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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.

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.gov NCT00662103

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.

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.

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 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 × 10−199), and thrombosis ORrs505922 1.33, p=2.2 ×10−265. 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 ×10−23, lupus OR 0.84, p=3.97 × 10−06. PheWAS stratified by genetic ancestry demonstrated differences in genotype-phenotype associations across ancestry. LMNA (rs581342) associated with neutropenia OR 1.29 p=4.1 × 10−13 among Veterans of African 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.

RationaleA commonMUC5Bgene polymorphism, rs35705950-T, is associated with idiopathic pulmonary fibrosis, but its role in the SARS-CoV-2 infection and disease severity is unclear.ObjectivesTo assess whether rs35705950-T confers differential risk for clinical outcomes associated with COVID-19 infection among participants in the Million Veteran Program (MVP) and COVID-19 Host Genetics Initiative (HGI).MethodsMVP participants were examined for an association between the incidence or severity of COVID-19 and the presence of aMUC5Brs35705950-T allele. Comorbidities and clinical events were extracted from the electronic health records (EHR). The analysis was performed within each ancestry group in the MVP, adjusting for sex, age, age2,and first twenty principal components followed by a trans-ethnic meta-analysis. We then pursued replication and performed a meta-analysis with the trans-ethnic summary statistics from the HGI. A phenome-wide association study (PheWAS) of the rs35705950-T was conducted to explore associated pathophysiologic conditions.Measurements and Main ResultsA COVID-19 severity scale was modified from the World Health Organization criteria, and phenotypes derived from the International Classification of Disease-9/10 were extracted from EHR. Presence of rs35705950-T was associated with fewer hospitalizations (Ncases=25353, Ncontrols=631,024; OR=0.86 [0.80-0.93], p=7.4 × 10−5) in trans-ethnic meta-analysis within MVP and joint meta-analyses with the HGI (N=1641311; OR=0.89 [0.85-0.93], p =1.9 × 10−6). Moreover, individuals of European Ancestry with at least one copy of rs35705950-T had fewer post-COVID-19 pneumonia events (OR=0.85 [0.76-0.96], p =0.008). PheWAS exclusively revealed pulmonary involvement.ConclusionsTheMUC5Bvariant rs35705950-T is protective in COVID-19 infection.

Background: Only 1-2 % of all breast cancers present as synchronous bilateral breast cancers. These tumors may be clonally related or clonally independent. Previous analyses of synchronous bilateral breast cancers were limited by the small sample size and lack of comprehensive genomic analysis. Comparative analysis of genomic alternations in these tumors presents a unique opportunity to address the following important questions: (1) are bilateral breast cancers clonally related, and (2) do bilateral breast cancers carry molecular and genomic alterations unique from those of unilateral breast cancers. Methods: We examined synchronous left and right breast tumor samples from (16) patients collected from 1988 -1998, flash frozen, and stored at -80C in the OHSU Knight Cancer Institute BioLibrary, and 10 pairs of FFPE preserved synchronous tumors from the Kaiser Permanente NW Research Bank, collected between 2004 and 2011. These samples and matching patient demographics, clinical staging, and biomarker configuration were acquired and research conducted under IRB regulatory approval. Tumor sections were cut and tumor rich areas identified and macro-dissected. Genomic DNA was isolated and whole exon-sequencing performed. For Kaiser specimens, a benign axillary lymph node was used as a matched germ line control. Clonal relationships were determined based on distribution of somatically acquired mutations and copy number variations in the bilateral breast cancer pairs. Results: Two out of 23 synchronous bilateral breast cancers (tumors excised on the same date or within a short interval of time) are clonally related based on distribution of somatically acquired mutations and copy number variation. Two out of three metachronous bilateral breast cancers (tumors excised 6, 12 and 18 months apart) are clonally related. Each tumor of a clonally related bilateral breast pair may have a different biomarker configuration. The number of unique somatic mutations in bilateral breast cancers from four clonally related pairs, i.e. present only in tumors from one side but not the contralateral side, is small and ranges from 0 to 8. The number and distribution of somatically acquired mutations in this set of bilateral breast cancers is similar to those previously seen in unilateral breast cancers. Conclusion: To our knowledge, our study represents the largest collection of synchronous bilateral breast cancers to have received comprehensive genomic analysis. Synchronous bilateral breast cancers appear to have similar breast cancer associated mutations as have been reported with unilateral breast cancers. The molecular differences between clonally related bilateral breast cancers appears to be limited suggesting that study of these differences may reveal the molecular underpinning of breast cancer metastasis. Citation Format: Shiuh-Wen Luoh, Myron Peto, Betsy Ramsey, Carol Halsey, Timothy Butler, Paul Spellman. Comprehensive genomic analysis of synchronous bilateral breast cancer tumors [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-21-04.

PURPOSE 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.

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.

