directed diagnostic workup. In pts with a cancer history and negative initial evaluations, and those with equivocal initial evaluations, there was still a risk of cancer, suggesting the need for additional evaluation. WBI was used mostly in those with a cancer history or non-localizing cancer signal origins, and had no impact on diagnosis in almost one-third of pts. Clinical trial information: NCT04241796 .
CDH1 incidental findings in patients with personal or family history of breast cancer.
Authors: Abdel-Salam Hiam , Mansfield Paul F. , Moskowitz Julie B , Arun Banu
Published: June 2023

10524

Background: Pathogenic variants in CDH1 ( CDH1+) are associated with hereditary diffuse gastric cancer (HDGC), with an increased risk for DGC (~40-83%) and lobular breast cancer (BC) (~64%) [1]. The National Cancer Center Network recommends the inclusion of CDH1 in multi-gene panel testing (MGPT) for patients with significant history of BC, given its classification as a high-risk BC gene [2]. Management includes prophylactic gastrectomy or consideration of annual endoscopic biopsies and high-risk breast screening, with consideration of prophylactic mastectomy. Several studies have identified CD H1+ patients who do not meet the International Gastric Linkage Consortium’s diagnostic criteria for HDGC [3.4,5,6]. These studies have brought concerns of CDH1 pathogenic variants in patients with low risk phenotypes, given the potential for total gastrectomy to reduce DGC risk. Our study aims to investigate our cohort of patients with a personal and/or family history of BC to determine if there is a significant number of CDH1+ patients with a non-classical presentation of HDGC. Methods: 17,208 families with a history of BC who underwent MGPT were seen in a Clinical Cancer Genetics (CCG) high-risk breast clinic between August 2013 and July 2022. They were identified using a prospectively maintained MD Anderson Cancer Center CCG database. Families were categorized by their history of GC and CDH1 status. Results: Among the families, 10,202 (59%) had a proband with a personal history of BC, with a mean age of onset of 51 years. 49 families (0.28%) were CDH1+. 21 CDH1+ families (43%) had no personal and/or family history of GC. Overall, 0.12% of families within the cohort were CDH1+ and had no family history of GC. A chi-square goodness of fit test was performed comparing observed (O) versus expected frequencies (E) (O/E) of families that were: 1) CDH1+ and had a history of GC (28/28), 2) CDH1+ and no history of GC (21/21), 3) CDH1 – (benign variant or variant of unknown significance (VUS)) and a history of GC (180/164), and 4) CDH1- and no history of GC (16,979/16,995). O was determined by using a general population risk of GC (0.81%) and estimated risk of DGC for CDH1+ individuals (58.2%). The X2 was determined to be 1.576, with a p-value of 0.66483. Conclusions: In comparison to the expected frequency of incidental CDH1+ families identified via MGPT, we found that there was not a significant difference in expected and observed frequencies of families based on CDH1 status and presence of GC. These results likely reflect the incomplete penetrance and variable expressivity of HDGC, in addition to reported cases of occult signet ring cell carcinomas in biopsy samples or surgical pathology that has been reported in low risk presenting families [7]. We seek to validate these results with cohort of patients in which the diffuse gastric cancer pathology is known and to expand the analysis in patients specifically with a personal history of lobular breast cancer.
Trends in diagnosis of de novo metastatic hormone sensitive prostate cancer in US Veterans, 2002-2021.
Authors: Al masalmeh Nada , Etzioni Ruth Douglas , Khan Saira , Babar Arslan , Sanfilippo Kristen Marie , Montgomery Robert Bruce , Knoche Eric Marshall , Owens Lukas , Wong Yu-Ning , Schoen Martin W.
Published: June 2023

