Browsing by Subject "Breast Neoplasms"
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Item Open Access A network of substrates of the E3 ubiquitin ligases MDM2 and HUWE1 control apoptosis independently of p53.(Sci Signal, 2013-05-07) Kurokawa, Manabu; Kim, Jiyeon; Geradts, Joseph; Matsuura, Kenkyo; Liu, Liu; Ran, Xu; Xia, Wenle; Ribar, Thomas J; Henao, Ricardo; Dewhirst, Mark W; Kim, Wun-Jae; Lucas, Joseph E; Wang, Shaomeng; Spector, Neil L; Kornbluth, SallyIn the intrinsic pathway of apoptosis, cell-damaging signals promote the release of cytochrome c from mitochondria, triggering activation of the Apaf-1 and caspase-9 apoptosome. The ubiquitin E3 ligase MDM2 decreases the stability of the proapoptotic factor p53. We show that it also coordinated apoptotic events in a p53-independent manner by ubiquitylating the apoptosome activator CAS and the ubiquitin E3 ligase HUWE1. HUWE1 ubiquitylates the antiapoptotic factor Mcl-1, and we found that HUWE1 also ubiquitylated PP5 (protein phosphatase 5), which indirectly inhibited apoptosome activation. Breast cancers that are positive for the tyrosine receptor kinase HER2 (human epidermal growth factor receptor 2) tend to be highly aggressive. In HER2-positive breast cancer cells treated with the HER2 tyrosine kinase inhibitor lapatinib, MDM2 was degraded and HUWE1 was stabilized. In contrast, in breast cancer cells that acquired resistance to lapatinib, the abundance of MDM2 was not decreased and HUWE1 was degraded, which inhibited apoptosis, regardless of p53 status. MDM2 inhibition overcame lapatinib resistance in cells with either wild-type or mutant p53 and in xenograft models. These findings demonstrate broader, p53-independent roles for MDM2 and HUWE1 in apoptosis and specifically suggest the potential for therapy directed against MDM2 to overcome lapatinib resistance.Item Open Access A recessive variant of XRCC4 predisposes to non- BRCA1/2 breast cancer in chinese women and impairs the DNA damage response via dysregulated nuclear localization.(Oncotarget, 2014-12) He, Min; Hu, Xin; Chen, Li; Cao, A-Yong; Yu, Ke-Da; Shi, Ting-Yan; Kuang, Xia-Ying; Shi, Wen-Biao; Ling, Hong; Li, Shan; Qiao, Feng; Yao, Ling; Wei, Qingyi; Di, Gen-Hong; Shao, Zhi-MingXRCC4 plays a crucial role in the non-homologous end joining pathway that maintains genome stability. In this two-stage case-control study with 1,764 non-BRCA1/2 breast cancer patients and 1,623 cancer-free controls, we investigated the contribution of genetic variants of XRCC4 to breast cancer susceptibility in Chinese women. We identified a recessive missense variant, rs3734091 (c.739G>T, p.Ala247Ser), of XRCC4 that was significantly associated with an increased risk of breast cancer (odds ratio [OR] = 3.92, P = 0.007), particularly with the risk of developing triple-negative breast cancer (OR = 18.65, P < 0.0001). This p.Ala247Ser variant disturbed the nuclear localization of XRCC4 in cells homozygous for the rs3734091-T allele but not in heterozygous cells at both the cellular and tissue levels. In heterozygous cells, wild-type XRCC4 facilitated the nuclear localization of the XRCC4A247S mutant, thus compensating for the impaired localization of XRCC4A247S. This provided a biological mechanism by which rs3734091 conferred an increased susceptibility to non-BRCA1/2 breast cancer exclusively under a recessive model. Further functional analyses revealed that p.Ala247Ser impaired the DNA damage repair capacity and ultimately perturbed genomic stability. Taken together, our findings document the role of XRCC4 in non-BRCA1/2 breast cancer predisposition and reveal its underlying biological mechanism of action.Item Open Access Adherence to adjuvant endocrine therapy for breast cancer: importance in women with low income.(Journal of women's health (2002), 2015-05) Ursem, Carling J; Bosworth, Hayden B; Shelby, Rebecca A; Hwang, Wenke; Anderson, Roger T; Kimmick, Gretchen GThere are wide disparities in breast cancer-specific survival by patient sociodemographic characteristics. Women of lower income, for instance, have higher relapse and death rates from breast cancer. One possible contributing factor for this disparity is low use of adjuvant endocrine therapy-an extremely efficacious therapy in women with early stage, hormone receptor positive breast cancer, the most common subtype of breast cancer. Alone, adjuvant endocrine therapy decreases breast cancer recurrence by 50% and death by 30%. Data suggest that low use of adjuvant endocrine therapy is a potentially important and modifiable risk factor for poor outcome in low-income breast cancer patients.Item Open Access Adherence to Adjuvant Endocrine Therapy in Insured Black and White Breast Cancer Survivors: Exploring Adherence Measures in Patient Data.(Journal of managed care & specialty pharmacy, 2019-05) Sheppard, Vanessa B; He, Jun; Sutton, Arnethea; Cromwell, Lee; Adunlin, Georges; Salgado, Teresa M; Tolsma, Dennis; Trout, Martha; Robinson, Brandi E; Edmonds, Megan C; Bosworth, Hayden B; Tadesse, Mahlet GBackground
Adjuvant endocrine therapy (AET) is a critical therapy in that it improves survival in women with hormone receptor-positive (HR+) breast cancer (BC), but adherence to AET is suboptimal. The purpose of this study was to fill scientific gaps about predictors of adherence to AET among black and white women diagnosed with BC.Objective
To assess AET adherence in black and white insured women using multiple measures, including one that uses an innovative statistical approach.Methods
Black and white women newly diagnosed with HR+ BC were identified from 2 health maintenance organizations. Pharmacy records captured the type of oral AET prescriptions and all fill dates. Multivariable logistic regression was used to identify predictors of adherence defined in terms of proportion of days covered (PDC; ≥ 80%) and medication gap of ≤ 10 days. A zero-inflated negative binomial (ZINB) regression model was used to identify variables associated with the total number of days of medication gaps.Results