BackgroundRecent 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 and readily available compounds that reduce COVID-19 host susceptibility is a critical next step.MethodsWe integrate COVID-19 genetic susceptibility variants, multi-tissue genetically regulated gene expression (GReX) and perturbargen signatures to identify candidate genes and compounds that reverse the predicted gene expression dysregulation associated with COVID-19 susceptibility. The top candidate gene is validated by testing both its GReX and observed blood transcriptome association with COVID-19 severity, as well as by in vitro perturbation to quantify effects on viral load and molecular pathway dysregulation. We validate the in silico drug repositioning analysis by examining whether the top candidate compounds decrease COVID-19 incidence based on epidemiological evidence.ResultsWe identify IL10RB as the top key regulator of COVID-19 host susceptibility. Predicted GReX up-regulation of IL10RB and higher IL10RB expression in COVID-19 patient blood is associated with worse COVID-19 outcomes. In vitro IL10RB overexpression is associated with increased viral load and activation of immune-related molecular pathways. Azathioprine and retinol are prioritized as candidate compounds to reduce the likelihood of testing positive for COVID-19.ConclusionsWe establish an integrative data-driven approach for gene target prioritization. We identify and validate IL10RB as a suitable molecular target for modulation of COVID-19 host susceptibility. Finally, we provide evidence for a few readily available medications that would warrant further investigation as drug repositioning candidates.

Background: Research has demonstrated that women with lower individual-level socioeconomic position (SEP) are at higher risk for breast cancer (BC) mortality. Census tract-level household educational attainment has been considered both as a proxy for individual-level SEP and an indicator of neighborhood social environment. Few studies have evaluated the association of census tract-level SEP on BC mortality by race/ethnicity, particularly within stage at diagnosis in young women. Objective: To determine associations between residential SEP, measured by household educational attainment, and BC mortality by race/ethnicity within stage at diagnosis among young women in California, 2006-2015. Methods: Data are from a pilot data product, the California Cancer Registry Data with Synthetic Census Tracts, which is available to external researchers coordinated with confidential data available to qualified internal users. The present study includes 41,886 young (25-49 years of age) California women who were diagnosed with primary invasive BC during 2006-2015. SEP was defined based on % of households completing a bachelor’s degree or higher (categorized as ≤30%, 30-60%, and ≥60% of households). Multivariate analyses were conducted to examine the association between SEP and BC mortality by race/ethnicity within stage at diagnosis by calculating hazard ratios (HR) and 95% confidence interval (CI), adjusting for age at diagnosis, marital status, tumor histology and diagnosis year. Results: For Stage I BC, compared to census tracts with ≤30% bachelor’s degree, the adjusted HR (95% CI) was 0.57 (0.44, 0.74) for tracts with 30-60% and 0.48 (0.32, 0.72) for tracts with ≥60% of households attaining a bachelor’s degree. For Stage II, the corresponding HRs (95% CIs) are 0.75 (0.66-0.84) and 0.54 (0.44-0.67); for Stage III, 0.80 (0.72-0.89) and 0.63 (0.51-0.76); and for Stage IV 0.73 (0.65-0.84) and 0.53 (0.41-0.69). When examined by race/ethnicity and stage at diagnosis, a significantly reduced mortality was associated with residing in census tracts with ≥60% of households having attained a bachelor’s degree compared to ≤30% for Stage I only among Asian (HR=0.30; 95% CI=0.11-0.77); for Stage II for White (HR=0.53; 95% CI=0.41-0.70) and Asian (HR=0.56; 95% CI=0.34-0.91); for Stage III White (HR=0.72; 95% CI=0.55-0.94) and Hispanic (HR=0.49; 95% CI=0.24-0.99); and for Stage IV White (HR=0.58; 95% CI=0.41-0.82) and Asian (HR=0.48; 95% CI=0.26-0.90) populations. Sample size was limited among Black and Asian Pacific Islander subgroups. Conclusion: Higher census tract-level SEP, defined as ≥60% of the population having a bachelor’s degree, is associated with a significantly decreased risk for BC-mortality at all stages of diagnosis. This effect isn't consistent across all stages of diagnosis among Hispanic populations, but is consistent among Non-Hispanic White and Asian populations in California, 2006-2015. Citation Format: Zhenzhen Zhang, Ellen Velie, Shangyuan Ye, Joe Zou, Lydia Marcus, Shiuh-Wen Luoh, Duo Jiang, Mandi Yu. Socioeconomic position, race/ethnicity and breast cancer mortality among young women in California [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5913.

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 anti-tumor 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.

Key Points Question Is the length of the interscreening period associated with breast cancer prognostic factors and mortality in interval breast cancers compared with cancers detected by screening? Findings In this study using data from the Women’s Health Initiative, a national study among postmenopausal women, interval breast cancers diagnosed within 1 year from a mammogram with negative results were associated with worse breast cancer–specific mortality compared with breast cancers detected by screening. Mortality remained statistically significantly higher after adjustment for trial group, molecular subtype, other risk factors, histologic characteristics, and either tumor size or lymph node but not when tumor size and lymph node were included in the model; no differences were observed between interval cancers diagnosed between 1 and 2.5 years from a mammogram with negative results and breast cancers detected by screening. Meaning Interval cancers occurring within 1 year from a mammogram with negative results may have a unique biology that accounts for aggressive features., 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., This cohort study uses data from the Women’s Health Initiative study to compare the prognostic features and mortality rate of women with interval breast cancers 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.