10527

Background: The incidence of non-localized prostate cancer in the US has been increasing since 2011. While the etiology of this increase is unknown, improved detection of metastatic disease and changes in prostate-specific antigen (PSA) screening may be contributing factors. In this retrospective study, we report the frequency and characteristics of veterans with de novo metastatic prostate cancer to understand changes in the diagnosis over time. Methods: The study population consisted of veterans diagnosed with de novo metastatic Hormone Sensitive Prostate Cancer (mHSPC) with a biopsy between 2002 and 2021 in the Veterans Health Affairs Prostate Cancer Data Core were included. All patients had no prior diagnosis of prostate cancer and were classified as SEER stage ‘distant’. We collected the highest PSA within 3 months of diagnosis, age, race, and calculated the Charlson Comorbidity Index. Year of diagnosis was categorized into 5-year periods and differences over tine were assessed by chi-square linear by linear ANOVA test for linearity as appropriate. Results: 15,485 patients were diagnosed with de novo mHSPC between 2002 and 2021. The mean age was 72.9 years and the median PSA was 88.0 ng/mL. There was a 39% increase of the number of patients diagnosed with mHSPC (from 3,274 between 2002-2006 to 4,560 between 2017-2021). Mean age increased from 71.6 years between 2002-2006 to 74.4 between 2017-2021 (p < 0.001). Median PSA decreased from 96.6 ng/mL in 2002-2006 to 80.3 ng/mL in 2006-2021 (p < 0.001). The percentage of patients who were identified as black decreased from 29.8% between 2002-2006 to 25.4% between 2017 and 2021 (p < 0.001). Mean comorbidity index increased from 3.2 between 2002-2006 to 4.5 between 2017-2021 (p < 0.001). BMI increased from 26.2 between 2002-2006 to 27.2 between 2017-2021 (p < 0.001). Median overall survival improved from 26.7 months in 2002-2006 to 31.7 months in 2016-2021 (p < 0.001). Conclusions: Over a 20-year period, the Veterans diagnosed with prostate cancer were older, with higher comorbidities and with decreased PSA at diagnosis. Additionally, overall survival improved from 26.7 to 31.7 months. The findings of this study are consistent with a reduction in screening and more sensitive imaging modalities to detect metastatic disease combined with changes in the veteran population and improvements in treatment of mHSPC. Further study is warranted to understand these trends over the same time period. [Table: see text]
Breast cancer: Global patterns of incidence, mortality, and trends.
Authors: Sedeta Ephrem Tadele , Jobre Bilain , Avezbakiyev Boris
Published: June 2023

10528

Background: The global burden of cancer incidence and mortality including that of female breast cancer continues to increase largely because of the growth and aging of the population and adoption of western lifestyle behaviors that increase cancer risk. In this study, we summarize the current burden, trends, and survivorship of female breast cancer that account for nearly 12% of the cancer burden worldwide. Methods: Estimates of incidence and mortality in the year 2020 were obtained from Global Cancer Observatory (GLOBOCAN) database. GLOBOCAN provides country-specific estimates of cancer incidence, mortality, and prevalence for 185 countries or territories and 36 cancer types by age group and sex. For US rates, data from Surveillance, Epidemiology, and End Results (SEER) program were assessed. Rates are age-standardized (ASRs) (per 100,000 person-years) using the 1966 Segi-Doll World Standard Population. Geographic variability was assessed using 20 predefined world regions, and the 4-tier Human Development Index (HDI). Finally, we provide a prediction of the future burden of female breast cancer in 2040 based on demographic projections. Results: Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death in females worldwide, with an estimated 2.3 million new cancer cases (1 in 4 new cancer cases) and 685,000 cancer deaths (1 in 6 deaths) in 2020. Breast cancer incidence rates varied by nearly 4-fold across WHO areas. The highest incidence rates (per 100,000) were found in Australia/New Zealand (95.5), Western Europe (90.7), and Northern America (89.4), while the lowest rates were in South-Central Asia (26.2), Middle and Eastern Africa (33), and Central America (39.5). In contrast, the highest breast cancer mortality rates were recorded in Melanesia (37.5), Polynesia and Western Africa (22.3), and the Caribbean (18.9), while the lowest rates were found in Eastern Asia (9.8), Central America (10.4), and Australia/New Zealand (12.1), a 2.8-fold difference. In the United States, the age-standardized breast cancer incidence rate (per 100,000) increased from 106 (1975) to 142 (1999), decreased to 128 (2004), and then slowly increased to 137 (per 100,000) in 2019. Similar broad temporal trend patterns were observed in other western countries. Incidence rates are rising in South America, Africa, and Asia where rates were historically low. Worldwide, an estimated 2,964,197 new female breast cancer cases are projected to occur in 2040, a 31% increase from the corresponding 2,260,127 cases in 2020. Conclusions: There is significant variation in female breast cancer incidence and mortality rates worldwide. Breast cancer incidence is increasing at different rates in various regions of the world. Mortality rates in many high HDI countries have been on the decline, in contrast to increasing rates in low HDI countries. This study also shows a substantial increase in new breast cancer diagnoses over the next two decades.
Comparison of 5- and 10-year breast cancer risk predictions.
Authors: Hopper John L. , Dite Gillian S. , Spaeth Tuff Erika Leigh
Published: June 2023

