Search

Purpose: To determine whether strength training or tai ji quan can reduce frailty in older, postmenopausal women treated with chemotherapy for cancer., Methods: We conducted a secondary data analysis from a 3-arm, single-blind, randomized controlled trial where older (50-75 years), postmenopausal women cancer survivors were randomized to supervised group exercise programs: tai ji quan, strength training, or stretching control for 6 months. We assessed frailty using a 4-criteria model consisting of weakness, fatigue, inactivity, and slowness. Using logistic regression, we determined whether the frailty phenotype (pre-frailty or frailty) decreased post-intervention, how many and which frailty criteria decreased, and what characteristics identified women most likely to reduce frailty., Results: Data from 386 women who completed baseline and 6-month testing were used (mean age of 62.0 ± 6.4 years). The odds of reducing overall frailty over 6 months were significantly higher in the strength training group compared to controls (OR [95%CI] 1.86 [1.09, 3.17]) but not for tai ji quan (1.44 [0.84, 2.50]). Both strength training (OR 1.99 [1.10, 3.65]) and tai ji quan (OR 2.10 [1.16, 3.84]) led to significantly higher odds of reducing ≥ 1 frailty criterion compared to controls. Strength training led to a three-fold reduction in inactivity (p < 0.01) and tai ji quan to a two-fold reduction in fatigue (p = 0.08) versus control. Higher baseline BMI, comorbidity score, and frailty status characterized women were more likely to reduce frailty than other women., Conclusions: Strength training appears superior to tai ji quan and stretching with respect to reducing overall frailty phenotype among postmenopausal women treated with chemotherapy for cancer, but tai ji quan favorably reduced the number of frailty criteria., Trial Registration: ClinicalTrials.gov identifier: GET FIT was registered as a clinical trial in clinicaltrials.gov: NCT01635413., Implications for Cancer Survivors: Supervised, group exercise training that emphasizes strength training and/or tai ji quan may help combat accelerated aging and reduce frailty after cancer treatment., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

One of the justifiable criticisms of human genetic studies is the underrepresentation of participants from diverse populations. Lack of inclusion must be addressed at-scale to identify causal disease factors and understand the genetic causes of health disparities. We present genome-wide associations for 2068 traits from 635,969 participants in the Department of Veterans Affairs Million Veteran Program, a longitudinal study of diverse United States Veterans. Systematic analysis revealed 13,672 genomic risk loci; 1608 were only significant after including non-European populations. Fine-mapping identified causal variants at 6318 signals across 613 traits. One-third ( n = 2069) were identified in participants from non-European populations. This reveals a broadly similar genetic architecture across populations, highlights genetic insights gained from underrepresented groups, and presents an extensive atlas of genetic associations.

Metastasis is the most dreaded outcome after a breast cancer diagnosis, and little is known regarding what triggers or promotes breast cancer to spread distally, or how to prevent or eradicate metastasis effectively. Bilateral breast cancers are an uncommon form of breast cancers. In our study, a percentage of bilateral breast cancers were clonally related based on copy number variation profiling. Whole exome sequencing and comparative sequence analysis revealed that a limited number of somatic mutations were acquired in this "breast-to-breast" metastasis that might promote breast cancer distant spread. One somatic mutation acquired was SIVA-D160N that displayed pro-metastatic phenotypes in vivo and in vitro. Over-expression of SIVA-D160N promoted migration and invasion of human MB-MDA-231 breast cancer cells in vitro, consistent with a dominant negative interfering function. When introduced via tail vein injection, 231 cells over-expressing SIVA-D160N displayed enhanced distant spread on IVIS imaging. Over-expression of SIVA-D160N promoted invasion and anchorage independent growth of mouse 4T1 breast cancer cells in vitro. When introduced orthotopically via mammary fat pad injection in syngeneic Balb/c mice, over-expression of SIVA-D160N in 4T1 cells increased orthotopically implanted mammary gland tumor growth as well as liver metastasis. Clonally related bilateral breast cancers represented a novel system to investigate metastasis and revealed a role of SIVA-D160N in breast cancer metastasis. Further characterization and understanding of SIVA function, and that of its interacting proteins, may elucidate mechanisms of breast cancer metastasis, providing clinically useful biomarkers and therapeutic targets., Competing Interests: The authors have declared that no competing interests exist., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Objectives: Growth factor receptor bound protein 7 (GRB7) is a multidomain signaling adaptor. Members of the Grb7/10/14 family, specifically Gbrb10/14, have important roles in metabolism. We ablated the Grb7 gene in mice to examine its metabolic function., Methods: Global ablation of Grb7 in FVB/NJ mice was generated. Growth, organ weight, food intake, and glucose homeostasis were measured. Insulin signaling was examined by Western blotting. Fat and lean body mass was measured by nuclear magnetic resonance, and body composition after fasting or high-fat diet was assessed. Energy expenditure was measured by indirect calorimetry. Expression of adiposity and lipid metabolism genes was measured by quantitative PCR., Results: Grb7-null mice were viable, fertile, and without obvious phenotype. Grb7 ablation improved glycemic control and displayed sensitization to insulin signaling in the liver. Grb7-null females but not males had increased gonadal white adipose tissue mass. Following a 12-week high-fat diet, Grb7-null female mice gained fat body mass and developed relative insulin resistance. With fasting, there was less decrease in fat body mass in Grb7-null female mice. Female mice with Grb7 ablation had increased baseline food intake, less energy expenditure, and displayed a decrease in the expression of lipolysis and adipose browning genes in gonadal white adipose tissue by transcript and protein analysis., Conclusion: Our study suggests that Grb7 is a negative regulator of glycemic control. Our results reveal a role for Grb7 in female mice in the regulation of the visceral adipose tissue mass, a powerful predictor of metabolic dysfunction in obesity., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Purpose: To compare the efficacy of tai ji quan versus strength training to prevent falls after chemotherapy in older, postmenopaual women., Methods: We conducted a three-arm, single-blind, randomized controlled trial where older (50+ years), postmenopausal women cancer survivors participated in one of three supervised group exercise programs (tai ji quan, strength training, or stretching control) twice weekly for 6 months and were followed up 6 months after training stopped. The primary outcome was the incidence of falls. Secondary outcomes included fall-related injuries, leg strength (1 repetition maximum; kg), and balance (sensory organization [equilibrium score] and limits of stability [LOS; %] tests)., Results: Four hundred sixty-two women were enrolled (mean age, 62 ± 6.3 years). Retention was 93%, and adherence averaged 72.9%. In primary analysis, there was no difference in the incidence of falls between groups after 6 months of training, nor during 6-month follow-up. A post hoc analysis detected a significantly reduced incidence of fall-related injuries within the tai ji quan group over the first 6 months, dropping from 4.3 falls per 100 person-months (95% CI, 2.9 to 5.6) at baseline to 2.4 falls per person-months (95% CI, 1.2 to 3.5). No significant changes occurred during 6-month follow-up. Over the intervention period, leg strength significantly improved in the strength group and balance (LOS) improved in the tai ji quan group, compared with controls ( P < .05)., Conclusion: We found no significant reduction in falls for tai ji quan or strength training relative to stretching control in postmenopausal women treated with chemotherapy.

Breast cancer is a leading cause of cancer and, therefore, a major health threat for women in the United States and worldwide. We have seen over the years major advances in breast cancer prevention and care. Breast cancer screening with mammography leads to reduction in breast cancer mortality, and breast cancer prevention treatment with antiestrogens results in reduction in breast cancer incidence. More progress, however, is urgently needed for this common cancer that affects 1 in 11 American women in their lifetime. Not all women have the same breast cancer risk. A personalized approach is highly desirable as women with higher breast cancer risk may benefit from more intense breast cancer screening and/or prevention intervention while lower risk women may be spared with the cost, inconvenience, and emotional burden of these procedures. In addition to age, demographics, family history, lifestyle, and personal health, genetics is an important determinant of an individual's risk for breast cancer. Over the past 10 years, advances in cancer genomics identified multiple common genetic variants from population studies that collectively can contribute significantly to an individual's breast cancer risk. The effects of these genetic variants can be summarized as a "polygenic risk score" (PRS). We are among the first groups to prospectively evaluate the performance of these risk prediction instruments among women veterans of the Million Veteran Program (MVP). A 313-variant PRS (PRS313) predicted incident breast cancer for a prospective cohort of European (EUR) ancestry women veterans with an area under the receiver operating characteristic curve (AUC) of 0.622. The PRS313 performed less well for AFR ancestry however, with an AUC of 0.579. This is not surprising as most genome-wide association studies were conducted in people of European ancestry. This is an important area of health disparity and unmet need. The large population size and diversity of the MVP provide a unique and important opportunity to explore novel approaches to produce accurate and clinically useful genetic risk prediction instruments for minority populations., Competing Interests: No competing financial interests exist., (© Shiuh-Wen Luoh et al., 2023; Published by Mary Ann Liebert, Inc.)