1,925 women met inclusion criteria. 80% were PDC adherent (> 80%); 44% had a medication gap of ≤ 10 days; and 24% had no medication gap days. Race and age were significant in all multivariable models. Black women were less likely to be adherent based on PDC than white women (OR = 0.72, 95% CI = 0.57-0.90, P < 0.01), and they were less likely to have a medication gap of ≤ 10 days (OR = 0.65, 95% CI = 0.54-0.79, P < 0.001). Women aged 25-49 years were less likely to be PDC adherent than women aged 65-93 years (OR = 0.65, 95% CI = 0.48-0.87, P < 0.001). In the ZINB model, women were without their medication for an average of 37 days (SD = 50.5).Conclusions
Racial disparities in adherence to AET in the study highlight a need for interventions among insured women. Using various measures of adherence may help better understand this multidimensional concept. There might be benefits from using both more common dichotomous measures (e.g., PDC) and integrating novel statistical approaches to allow tailoring adherence to patterns within a specific sample.Disclosures
This research was funded by the National Institutes of Health (R01CA154848). It was also supported in part by the NIH-NCI Cancer Center Support Grant P30 CA016059, the Laboratory of Telomere Health P30 CA51008, and the TSA Award No. UL1TR002649 from the National Center for Advancing Translational Sciences. The contents of this study are solely the responsibility of the authors and do not necessarily represent official views of the National Center for Advancing Translational Sciences or the National Institutes of Health. Bosworth reports grants from Sanofi, Otsuka, Johnson & Johnson, and Blue Cross/Blue Shield of NC and consulting fees from Sanofi and Otsuka. The other authors have nothing to disclose. The datasets generated during and/or analyzed during the current study are not publicly available due to privacy reasons but are available from the corresponding author on reasonable request. The author does not own these data. Data use was granted to the author as part of a data use agreement between specific agencies and organizations.Item Open Access Age-specific differences in oncogenic pathway deregulation seen in human breast tumors.(PLoS One, 2008-01-02) Anders, Carey K; Acharya, Chaitanya R; Hsu, David S; Broadwater, Gloria; Garman, Katherine; Foekens, John A; Zhang, Yi; Wang, Yixin; Marcom, Kelly; Marks, Jeffrey R; Mukherjee, Sayan; Nevins, Joseph R; Blackwell, Kimberly L; Potti, AnilPURPOSE: To define the biology driving the aggressive nature of breast cancer arising in young women. EXPERIMENTAL DESIGN: Among 784 patients with early stage breast cancer, using prospectively-defined, age-specific cohorts (young or=65 years), 411 eligible patients (n = 200or=65 years) with clinically-annotated Affymetrix microarray data were identified. GSEA, signatures of oncogenic pathway deregulation and predictors of chemotherapy sensitivity were evaluated within the two age-defined cohorts. RESULTS: In comparing deregulation of oncogenic pathways between age groups, a higher probability of PI3K (p = 0.006) and Myc (p = 0.03) pathway deregulation was observed in breast tumors arising in younger women. When evaluating unique patterns of pathway deregulation, a low probability of Src and E2F deregulation in tumors of younger women, concurrent with a higher probability of PI3K, Myc, and beta-catenin, conferred a worse prognosis (HR = 4.15). In contrast, a higher probability of Src and E2F pathway activation in tumors of older women, with concurrent low probability of PI3K, Myc and beta-catenin deregulation, was associated with poorer outcome (HR = 2.7). In multivariate analyses, genomic clusters of pathway deregulation illustrate prognostic value. CONCLUSION: Results demonstrate that breast cancer arising in young women represents a distinct biologic entity characterized by unique patterns of deregulated signaling pathways that are prognostic, independent of currently available clinico-pathologic variables. These results should enable refinement of targeted treatment strategies in this clinically challenging situation.Item Metadata only An integrated approach to the prediction of chemotherapeutic response in patients with breast cancer.(PLoS One, 2008-04-02) Salter, Kelly H; Acharya, Chaitanya R; Walters, Kelli S; Redman, Richard; Anguiano, Ariel; Garman, Katherine S; Anders, Carey K; Mukherjee, Sayan; Dressman, Holly K; Barry, William T; Marcom, Kelly P; Olson, John; Nevins, Joseph R; Potti, AnilBACKGROUND: A major challenge in oncology is the selection of the most effective chemotherapeutic agents for individual patients, while the administration of ineffective chemotherapy increases mortality and decreases quality of life in cancer patients. This emphasizes the need to evaluate every patient's probability of responding to each chemotherapeutic agent and limiting the agents used to those most likely to be effective. METHODS AND RESULTS: Using gene expression data on the NCI-60 and corresponding drug sensitivity, mRNA and microRNA profiles were developed representing sensitivity to individual chemotherapeutic agents. The mRNA signatures were tested in an independent cohort of 133 breast cancer patients treated with the TFAC (paclitaxel, 5-fluorouracil, adriamycin, and cyclophosphamide) chemotherapy regimen. To further dissect the biology of resistance, we applied signatures of oncogenic pathway activation and performed hierarchical clustering. We then used mRNA signatures of chemotherapy sensitivity to identify alternative therapeutics for patients resistant to TFAC. Profiles from mRNA and microRNA expression data represent distinct biologic mechanisms of resistance to common cytotoxic agents. The individual mRNA signatures were validated in an independent dataset of breast tumors (P = 0.002, NPV = 82%). When the accuracy of the signatures was analyzed based on molecular variables, the predictive ability was found to be greater in basal-like than non basal-like patients (P = 0.03 and P = 0.06). Samples from patients with co-activated Myc and E2F represented the cohort with the lowest percentage (8%) of responders. Using mRNA signatures of sensitivity to other cytotoxic agents, we predict that TFAC non-responders are more likely to be sensitive to docetaxel (P = 0.04), representing a viable alternative therapy. CONCLUSIONS: Our results suggest that the optimal strategy for chemotherapy sensitivity prediction integrates molecular variables such as ER and HER2 status with corresponding microRNA and mRNA expression profiles. Importantly, we also present evidence to support the concept that analysis of molecular variables can present a rational strategy to identifying alternative therapeutic opportunities.Item Open Access Assessing risk of breast cancer in an ethnically South-East Asia population (results of a multiple ethnic groups study).(BMC cancer, 2012-11-19) Gao, Fei; Machin, David; Chow, Khuan-Yew; Sim, Yu-Fan; Duffy, Stephen W; Matchar, David B; Goh, Chien-Hui; Chia, Kee-SengBackground
Gail and others developed a model (GAIL) using age-at-menarche, age-at-birth of first live child, number of previous benign breast biopsy examinations, and number of first-degree-relatives with breast cancer as well as baseline age-specific breast cancer risks for predicting the 5-year risk of invasive breast cancer for Caucasian women. However, the validity of the model for projecting risk in South-East Asian women is uncertain. We evaluated GAIL and attempted to improve its performance for Singapore women of Chinese, Malay and Indian origins.Methods
Data from the Singapore Breast Screening Programme (SBSP) are used. Motivated by lower breast cancer incidence in many Asian countries, we utilised race-specific invasive breast cancer and other cause mortality rates for Singapore women to produce GAIL-SBSP. By using risk factor information from a nested case-control study within SBSP, alternative models incorporating fewer then additional risk factors were determined. Their accuracy was assessed by comparing the expected cases (E) with the observed (O) by the ratio (E/O) and 95% confidence interval (CI) and the respective concordance statistics estimated.Results
From 28,883 women, GAIL-SBSP predicted 241.83 cases during the 5-year follow-up while 241 were reported (E/O=1.00, CI=0.88 to 1.14). Except for women who had two or more first-degree-relatives with breast cancer, satisfactory prediction was present in almost all risk categories. This agreement was reflected in Chinese and Malay, but not in Indian women. We also found that a simplified model (S-GAIL-SBSP) including only age-at-menarche, age-at-birth of first live child and number of first-degree-relatives performed similarly with associated concordance statistics of 0.5997. Taking account of body mass index and parity did not improve the calibration of S-GAIL-SBSP.Conclusions
GAIL can be refined by using national race-specific invasive breast cancer rates and mortality rates for causes other than breast cancer. A revised model containing only three variables (S-GAIL-SBSP) provides a simpler approach for projecting absolute risk of invasive breast cancer in South-East Asia women. Nevertheless its role in counseling the individual women regarding their risk of breast cancer remains problematical and needs to be validated in independent data.Item Open Access Association between p21 Ser31Arg polymorphism and cancer risk: a meta-analysis.(Chinese journal of cancer, 2011-04) Ma, Hongxia; Zhou, Ziyuan; Wei, Sheng; Wei, QingyiP21 (CDKN1A), a key cell cycle regulatory protein that governs cell cycle progression from G1 to S phase, can regulate cell proliferation, growth arrest, and apoptosis. The Ser31Arg polymorphism is located in the highly conserved region of p21 and may encode functionally distinct proteins. Although many epidemiological studies have been conducted to evaluate the association between the p21 Ser31Arg polymorphism and cancer risk, the findings remain conflicting. This meta-analysis with 33 077 cases and 45 013 controls from 44 published case-control studies showed that the variant homozygous 31Arg/Arg genotype was associated with an increased risk of numerous types of cancers in a random-effect model (homozygote comparison: OR = 1.17, 95% CI = 0.99 to 1.37, P = 0.0002 for the heterogeneity test; recessive model comparison: OR = 1.16, 95% CI = 1.01 to 1.33, P = 0.0001 for the heterogeneity test). Stratified analysis revealed that increased cancer risk associated with the 31Arg/Arg genotype remained significant in subgroups of colorectal cancer, estrogen-related cancer, Caucasians, population-based studies, studies with matching information or a larger sample size. Heterogeneity analysis showed that tumor type contributed to substantial between-study heterogeneity (recessive model comparison: Χ(2) = 21.83, df = 7, P = 0.003). The results from this large-sample sized meta-analysis suggest that the p21 31Arg/Arg genotype may serve as a potential marker for increased cancer risk.Item Open Access Association of self-directed walking with toxicity moderation during chemotherapy for the treatment of early breast cancer.(Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer, 2023-12) Nyrop, KA; Page, A; Deal, AM; Wagoner, C; Kelly, EA; Kimmick, Gretchen G; Copeland, Anureet; Speca, JoEllen; Wood, William A; Muss, HBBackground
In the field of exercise oncology, there is a need to quantify the potential benefits of moderate, self-directed physical activity during active treatment. In a pooled analysis of three identical single-arm intervention studies, we investigate the association of activity tracker steps with patient-reported toxicities during chemotherapy.Methods
