Stage Breast Research Articles

The concordance between ultrasonographic stage of breast and Tanner stage of breast for overweight and obese girls: a school population-based study

In this study, we evaluated the concordance between the ultrasonographic stage of breast (US B) and Tanner stage of breast (TS B) for overweight and obese girls based on a school population study. We conducted multistage, stratified cluster, and random-proportional sampling and ultimately included 221 girls (aged 6-10 years). This study revealed that the concordance was poor (accuracy=0.19 (95% confidence interval: 0.14, 0.25)) between US B and TS B among the 221 participants. When our subjects were stratified by weight, we observed a weak association between US B and TS B in the thin/normal weight group (r=0.34, p=0.001) but not in the overweight (r=0.097, p=0.38) or obese groups (r=-0.19, p=0.206), and as the body mass index (BMI) z-score increased, the overestimation ratio of TS B increased. US B manifested a positive correlation with breast bud diameter (BD) (r=0.885, p<0.001), follicle-stimulating hormone (r=0.235, p=0.009), and luteinizing hormone (r=0.192, p=0.037), but this was not the case with TS B. As the BMI z-score increased, the correlation between the two methods declined, and the overestimation ratio of TS B increased. US B is an objective and quantitative method used to evaluate breast development, and whether BD might replace US B as a routine diagnostic method to evaluate breast development in clinical practice needs to be confirmed in larger-sample studies.

Privacy preserving distributed learning classifiers - Sequential learning with small sets of data.

Artificial intelligence (AI) typically requires a significant amount of high-quality data to build reliable models, where gathering enough data within a single institution can be particularly challenging. In this study we investigated the impact of using sequential learning to exploit very small, siloed sets of clinical and imaging data to train AI models. Furthermore, we evaluated the capacity of such models to achieve equivalent performance when compared to models trained with the same data over a single centralized database. We propose a privacy preserving distributed learning framework, learning sequentially from each dataset. The framework is applied to three machine learning algorithms: Logistic Regression, Support Vector Machines (SVM), and Perceptron. The models were evaluated using four open-source datasets (Breast cancer, Indian liver, NSCLC-Radiomics dataset, and Stage III NSCLC). The proposed framework ensured a comparable predictive performance against a centralized learning approach. Pairwise DeLong tests showed no significant difference between the compared pairs for each dataset. Distributed learning contributes to preserve medical data privacy. We foresee this technology will increase the number of collaborative opportunities to develop robust AI, becoming the default solution in scenarios where collecting enough data from a single reliable source is logistically impossible. Distributed sequential learning provides privacy persevering means for institutions with small but clinically valuable datasets to collaboratively train predictive AI while preserving the privacy of their patients. Such models perform similarly to models that are built on a larger central dataset.

Estimation of Annual Secondary Lung Cancer Deaths Using Various Adjuvant Breast Radiotherapy Techniques for Early-Stage Cancers.

PurposeSecondary lung cancer (SLC) can offset the benefit of adjuvant breast radiotherapy (RT), and risks compound sharply after 25 to 30 years. We hypothesized that SLC risk is mainly an issue for early-stage breast cancer, and that lives could be saved using different RT techniques.Patients and MethodsThe SEER database was used to extract breast patient age, stage survival, and radiotherapy utilization over time and per stage and to assess the factors associated with increased SLC risk with a multivariable competing risk Cox model. The number of SLC was calculated using the BEIR model modified with patient survival, age, and use of RT from the SEER database. Stage distribution and number of new breast cancer cases were obtained from the NAACCR. Mean lung dose for various irradiation techniques was obtained from measurement or literature.ResultsOut of the 765,697 non-metastatic breast cancers in the SEER database from 1988 to 2012, 49.8% received RT. RT significantly increased the SLC risk for longer follow-up (HR=1.58), early stage including DCIS, stage I and IIA (HR = 1.11), and younger age (HR=1.061) (all p<0.001). More advanced stages did not have significantly increased risk. In 2019, 104,743 early-stage breast patients received radiotherapy, and an estimated 3,413 will develop SLC (3.25%) leading to an excess of 2,900 deaths (2.77%). VMAT would reduce this mortality by 9.9%, hypofractionation 26 Gy in five fractions by 38.8%, a prone technique by 70.3%, 3D-CRT APBI by 43.3%, HDR brachytherapy by 71.1%, LDR by 80.7%, and robotic 4π APBI by 85.2%.ConclusionsSLC after breast RT remains a clinically significant issue for early-stage breast cancers. This mortality could be significantly reduced using a prone technique or APBI.