In this retrospective cohort study of 94 595 severe acute respiratory syndrome coronavirus 2-positive cases, we developed and validated an algorithm to assess the association between coronavirus disease 2019 (COVID-19) severity and long-term complications (stroke, myocardial infarction, pulmonary embolism/deep vein thrombosis, heart failure, and mortality). COVID-19 severity was associated with a greater risk of experiencing a long-term complication 31-120 days postinfection. Most incident events occurred 31-60 days postinfection and diminished after day 91, except heart failure for severe patients and death for moderate patients, which peaked on days 91-120. Understanding the differential impact of COVID-19 severity on long-term events provides insight into possible intervention modalities and critical prevention strategies., Competing Interests: Potential conflicts of interest. The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2022.)

Rationale: A common MUC5B gene polymorphism, rs35705950-T, is associated with idiopathic pulmonary fibrosis (IPF), but its role in severe acute respiratory syndrome coronavirus 2 infection and disease severity is unclear. Objectives: To assess whether rs35705950-T confers differential risk for clinical outcomes associated with coronavirus disease (COVID-19) infection among participants in the Million Veteran Program (MVP). Methods: The MUC5B rs35705950-T allele was directly genotyped among MVP participants; clinical events and comorbidities were extracted from the electronic health records. Associations between the incidence or severity of COVID-19 and rs35705950-T were analyzed within each ancestry group in the MVP followed by transancestry meta-analysis. Replication and joint meta-analysis were conducted using summary statistics from the COVID-19 Host Genetics Initiative (HGI). Sensitivity analyses with adjustment for additional covariates (body mass index, Charlson comorbidity index, smoking, asbestosis, rheumatoid arthritis with interstitial lung disease, and IPF) and associations with post-COVID-19 pneumonia were performed in MVP subjects. Measurements and Main Results: The rs35705950-T allele was associated with fewer COVID-19 hospitalizations in transancestry meta-analyses within the MVP (N cases  = 4,325; N controls  = 507,640; OR = 0.89 [0.82-0.97]; P  = 6.86 × 10 -3 ) and joint meta-analyses with the HGI (N cases  = 13,320; N controls  = 1,508,841; OR, 0.90 [0.86-0.95]; P  = 8.99 × 10 -5 ). The rs35705950-T allele was not associated with reduced COVID-19 positivity in transancestry meta-analysis within the MVP (N cases  = 19,168/N controls  = 492,854; OR, 0.98 [0.95-1.01]; P  = 0.06) but was nominally significant ( P  < 0.05) in the joint meta-analysis with the HGI (N cases  = 44,820; N controls  = 1,775,827; OR, 0.97 [0.95-1.00]; P  = 0.03). Associations were not observed with severe outcomes or mortality. Among individuals of European ancestry in the MVP, rs35705950-T was associated with fewer post-COVID-19 pneumonia events (OR, 0.82 [0.72-0.93]; P  = 0.001). Conclusions: The MUC5B variant rs35705950-T may confer protection in COVID-19 hospitalizations.

Recent efforts have identified genetic loci that are associated with coronavirus disease 2019 (COVID-19) infection rates and disease outcome severity. Translating these genetic findings into druggable genes that reduce COVID-19 host susceptibility is a critical next step. Using a translational genomics approach that integrates COVID-19 genetic susceptibility variants, multi-tissue genetically regulated gene expression (GReX), and perturbagen signatures, we identified IL10RB as the top candidate gene target for COVID-19 host susceptibility. In a series of validation steps, we show that predicted GReX upregulation of IL10RB and higher IL10RB expression in COVID-19 patient blood is associated with worse COVID-19 outcomes and that in vitro IL10RB overexpression is associated with increased viral load and activation of disease-relevant molecular pathways., (© 2022. The Author(s).)

Remdesivir is the first US Food and Drug Administration (FDA)-approved drug for the treatment of coronavirus disease 2019 (COVID-19). We conducted a retrospective pharmacogenetic study to examine remdesivir-associated liver enzyme elevation among Million Veteran Program participants hospitalized with COVID-19 between March 15, 2020, and June 30, 2021. Pharmacogene phenotypes were assigned using Stargazer. Linear regression was performed on peak log-transformed enzyme values, stratified by population, adjusted for age, sex, baseline liver enzymes, comorbidities, and 10 population-specific principal components. Patients on remdesivir had higher peak alanine aminotransferase (ALT) values following treatment initiation compared with patients not receiving remdesivir. Remdesivir administration was associated with a 33% and 24% higher peak ALT in non-Hispanic White (NHW) and non-Hispanic Black (NHB) participants (p < 0.001), respectively. In a multivariable model, NHW CYP2C19 intermediate/poor metabolizers had a 9% increased peak ALT compared with NHW normal/rapid/ultrarapid metabolizers (p = 0.015); this association was not observed in NHB participants. In summary, remdesivir-associated ALT elevations appear to be multifactorial, and further studies are needed., (© 2022 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Importance: Sickle cell trait (SCT), defined as the presence of 1 hemoglobin beta sickle allele (rs334-T) and 1 normal beta allele, is prevalent in millions of people in the US, particularly in individuals of African and Hispanic ancestry. However, the association of SCT with COVID-19 is unclear., Objective: To assess the association of SCT with the prepandemic health conditions in participants of the Million Veteran Program (MVP) and to assess the severity and sequelae of COVID-19., Design, Setting, and Participants: COVID-19 clinical data include 2729 persons with SCT, of whom 353 had COVID-19, and 129 848 SCT-negative individuals, of whom 13 488 had COVID-19. Associations between SCT and COVID-19 outcomes were examined using firth regression. Analyses were performed by ancestry and adjusted for sex, age, age squared, and ancestral principal components to account for population stratification. Data for the study were collected between March 2020 and February 2021., Exposures: The hemoglobin beta S (HbS) allele (rs334-T)., Main Outcomes and Measures: This study evaluated 4 COVID-19 outcomes derived from the World Health Organization severity scale and phenotypes derived from International Classification of Diseases codes in the electronic health records., Results: Of the 132 577 MVP participants with COVID-19 data, mean (SD) age at the index date was 64.8 (13.1) years. Sickle cell trait was present in 7.8% of individuals of African ancestry and associated with a history of chronic kidney disease, diabetic kidney disease, hypertensive kidney disease, pulmonary embolism, and cerebrovascular disease. Among the 4 clinical outcomes of COVID-19, SCT was associated with an increased COVID-19 mortality in individuals of African ancestry (n = 3749; odds ratio, 1.77; 95% CI, 1.13 to 2.77; P = .01). In the 60 days following COVID-19, SCT was associated with an increased incidence of acute kidney failure. A counterfactual mediation framework estimated that on average, 20.7% (95% CI, -3.8% to 56.0%) of the total effect of SCT on COVID-19 fatalities was due to acute kidney failure., Conclusions and Relevance: In this genetic association study, SCT was associated with preexisting kidney comorbidities, increased COVID-19 mortality, and kidney morbidity.