Women with early breast cancer who were enrolled in the intervention studies reported their symptom severity every 2-3 weeks throughout chemotherapy, and daily steps were documented through a Fitbit activity tracker. Relative risks (RR) and 95% confidence intervals (CI) were calculated using Poisson regression models with robust variance. For outcomes significant in unadjusted models, adjusted RRs were calculated controlling for race, age, and education level. Tracker step cut point (high step, low step) was determined by the means. Cumulative incidence functions of moderate, severe, and very severe (MSVS) symptoms were estimated using the Kaplan-Meier method and compared using a Cox proportional hazard model.Results
In a sample of 283 women, mean age was 56 years and 76% were White. Mean tracker-documented steps/week were 29,625, with 55% walking below the mean (low step) and 45% above (high step). In multivariable analysis, high step patients had lower risk for fatigue [RR 0.83 (0.70, 0.99)] (p = 0.04), anxiety [RR 0.59 (0.42, 0.84)] (p = 0.003), nausea [RR 0.66 (0.46, 0.96)] (p = 0.03), depression [RR 0.59 (0.37, 0.03)] (p = 0.02), and ≥ 6 MSVS symptoms [RR 0.73 (0.54, 1.00)] (p = 0.05) and had 36% lower risk for dose reductions [RR 0.64 (95% CI 0.43, 0.97)] (p = 0.03).Conclusion
Self-directed walking at a rate of at least 30,000 steps/week may moderate the severity of treatment side effects during chemotherapy for early breast cancer.Trial numbers
NCT02167932, NCT02328313, NCT03761706.Item Open Access Breast cancer as heterogeneous disease: contributing factors and carcinogenesis mechanisms.(Breast Cancer Res Treat, 2011-07) Kravchenko, Julia; Akushevich, Igor; Seewaldt, Victoria L; Abernethy, Amy P; Lyerly, H KimThe observed bimodal patterns of breast cancer incidence in the U.S. suggested that breast cancer may be viewed as more than one biological entity. We studied the factors potentially contributing to this phenomenon, specifically focusing on how disease heterogeneity could be linked to breast carcinogenesis mechanisms. Using empirical analyses and population-based biologically motivated modeling, age-specific patterns of incidence of ductal and lobular breast carcinomas from the SEER registry (1990-2003) were analyzed for heterogeneity and characteristics of carcinogenesis, stratified by race, stage, grade, and estrogen (ER)/progesterone (PR) receptor status. The heterogeneity of breast carcinoma age patterns decreased after stratification by grade, especially for grade I and III tumors. Stratification by ER/PR status further reduced the heterogeneity, especially for ER(+)/PR(-) and ER(-)/(-) tumors; however, the residual heterogeneity was still observed. The number of rate-limiting events of carcinogenesis and the latency of ductal and lobular carcinomas differed, decreasing from grade I to III, with poorly differentiated tumors associated with the least number of carcinogenesis stages and the shortest latency. Tumor grades play important role in bimodal incidence of breast carcinoma and have distinct mechanisms of carcinogenesis. Race and cancer subtype could play modifying role. ER/PR status contributes to the observed heterogeneity, but is subdominant to tumor grade. Further studies on sources of "remaining" heterogeneity of population with breast cancer (such as genetic/epigenetic characteristics) are necessary. The results of this study could suggest stratification rather than unification of breast cancer prevention strategies, risk assessment, and treatment.Item Open Access Breast cancer oral anti-cancer medication adherence: a systematic review of psychosocial motivators and barriers.(Breast cancer research and treatment, 2017-09) Lin, Cheryl; Clark, Rachel; Tu, Pikuei; Bosworth, Hayden B; Zullig, Leah LPurpose
In the past decade, there has been an increase in the development and use of oral anti-cancer medications (OAMs), especially for breast cancer-the most prevalent cancer in women. However, adherence rates for OAMs are often suboptimal, leading to lower survival rate, increased risk of recurrence, and higher healthcare costs. Our goal was to identify potentially modifiable psychosocial facilitators and barriers that may be targeted to increase OAM adherence for breast cancer patients.Methods
We systematically searched PubMed for studies published in the U.S. by June 15, 2016 that addressed the following: (1) OAMs for breast cancer; (2) medication adherence; and (3) at least one psychosocial aspect of adherence.Results
Of the 1752 papers screened, 21 articles were included and analyzed. The most commonly reported motivators for adherence are patient-provider relationships (n = 11 studied, 82% reported significant association) and positive views and beliefs of medication (n = 9 studied, 89% reported significant association). We also identified consistent evidence of the impact of depression and emotions, perception of illness, concern of side effects, self-efficacy in medication management and decision making, knowledge of medication, and social support on OAM adherence.Conclusions