10529

Background: Breast cancer risk assessment is valuable in personalizing risk-reduction and screening approaches for the general population. Maximizing the benefits while reducing the harms associated with current breast cancer screening and risk-reduction recommendations should increase the efficacy of these paradigms. Because healthcare providers have limited time with their patients, we developed a risk prediction model, BRISK, which uses the most important clinical risk factors for breast cancer (in an easily collected format), polygenic risk and mammographic density. We previously validated BRISK 5-year risk predictions and found that it performed better than IBISv7 and BCRAT. Methods: The dataset comprised 241,633 women (mean age at baseline assessment = 56.6 years). We included all races/ethnicities available in the UK Biobank. There were 3726 women affected during the first five years of follow-up and 7482 women affected during the full 10 years of follow-up. We compared the performance of the 5-year and 10-year risk predictions by assessing the association with breast cancer using Cox regression to estimate the hazard ratio (HR) per SD of risk, discrimination using calculating Harrell’s C-index and calibration using logistic regression to estimate the slope and the intercept of the logit of the risk predictions. Nelson–Aalen estimates of the hazard function by quintiles of risk and standardized incidence ratios (SIRs) of the number of breast cancer cases expected were used to illustrate performance. Results: The predictive performance of BRISK was consistent for 5-year and 10-year risk predictions. Discrimination was similar, with a Harrell’s C-index of 0.645 (95% CI = 0.636, 0.654) for the 5-year risk and of 0.638 (95% CI = 0.632, 0.645) for the 10-year risk. We used Nelson_Aalen cumulative hazard estimates to compare breast cancer incidence by risk quintile for both 5 and 10-year risk. Both risk scores overestimated risk in the top two deciles with the 5-year expected risks of 2.8% and 5.0% corresponding to observed risks of 2.3% and 3.3%. The 10-year expected risks for the top two deciles were 5.6% and 9.8% while the corresponding observed risks were 4.6% and 6.4%. Finally, we used clinically actionable thresholds to show the standard incidence ratios (SIR) of 1.77 (95% CI = 1.69, 1.85) for women ≥3% 5-year risk and 2.05 (95% CI = 1.93, 2.18) ≥8% 10-year risk. Conclusions: The BRISK 5-year and 10-year risk prediction perform equally well. There is an overestimation of risk for the top decile in both models. This is important to consider in risk-management conversations between clinician and patient. While the observed risk of the top decile remained above the 3% 5-year risk threshold used in the United States, the top decile observed risk dropped below the 8% 10-year risk threshold used in the United Kingdom. Risk scores are not used in isolation, but it may be preferable to err on the side of overestimation rather than underestimation.
Epidemiologic effectors on the breast tumor microenvironment: Results from the Cancer Prevention Study-II and -3 cohorts.
Authors: Elsebaie Maha AT , Amgad Mohamed , Hodge James M. , Gaudet Mia M. , Teras Lauren R. , Shah Ami N. , Cooper Lee A.D.
Published: June 2023

10530

Background: Despite breast cancer being the leading cancer among women, we have a poor understanding of the impact of epidemiologic risk factors on its tumor microenvironment (TME). We examined risk factors for TME favorability using a novel aggregate marker: the Histomic Prognostic Score (HiPS). Methods: Data were from whole slide image (WSI) scans of hematoxylin & eosin slides from women in the Cancer Prevention Studies CPS-II and -3, diagnosed with nonmetastatic breast cancer. Diagnoses occurred between enrollment and the last administrative date (1992/1993 to 2011 in CPS-II and 2006–2013 to 2018 in CPS-3). Median year of diagnosis was 2004 in CPS-II and 2014 in CPS-3. Using the WSI, a deep-learning model was trained to extract features and summarize the morphology of the epithelium, stroma, and tumor-infiltrating lymphocytes within the TME. These features, along with demographic, tumor biomarkers, and survival data, were then used to generate the HiPS, a novel measurement of “ prognostic favorability” of TME, ranging from 0 (favorable) to 10 (unfavorable). Multivariable linear models estimated associations between the HiPS score and epidemiologic risk factors: hormone replacement therapy use (HRT; current vs. former/never), cigarette smoking (current vs. former/never), alcohol intake (>1 drink vs. <1 drink/day), aspirin intake (daily vs. not daily) controlled for, age at diagnosis, body mass index (BMI), race, and cancer detection method (screen- vs. self-detected). Results: We included 1264 CPS-II and 651 CPS-3 participants in the analysis. Compared to CPS-II, CPS-3 participants were younger (mean (± sd) age 54.7 ± 7.6 vs. 72.2 ± 7, p<0.001), heavier (mean (± sd) BMI 27.1 ± 5.8 vs. 26 ± 4.8, p<0.001), and more diverse (7.4% vs. 2.1% non-White, p<0.001). Most breast cancers (69.9% of CPS-II and 64.1% of CPS-3) were screen-detected, p=0.206. Increasing age and BMI were associated with higher HiPS score in both cohorts, Table. Daily aspirin use and current HRT use were associated with lower HiPS scores in CPS-3 only. The inverse association for HRT use was lost in the following subgroups age < 50, ER-, HER2+, TNM stage-1, and screen-detected cancers. Conclusions: Increasing age and BMI have independent adverse effects on breast TME. Daily aspirin intake and current HRT use were only associated with a favorable TME in the younger, more contemporary cohort. Additional studies are needed to confirm these findings and better understand the role of these epidemiologic factors on the TME. [Table: see text]
Trends in mortality caused by neoplasms of the heart in the United States between 2000 and 2019: An observational analysis of disparities by gender and race.
Authors: Shahapurkar Abhishek , Alhariri Housam , Jani Chinmay , Ganatra Sarju
Published: June 2023