The study aims to determine the shared genetic architecture between COVID-19 severity with existing medical conditions using electronic health record (EHR) data. We conducted a Phenome-Wide Association Study (PheWAS) of genetic variants associated with critical illness (n = 35) or hospitalization (n = 42) due to severe COVID-19 using genome-wide association summary data from the Host Genetics Initiative. PheWAS analysis was performed using genotype-phenotype data from the Veterans Affairs Million Veteran Program (MVP). Phenotypes were defined by International Classification of Diseases (ICD) codes mapped to clinically relevant groups using published PheWAS methods. Among 658,582 Veterans, variants associated with severe COVID-19 were tested for association across 1,559 phenotypes. Variants at the ABO locus (rs495828, rs505922) associated with the largest number of phenotypes (nrs495828 = 53 and nrs505922 = 59); strongest association with venous embolism, odds ratio (ORrs495828 1.33 (p = 1.32 x 10-199), and thrombosis ORrs505922 1.33, p = 2.2 x10-265. Among 67 respiratory conditions tested, 11 had significant associations including MUC5B locus (rs35705950) with increased risk of idiopathic fibrosing alveolitis OR 2.83, p = 4.12 × 10-191; CRHR1 (rs61667602) associated with reduced risk of pulmonary fibrosis, OR 0.84, p = 2.26× 10-12. The TYK2 locus (rs11085727) associated with reduced risk for autoimmune conditions, e.g., psoriasis OR 0.88, p = 6.48 x10-23, lupus OR 0.84, p = 3.97 x 10-06. PheWAS stratified by ancestry demonstrated differences in genotype-phenotype associations. LMNA (rs581342) associated with neutropenia OR 1.29 p = 4.1 x 10-13 among Veterans of African and Hispanic ancestry but not European. Overall, we observed a shared genetic architecture between COVID-19 severity and conditions related to underlying risk factors for severe and poor COVID-19 outcomes. Differing associations between genotype-phenotype across ancestries may inform heterogenous outcomes observed with COVID-19. Divergent associations between risk for severe COVID-19 with autoimmune inflammatory conditions both respiratory and non-respiratory highlights the shared pathways and fine balance of immune host response and autoimmunity and caution required when considering treatment targets., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: RC has received research support from Intercept Pharmaceuticals, Inc and Merck & Co. SMD receives research support from RenalytixAI and personal consulting fees from Calico Labs, outside the scope of the current research. MDR is on the scientific advisory board for Goldfinch Bio and Cipherome. CO’D is an employee of Novartis Institute for Biomedical Research. PN reports grant support from Amgen, Apple, AstraZeneca, Boston Scientific, and Novartis, personal fees from Apple, AstraZeneca, Blackstone Life Sciences, Genentech, and Novartis, and spousal employment at Vertex, all unrelated to the present work.

Importance: Coronavirus disease 2019 (COVID-19) confers significant risk of acute kidney injury (AKI). Patients with COVID-19 with AKI have high mortality rates., Objective: Individuals with African ancestry with 2 copies of apolipoprotein L1 (APOL1) variants G1 or G2 (high-risk group) have significantly increased rates of kidney disease. We tested the hypothesis that the APOL1 high-risk group is associated with a higher-risk of COVID-19-associated AKI and death., Design, Setting, and Participants: This retrospective cohort study included 990 participants with African ancestry enrolled in the Million Veteran Program who were hospitalized with COVID-19 between March 2020 and January 2021 with available genetic information., Exposures: The primary exposure was having 2 APOL1 risk variants (RV) (APOL1 high-risk group), compared with having 1 or 0 risk variants (APOL1 low-risk group)., Main Outcomes and Measures: The primary outcome was AKI. The secondary outcomes were stages of AKI severity and death. Multivariable logistic regression analyses adjusted for preexisting comorbidities, medications, and inpatient AKI risk factors; 10 principal components of ancestry were performed to study these associations. We performed a subgroup analysis in individuals with normal kidney function prior to hospitalization (estimated glomerular filtration rate ≥60 mL/min/1.73 m2)., Results: Of the 990 participants with African ancestry, 905 (91.4%) were male with a median (IQR) age of 68 (60-73) years. Overall, 392 (39.6%) patients developed AKI, 141 (14%) developed stages 2 or 3 AKI, 28 (3%) required dialysis, and 122 (12.3%) died. One hundred twenty-five (12.6%) of the participants were in the APOL1 high-risk group. Patients categorized as APOL1 high-risk group had significantly higher odds of AKI (adjusted odds ratio [OR], 1.95; 95% CI, 1.27-3.02; P = .002), higher AKI severity stages (OR, 2.03; 95% CI, 1.37-2.99; P < .001), and death (OR, 2.15; 95% CI, 1.22-3.72; P = .007). The association with AKI persisted in the subgroup with normal kidney function (OR, 1.93; 95% CI, 1.15-3.26; P = .01). Data analysis was conducted between February 2021 and April 2021., Conclusions and Relevance: In this cohort study of veterans with African ancestry hospitalized with COVID-19 infection, APOL1 kidney risk variants were associated with higher odds of AKI, AKI severity, and death, even among individuals with prior normal kidney function.

Introduction: This study compared the relative efficacy of aerobic training to resistance training on physical functioning in older breast cancer survivors and determined whether benefits could be maintained by transitioning to unsupervised home-based training., Materials and Methods: Early-stage, post-treatment, older (≥65 years) breast cancer survivors (n = 114; mean age 72 years) were randomized to 12 months of supervised aerobic (n = 37), resistance (n = 39) or stretching (active control; n = 38) training followed by 6 months of unsupervised home-based training. Outcomes included aerobic capacity by 6-min walk distance (6MWD; m), maximal upper and lower body strength (1-repetition maximum; kg); physical function by short physical performance battery (SPPB), SF-36 and Late Life Function and Disability Instruments., Results: Over 12-months of supervised exercise, all groups improved in muscle strength and SPPB scores, but resistance trained women also improved 6MWD. Improvements in upper and lower body strength in the resistance group were significantly greater than those in the stretching control (+2.5 kg vs. +1.8 kg; p = 0.05) and aerobic groups (+8.3 kg vs +2.7 kg; p = 0.047), respectively, with trends for greater improvements in 6MWD (+57.9 m vs. +22.5 m; p = 0.057) and self-report physical function (+4.8 vs. -4.4; 0.066) in resistance trained women versus controls. Compared to values at 12 months, there were no changes during unsupervised training in any measure within or between groups, except for self-reported advanced lower extremity function which improved in the resistance group and fell in the aerobic group (+1.3 vs. -3.1; p = 0.043)., Discussion: Supervised exercise can improve strength and physical functioning among older breast cancer survivors. Resistance training may lead to better improvements compared to aerobic or flexibility training, whether in a supervised or unsupervised setting. Clinicaltrials.govNCT00662103., Competing Interests: Declaration of competing interest The authors have no conflicts to declare., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The success of immunotherapy with immune checkpoint inhibitors (ICIs) in a subset of individuals has been very exciting. However, in many cancers, responses to current ICIs are modest and are seen only in a small subsets of patients. Herein, a widely applicable approach that increases the benefit of ICIs is reported. Intratumoral administration of augmenting immune response and inhibiting suppressive environment of tumors-AIRISE-02 nanotherapeutic that co-delivers CpG and STAT3 siRNA-results in not only regression of the injected tumor, but also tumors at distant sites in multiple tumor model systems. In particular, three doses of AIRISE-02 in combination with systemic ICIs completely cure both treated and untreated aggressive melanoma tumors in 63% of mice, while ICIs alone do not cure any mice. A long-term memory immune effect is also reported. AIRISE-02 is effective in breast and colon tumor models as well. Lastly, AIRISE-02 is well tolerated in mice and nonhuman primates. This approach combines multiple therapeutic agents into a single nanoconstruct to create whole-body immune responses across multiple cancer types. Being a local therapeutic, AIRISE-02 circumvents regulatory challenges of systemic nanoparticle delivery, facilitating rapid translation to the clinic. AIRISE-02 is under investigational new drug (IND)-enabling studies, and clinical trials will soon follow., (© 2021 Wiley-VCH GmbH.)