Performance Analysis of Data Mining Techniques for the Prediction Breast Cancer Risk on Big Data

Introduction: Early detection breast cancer Causes it most curable cancer in among other types of cancer, early detection and accurate examination for breast cancer ensures an extended survival rate of the patients. Risk factors are an important parameter in breast cancer has an important effect on breast cancer. Data mining techniques have a growing reputation in the medical field because of high predictive capability and useful classification. These methods can help practitioners to develop tools that allow detecting the early stages of breast cancer.Material and Methods: The database used in this paper is provided by Motamed Cancer Institute, ACECR Tehran, Iran. It contains of 7834 records of breast cancer patients clinical and risk factors data. There were 4008 patients (52.4%) with breast cancers (malignant) and the remaining 3617 patients (47.6%) without breast cancers (benign). Support vector machine, multi-layer perceptron, decision tree, K nearest neighbor, random forest, naïve Bayesian models were developed using 20 fields (risk factor) of the database because database feature was restrictions. Used 10-fold crossover for models evaluate. Ultimately, the comparison of the models was made based on sensitivity, specificity and accuracy indicators.Results: Naïve Bayesian and artificial neural network are better models for the prediction of breast cancer risks. Naïve Bayesian had accuracy of 93%, specificity of 93.32%, sensitivity of 95056%, ROC of 0.95 and artificial neural network had accuracy of 93.23%, specificity of 91.98%, sensitivity of 92.69%, and ROC of 0.8.Conclusion: Strangely the different artificial intelligent calculations utilized in this examination yielded close precision subsequently these techniques could be utilized as option prescient instruments in the bosom malignancy risk considers. The significant prognostic components affecting risk pace of bosom disease distinguished in this investigation, which were approved by risk, are helpful and could be converted into choice help devices in the clinical area.

Psychological and Aesthetic Outcomes in Breast Cancer Patients.

Background:Patients who undergo breast cancer treatment require psychosocial and aesthetic rehabilitation. Advantages of breast reconstruction in-patient rehabilitation are well known. Oncoplastic organ-preserving surgery offers aesthetically better results, yet is often considered less safe than more radical procedures. We compared the aesthetic and psychological outcomes in patients undergoing breast reconstruction and oncoplastic breast cancer treatment.Methods:In total, 1130 patients who received either breast reconstruction or oncoplastic breast cancer surgery were included in the study. Patients were classified into two groups. Group 1 included 510 patients who received breast reconstruction surgery. Group 2 included 620 patients who received oncoplastic surgery. The following aspects were compared between the two groups: demographics, tumor progression, and immunohistochemical aspects, complications, hospitalization stay, and psychological and aesthetic outcomes.Results:Patients in the oncoplastic group showed statistically significant higher psychosocial and aesthetic outcomes, as well as lower incidence of complications, revision rate, disease progression, and recurrence. The majority of oncoplastic patients were treated in early stages of breast cancer.Conclusion:Offering superior treatment results, oncoplastic organ-preserving surgery should be favored in patients with earlier stages of cancer progression.

Association between pubertal development and elevated blood pressure in children.

Blood pressure (BP) increased with age and height development, but little was known about the effect of pubertal development on blood pressure in children. A cross‐sectional study was performed among 4146 children aged 7–12 years old in China. Pubertal development was assessed based on breast stages and testicular volume. The associations of pubertal development with BP levels and the rate of elevated blood pressure (EBP) were quantified using multiple linear and logistic regressions. We found that pubertal developmental level was positively correlated with BP, and children who experienced puberty onset and early pubertal timing had higher BP levels and prevalence of EBP. After adjusting for covariates, children experienced puberty onset had 3.84 and 2.24 mmHg increase in systolic blood pressure and diastolic blood pressure, and 70%, 53%, and 62% increased odds of EBP, ESBP, and EDBP, respectively, compared with those without puberty onset. Similar results were observed for children who had early pubertal timing. The change of BP in puberty is greater and the association between pubertal development and BP is stronger in girls than boys. These findings suggested that pubertal development could be an important independent factor and one critical period for the EBP progress. Monitoring and management of pubertal development are necessary particularly among girls.

Effects of deprivation and age on staging of breast, colon, rectum and prostate cancer in Umbria region, Italy: a multilevel approach.