10532

Background: Neoplasms of the heart, primary and metastatic, are relatively rare diseases in the US. Metastatic neoplasms are 30 times more common than primary neoplasms and constitute more than 99.3% of the total neoplasms of the heart. Only a few studies have evaluated the mortality trends of this rare disease. Therefore, we aim to analyze the trends of mortality caused by benign and malignant neoplasms of the heart from 2000-2019 and compare them based on gender and race. Methods: We utilized the CDC WONDER database to extract data on Heart Benign Neoplasms (ICD 10 D15.1), Heart Malignant Neoplasms (C38.0), and overlapping lesions of Heart, Mediastinum, and pleura (C38.8) mortality in the United States between 2000 to 2019. ICD codes were applied to multiple causes of death. Age-standardized mortality rates (ASMR) per 1,000,000 with a 95% confidence interval were presented for the total population, stratified by gender and race. We assessed the mortality trends using joinpoint trend analysis. Results: From 2000 to 2019, 3493 deaths were reported due to neoplasms of the heart, out of which 1672 (47.86%) were due to benign neoplasms, and 1821 (52.13%) were due to malignant neoplasms. Overall, total deaths and ASMR decreased from 221 to 139 and 0.82 to 0.35, respectively, with an Average Annual Percentage change (AAPC) of -3.5. Out of 3493, the majority were females (2254, 64.5%). On evaluating ASMR based on gender, it decreased from 0.65 to 0.32 (AAPC -2.6) for males and from 0.89 to 0.35 for females (AAPC -3.9). On dividing based on racial subgroups, 2962 deaths were in whites, 413 were in African Americans (AA), and 118 were from other races (Asian, Pacific Islanders, Native Indians). On further comparison between Whites and AA, ASMR was found to be higher in AA throughout the study period. For AA, ASMR decreased from 1.18 to 0.51 (AAPC -4.9), and for Whites, from 0.76 to 0.33 (AAPC -2.5). Conclusions: This study has shown a decline in overall mortality trends across genders and races. This could be attributed to increased cardiac workups for cardiovascular conditions and advances in imaging modalities, cardiac oncology, and therapeutic interventions. Although the mortality trend in females is decreasing, they still have higher mortality rates than males. At the same time, although AA showed a higher rate of reduction in ASMR, they showed an overall higher ASMR throughout the study period. Further studies are needed to assess if increased screening, early detection, and management plans are causing a decrease in overall mortality in neoplasms of the heart. [Table: see text]
Association between excess body mass index trajectory and change in monoclonal protein level in patients diagnosed with monoclonal gammopathy of undetermined significance.
Authors: Liu Lawrence , Grandhi Nikhil , Wang Mei , Thomas Theodore Seth , Kumar Akhil , Sanfilippo Kristen Marie , Colditz Graham A. , Chang Su-Hsin
Published: June 2023