Compared to traditional demographic, system, and clinical-related factors that have been well documented in the literature but are not easily changed, these cognitive, psychological, and interpersonal factors are more amendable via intervention and therefore could generate greater benefit in improving patient compliance and health outcomes. As OAMs shift treatment administration responsibility onto patients, continuous provider communication and education on illness and regimen are the keys to supporting patients' medication behavior.Item Open Access Clinical characteristics, racial inequities, and outcomes in patients with breast cancer and COVID-19: A COVID-19 and cancer consortium (CCC19) cohort study.(eLife, 2023-10) Nagaraj, Gayathri; Vinayak, Shaveta; Khaki, Ali Raza; Sun, Tianyi; Kuderer, Nicole M; Aboulafia, David M; Acoba, Jared D; Awosika, Joy; Bakouny, Ziad; Balmaceda, Nicole B; Bao, Ting; Bashir, Babar; Berg, Stephanie; Bilen, Mehmet A; Bindal, Poorva; Blau, Sibel; Bodin, Brianne E; Borno, Hala T; Castellano, Cecilia; Choi, Horyun; Deeken, John; Desai, Aakash; Edwin, Natasha; Feldman, Lawrence E; Flora, Daniel B; Friese, Christopher R; Galsky, Matthew D; Gonzalez, Cyndi J; Grivas, Petros; Gupta, Shilpa; Haynam, Marcy; Heilman, Hannah; Hershman, Dawn L; Hwang, Clara; Jani, Chinmay; Jhawar, Sachin R; Joshi, Monika; Kaklamani, Virginia; Klein, Elizabeth J; Knox, Natalie; Koshkin, Vadim S; Kulkarni, Amit A; Kwon, Daniel H; Labaki, Chris; Lammers, Philip E; Lathrop, Kate I; Lewis, Mark A; Li, Xuanyi; Lopes, Gilbert de Lima; Lyman, Gary H; Makower, Della F; Mansoor, Abdul-Hai; Markham, Merry-Jennifer; Mashru, Sandeep H; McKay, Rana R; Messing, Ian; Mico, Vasil; Nadkarni, Rajani; Namburi, Swathi; Nguyen, Ryan H; Nonato, Taylor Kristian; O'Connor, Tracey Lynn; Panagiotou, Orestis A; Park, Kyu; Patel, Jaymin M; Patel, Kanishka GopikaBimal; Peppercorn, Jeffrey; Polimera, Hyma; Puc, Matthew; Rao, Yuan James; Razavi, Pedram; Reid, Sonya A; Riess, Jonathan W; Rivera, Donna R; Robson, Mark; Rose, Suzanne J; Russ, Atlantis D; Schapira, Lidia; Shah, Pankil K; Shanahan, M Kelly; Shapiro, Lauren C; Smits, Melissa; Stover, Daniel G; Streckfuss, Mitrianna; Tachiki, Lisa; Thompson, Michael A; Tolaney, Sara M; Weissmann, Lisa B; Wilson, Grace; Wotman, Michael T; Wulff-Burchfield, Elizabeth M; Mishra, Sanjay; French, Benjamin; Warner, Jeremy L; Lustberg, Maryam B; Accordino, Melissa K; Shah, Dimpy P; COVID-19 and Cancer ConsortiumBackground
Limited information is available for patients with breast cancer (BC) and coronavirus disease 2019 (COVID-19), especially among underrepresented racial/ethnic populations.Methods
This is a COVID-19 and Cancer Consortium (CCC19) registry-based retrospective cohort study of females with active or history of BC and laboratory-confirmed severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection diagnosed between March 2020 and June 2021 in the US. Primary outcome was COVID-19 severity measured on a five-level ordinal scale, including none of the following complications, hospitalization, intensive care unit admission, mechanical ventilation, and all-cause mortality. Multivariable ordinal logistic regression model identified characteristics associated with COVID-19 severity.Results
1383 female patient records with BC and COVID-19 were included in the analysis, the median age was 61 years, and median follow-up was 90 days. Multivariable analysis revealed higher odds of COVID-19 severity for older age (aOR per decade, 1.48 [95% CI, 1.32-1.67]); Black patients (aOR 1.74; 95 CI 1.24-2.45), Asian Americans and Pacific Islander patients (aOR 3.40; 95 CI 1.70-6.79) and Other (aOR 2.97; 95 CI 1.71-5.17) racial/ethnic groups; worse ECOG performance status (ECOG PS ≥2: aOR, 7.78 [95% CI, 4.83-12.5]); pre-existing cardiovascular (aOR, 2.26 [95% CI, 1.63-3.15])/pulmonary comorbidities (aOR, 1.65 [95% CI, 1.20-2.29]); diabetes mellitus (aOR, 2.25 [95% CI, 1.66-3.04]); and active and progressing cancer (aOR, 12.5 [95% CI, 6.89-22.6]). Hispanic ethnicity, timing, and type of anti-cancer therapy modalities were not significantly associated with worse COVID-19 outcomes. The total all-cause mortality and hospitalization rate for the entire cohort was 9% and 37%, respectively however, it varied according to the BC disease status.Conclusions
Using one of the largest registries on cancer and COVID-19, we identified patient and BC-related factors associated with worse COVID-19 outcomes. After adjusting for baseline characteristics, underrepresented racial/ethnic patients experienced worse outcomes compared to non-Hispanic White patients.Funding
This study was partly supported by National Cancer Institute grant number P30 CA068485 to Tianyi Sun, Sanjay Mishra, Benjamin French, Jeremy L Warner; P30-CA046592 to Christopher R Friese; P30 CA023100 for Rana R McKay; P30-CA054174 for Pankil K Shah and Dimpy P Shah; KL2 TR002646 for Pankil Shah and the American Cancer Society and Hope Foundation for Cancer Research (MRSG-16-152-01-CCE) and P30-CA054174 for Dimpy P Shah. REDCap is developed and supported by Vanderbilt Institute for Clinical and Translational Research grant support (UL1 TR000445 from NCATS/NIH). The funding sources had no role in the writing of the manuscript or the decision to submit it for publication.Clinical trial number
CCC19 registry is registered on ClinicalTrials.gov, NCT04354701.Item Open Access Co-occurring Fatigue and Lymphatic Pain Incrementally Aggravate Their Negative Effects on Activities of Daily Living, Emotional Distress, and Overall Health of Breast Cancer Patients.(Integrative cancer therapies, 2022-01) Fu, Mei Rosemary; McTernan, Melissa L; Qiu, Jeanna M; Miaskowski, Christine; Conley, Yvette P; Ko, Eunjung; Axelrod, Deborah; Guth, Amber; Somers, Tamara J; Wood, Lisa J; Wang, YaoBackground
Fatigue and lymphatic pain are the most common and debilitating long-term adverse effects of breast cancer treatment. Fatigue and pain independently have negative effects on quality of life, physical functions, and cancer recurrence-free survival. The interactions between fatigue and pain may aggravate their negative effects.Objectives
Examine the effects of co-occurring fatigue and lymphatic pain on activities of daily living (ADLs), emotional distress, and overall health of breast cancer patients.Methods
A cross-sectional and observational design was used to enroll 354 breast cancer patients. Valid and reliable instruments were used to assess fatigue, lymphatic pain, ADLs, emotional distress, and overall health. Descriptive statistics and multivariable regression models were used for data analysis.Results