Accurate breast cancer (BC) risk assessment allows personalized screening and prevention. Prospective validation of prediction models is required before clinical application. Here, we evaluate clinical- and genetic-based BC prediction models in a prospective cohort of women from the Million Veteran Program., Materials and Methods: Clinical BC risk prediction models were validated in combination with a genetic polygenic risk score of 313 (PRS313) single-nucleotide polymorphisms in genetic females without prior BC diagnosis (n = 35,130, mean age 49 years) with 30% non-Hispanic African ancestry (AA). Clinical risk models tested were Breast and Prostate Cancer Cohort Consortium, literature review, and Breast Cancer Risk Assessment Tool, and implemented with or without PRS313. Prediction accuracy and association with incident breast cancer was evaluated with area under the receiver operating characteristic curve (AUC), hazard ratios, and proportion with high absolute lifetime risk., Results: Three hundred thirty-eight participants developed incident breast cancers with a median follow-up of 3.9 years (2.5 cases/1,000 person-years), with 196 incident cases in women of European ancestry and 112 incident cases in AA women. Individualized Coherent Absolute Risk Estimator-literature review in combination with PRS313 had an AUC of 0.708 (95% CI, 0.659 to 0.758) in women with European or non-African ancestries and 0.625 (0.539 to 0.711) in AA women. Breast Cancer Risk Assessment Tool with PRS313 had an AUC of 0.695 (0.62 to 0.729) in European or non-AA and 0.675 (0.626 to 0.723) in AA women. Incorporation of PRS313 with clinical models improved prediction in European but not in AA women. Models estimated up to 9% of European and 18% of AA women with absolute lifetime risk > 20%., Conclusion: Clinical and genetic BC risk models predict incident BC in a large prospective multiracial cohort; however, more work is needed to improve genetic risk estimation in AA women., Competing Interests: Paul Spellman Expert Testimony: Natera, Foundation Medicine No other potential conflicts of interest were reported.Paul Spellman Expert Testimony: Natera, Foundation Medicine No other potential conflicts of interest were reported., (© 2021 by American Society of Clinical Oncology.)

Increased levels of total tumor-infiltrating lymphocytes (TILs) are generally associated with good prognosis in several breast cancer subtypes. Subtypes of TILs impact both tumor cells and immune cells in a variety of different ways, leading to either a pro-tumor or antitumor effect. Tumor-infiltrating CD8 + T cells and natural killer (NK) cells perform as effector cells against tumor cells and are associated with better clinical outcome. Immunotherapy approaches that improve the antitumor activity and proliferation of CD8 + T and NK cells include PD-1/PD-L1 blockade, CAR T cell therapy, or ex vivo-stimulated NK cells. A subset of CD8 + T cells, tissue-resident memory T cells, has also recently been associated with good prognosis in breast cancer patients, and has potential to serve as a predictive biomarker and therapeutic target. Tumor-infiltrating B cells also secrete apoptosis-inducing IgG antibodies and can act as antigen-presenting cells to prime CD4 + and CD8 + T cells. On the other hand, regulatory T and regulatory B cells modulate the immune response from CD8 + T cells and NK cells by secreting immunosuppressive cytokines and inhibiting maturation of antigen-presenting cells (APCs). These regulatory cells are typically associated with poor prognosis, therefore rendering suppression of their regulatory function a key immunotherapeutic strategy.

Background: To explore the potential advantage of preoperative anti-angiogenosis therapy, we implemented a study to evaluate the efficacy of recombinant human endostatin (EN) in combination with neoadjuvant chemotherapy in the treatment of stage III breast cancer., Patients and Methods: Eighty-seven patients were randomized to neoadjuvant TEC (docetaxel, epirubicin, and cyclophosphamide) or to EN+TEC, followed by surgery. The primary endpoint was the objective response rate (ORR). Secondary endpoints included pathologic complete response (pCR), relapse-free survival (RFS), overall survival (OS), and safety., Results: Patients receiving EN+TEC achieved significantly higher ORR (81.82%; 36/44) compared with those receiving TEC (58.14%; 25/43; P=0.016). There was a non-significant trend of increased pCR with EN treatment (15.91% vs. 6.98%). The median follow-up was 54 months and revealed a significantly higher RFS with EN+TEC (median, 67.3 months; 95% confidence interval [CI], 61.0-73.7 months), compared with TEC (median, 55.0 months; 95% CI, 48.3-61.7 months; P =0.014). EN+TEC also significantly improved OS (74.2 months; 95% CI, 68.9-79.6 months), compared with TEC (59.1 months; 95% CI, 52.0-66.1 months; P =0 .006). The 3- and 5-year OS rates are estimated to be 88.5% and 82.8% with EN+TEC and 76.7% and 54.4% with TEC, respectively. Cox proportional regression analyses showed that EN+TEC was associated with improved OS (hazard ratio, 0.377; 95% CI, 0.418-0.959; P =0 .041). There was no significant difference in adverse events between EN+TEC and TEC., Conclusion: The combination of EN+TEC neoadjuvant chemotherapy significantly improved the ORR and OS, suggesting a benefit of adding anti-angiogenesis to standard chemotherapy in the treatment of locally advanced breast cancer., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: To study GRB7 protein expression in normal human tissues and breast and ovarian cancers, and determine its clinical significance. Results: GRB7 protein was expressed in multiple tissues, including myoepithelial cells of normal breast and fibroadenoma. Cytoplasmic GRB7 expression was seen predominantly in HER-2 positive and, to a lesser extent, triple negative breast cancer. Membrane localization of GRB7 was present in a subset of breast cancers with high cytoplasmic GRB7 expression. Univariate and multivariate analysis found that cytoplasmic GRB7 expression was associated with a negative progesterone receptor status, while membrane GRB7 expression was associated with a negative axillary nodal status. Membrane associated GRB7 expression was present in a subset of ovarian cancers with high cytoplasmic GRB7 expression. Membrane GRB7 expression displayed a trend towards improved recurrence free survival (RFS). Landmark analysis suggested an RFS advantage for ovarian cancers that had GRB7 membrane expression and survived beyond 27 months; GRB7 membrane expression in two or more cores (out of three) predicted an improved RFS. Membrane expression of GRB7 protein was observed in breast cancer cell lines with high GRB7 protein expression in vitro . Conclusion: GRB7 protein membrane expression may be associated with a better prognosis in breast and ovarian cancers. The favorable prognostic value of GRB7 protein membrane expression and its underlying mechanism is worthy of further investigation. Methods: Immunohistochemistry of normal human tissues, breast tissues of various pathologies, and clinically annotated ovarian cancers was performed to correlate the patterns of GRB7 expression with biomarkers or clinical outcome., Competing Interests: CONFLICTS OF INTEREST The authors declare no competing financial interests., (Copyright: © 2020 Vermehren-Schmaedick et al.)

Importance: Interval breast cancers (IBCs) are cancers that emerge after a mammogram with negative results but before the patient's next scheduled screening. Interval breast cancer has a worse prognosis than cancers detected by screening; however, it is unknown whether the length of the interscreening period is associated with prognostic features and mortality., Objective: To compare the prognostic features and mortality rate of women with IBCs diagnosed within 1 year or between 1 and 2.5 years of a mammogram with negative results with the prognostic features and mortality rate of women with breast cancers detected by screening., Design, Setting, and Participants: This cohort study used mammography data, tumor characteristics, and patient demographic data from the Women's Health Initiative study, which recruited participants from 1993 to 1998 and followed up with participants for a median of 19 years. The present study sample for these analyses included women aged 50 to 79 years who participated in the Women's Health Initiative study and includes data collected through March 31, 2018. There were 5455 incidents of breast cancer; only 3019 women compliant with screening were retained in analyses. Statistical analysis was performed from October 25, 2018, to November 24, 2019. Breast cancers detected by screening and IBCs were defined based on mammogram history, date of last mammogram, type of visit, and results of examination. Interval breast cancers were subdivided into those occurring within 1 year or between 1 and 2.5 years after the last protocol-mandated mammogram with negative results., Main Outcomes and Measures: The primary outcome of this study was breast cancer-specific mortality for each case of breast cancer detected by screening and IBCs detected within 1 year or between 1 and 2.5 years from a mammogram with negative results. Secondary outcomes included prognostic and tumor characteristics for each group. Comparisons between groups were made using the t test, the χ2 test, and Fine-Gray multivariable cumulative incidence regression analyses., Results: Among the 3019 participants in this analysis, all were women with a mean (SD) age of 63.1 (6.8) years at enrollment and 68.5 (7.1) years at diagnosis. A total of 1050 cases of IBC were identified, with 324 (30.9%) diagnosed within 1 year from a mammogram with negative results and 726 (69.1%) diagnosed between 1 and 2.5 years after last mammogram with negative results. The remaining 1969 cases were breast cancers detected by screening. Interval breast cancers diagnosed within 1 year from a mammogram with negative results had significantly more lobular histologic characteristics (13.0% vs. 8.1%), a larger tumor size (1.97 cm vs 1.43 cm), a higher clinical stage (28.4% vs 17.3% regional and 3.7% vs 0.6% distant), and more lymph node involvement (27.1% vs 17.0%) than cancers detected by screening. Unadjusted breast cancer-specific mortality hazard ratios were significantly higher for IBCs diagnosed within 1 year from a mammogram with negative results compared with breast cancers detected by screening (hazard ratio, 1.92; 95% CI, 1.39-2.65). Higher breast cancer-specific mortality remained statistically significant for IBCs diagnosed within 1 year after adjusting for trial group, molecular subtype, waist to hip ratio, histologic characteristics, and either tumor size (hazard ratio, 1.46; 95% CI, 1.03-2.08) or lymph node involvement (hazard ratio, 1.44; 95% CI, 1.03-2.01). However, significance was lost when tumor size and lymph node involvement were both included in the model (hazard ratio, 1.34; 95% CI, 0.96-1.88). Interval breast cancers diagnosed between 1 and 2.5 years from a mammogram with negative results were not different from breast cancers detected by screening based on prognostic factors or mortality., Conclusions and Relevance: Women with IBCs diagnosed within 1 year of negative mammogram results overall were associated with worse survival than women with breast cancers detected by screening. These differences in survival may be due to a uniquely aggressive biology among IBC cases.