10538

Background: Obesity is a known risk factor for the development of multiple myeloma (MM) and for progression of its asymptomatic premalignant state, monoclonal gammopathy of undetermined significance (MGUS) to MM. Prior studies have demonstrated that monoclonal protein (M-spike) at MGUS diagnosis as well as high M-spike velocity within a year following MGUS diagnosis predict progression of MGUS to MM, making M-spike a useful, readily available, and less invasive (compared to bone marrow biopsy) marker to assess progression risk. However, no studies have evaluated to what extent exposure to high body mass index (BMI) over time influences M-spike trajectory. Methods: Patients diagnosed with MGUS from 1999-2021 in the Veterans Health Administration were identified. We used a natural language processing-based algorithm to confirm MGUS diagnosis and progression to smoldering MM or MM. MGUS patients without IgM or IgD subtype or Diabetes Mellitus and were black or white were included in the analysis. Other exclusion criteria were progression within 5 years of MGUS diagnosis, patients without M-spike level within a year before or after MGUS diagnosis, and patients without BMI data 3 years or more after MGUS diagnosis. The exposure was the trajectory of excess BMI (defined as BMI > 25 kg/m2), defined by an area under the curve (AUC) of excess BMI during the 5 years following MGUS diagnosis. The outcome was continuous M-spike trajectory post-MGUS diagnosis since a prior study demonstrated that this was a reliable marker for progression risk A multivariable mixed model was used to estimate the association of excess BMI trajectory AUC with M-spike trajectory to control for correlation between M-spike values overtime. The covariates included BMI at MGUS diagnosis, M-spike level ( > = 1.5g/dL) at MGUS diagnosis, age at MGUS diagnosis, sex, race, MGUS heavy chain subtype, and light-chain MGUS. Results: After applying the inclusion and exclusion criteria, the analytic cohort consisted of 6757 MGUS patients. Our multivariable analysis demonstrated a positive association between excess BMI trajectory and increasing M-spike trajectory (β = 0.005, p = 0.007). Conclusions: In patients diagnosed with MGUS, increasing BMI over time following MGUS diagnosis was associated with increasing M-spike level. This further supports the relationship between obesity and weight gain in the pathway of MGUS to MM progression.
County-level food insecurity to predict cancer incidence and mortality in the United States, 2015-2020.
Authors: Chen Krista Y. , Blackford Amanda L. , Hussaini S. M. Qasim
Published: June 2023

10539

Background: Modifiable dietary patterns incorporating inexpensive, calorie-dense, processed foods and meals low in fiber and other nutrients are associated with development of cancer. Inadequate access to quality nutrition is a crucial but underappreciated social determinant of health and predictor of poor cancer outcomes. We investigated the impact of county-level food insecurity on age-adjusted incidence and mortality rates (AAIR, AAMR) for all cancers. Methods: We linked county-level cancer incidence and mortality rates for 2015-2020 from NCI State Cancer Profiles to food insecurity measures from Feeding America and County Business Patterns. Measures included percentage of individuals experiencing food insecurity (as defined by USDA), percentage on Supplemental Nutrition Assistance Program (SNAP) benefits, average cost per meal, and density of fast-food restaurants. AAIR and AAMRs of all cancers per 100,000 individuals were compared between 1st and 4th quartiles for each measure using robust linear regression models with log transformation and population weights. Results: There was an annual average of 1,728,431 cancer diagnoses with AAIR 449 and 599,666 deaths with AAMR 149. Highest AAIRs were observed in >50y (1351), men (488), non-Hispanic Whites (467), and urban counties (459). This differed from highest AAMR groups including >50y (502), men (178), non-Hispanic Blacks (175), and rural counties (168) suggesting factors of increased disease severity or decreased access to care in the latter. Both AAIRs and AAMRs increased significantly when moving from least to most insecure counties, as defined by overall food insecurity, higher proportion of population on SNAP, higher fast-food density, and lower meal cost. AAMRs and AAIRs for lung cancer and CRC, and for rural residents were most exacerbated by changes in all measures of food insecurity, even when adjusting for screening rates for CRC in low access areas. Conclusions: Our study highlights the most food insecure counties have higher cancer incidence and even greater mortality burden. We recognize food insecurity as a proxy for socioeconomic disadvantage prior to and during cancer treatment. These results encourage prioritization of policies that optimize food assistance programs and clinical practices that incorporate food insecurity-related screenings in care delivery models. [Table: see text]
The role of metabolic perturbations in mediating the effects of ambient air pollution on lung cancer in the cancer prevention studies.
Authors: Liang Donghai , Chow Sabrina S. , Sarnat Jeremy A , Diver Ryan , Deubler Emily L , Tang Ziyin , Pope C. Arden , Jerrett Michael , Turner Michele , Wang Ying
Published: June 2023