After controlling for demographic and clinical factors, patients with co-occurring fatigue and lymphatic pain had higher odds of having impaired ADLs (OR = 24.43, CI = [5.44-109.67], P < .001) and emotional distress (OR = 26.52, CI = [9.64-72.90], P < .001) compared to patients with only fatigue and only lymphatic pain. Patients with co-occurring fatigue and lymphatic pain had 179% increase in impaired ADL scores (B = 8.06, CI = [5.54-10.59]) and 211% increase in emotional distress scores (B = 9.17, CI = [5.52-12.83]) compared to those without co-occurring fatigue and lymphatic pain. Patients with co-occurring fatigue and lymphatic pain had a 34% decrease (B = -26.29, CI = [-31.90 to -20.69]) and patients with only fatigue had a 33% decrease in overall health scores (B = -25.74, 95% CI = [-34.14 to -17.33]), indicating poor overall health.Conclusions
Fatigue and lymphatic pain affected 66.4% of breast cancer patients. Findings from this study suggest that co-occurring fatigue and lymphatic pain have negative effects on breast cancer patients' ADLs, emotional distress, and overall health. The synergistic interactions between fatigue and lymphatic pain incrementally aggravated their negative effects on ADLs and emotional distress. Findings of the study highlight the need to evaluate the underlying mechanisms for co-occurring fatigue and lymphatic pain and develop interventions that target both fatigue and lymphatic pain to improve breast cancer patients' the quality of life.Item Open Access Comparative performance of multiview stereoscopic and mammographic display modalities for breast lesion detection.(2010) Webb, Lincoln JonPURPOSE: Mammography is known to be one of the most difficult radiographic exams to interpret. Mammography has important limitations, including the superposition of normal tissue that can obscure a mass, chance alignment of normal tissue to mimic a true lesion and the inability to derive volumetric information. It has been shown that stereomammography can overcome these deficiencies by showing that layers of normal tissue lay at different depths. If standard stereomammography (i.e., a single stereoscopic pair consisting of two projection images) can significantly improve lesion detection, how will multiview stereoscopy (MVS), where many projection images are used, compare to mammography? The aim of this study was to assess the relative performance of MVS compared to mammography for breast mass detection. METHODS: The MVS image sets consisted of the 25 raw projection images acquired over an arc of approximately 45 degrees using a Siemens prototype breast tomosynthesis system. The mammograms were acquired using a commercial Siemens FFDM system. The raw data were taken from both of these systems for 27 cases and realistic simulated mass lesions were added to duplicates of the 27 images at the same local contrast. The images with lesions (27 mammography and 27 MVS) and the images without lesions (27 mammography and 27 MVS) were then postprocessed to provide comparable and representative image appearance across the two modalities. All 108 image sets were shown to five full-time breast imaging radiologists in random order on a state-of-the-art stereoscopic display. The observers were asked to give a confidence rating for each image (0 for lesion definitely not present, 100 for lesion definitely present). The ratings were then compiled and processed using ROC and variance analysis. RESULTS: The mean AUC for the five observers was 0.614 +/- 0.055 for mammography and 0.778 +/- 0.052 for multiview stereoscopy. The difference of 0.164 +/- 0.065 was statistically significant with a p-value of 0.0148. CONCLUSIONS: The differences in the AUCs and the p-value suggest that multiview stereoscopy has a statistically significant advantage over mammography in the detection of simulated breast masses. This highlights the dominance of anatomical noise compared to quantum noise for breast mass detection. It also shows that significant lesion detection can be achieved with MVS without any of the artifacts associated with tomosynthesis.Item Open Access Distinct Receptor Tyrosine Kinase Subsets Mediate Anti-HER2 Drug Resistance in Breast Cancer.(J Biol Chem, 2017-01-13) Alexander, Peter B; Chen, Rui; Gong, Chang; Yuan, Lifeng; Jasper, Jeff S; Ding, Yi; Markowitz, Geoffrey J; Yang, Pengyuan; Xu, Xin; McDonnell, Donald P; Song, Erwei; Wang, Xiao-FanTargeted inhibitors of the human epidermal growth factor receptor 2 (HER2), such as trastuzumab and lapatinib, are among the first examples of molecularly targeted cancer therapy and have proven largely effective for the treatment of HER2-positive breast cancers. However, approximately half of those patients either do not respond to these therapies or develop secondary resistance. Although a few signaling pathways have been implicated, a comprehensive understanding of mechanisms underlying HER2 inhibitor drug resistance is still lacking. To address this critical question, we undertook a concerted approach using patient expression data sets, HER2-positive cell lines, and tumor samples biopsied both before and after trastuzumab treatment. Together, these methods revealed that high expression and activation of a specific subset of receptor tyrosine kinases (RTKs) was strongly associated with poor clinical prognosis and the development of resistance. Mechanistically, these RTKs are capable of maintaining downstream signal transduction to promote tumor growth via the suppression of cellular senescence. Consequently, these findings provide the rationale for the design of therapeutic strategies for overcoming drug resistance in breast cancer via combinational inhibition of the limited number of targets from this specific subset of RTKs.Item Open Access E2112: Randomized Phase III Trial of Endocrine Therapy Plus Entinostat or Placebo in Hormone Receptor-Positive Advanced Breast Cancer. A Trial of the ECOG-ACRIN Cancer Research Group.(Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2021-10) Connolly, Roisin M; Zhao, Fengmin; Miller, Kathy D; Lee, Min-Jung; Piekarz, Richard L; Smith, Karen L; Brown-Glaberman, Ursa A; Winn, Jennifer S; Faller, Bryan A; Onitilo, Adedayo A; Burkard, Mark E; Budd, George T; Levine, Ellis G; Royce, Melanie E; Kaufman, Peter A; Thomas, Alexandra; Trepel, Jane B; Wolff, Antonio C; Sparano, Joseph APurpose