Immunotherapy harnesses the power of the adaptive immune system and has revolutionized the field of oncotherapy, as novel therapeutic strategies have been introduced into clinical use. The development of immune checkpoint inhibitors has led to durable control of disease in a subset of advanced cancer patients, such as those with melanoma and non-small cell lung cancer. However, predicting patient responses to therapy remains a major challenge, due to the remarkable genomic, epigenetic, and microenvironmental heterogeneity present in each tumor. Breast cancer (BC) is the most common cancer in women, where hormone receptor-positive (HR+; estrogen receptor and/or progesterone receptor) BC comprises the majority (>50%) and has better prognosis, while a minority (<20%) are triple negative BC (TNBC), which has an aggressive phenotype. There is a clinical need to identify predictors of late recurrence in HR+ BC and predictors of immunotherapy outcomes in advanced TNBC. Tumor-infiltrating lymphocytes (TILs) have recently been shown to predict late recurrence in HR+, counter to the findings that TILs confer good prognosis in TNBC and human epidermal growth factor receptor 2 positive (HER2+) subtypes. Furthermore, the spatial arrangement of TILs also appears to have prognostic value, with dense clusters of immune cells predicting poor prognosis in HR+ and good prognosis in TNBC. Whether TIL clusters in different breast cancer subtypes represent the same or different landscapes of TILs is unknown and may have treatment implications for a significant portion of breast cancer patients. Current histopathological staining technology is not sufficient for characterizing the ensembles of TILs and their spatial patterns, in addition to tumor and microenvironmental heterogeneity. However, recent advances in cyclic immunofluorescence enable differentiation of the subsets based on TILs, tumor heterogeneity, and microenvironment composition between good and poor responders. A computational framework for understanding the importance of the spatial relationships between TILs and tumor cells in cancer tissues, which will allow for quantitative interpretation of cyclic immunostaining, is also under development. This chapter will explore the workflow for a newly developed cyclic multiplexed-immunofluorescence (cmIF) assay, which has been optimized for formalin-fixed. paraffin-embedded tissues and developed to process digital images for quantitative single-cell based spatial analysis of tumor heterogeneity and microenvironment, including immune cell composition.

Background: The National Cancer Institute-Molecular Analysis for Therapy Choice (NCI-MATCH) is a national precision medicine study incorporating centralized genomic testing to direct refractory cancer patients to molecularly targeted treatment subprotocols. This treatment subprotocol was designed to screen for potential signals of efficacy of ado-trastuzumab emtansine (T-DM1) in HER2-amplified histologies other than breast and gastroesophageal tumors., Methods: Eligible patients had HER2 amplification at a copy number (CN) >7 based on targeted next-generation sequencing (NGS) with a custom Oncomine AmpliSeq™ (ThermoFisher Scientific) panel. Patients with prior trastuzumab, pertuzumab or T-DM1 treatment were excluded. Patients received T-DM1 at 3.6 mg/kg i.v. every 3 weeks until toxicity or disease progression. Tumor assessments occurred every three cycles. The primary end point was centrally assessed objective response rate (ORR). Exploratory end points included correlating response with HER2 CN by NGS. The impact of co-occurring genomic alterations and PTEN loss by immunohistochemistry were also assessed., Results: Thirty-eight patients were enrolled and 36 included in efficacy analysis. Median prior therapies in the metastatic setting was 3 (range 0-9; unknown in one patient). Median HER2 CN was 17 (range 7-139). Partial responses were observed in two (5.6%) patients: one mucoepidermoid carcinoma of parotid gland and one parotid gland squamous cell cancer. Seventeen patients (47%) had stable disease including 8/10 (80%) with ovarian and uterine carcinomas, with median duration of 4.6 months. The 6-month progression-free survival rate was 23.6% [90% confidence interval 14.2% to 39.2%]. Common toxicities included fatigue, anemia, fever and thrombocytopenia with no new safety signals. There was a trend for tumor shrinkage with higher levels of gene CN as determined by the NGS assay., Conclusion: T-DM1 was well tolerated. While this subprotocol did not meet the primary end point for ORR in this heavily pre-treated diverse patient population, clinical activity was seen in salivary gland tumors warranting further study in this tumor type in dedicated trials., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

GRB7 gene encodes a multi-domain signal transduction molecule and is part of the core of the HER-2 amplicon. GRB7 is commonly co-amplified and overexpressed with HER-2 in human breast cancer. This study addresses the role of GRB7 in HER-2 positive human breast cancers resistant to HER-2 targeted therapy. HCC1954, 21MT1, and JIMT1 are basal like HER-2 positive breast cancer cell lines based on expression profiling. These three cell lines are resistant to trastuzumab and lapatinib treatment. Knockdown of GRB7 protein expression with siRNA transfection as well as lentiviral vector mediated shRNA over-expression decreased the growth of HCC1954, 21MT1, and JIMT1 cells in vitro and the growth of tumor xenografts these cells formed in animal models. When assayed by ki-67 staining and TUNEL assay, the mechanism of reduced tumor xenograft growth appeared to be distinct. Reduced proliferation and increased apoptosis were seen in 21MT1 cells, while reduced proliferation was seen in HCC1954 cells and increased apoptosis in JIMT1 cells. Phospho-proteome profiling found HER-1 tyrosine phosphorylation was reduced with GRB7 knock down in JIMT1 cells. Immuno-blotting and immuno-precipitation experiments found HER-1 phosphorylation was reduced with GRB7 knock down in all three cell lines. HER-1 knock down via siRNA transient transfection as well as blocking HER-1 function with panitumumab decreased proliferation of all three cell lines in vitro. Our study finds that GRB7 has an essential growth promoting function which is mediated in part by HER-1 activation. The potential of HER-1 targeting in therapy resistant HER-2 positive breast cancer merits further study., (© 2019 Wiley Periodicals, Inc.)

Matching unique features of cancer types with effective therapies is a cornerstone of precision medicine. Clinical success has been seen in inhibiting specific molecular alterations that drive the growth of cancer cells and targeting molecules whose elevated expression is confined to cancer cells. In addition, cancer cells can have vulnerabilities induced by somatic mutations they carry; attacks on these vulnerabilities range from specific molecular alterations pointing to direct drug strategies to harnessing immune recognition of genetically altered epitopes produced by the cancer cells. Recent advances have found that the success of biomarker-driven cancer therapy may be relevant across sites of origin. For example, cancer types that show DNA mismatch repair deficiency, such as colon, biliary, and endometrial cancer, are more sensitive to immune checkpoint inhibition. Several large, ongoing clinical trials with a "basket" design are combining tumor tissue genomics with potential off-the-shelf therapies in drug development, and more tissue-agnostic biomarker therapies are reaching the bedside.