Early diagnosis of breast, colon, rectum and prostate cancers improves health outcomes. Low socioeconomic status (SES) is related to advanced stages at diagnosis; inequalities could explain differences in outcomes by age. The influence of SES, age and residence area on staging was explored in the Umbrian population. 2001-2010 cases were geo-coded by census tract of residence. Stage distribution or Gleason score were analyzed by multilevel multinomial logistic regression with age and SES as the fixed effects and census tract as the random-effect. For breast and colorectal cancers, the screening age class was advantaged. For breast, age effect was modulated by deprivation and census tract. In the elderly, the richest were advantaged, the poorest disadvantaged; issues emerged for the young. For colon, age effect is modulated by census tract in early stages and deprivation in late stages. The elderly were disadvantaged; the young and the deprived had more stages IV. About rectum, age effect was modulated by deprivation in the late stages. The elderly were disadvantaged; the young and the deprived presented more stages IV. For prostate, age effect was modulated by deprivation and census tract. The intermediate age class was advantaged, the elderly disadvantaged. Age was not always the determinant of a delayed staging when SES was considered. For breast and colorectal cancers, issues of delayed diagnosis emerged in the young. If the care center was near the residence, the census tract modified the stage at diagnosis. These results are useful to reduce SES barriers by specific programs adapted to the age of the patient and area of residence.

Bilateral femoral head osteonecrosis in a patient with metastatic breast cancer receiving long‑term zoledronic acid treatment: A case report

Bone-modifying agents (BMAs), including bisphosphonate and anti-receptor activator of NF-κB ligand (RANKL) antibodies, are effective in treating bone metastases. The present study is a case report on the efficacy and side effects of long-term treatment with zoledronic acid, a BMA, in a 57-year-old woman. The patient was diagnosed with concurrent stage IV triple-negative breast cancer and stage II colon cancer. The patient experienced complete remission of both these cancers following chemotherapy, zoledronic acid treatment and irradiation for breast cancer and surgery for colon cancer. The patient received long-term zoledronic acid treatment and has survived >7 years after her initial diagnosis. The patient subsequently reported bilateral hip pain that was diagnosed as osteonecrosis of the femoral head, after the presence of bone metastases was ruled out using magnetic resonance imaging. The patient underwent bilateral artificial hip joint replacements. After orthopedic surgery, the multiple distant metastases, including a brain metastasis, remained in complete remission. It is well established that BMAs, such as zoledronic acid, increase the risk of osteonecrosis of the jaw, but it is not well understood if they can increase this risk in other anatomical locations. The findings of the present case study suggested that while long-term use of BMAs may be effective in managing bone metastases, it may increase the risk of osteonecrosis in anatomical locations other than the jaw.

Cancer Aging Research Group (CARG) score in older adults undergoing curative intent chemotherapy: a prospective cohort study

ImportanceThe Cancer Aging Research Group (CARG) toxicity score is used to assess toxicity risk in geriatric patients receiving chemotherapy.ObjectiveThe primary aim was to validate the CARG score in geriatric patients...

Randomized double-blind, placebo-controlled study of topical diclofenac in prevention of hand-foot syndrome in patients receiving capecitabine.

TPS12135 Background: The pathophysiology of capecitabine induced hand-foot syndrome (HFS) includes activation of cyclooxygenase (COX)-2, leading to an upregulation of the inflammatory cascade. Prophylaxis with oral celecoxib was previously reported to be associated with a significantly lower frequency of HFS (grade 1 [29.0% vs. 72.0%, p &lt; 0.001] and grade 2 [11.8% vs. 30.0%, p=0.024]) (1). The findings were confirmed in a phase III trial (2). However, the associated systemic adverse events limit routine prophylactic use. Till date, no clinical trials have assessed the role of topical non-steroidal anti-inflammatory drugs (NSAIDs) in preventing HFS. Methods: In this investigator-initiated randomised phase III double-blind, placebo controlled, parallel group trial, a total of 264 patients with any stage breast or gastrointestinal cancer planned to receive capecitabine as a single agent or in combination with other chemotherapy will be randomised (1:1) to 1% topical diclofenac or placebo (base for 1% topical diclofenac) arm at a single tertiary care cancer centre in India. Randomization will be done by stratified (male vs female, and capecitabine mono therapy vs combination) permuted block method using a computer generated random sequence and allocation concealment will be done by using sealed opaque envelopes. In both the arms, patients will be asked to apply 1 fingertip unit (FTU) of topical medication on both surfaces of bilateral hands twice daily for a total duration of 12 weeks or till development of grade 2 or higher HFS, whichever is earlier. The primary objective is to compare the effect of topical diclofenac with placebo in preventing clinically significant HFS (incidence of the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 grade 2 or higher HFS). The secondary objectives include comparison of topical diclofenac with placebo on (i) incidence of NCI CTCv5.0 all grade HFS, (ii) time to develop grade ≥2 HFS from start of capecitabine, (iii) patient-reported outcomes using HFS-14 questionnaire (iv) adherence with topical application using self-reported adherence diary, (v) capecitabine dose reductions, delays and cessation due to HFS and (vi) safety profile (NCICTCv5.0). The tertiary correlative endpoint is to correlate the occurrence and severity of HFS with serum COX-2 levels and polymorphism of dihydropyrimidine dehydrogenase (DPPD) enzyme. The trial is registered at the Clinical Trial Registry of India (CTRI/2021/01/030592). Till date, we have enrolled 12/264 patients. (1) Zhang RX et al. J Cancer Res Clin Oncol. 2011;137(6):953-957. (2) Zhang RX et al. Annals of oncology. 2012;23(5):1348-1353. Clinical trial information: CTRI/2021/01/030592.