Endocrine therapy resistance in advanced breast cancer remains a significant clinical problem that may be overcome with the use of histone deacetylase inhibitors such as entinostat. The ENCORE301 phase II study reported improvement in progression-free survival (PFS) and overall survival (OS) with the addition of entinostat to the steroidal aromatase inhibitor (AI) exemestane in advanced hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer.Patients and methods
E2112 is a multicenter, randomized, double-blind, placebo-controlled phase III study that enrolled men or women with advanced HR-positive, HER2-negative breast cancer whose disease progressed after nonsteroidal AI. Participants were randomly assigned to exemestane 25 mg by mouth once daily and entinostat (EE) or placebo (EP) 5 mg by mouth once weekly. Primary end points were PFS by central review and OS. Secondary end points included safety, objective response rate, and lysine acetylation change in peripheral blood mononuclear cells between baseline and cycle 1 day 15.Results
Six hundred eight patients were randomly assigned during March 2014-October 2018. Median age was 63 years (range 29-91), 60% had visceral disease, and 84% had progressed after nonsteroidal AI in metastatic setting. Previous treatments included chemotherapy (60%), fulvestrant (30%), and cyclin-dependent kinase inhibitor (35%). Most common grade 3 and 4 adverse events in the EE arm included neutropenia (20%), hypophosphatemia (14%), anemia (8%), leukopenia (6%), fatigue (4%), diarrhea (4%), and thrombocytopenia (3%). Median PFS was 3.3 months (EE) versus 3.1 months (EP; hazard ratio = 0.87; 95% CI, 0.67 to 1.13; P = .30). Median OS was 23.4 months (EE) versus 21.7 months (EP; hazard ratio = 0.99; 95% CI, 0.82 to 1.21; P = .94). Objective response rate was 5.8% (EE) and 5.6% (EP). Pharmacodynamic analysis confirmed target inhibition in entinostat-treated patients.Conclusion
The combination of exemestane and entinostat did not improve survival in AI-resistant advanced HR-positive, HER2-negative breast cancer.Item Open Access Early and Locally Advanced Metaplastic Breast Cancer: Presentation and Survival by Receptor Status in Surveillance, Epidemiology, and End Results (SEER) 2010-2014.(The oncologist, 2018-04) Schroeder, Mary C; Rastogi, Priya; Geyer, Charles E; Miller, Lance D; Thomas, AlexandraBackground
Metaplastic breast cancer (MBC) is a rare disease subtype characterized by an aggressive clinical course. MBC is commonly triple negative (TN), although hormone receptor (HR) positive and human epidermal growth receptor 2 (HER2) positive cases do occur. Previous studies have reported similar outcomes for MBC with regard to HR status. Less is known about outcomes for HER2 positive MBC.Materials and methods
Surveillance, Epidemiology, and End Results Program data were used to identify women diagnosed 2010-2014 with MBC or invasive ductal carcinoma (IDC). Kaplan-Meier curves estimated overall survival (OS) and multivariate Cox models were fitted. For survival analyses, only first cancers were included, and 2014 diagnoses were excluded to allow for sufficient follow-up.Results
Our MBC sample included 1,516 women. Relative to women with IDC, women with MBC were more likely to be older (63 vs. 61 years), black (16.0% vs. 11.1%), and present with stage III disease (15.6% vs. 10.8%). HER2 positive and HER2 negative/HR positive MBC tumors represented 5.2% and 23.0% of cases. For MBC overall, 3-year OS was greatest for women with HER2 positive MBC (91.8%), relative to women with TN (75.4%) and HER2 negative/HR positive MBC (77.1%). This difference was more pronounced for stage III MBC, for which 3-year OS was 92.9%, 47.1%, and 42.2% for women with HER2 positive, TN, and HER2 negative/HR positive MBC, respectively. A multivariate Cox model of MBC demonstrated that HER2 positive tumors (relative to TN) were associated with improved survival (hazard ratio = 0.32, 95% confidence interval [CI] 0.13-0.79). In a second Cox model of exclusively HER2 positive tumors, OS did not differ between MBC and IDC disease subtypes (hazard ratio = 1.16, 95% CI 0.48-2.81).Conclusion
In this contemporary, population-based study of women with MBC, HER2 but not HR status was associated with improved survival. Survival was similar between HER2 positive MBC and HER2 positive IDC. This suggests HER2 positive MBC is responsive to HER2-directed therapy, a finding that may offer insights for additional therapeutic approaches to MBC.Implications for practice
This population-based study reports recent outcomes, by receptor status, for women with metaplastic breast cancer. Survival in metaplastic breast cancer is not impacted by hormone receptor status. To the authors' knowledge, this is the first report indicating that women with human epidermal growth receptor 2 (HER2) positive metaplastic breast cancer have survival superior to women with HER2 negative metaplastic breast cancer and survival similar to women with HER2 positive invasive ductal carcinoma. This information can be used for counseling patients diagnosed with metaplastic breast cancer. Further understanding of HER2 positive metaplastic breast cancer could offer insights for the development of therapeutic approaches to metaplastic breast cancer more broadly.Item Open Access Effect at One Year of Adjuvant Trastuzumab for HER2+ Breast Cancer Combined with Radiation or an Anthracycline on Left Ventricular Ejection Fraction.