The central role of estrogen receptor (ER) presence in predicting which breast cancer patients are likely to benefit from anti-estrogen therapies is well-established, but the added benefit of progesterone receptor (PR) and in particular low levels of PR is less well understood. The objective of this study was to determine the quantitative relationship between borderline levels of PR and subsequent benefit from anti-estrogen therapy. We examined data from 447 patients, age 50 or older. ER and PR levels were quantitated by conventional ligand binding assay and Scatchard plot analysis or by enzyme-linked immunoassay. Comparison of clinical outcome in relation with ER and PR status was calculated using Kaplan-Meier actuarial survival analysis and the log-rank test. Subpopulation treatment effect pattern plot (STEPP) analysis was used to explore the interaction between treatment effects and ER or PR levels for the 409 patients with ER values greater than 0. For anti-estrogen treated patients, when the ER and PR positivity cut-off was set at 1.0 fmole/mg protein, there was a statistically significant advantage for patients with ER+PR+ over ER+ PR- tumors for both breast cancer-free interval (BCFI) and overall survival (OS). STEPP analysis found no overall interaction between treatment outcome (5 year survival probability) and levels of hormone receptor. However, patients with borderline PR levels did not appear to benefit from anti-estrogen therapy. PR levels above borderline in addition to the presence of ER predicts an increased probability of benefit from anti-estrogen therapy in breast cancer patients., (© 2013 Wiley Periodicals, Inc.)

Background: Testing for human epidermal growth factor receptor-2 (HER-2) in breast cancer is performed by either immunohistochemistry (IHC) or in situ hybridization (ISH). The growth factor receptor-bound protein-7 (GRB7) gene is in close proximity to HER-2 on chromosome 17q11-12 and codes a signal transduction molecule shown to be an independent adverse marker in breast cancer., Methods: HER-2 and GRB7 protein expression from 613 frozen breast tumors was determined by Western analysis. HER-2 protein results were confirmed with IHC. Commercial HER-2 FISH was performed on a subset of tumors with multi-probe FISH used to assess the extent of HER-2 gene amplification. mRNA expression was determined by Multi-plex RT-PCR., Results: Seven tumors with GRB7 protein over-expression scored HER-2 FISH amplified but had no HER-2 protein over-expression. Four of the 7 tumors showed elevated GRB7 but not HER-2 mRNA over-expression. The breast cancer cell line HCC3153 did not over-express HER-2 protein but showed HER-2 FISH amplification of a limited segment around the HER-2 gene. Ten breast cancer tumors from the TCGA database had gene copy number increases around HER-2 without HER-2 mRNA or protein over-expression., Conclusions: A subset of human breast cancers that test positive with FISH for HER-2 gene amplification do not over-express HER-2 protein. One mechanism for this discordance is the incomplete amplification of the smallest HER-2 region of chromosome 17q11-12, which includes GRB7. HER-2 gene amplification without protein over-expression is clinically significant because patients with such tumors are unlikely to benefit from HER-2 targeted therapy.

Unlabelled: Our randomized controlled trial in prematurely menopausal breast cancer survivors showed that impact + resistance training prevented increases in percentage of body fat compared with controls and also improved BMD at the hip and prevented BMD loss at the spine among exercise-trained women who were menopausal for >1 year., Introduction: Cancer treatment-related menopause worsens bone health and body composition in breast cancer survivors (BCS). We investigated whether impact + resistance training could improve bone mineral density (BMD), reduce bone turnover, build muscle, and decrease fat mass in BCS with premature menopause., Methods: We conducted a randomized controlled trial in 71 BCS (mean age, 46.5 years) within 5 years of treatment-related menopause. Women were randomly assigned to one of two groups: (1) impact + resistance training (prevent osteoporosis with impact + resistance (POWIR)) or (2) exercise placebo (FLEX) 3×/week for 1 year. Outcomes were hip and spine BMD (in grams per square centimeter) and body composition (percent body fat (%BF) and lean and fat mass (in kilograms)) by DXA and bone turnover markers (serum osteocalcin (in nanograms per milliliter) and urinary deoxypryrodinoline (in nanomoles per milliliter)., Results: There were no significant group × time interactions for bone outcomes when using an intent-to-treat approach on the full sample. In analyses restricted to BCS who were menopausal for ≥1 year, POWIR increased BMD at the hip and slowed BMD loss at the spine compared with FLEX (femoral neck-POWIR, 0.004 ± 0.093 g/cm(2) vs. FLEX, -0.010 ± 0.089 g/cm(2); p < 0.01; spine-POWIR, -0.003 ± 0.114 g/cm(2) vs. FLEX, -0.020 ± 0.110 g/cm(2); p = 0.03). POWIR prevented increases in %BF (POWIR, 0.01 % vs. FLEX, 1.3 %; p < 0.04). Women with attendance to POWIR at ≥64 % had better improvements in %BF than women attending less often (p < 0.03)., Conclusion: Impact + resistance training may effectively combat bone loss and worsening body composition from premature menopause in BCS.

Background: Women with cancer are significantly more likely to fall than women without cancer placing them at higher risk of fall-related fractures, other injuries and disability. Currently, no evidence-based fall prevention strategies exist that specifically target female cancer survivors. The purpose of the GET FIT (Group Exercise Training for Functional Improvement after Treatment) trial is to compare the efficacy of two distinct types of exercise, tai chi versus strength training, to prevent falls in women who have completed treatment for cancer. The specific aims of this study are to: 1) Determine and compare the efficacy of both tai chi training and strength training to reduce falls in older female cancer survivors, 2) Determine the mechanism(s) by which tai chi and strength training each reduces falls and, 3) Determine whether or not the benefits of each intervention last after structured training stops., Methods/design: We will conduct a three-group, single-blind, parallel design, randomized controlled trial in women, aged 50-75 years old, who have completed chemotherapy for cancer comparing 1) tai chi 2) strength training and 3) a placebo control group of seated stretching exercise. Women will participate in supervised study programs twice per week for six months and will be followed for an additional six months after formal training stops. The primary outcome in this study is falls, which will be prospectively tracked by monthly self-report. Secondary outcomes are maximal leg strength measured by isokinetic dynamometry, postural stability measured by computerized dynamic posturography and physical function measured by the Physical Performance Battery, all measured at baseline, 3, 6 and 12 months. The sample for this trial (N=429, assuming 25% attrition) will provide adequate statistical power to detect at least a 47% reduction in the fall rate over 1 year by being in either of the 2 exercise groups versus the control group., Discussion: The GET FIT trial will provide important new knowledge about preventing falls using accessible and implementable exercise interventions for women following chemotherapy for cancer. ClinicalTrials.gov NCT01635413.

This review concerns the effects on vision and the eye of medications prescribed at three phases of treatment for women with early-stage breast cancer (BC): (1) adjuvant cytotoxic chemotherapy, (2) adjuvant endocrine therapy, and (3) symptomatic relief. The most common side effects of cytotoxic chemotherapy are epiphora and ocular surface irritation, which can be caused by any of several different regimens. Most notably, the taxane docetaxel can lead to epiphora by inducing canalicular stenosis. The selective-estrogen-receptor-modulator (SERM) tamoxifen, long the gold-standard adjuvant-endocrine-therapy for women with hormone-receptor-positive BC, increases the risk of posterior subcapsular cataract. Tamoxifen also affects the optic nerve head more often than previously thought, apparently by causing subclinical swelling within the first 2 years of use for women older than ~50 years. Tamoxifen retinopathy is rare, but it can cause foveal cystoid spaces that are revealed with spectral-domain optical coherence tomography (OCT) and that may increase the risk for macular holes. Tamoxifen often alters the perceived color of flashed lights detected via short-wavelength-sensitive (SWS) cone response isolated psychophysically; these altered perceptions may reflect a neural-response sluggishness that becomes evident at ~2 years of use. The aromatase inhibitor (AI) anastrozole affects perception similarly, but in an age-dependent manner suggesting that the change of estrogen activity towards lower levels is more important than the low estrogen activity itself. Based on analysis of OCT retinal thickness data, it is likely that anastrozole increases the tractional force between the vitreous and retina. Consequently, AI users, myopic AI users particularly, might be at increased risk for traction-related vision loss. Because bisphosphonates are sometimes prescribed to redress AI-induced bone loss, clinicians should be aware of their potential to cause scleritis and uveitis occasionally. We conclude by suggesting some avenues for future research into the visual and ocular effects of AIs, particularly as relates to assessment of cognitive function.