Investigating survivin as a novel target in black women with breast cancer.

594 Background: Black women with breast cancer have higher mortality than White women. Differences in tumor biology contribute to racial disparities in breast cancer outcomes. BIRC5 gene encodes survivin, an inhibitor of apoptosis protein, and an independent marker of poor prognosis in breast cancer. Cancer patients have anti-survivin antibodies and circulating survivin-specific T cells, suggesting that survivin may be targetable. Several ongoing antibody-mediated, vaccine strategies that target survivin are being developed. Nevertheless, most survivin studies were conducted in cohorts of White women. To date, the prevalence and/or role of survivin expression in breast tumors from Black women has not been studied. Methods: Associations between BIRC5 expression, clinicopathological and molecular features were measured in the population-based Carolina Breast Cancer Study (CBCS) and The Cancer Genome Atlas (TCGA) breast cancer cohort. Gene expression was measured by Nanostring RNA counting and split into BIRC5 high (4th quartile) and low categories based on log2 gene expression values. Relative frequency differences (RFD) for the association between BIRC5 high and clinicopathologic features were estimated. RNA based p53 mutant status and homologous recombination deficiency (HRD) status were included in RFD analysis. Receiver operating characteristic (ROC) curves were used to illustrate the potential of BIRC5 expression to distinguish patients who achieved pathological complete response (pCR) after receiving neoadjuvant chemotherapy in CBCS (133 Black, 49 non-Black). Results: BIRC5 gene expression was significantly increased in tumors from 966 Black patients compared to 1,497 non-Black (p &lt; 0.00001), adjusting for stage and subtype. BIRC5 high tumors were significantly more expressed in higher stage and basal-like breast cancer subtypes. BIRC5 high tumors were also significantly enriched for expression of genes involved in p53 loss and HRD. Furthermore, in an analysis of 182 CBCS patients, BIRC5 gene expression alone predicted pCR with similar overall AUC to ROR-PT multigene signatures (AUC 0.62 vs 0.64). Conclusions: Our study shows that survivin expression is particularly high in breast tumors from Black women. This was associated with more aggressive clinicopathological features in addition to p53 mutant and HRD status. Black women with breast cancer represent an area of unmet clinical need and could potentially benefit from anti-survivin targetable treatment strategies. Further studies are needed to help close this gap which constitutes the largest disparity among cancer-specific diseases.[Table: see text]

Urinary and salivary endocrine measurements to complement Tanner staging in studies of pubertal development.

BackgroundMany studies investigating pubertal development use Tanner staging to assess maturation. Endocrine markers in urine and saliva may provide an objective, sensitive, and non-invasive method for assessing development.ObjectiveOur objective was to examine whether changes in endocrine levels can indicate the onset of pubertal development prior to changes in self-rated Tanner stage.MethodsThirty-five girls and 42 boys aged 7 to 15 years were enrolled in the Growth and Puberty (GAP) study, a longitudinal pilot study conducted from 2007–2009 involving children of women enrolled in the Agricultural Health Study (AHS) in Iowa. We collected saliva and urine samples and assessed pubertal development by self-rated Tanner staging (pubic hair, breast development (girls), genital development (boys)) at three visits over six months. We measured dehydroepiandrosterone (DHEA) in saliva and creatinine-adjusted luteinizing hormone (LH), testosterone, follicle stimulating hormone (FSH), estrone 3-glucuronide (E13G) and pregnanediol 3-glucuronide (Pd3G) concentrations in first morning urine. We evaluated the relationships over time between Tanner stage and each biomarker using repeated measures analysis.ResultsAmong girls still reporting Tanner breast stage 1 at the final visit, FSH levels increased over the 6-month follow-up period and were no longer lower than higher stage girls at the end of follow-up. We observed a similar pattern for testosterone in boys. By visit 3, boys still reporting Tanner genital stage 1 or pubic hair stage 1 had attained DHEA levels that were comparable to those among boys reporting Tanner stages 2 or 3.ConclusionsIncreasing concentrations of FSH in girls and DHEA and testosterone in boys over a 6-month period revealed the start of the pubertal process prior to changes in self-rated Tanner stage. Repeated, non-invasive endocrine measures may complement the more subjective assessment of physical markers in studies determining pubertal onset.