10541

Background: Exposure to ambient air pollution is an established risk factor for lung cancer. Investigation on the underlying mechanisms of air pollution carcinogenicity remains challenging due to the complex composition of air pollution and a lack of sensitive biomarkers to accurately measure exposure and corresponding response. To address the knowledge gaps, we applied high-resolution metabolomics to identify metabolic signatures of exogenous air pollution exposures and endogenous processes involved in lung carcinogenesis. Methods: A total of 683 matched lung cancer and control pairs within the established Cancer Prevention Study-II (CPS-II) Nutrition and CPS-3 cohorts were included in this study. The plasma metabolome was profiled with ultrahigh-performance liquid chromatography-tandem mass spectrometry. Assessment of exposure to six ambient air pollutants, including carbon monoxide (CO), nitrogen dioxide (NO2), particulate matter (PM10), fine particulate matter (PM2.5), sulfur dioxide (SO2), and ozone (O3), was conducted using spatiotemporally-resolved models based on residential address at blood draw and calculated based on yearly average levels. We conducted metabolome-wide association studies with multiple linear regression models to assess associations of ambient air pollution and lung cancer with a meet-in-the-middle approach. Models controlled for potential confounders and covariates including age at blood draw, sex, race, body mass index, alcohol consumption, smoking status, passive smoke exposure, vegetable and fruit intake, and educational level. Metabolites significant at the FDR < 0.2 level in the air pollution model were analyzed in the lung cancer model. High-dimensional mediation analysis was used as a secondary analysis to compare results from the meet-in-the-middle analysis. Results: Among 1,204 metabolic features extracted from the blood samples, seven features were significantly associated with air pollution exposure and lung cancer incidence at the FDR < 0.2 level in the meet-in-the-middle analysis. Six features were significant at the p < 0.01 level through high-dimensional mediation analysis. All confirmed metabolites are enriched within peptide, lipid, and amino acid pathways. Gamma-glutamylglutamine and gamma-glutamylmethionine were statistically significantly associated with CO, NO2, and PM10 exposure and lung cancer incidence in both analyses. Conclusions: This is the largest prospective metabolomics study examining biological perturbations associated with air pollution exposure and lung cancer incidence. Peptide metabolism may play an important role in mediating the association between air pollution and lung cancer. Findings from this study will lay the foundation for future studies to further understand the biological mechanisms underlying the carcinogenicity of air pollution.
Global burden and economic impact of vaccine-preventable cancer mortality.
Authors: Bencina Goran , Oliver Edward , Meiwald Anne , Hughes Robert , Morais Edith , Schillinger Julia A , Weston Georgie
Published: June 2023

10542

Background: Cancer has a high clinical and economic burden, with ~10 million deaths globally in 2020. In Europe, the total cost of cancer was €199 billion in 2018. Infections are responsible for approximately 13% of cancer cases worldwide. Human papillomavirus (HPV) and hepatitis B (HBV) are among the most important infections associated with cancer for which vaccines are available. However, global vaccination rates for these cancer-causing infections remain low (~12% for HPV; 42% for HBV). Elimination of vaccine-preventable cancers is a public health priority, and the World Health Organization (WHO) has proposed a strategy to eliminate cervical cancer and viral hepatitis by 2030. This analysis aims to estimate the global burden and economic impact due to vaccine-preventable cancer mortality. Methods: The number of deaths and Years of Life Lost (YLL) in 2019 from liver cancer caused by hepatitis B (ICD-10 C22), head and neck cancers (ICD-10 C00-14 and C32), and cancer of the cervix uteri (ICD-10 C53) were sourced from the Institute for Health Metrics Evaluation (IHME) Global Burden of Disease. Deaths and YLL were applied to attributable fractions for each vaccine-preventable cancer based on published data. The Value of YLL (VYLL) was estimated by multiplying the GDP per capita (World Bank; in USD) and YLL for each cancer, in each WHO region. Sensitivity and scenario analyses were performed to test the robustness of results. Results: In 2019, there were 479,750 potentially vaccine-preventable cancer deaths and 14,561,049 YLL (38% in males) across WHO regions (Table). The estimated economic impact due to vaccine-preventable cancer deaths was over $171 billion globally with the Americas and European region accounting for 63% of the total cost ($107 billion). Cervical cancer had the highest mortality burden (52% of total deaths). Globally, 78% of non-cervical HPV-related cancer deaths were in males. Conclusions: In 2019, 1,314 people died per day due to vaccine-preventable cancers leading to substantial YLL and economic impact. The overall burden is likely to be higher since several other HPV-related cancers were not included in this analysis. Improved implementation of HPV and HBV vaccination programs should be prioritized to decrease this burden.[Table: see text]