The growth factor receptor-bound protein-7 gene (GRB7) encodes a multi-domain signal transduction molecule. The purpose of this study was to examine the clinical significance of GRB7 protein expression in human breast cancer. Western blotting analysis of protein extracts from 563 annotated frozen breast tumors was performed. Expression status of GRB7 and HER-2 was correlated with clinical covariates and outcomes. Cox proportional hazards were used to identify factors associated with breast cancer-free interval. The median follow-up was 71 months. P values <0.05 were considered statistically significant (two-sided). A discrepancy between HER-2 and GRB7 protein over-expression was observed. GRB7 protein over-expression was associated with negative estrogen and progesterone receptor status, higher tumor grade, larger primary tumor size, (more) axillary lymph node involvement, higher clinical stage, and shortened breast cancer-free interval. HER-2 protein over-expression was associated only with higher tumor grade. Multi-variate analysis revealed that GRB7 protein over-expression was an independent adverse prognostic factor for breast cancer-free interval (hazard ratio 1.69, 95% confidence interval 1.07-2.67; P = 0.024). The same was true of the subset of patients who did not receive any adjuvant systemic therapy (hazard ratio 1.68, 95% confidence interval 1.16-2.31; P = 0.0055). Using FISH analysis, 32/32 (100%; 95% CI 89-100%) tumors which over-expressed both HER-2 and GRB7 proteins and 1/35 (3%; 95% CI 0-15%) tumors with HER-2 but no GRB7 protein over-expression with Western blotting analysis demonstrated HER-2 gene amplification. GRB7 protein over-expression is an independent adverse prognostic factor in human breast cancer.

Objective: To identify neuromuscular, balance, and vision factors that contribute to falls in recently treated breast cancer survivors (BCS) and explore links between fall risk factors and cancer treatment., Design: Case-control plus prospective observation., Setting: Comprehensive cancer center., Participants: BCS (N=59; mean age, 58y) within 2 years of chemotherapy completion and/or on adjuvant endocrine therapy., Interventions: Not applicable., Main Outcome Measures: Objective measures of postural control, vision, and neuromuscular function included: (1) a sensory organization test (SOT), (2) a visual assessment battery, (3) muscle mass by dual energy x-ray absorptiometry, and (4) neuromuscular function with strength by repetition maximum, power by timed stair climb, and gait speed by 4m walk. Falls were self-reported for the past year (retrospective) and monthly for 6 months (prospective)., Results: Fifty eight percent of BCS reported falls in the past year. BCS with a history of falls had lower SOT scores with a vestibular deficit pattern in postural control (P<.01) and took longer to read letters on the contrast sensitivity chart (P<.05). Vestibular score on the SOT mediated the relationship between treatment and falls among BCS who received chemotherapy only, but not adjuvant endocrine therapy., Conclusions: Results of this project suggest that balance disturbances of vestibular origin and delays in detecting low contrast visual stimuli are associated with falls in BCS. Future studies that track falls and fall risk factors in BCS from diagnosis through treatment are warranted, as are studies that can identify treatment-related vestibular dysfunction and altered visual processing., (Copyright © 2011 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

Sagopilone is a novel, fully synthetic epothilone that has shown promising preclinical activity in a range of tumor models, including platinum-resistant ovarian cancer and metastatic breast cancer (MBC). This open-label, multicenter, Phase II study investigated the efficacy, safety, and tolerability of sagopilone administered to patients with MBC. Women with MBC whose previous chemotherapy regimen included a taxane and an anthracycline received sagopilone 16 or 22 mg/m(2) as a 3-h intravenous infusion every 21 days. Efficacy (using modified Response Evaluation Criteria in Solid Tumors), safety, and tolerability were assessed in this population. A total of 65 patients received sagopilone at either 16 mg/m(2) (N = 39) or 22 mg/m(2) (N = 26). Patients received a median of two cycles of sagopilone. Among the 65 patients who were evaluable for efficacy, there were three confirmed tumor responses over both treatment arms; however, the primary target of the study was not reached. The main treatment-related adverse events were sensory neuropathy (81.5%) and fatigue (44.6%). There were no deaths related to the study drug. Sagopilone was moderately tolerated in both treatment arms and showed limited activity in heavily pre-treated patients with MBC.

Growth factor receptor-bound protein-7 (GRB-7), an adaptor molecule, can interact with multiple signal transduction molecules. GRB-7 is amplified concurrently with HER-2/Neu in most, if not all, of breast cancer with chromosome 17q11-21 amplification. GRB-7 gene amplification is associated with RNA over-expression. We show GRB-7 protein is over-expressed by immunoblotting in breast cancer cell lines and primary breast tumors with HER-2/Neu protein over-expression. Over-expression of GRB-7 in MCF-7 breast cancer cells that over-express HER-2/Neu leads to activation of tyrosine phosphorylation of HER-2/Neu. Knockdown of GRB-7 expression in SKBR-3 breast cancer cells with naturally occurring HER-2/Neu gene amplification decreases tyrosine phosphorylation of HER-2/Neu. Activation of HER-2/Neu phosphorylation is associated with increase in tyrosine phosphorylation of phosphoinositide-specific lipase C-gamma-1 (PLC-gamma-1) and recruitment of PLC-gamma-1 to HER-2/Neu protein molecule. Activation of downstream protein kinase C (PKC) pathway is evidenced by increase in the phosphorylation of a common PKC substrate-myristoylated alanine-rich protein kinase C substrate (MARCKS). In addition, over-expression of GRB-7 in MCF-7 breast cancer cells that over-express HER-2/Neu leads to activation of AKT phosphorylation. Knockdown of GRB-7 expression in MB-453 and SKBR-3 breast cancer cells results in decrease in AKT phosphorylation. GRB-7 over-expression therefore facilitates activation of phosphorylation of HER-2/Neu and AKT in breast cancer cells with HER-2/Neu over-expression. GRB-7 over-expression in MCF-7 cells over-expressing HER-2/Neu leads to morphologic change of cells and promotes tumor xenograft growth in nude mice. GRB-7 over-expression therefore plays pivotal roles in activating signal transduction and promoting tumor growth in breast cancer cells with chromosome 17q11-21 amplification.

Hormonal therapy is the mainstay of adjuvant treatment for women with early-stage estrogen receptor-positive breast cancer. Recently, the aromatase inhibitors have moved to the forefront of adjuvant hormonal therapy, however, the adverse effects of these agents are not yet fully understood. It is generally accepted that tamoxifen, but not the aromatase inhibitors, is associated with an increased risk of thrombosis in women with breast cancer. Studies comparing aromatase inhibitors to tamoxifen in the adjuvant setting have reported a lower rate of venous thromboembolism with the aromatase inhibitors, yet the incidence of venous thromboembolism with these new agents is higher than that expected in the general population. Here we report a case of acute bilateral pulmonary emboli occurring while on adjuvant aromatase inhibitor therapy with anastrozole, and review the literature on the incidence of venous thromboembolism during the use of aromatase inhibitors in the adjuvant setting.