Solid-state nanopore analysis of human genomic DNA shows unaltered global 5-hydroxymethylcytosine content associated with early-stage breast cancer

5-Hydroxymethylcytosine (5hmC), the first oxidized form of the well-known epigenetic modification 5-methylcytosine, is an independent regulator of gene expression and therefore a potential marker for disease. Here, we report on methods developed for a selective solid-state nanopore assay that enable direct analysis of global 5hmC content in human tissue. We first describe protocols for preparing genomic DNA derived from both healthy breast tissue and stage 1 breast tumor tissue and then use our approach to probe the net abundance of the modified base in each cohort. Then, we employ empirical data to adjust for the impact of nanopore diameter on the quantification. Correcting for variations in nanopore diameter among the devices used for analysis reveals no detectable difference in global 5hmC content between healthy and tumor tissue. These results suggest that 5hmC changes may not be associated with early-stage breast cancer and instead are a downstream consequence of the disease.

Impact of the COVID-19 pandemic on diagnosis, stage, and initial treatment of breast cancer in the Netherlands: a population-based study

BackgroundThe onset of the COVID-19 pandemic forced the Dutch national screening program to a halt and increased the burden on health care services, necessitating the introduction of specific breast cancer treatment recommendations from week 12 of 2020. We aimed to investigate the impact of COVID-19 on the diagnosis, stage and initial treatment of breast cancer.MethodsWomen included in the Netherlands Cancer Registry and diagnosed during four periods in weeks 2–17 of 2020 were compared with reference data from 2018/2019 (averaged). Weekly incidence was calculated by age group and tumor stage. The number of women receiving initial treatment within 3 months of diagnosis was calculated by period, initial treatment, age, and stage. Initial treatment, stratified by tumor behavior (ductal carcinoma in situ [DCIS] or invasive), was analyzed by logistic regression and adjusted for age, socioeconomic status, stage, subtype, and region. Factors influencing time to treatment were analyzed by Cox regression.ResultsIncidence declined across all age groups and tumor stages (except stage IV) from 2018/2019 to 2020, particularly for DCIS and stage I disease (p < 0.05). DCIS was less likely to be treated within 3 months (odds ratio [OR]wks2–8: 2.04, ORwks9–11: 2.18). Invasive tumors were less likely to be treated initially by mastectomy with immediate reconstruction (ORwks12–13: 0.52) or by breast conserving surgery (ORwks14–17: 0.75). Chemotherapy was less likely for tumors diagnosed in the beginning of the study period (ORwks9–11: 0.59, ORwks12–13: 0.66), but more likely for those diagnosed at the end (ORwks14–17: 1.31). Primary hormonal treatment was more common (ORwks2–8: 1.23, ORwks9–11: 1.92, ORwks12–13: 3.01). Only women diagnosed in weeks 2–8 of 2020 experienced treatment delays.ConclusionThe incidence of breast cancer fell in early 2020, and treatment approaches adapted rapidly. Clarification is needed on how this has affected stage migration and outcomes.

Genetic Association Analysis Implicates Six MicroRNA-Related SNPs With Increased Risk of Breast Cancer in Australian Caucasian Women

IntroductionBreast cancer (BC), a heterogeneous disease, features microRNA-related single nucleotide polymorphisms (miRSNPs) as underlying factors of BC development, thus providing targets for novel diagnostic and therapeutic strategies. This study investigated miRSNPs in BC susceptibility in Australian Caucasian women. Patients and MethodsThe study population included patients 33 to 80 years of age stratified by molecular subtypes of breast tumors (luminal A, 47.59%), stage (stage I, 36.96%), tumor-type (ductal, 44.95%), grading (intermediate, 35.52%), size (10.1-25 mm, 31.14%), and lymph node (sentinel negative, 38.93%). Sixty-five miRSNPs underwent allelic analysis in two independent case–control cohorts (GU-CCQ-BB, 377 cases and 521 controls; GRC-BC, 267 cases and 201 controls) using a MassARRAY platform. GU-CCQ-BB, GRC-BC, and the combined populations (BC-CA) (644 cases and 722 controls) underwent independent statistical analysis. ResultsIn the GU-CCQ-BB population, miRSNPs TET2-rs7670522, ESR1-rs2046210, FGFR2-rs1219648, MIR210-rs1062099, HIF1A-rs2057482, and CASC16-rs4784227 were found to be associated with increased BC risk (P ≤ .05). Only ESR1-rs2046210 was also significantly associated (P ≤ .05) when replicated in the GRC-BC and BC-CA populations. No significant association was correlated with BC-clinical features (pathological types and ER/PR/HER2 status); however, MIR210-rs1062099 was found to be significantly associated (P ≤ .05) with age (>50 years) in the GU-CCQ-BB cohort. ConclusionThis is the first study to demonstrate the association of MIR210-rs1062099 and TET2-rs7670522 with increased BC risk. Additionally, four previously reported SNPs (ESR1-rs2046210, FGFR2-rs1219648, HIF1A-rs2057482, and CASC16-rs4784227) were confirmed as BC risk variants. Replication and functional studies in larger Caucasian cohorts are necessary to elucidate the role of these miRSNPS in the development of BC.