(The American journal of cardiology, 2020-06) Andersen, Mousumi M; Ayala-Peacock, Diandra; Bowers, Jessie; Kooken, Banks W; D'Agostino, Ralph B; Jordan, Jennifer H; Vasu, Sujethra; Thomas, Alexandra; Klepin, Heidi D; Brown, Doris R; Hundley, W GregoryTo determine the impact of radiation therapy (XRT) in addition to trastuzumab (TZB) adjuvant chemotherapy for HER2+ breast cancer on left ventricular systolic function, we assessed demographics, oncologic treatment history including XRT exposure, and serial measurements of left ventricular ejection fraction (LVEF) in 135 consecutively identified women receiving TZB for treatment of adjuvant breast cancer. Longitudinal mixed effects models were fit to identify baseline to treatment changes in LVEF among those receiving TZB with or without concomitant anthracycline or XRT. Women averaged 53 ± 3 years in age, 77% were white, 62% patients had 1 or more cardiovascular risk factors at baseline, and mean duration of TZB was 11 ± 5 months. Seventy-seven women were treated with XRT and received between 4000 and 5500 cGy of radiation. The LVEF declined by an average of 3.4% after 1 year for those in the study. Relative to baseline upon completion of adjuvant TZB, LVEF remained reduced for those receiving anthracycline with or without XRT (p=0.002 for both), or XRT alone (p=0.002), but not in those without these therapies. Amongst patients treated only with XRT and TZB, LVEF declined 3.1% on average in those with left-sided disease and 6.9% on average in those with right-sided disease (p= 0.06, p= 0.008 respectively). Among women receiving TZB for adjuvant treatment of HER-2 positive breast cancer, the administration of XRT, anthracycline, or the combination of the 2 is associated with a persistent post-treatment as opposed to a temporary treatment related decline in LVEF.Item Open Access Effect of socioeconomic status as measured by education level on survival in breast cancer clinical trials.(Psychooncology, 2013-02) Herndon, James E; Kornblith, Alice B; Holland, Jimmie C; Paskett, Electra DOBJECTIVES: This paper aims to investigate the effect of socioeconomic status, as measured by education, on the survival of breast cancer patients treated on 10 studies conducted by the Cancer and Leukemia Group B. METHODS: Sociodemographic data, including education, were reported by the patient at trial enrollment. Cox proportional hazards model stratified by treatment arm/study was used to examine the effect of education on survival among patients with early stage and metastatic breast cancer, after adjustment for known prognostic factors. RESULTS: The patient population included 1020 patients with metastatic disease and 5146 patients with early stage disease. Among metastatic patients, factors associated with poorer survival in the final multivariable model included African American race, never married, negative estrogen receptor status, prior hormonal therapy, visceral involvement, and bone involvement. Among early stage patients, significant factors associated with poorer survival included African American race, separated/widowed, post/perimenopausal, negative/unknown estrogen receptor status, negative progesterone receptor status, >4 positive nodes, tumor diameter >2 cm, and education. Having not completed high school was associated with poorer survival among early stage patients. Among metastatic patients, non-African American women who lacked a high school degree had poorer survival than other non-African American women, and African American women who lacked a high school education had better survival than educated African American women. CONCLUSIONS: Having less than a high school education is a risk factor for death among patients with early stage breast cancer who participated in a clinical trial, with its impact among metastatic patients being less clear. Post-trial survivorship plans need to focus on women with low social status, as measured by education.Item Open Access From Community Laywomen to Breast Health Workers: A Pilot Training Model to Implement Clinical Breast Exam Screening in Malawi.(PloS one, 2016-01) Gutnik, Lily; Moses, Agnes; Stanley, Christopher; Tembo, Tapiwa; Lee, Clara; Gopal, SatishBACKGROUND:Breast cancer burden is high in low-income countries. Inadequate early detection contributes to late diagnosis and increased mortality. We describe the training program for Malawi's first clinical breast exam (CBE) screening effort. METHODS:Laywomen were recruited as Breast Health Workers (BHWs) with the help of local staff and breast cancer advocates. The four-week training consisted of lectures, online modules, role-playing, case discussions, CBE using simulators and patients, and practice presentations. Ministry of Health trainers taught health communication, promotion, and education skills. Breast cancer survivors shared their experiences. Clinicians taught breast cancer epidemiology, prevention, detection, and clinical care. Clinicians and research staff taught research ethics, informed consent, data collection, and professionalism. Breast cancer knowledge was measured using pre- and post-training surveys. Concordance between BHW and clinician CBE was assessed. Breast cancer talks by BHW were evaluated on a 5-point scale in 22 areas by 3 judges. RESULTS:We interviewed 12 women, and 4 were selected as BHWs including 1 breast cancer survivor. Training was dynamic with modification based on trainee response and progress. A higher-than-anticipated level of comprehension and interest led to inclusion of additional topics like breast reconstruction. Pre-training knowledge increased from 49% to 91% correct (p<0.0001). Clinician and BHW CBE had 88% concordance (kappa 0.43). The mean rating of BHW educational talks was 4.4 (standard deviation 0.7). CONCLUSIONS:Malawian laywomen successfully completed training and demonstrated competency to conduct CBE and deliver breast cancer educational talks. Knowledge increased after training, and concordance was high between BHW and clinician CBE.
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