Gene amplification is common in solid tumors and is associated with adverse prognosis, disease progression, and development of drug resistance. A small segment from chromosome 17q11-12 containing the HER-2/Neu gene is amplified in about 25% of breast cancer. HER-2/Neu amplification is associated with adverse prognosis and may predict response to chemotherapy and hormonal manipulation. Moreover, HER-2/Neu amplification may select patients for anti-HER-2/Neu-based therapy with Herceptin. We and others recently described a common sequence element from the HER-2/Neu region that was amplified in breast cancer cells. In addition, most, if not all, of the amplified genes from this region display overexpression. This raises the intriguing possibility that genes immediately adjacent to HER-2/Neu may influence the biological behavior of breast cancer carrying HER-2/Neu amplification and serve as rational targets for therapy. By extracting sequence information from public databases, we have constructed a contig in bacterial artificial chromosomes (BACs) that extends from HER-2/Neu to a phosphotidylinositol phosphate kinase (PIPK), Pip4k2beta from 17q11-12. Although a role of PI-3-kinase and AKT in cancer biology has been previously described, PIPK has not been previously implicated. We show that Pip4k2beta, initially known as Pip5k2beta, is amplified in a subset of breast cancer cell lines and primary breast cancer samples that carry HER-2/Neu amplification. Out of eight breast cancer cell lines with HER-2/Neu amplification, three have concomitant amplification of the Pip4k2beta gene--UACC-812, BT-474 and ZR-75-30. Similarly, two out of four primary breast tumors with HER-2/Neu amplification carry Pip4k2beta gene amplification. Intriguingly, one tumor displays an increase in the gene copy number of Pip4k2beta that is significantly more than that of HER-2/Neu. Moreover, dual color FISH reveals that amplified Pip4k2beta gene may exist in a distinct structure from that of HER-2/Neu in ZR-75-30 cell line. These studies suggest that Pip4k2beta may reside on an amplification maximum distinct from that of HER-2/Neu and serve as an independent target for amplification and selective retention. Pip4k2beta amplification is associated with overexpression at the RNA and protein level in breast cancer cell lines. Stable expression of Pip4k2beta in breast cancer cell lines with and without HER-2/Neu amplification increases cell proliferation and anchorage-independent growth. The above observations implicate Pip4k2beta in the development and/or progression of breast cancer. Our study suggests that Pip4k2beta may be a distinct target for gene amplification and selective retention from 17q11-12.

Amplification of a portion of 17q11 approximately q12 involving the human epidermal growth factor receptor-2 (HER-2/neu) gene is common in solid tumors. HER-2/neu amplification in breast cancer is associated with a poor prognosis and may predict response to therapeutic interventions. The molecular complexity and informative content of the 17q11 approximately q12 amplified DNA remain largely unknown. Study of available sequence information in public database allowed us to construct a contig in bacterial artificial chromosome that covers this region. We have identified a several hundred kilobase core segment from this region that is amplified in three out of three breast cancer cell lines with HER-2/neu amplification. There is striking correlation between amplification and overexpression of genes from this region. Amplified and overexpressed genes, in addition to HER-2/neu, may play functional roles in the pathogenesis of breast cancer and may serve as additional targets for therapy. Published by Elsevier Science Inc.

G2A is an orphan G protein-coupled receptor (GPCR), expressed predominantly in T and B cells and homologous to a small group of GPCRs of unknown function expressed in lymphoid tissues. G2A is transcriptionally induced in response to diverse stimuli, and its ectopic expression suppresses transformation of B lymphoid precursors by BCR-ABL. G2A induces morphological transformation of NIH 3T3 fibroblasts. Microinjection of constructs encoding G2A into Swiss 3T3 fibroblasts induces actin reorganization into stress fibers that depends on RhoA, but not CDC42 or RAC. G2A elicits RhoA-dependent transcriptional activation of serum response factor. Direct evaluation of RhoA activity demonstrates elevated levels of RhoA-GTP in G2A-expressing cells. Microinjection of embryonic fibroblasts derived from various G alpha knockout mice establishes a requirement for G alpha 13 but not G alpha 12 or G alpha q/11 in G2A-induced actin rearrangement. In conclusion, G2A represents a family of GPCRs expressed in lymphocytes that may link diverse stimuli to cytoskeletal reorganization and transcriptional activation through a pathway involving G alpha 13 and RhoA.

The zinc-finger proteins ZFX and ZFY, encoded by genes on the mammalian X and Y chromosomes, have been speculated to function in sex differentiation, spermatogenesis, and Turner syndrome. We derived Zfx mutant mice by targeted mutagenesis. Mutant mice (both males and females) were smaller, less viable, and had fewer germ cells than wild-type mice, features also found in human females with an XO karyotype (Turner syndrome). Mutant XY animals were fully masculinized, with testes and male genitalia, and were fertile, but sperm counts were reduced by one half. Homozygous mutant XX animals were fully feminized, with ovaries and female genitalia, but showed a shortage of oocytes resulting in diminished fertility and shortened reproductive lifespan, as in premature ovarian failure in humans. The number of primordial germ cells was reduced in both XX and XY mutant animals at embryonic day 11.5, prior to gonadal sex differentiation. Zfx mutant animals exhibited a growth deficit evident at embryonic day 12.5, which persisted throughout postnatal life and was not complemented by the Zfy genes. These phenotypes provide the first direct evidence for a role of Zfx in growth and reproductive development.

The human ZFX, human ZFY, and mouse Zfx genes have CpG islands near their 5; ends. These islands are typical in that they span about 1.5 kb, contain transcription initiation sites, and encompass some 5' untranslated exons and introns. However, comparitive nucleotide sequencing of these human and mouse islands provided evidence of evolutionary conservation to a degree unprecedented among mammalian 5' CpG islands. In one stretch of 165 nucleotides containing 19 CpGs, mouse Zfx and human ZFX are identical to each other and differ from human ZFY at only 9 nucleotides. In contrast, we found no evidence of homologous CpG islands in the mouse Zfy genes, whose transcription is more circumscribed than that of human ZFX, human ZFY, and mouse Zfx. Using the isoschizomers HpaII and MspI to examine a highly conserved segment of the ZFX CpG island, we detected methylation on inactive mouse X chromosomes but not on inactive human X chromosomes. These observations parallel the previous findings that mouse Zfx undergoes X inactivation while human ZFX escapes it.

Genes homologous to mouse Zfx have been identified on the X and Y chromosomes of all placental mammals examined. The genes of this ZFX/ZFY family appear to encode proteins comprising an amino-terminal acidic domain, a putative nuclear localizing signal, and a carboxy-terminal domain of 13 zinc fingers. These proteins likely function as transcription activators. Although roles for these proteins in sex determination, Turner syndrome, and spermatogenesis have been proposed, the biological processes in which these proteins function are not known. No comprehensive studies of gene structure have been reported for any member of the ZFX/ZFY family. Here, we report that mouse Zfx spans 50 kb and contains at least 11 exons. Exons 1 through 4 contain 5' untranslated sequences, exons 5 through 10 encode the acidic domain, exon 10 also encodes the putative nuclear localizing signal, and exon 11 encodes 13 zinc fingers and contains the 3' untranslated sequences. The 5' untranslated exons exhibit complex patterns of differential splicing. At the 5' end of this widely expressed gene, a 1.5-kb CpG island encompasses multiple transcription initiation sites as well as the first and second exons. The 5' portion of the CpG island displays promoter activity. This knowledge of the Zfx gene structure allowed us to reconstruct the splicing and retroposition events by which the Zfa gene on mouse chromosome 10 arose from a Zfx transcript.

Several categories of human X-Y homologous DNA sequences have been recognized. We report that a locus (DXYS77) approximately 14 kb distal to the pseudoautosomal boundary (PAB) is 93% identical in nucleotide sequence to a locus (DYS148) on the long arm of the Y chromosome (Yq). Within this segment of pseudoautosomal/Yq homology we identified a member of a family of repeats that are concentrated in Xp22.3 and in the euchromatic portion of the Y chromosome. The repeat sequence structure--a dimer bounded by short terminal repeats--is reminiscent of retroposons derived from RNA polymerase III transcripts.

The Zfy gene is located on the Y chromosome of placental mammals and encodes a zinc finger protein which may serve as the primary sex-determining signal. A related gene, Zfx, is similarly conserved on the X chromosome. Unlike that in most mammals, the mouse genome contains four homologous zinc finger loci: Zfy-1, Zfy-2, Zfx, and Zfa (on an autosome). We report that, in contrast to the mouse Zfy genes, Zfx is widely transcribed in embryos, newborns, and adults, both male and female. Moreover, Zfx transcripts contain long 3' untranslated sequences which are phylogenetically conserved. Zfa is a processed gene derived from Zfx. An analysis of cDNA clones demonstrated that Zfx encodes a 799-amino-acid protein that is 70% identical to the mouse Zfy-1 and Zfy-2 proteins. Zfx, Zfy-1, and Zfy-2 contain highly acidic amino-terminal domains and carboxy-terminal regions containing 13 zinc fingers. When fused to the DNA-binding domain of GAL4, the acidic domains of Zfx and Zfy-2 activated transcription in yeast cells.