Characterization of Cell Free Plasma Methyl-DNA From Xenografted Tumors to Guide the Selection of Diagnostic Markers for Early-Stage Cancers

Circulating cell-free methyl-DNA (mcfDNA) contains promising cancer markers but its low abundance and possibly diverse origin pose challenges toward the accurate diagnosis of early stage cancers. By whole-genome bisulfite sequencing (WGBS) of cell-free DNA (cfDNA) from about 0.5 mL plasma of mice xenografted with human tumors, we obtained and aligned the reads to the human genome, filtered out the mouse and carrier bacterial sequences, and confirmed the tumor origin of methyl-cfDNA (mctDNA) by methylation-sensitive restriction enzyme digestion prior to species-specific PCR. We estimated that human tumor-specific reads (ctDNA) or mctDNA comprised about 0.29 or 0.01%, respectively of the xenograft mouse cfDNA, and about 0.029 or 0.001% of the cfDNA of human early stage cancer patients. Similar WGBS of early stage (0-II, node- and metastasis-free) breast, lung or colorectal cancer samples identified hundreds of specific DMRs (differentially methylated regions) compared to healthy controls. Their association with tumourigenesis was supported by stage-dependent methylation, tumor suppressor or oncogene clusters, and genes also identified in the xenograft samples. Using 20 three-cancer-common and 17 colorectal cancer-specific DMRs in combination (top 0.0018% of the WGBS methylation clusters) was sufficient to distinguish the stage I colorectal cancers from breast and lung cancers and healthy controls. Our data thus confirmed the tumor origin of mctDNA by sequence specificity, and provide a selection threshold for authentic tumor mctDNA markers toward precise diagnosis of early stage cancers solely by top DMRs in combination.

Abstract IA024: Tumor exosome and exomere biomarkers for early cancer detection

Abstract In 1889, Stephen Paget first proposed that organ distribution of metastases is a non-random event, yet metastatic organotropism remains one of the greatest mysteries in cancer biology. A growing number of studies demonstrate that tumor-derived microvesicles, referred to as exosomes, may alter the tumor microenvironment at future sites of metastasis promoting pre-metastatic niche formation, and thus creating a favorable “soil” for incoming metastatic “seeds.” However, by what mechanism, and whether their role is significant in tumor progression remains unknown. We have recently demonstrated that exosomes released by lung-, liver- and brain-tropic tumor cells preferentially fuse with resident cells at their future metastatic sites, such as fibroblasts and epithelial cells in the lung, Kupffer cells in the liver, and endothelial cells in the brain. We found that tumor-derived exosome homing to organ-specific cell types prepares the pre-metastatic niche. Moreover, treatment with exosomes derived from lung-tropic models can redirect to the lung the metastatic distribution of cells that normally lack the capacity to form lung metastasis. Proteomic profiling of exosomes revealed distinct integrin expression patterns associated with each organ-specific metastatic site. Whereas exosomal α6β4 integrins were associated with lung metastasis, exosomal integrin αvβ5 was linked to liver metastasis and αvβ3 to brain metastasis. Targeting α6β4 and αvβ5 integrins decreased exosome uptake and metastasis in the lung and liver, respectively. Moreover, our clinical data indicate that integrin expression profiles in circulating plasma exosomes from cancer patients could be used to predict organ-specific metastasis. To gain a more comprehensive understanding of the relationship between exosomal protein cargo and tumor progression, we have built one of the largest exosome proteomics databases, including human and murine normal, pre-cancer and cancer exosomes from a variety sources, from cell lines to plasma and other bodily fluids. This dataset has allowed us to extend the list of markers that can be used to identify and isolate exosomes from human samples. When comparing the protein cargo of blood plasma exosomes isolated from normal subjects versus cancer patients with early stage pancreatic, colorectal, breast and lung cancer, we were able to define a cancer-specific proteomic signature that distinguishes cancer exosomes. Using paired samples from tumor tissue and plasma of the same cancer patients with breast, lung or pancreatic cancer, we were able to derive cancer type-specific exosomal signatures, which can be used as biomarkers to identify and classify tumors of unknown origin. Therefore, proteomic profiling of exosomes has great clinical potential as a non-invasive, rapid liquid biopsy that could aid in tumor detection classification. Citation Format: Ayuko Hoshino, Han Sang Kim, Linda Bojmar, Kofi Ennu Gyan, Haiying Zhang, Irina Matei, David Lyden. Tumor exosome and exomere biomarkers for early cancer detection [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr IA024.

Premalignant pancreatic cells seed stealth metastasis in distant organs in mice.

Recent findings suggest that the dissemination of tumor cells occurs at the early stage of breast and pancreatic carcinogenesis, which is known as early dissemination. The evidence of early dissemination has been demonstrated predominantly in the bloodstream and bone marrow; however, limited evidence has revealed the existence and behavior of disseminated cells in distant organs. Here, we show that premalignant pancreatic cells seed distant stealth metastasis that eventually develops into manifest metastasis. By analyzing lineage-labeled pancreatic cancer mouse models (KPCT/TFF1KO; Pdx1-Cre/LSL-KRASG12D/LSL-p53R172H/LSL-tdTomato/TFF1KO), we found that premalignant pancreatic cells, rather than mature malignant cells, were prone to enter the bloodstream and reside in the bone marrow, liver, and lung. While these metastatic cells exhibited the characteristics of the cells of host organs and did not behave as malignant cells, they underwent malignant transformation and formed distinct tumors. Surprisingly, the manifestation of distant metastasis occurred even before tumor development in the primary site. Our data revealed that disseminated premalignant cells reside stealthily in distant organs and evolve in parallel with the progression of the primary tumor. These observations suggest that we must rebuild a therapeutic strategy for metastatic pancreatic cancer.

Abstract SS1-08: Did Medicaid expansion under the Affordable Care Act narrow the gap between American Indians and Whites on breast cancer management and prognosis?

Abstract Prior studies have shown that over a span of 20 years (1990-2009), breast cancer death rates in the U.S. have not significantly declined for American Indians (AIs) in comparison to the White population. Health insurance coverage contributes independently and positively to the health of individuals through the receipt of adequate preventive services and care for diseases such as breast cancer. To this end, the 2010 Medicaid Expansion as part of the Affordable Care Act (ACA) has extended the health insurance coverage eligibility to adults with incomes up to 133 percent of the federal poverty level. In this study, we examined whether Medicaid expansion resulted in the improvement of breast cancer management and prognosis for AIs relative to the White population. Methods: We abstracted information from the National Cancer Data Base (NCDB) for AI and White breast cancer patients diagnosed between the years 2004-2016 who lived in states that expanded Medicaid in January 2014, and those that did not expand Medicaid. Data on age, race, stage at diagnosis, insurance status, definitive treatment initiation within 30 days of diagnosis, and 3-year mortality was analyzed. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using multiple logistic regression to determine the impact of race (White vs. AI), Medicaid expansion status, and pre- vs. post-expansion periods on breast cancer management and prognosis. All p-values are two-sided. Analyses were performed using SPSS software V25. Results: There were 1,465,103 newly diagnosed White and AI breast cancers between the years 2004-2016; 99.7% were Whites and 0.3% were AIs. Of these, 46.9% resided in states that expanded Medicaid in January 2014 and 53.1% in states that did not expand Medicaid; 73.8% were diagnosed in the pre-expansion period (January 2004-December 2013) and 26.2% were diagnosed in the post-expansion period (January 2014-December 2016). There was an increase in the proportion of early stage (0, 1) breast cancer diagnosis in the period 2014-2016 as compared to the period 2004-2013 (OR=1.434, 95% CI:1.159- 1.775; p = 0.001), and this increase was significantly greater for AIs than for Whites (6% vs 3%; p=0.027) in both expansion and non-expansion states. An independent chi-square analysis of AIs found that there was a significant increase of the early stage diagnosis in the expansion states during the post-expansion period (p=0.001). The proportion of uninsured declined in the period 2014-2016 as compared to the period prior (OR=0.331, 95% CI: 0.129- 0.850; p=0.022), more so in the expansion states (decrease from 1.4% to 0.8%), vs. non expansion states (decrease from 2.3% to 2.2%) (p=0.019); no difference in decline was found between Whites and AIs. The probability of getting first definitive treatment within 30 days of diagnosis declined more in states without Medicaid expansion (decrease from 54% to 43%) than in states with Medicaid expansion (decrease from 50% to 43%) (p=0.028) for both AIs and Whites; and the decline was more in Whites (decrease from 55% to 44%) than in AIs (decrease from 49% to 42%) from pre-expansion period to post-expansion period (p=0.018). The 3-year mortality rates did not show any significant relationship to race, expansion status, or the pre- or post-expansion periods. Conclusion: In patients newly diagnosed with breast cancer, the proportion of uninsured declined significantly with Medicaid expansion and the proportion of patients who received first definitive treatment within 30 days of diagnosis decreased significantly less in AIs and in states that expanded Medicaid under the Affordable Care Act. Medicaid expansion increased early breast cancer diagnosis in AIs; this effect was not seen in non-expansion states. Medicaid expansion did not affect 3-year mortality rate. Citation Format: Anu G Gaba, Li Cao, Rebecca Renfrew, Kristi A Egland, DeAnn L Witte, Janet Wernisch, Ross Crosby. Did Medicaid expansion under the Affordable Care Act narrow the gap between American Indians and Whites on breast cancer management and prognosis? [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr SS1-08.

Abstract PS9-54: Healthcare costs for metastatic breast cancer patients treated with human epidermal growth factor receptor 2 targeted agents

Abstract Background: Human Epidermal Growth Factor Receptor 2 positive (HER2+) breast cancer (BC) represents approximately 15% of early stage BC cases and is associated with a more aggressive clinical phenotype and poor prognosis with respect to most BC. Over the last decade new HER2-targeted therapies have become available that have prolonged survival for both early stage and metastatic breast cancer (mBC). However, the cost impact of these therapies has not been fully assessed in recent years. Given the evidence for major clinical benefit, it is imperative that health systems evaluate new treatments to maximize the value of health care expenditures. This study evaluated healthcare costs among mBC patients treated with HER2-targeted therapy. Methods: A retrospective cohort study using the IQVIA Real-World Data Adjudicated Claims Database (1/1/2015-7/31/2019) was conducted. Adult (≥18-years) female patients who initiated HER2-targeted therapy with evidence of mBC diagnosis in the prior year were identified. The study index date was the initiation date of the HER2-targeted agent after which, patients were required to have ≥12 months of follow-up. Annual all-cause and BC-related healthcare costs per patient (2019 USD) were computed using payer-paid amounts in the first and second year following the index date. BC-related costs were defined as costs for claims with a primary diagnosis for BC (ICD-9-CM: 174.% or ICD-10-CM: C50.%) or BC-related treatment (surgery – mastectomy or lumpectomy, HER2-targeted therapy, chemotherapy, hormone therapy, immunotherapy, and radiation). Results: 708 mBC patients treated with HER2-targeted therapy were included with a mean age (SD) of 53.2 (10.2) years and mean follow-up of about 2 years. During the follow-up period, trastuzumab (96.5%) and pertuzumab (81.2%) were the most common HER2-targeted therapies used followed by ado-trastuzumab (15.4%), neratinib (6.3%), and lapatinib (5.3%). Additionally, patients received other treatments including chemotherapy (88.0%), hormone therapy (56.6%), and radiation therapy (57.6%). Of note, 40.3% of patients underwent surgery (mastectomy or lumpectomy) following evidence of metastasis. Following initiation of HER2-targeted therapy, mean annual costs per patient in Year 1 and Year 2 were $330,784 and $196,139, respectively. Correspondingly, BC-related costs in Year 1 and Year 2 were $255,273 and $144,978, respectively. HER2-targeted therapies accounted for 72% of BC-related costs in both Year 1 and 2. Surgery patients incurred $37,822 higher BC-related costs in Year 1 compared to non-surgery patients. However, in Year 2, the opposite was noted with non-surgery patients having $70,885 higher BC-related costs, mainly due to a differences in BC treatment rates in Year 2 for HER2 targeted drugs, other BC drugs and radiation. Conclusion: Total BC-related costs of mBC patients treated with HER2-targeted therapy is highest in the first year following treatment initiation, with the main cost driver being the cost of HER2-targeted therapy. While total costs decreased in the subsequent year, the cost of HER2 targeted therapy remained the dominant component. Results of this study highlight the significant economic burden of treating HER2+ mBC and also the need for therapies that limit disease progression. Page 1 of 1 Citation Format: Reshma Mahtani, Deepa Lalla, Nina Oestreicher, Augustina Ogbonnaya, Vishal Saundankar, Joanne Willey, Anna Coutinho, Kelly McCann. Healthcare costs for metastatic breast cancer patients treated with human epidermal growth factor receptor 2 targeted agents [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS9-54.