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.

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.

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.

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 (

12059 Background: Women with cancer are significantly more likely to fall than women without cancer but there are not yet any evidence-based fall prevention strategies that specifically target cancer survivors. The GET FIT trial compares the efficacy of two distinct types of exercise, strength training vs. tai ji quan, to prevent falls in women finished with chemotherapy. Methods: We conducted a 3 group, single-blind, parallel design, randomized controlled trial in older, inactive women cancer survivors treated with chemotherapy. Women were randomly assigned to 1 of 3 intervention groups: 1) strength training, 2) tai ji quan or 3) a placebo control group (stretching) that trained 2x/week for 6 months. Additional follow-up occurred 6 months after formal training stopped. The primary outcome was fall rate across 6-and 12 months; secondary outcomes, reflective of training fidelity, were maximal leg strength (by 1-repetition maximum) and dynamic postural control (by computerized dynamic posturography), collected at 0, 3, and 6 months. Results: 442 women (mean age 62.4 + 6.3 yrs.) were enrolled and randomly assigned to study groups. Over the 6 months prior to enrollment, 21% of the sample (n = 94) reported at least one fall (of which, 37% (n = 35) reported two or more falls)), and 12% (n = 51) reported at least one injurious fall. Retention across the 12 months study period was 88%, while adherence to the study interventions over 6 months averaged 73%, 71%, and 74% for the strength, tai ji quan and stretching (control) groups, respectively. 26% of the sample (n = 99 of 382) reported at least one fall during the intervention and 27% (n = 102) reported falls during follow up. Using regression models, there were no significant differences in the odds of having at least one fall during the intervention period (1-6 months) or across the entire follow-up period (1-12 months) between the control and either the strength or tai ji quan groups. At 6 months, the strength group showed a greater increase from baseline in maximal leg strength (+14.3 kg, 95% CI: 11.4-17.1) than the control group (+7.5 kg, 95% CI: 4.6-10.4, p = 0.002). Whereas, the tai ji quan group showed a greater increase in dynamic postural control (+2.42%, 95% CI: 1.36-3.48) compared to the control group (+0.35%, 95% CI: -0.69-1.38, p = 0.007). Conclusions: Despite evidence for fidelity of strength and tai ji quan training to improve muscle strength and postural control, respectively, neither program significantly lowered fall rates over a placebo control group. It is possible that the dose of exercise was too low and/or the sample was not at high risk of falls. The etiology of fall risk in women cancer survivors needs to be better understood as it may differ from risk factors in older adults. Future trials should consider patient-centered, tailored fall-prevention interventions for cancer survivors based on identified fall risk factors. Clinical trial information: NCT01635413.

12075 Background: Women treated for cancer are more likely to fall than women without a cancer history. Exercise is a fall prevention strategy for older adults that we are testing in the GET FIT trial as a fall prevention approach in women cancer survivors. Increasing physical activity, though, could acutely increase the risk of falls in inactive survivors with known fall risk related to treatment. Knowing who might be at risk prior to beginning an exercise program would inform additional safety precautions during exercise. Methods: We conducted a secondary analysis of baseline data from the GET FIT trial that enrolled inactive, older women who had completed chemotherapy for cancer. Women completed objective (muscle strength, static postural control, range of motion, physical functioning) and self-report (fall history, comorbidities, presence of neuropathy symptoms, pain severity, depressive symptoms, cognitive functioning, perceptions of lower extremity functioning, disability, fear of falling, demographic, and clinical characteristics) measures at baseline. Falls were prospectively collected during the 6 month intervention using monthly self report. Potential predictors of falls were included if univariate tests revealed significant differences between fallers and non-fallers. To identify the strongest predictors of falls, we used an automated model selection and multimodel inference approach to perform an exhaustive model search. Results: Baseline data were available for 415 participants with known faller status at the end of the intervention, of whom 31.3% (n = 130) reported at least one fall. The average age of the sample was 62.1±6.4 years and consisted mostly of non-Hispanic white, married, highly educated, overweight or obese women treated for breast cancer. Fallers (1+ falls) and non-fallers significantly differed on measures of fall history, comorbidities, pain, neuropathy, fear of falling, disability, perceived lower extremity functioning, cognitive functioning, depression, and postural control. The best model of faller status (per BIC) included postural control (p = 0.004), perceived lower extremity functioning (p = 0.072), and fear of falling (p = 0.030). Odds of ≥1 fall during the intervention increased by 1.72 (95% CI: 1.05-2.83) times for a 0.1-point decrease in postural control, 1.11 (1.04-1.19) times for a 0.1-point increase in fear of falling, and 1.02 (1.00-1.03) times for a 1-point decrease in perceived lower extremity functioning. Conclusions: Women cancer survivors with poor balance, poor self-rated functioning, and a fear of falling may need to take additional fall precautions when starting an exercise program. Clinical trial information: NCT01635413.

BackgroundAccurate breast cancer risk assessment allows personalized approach in breast cancer screening and/or prevention. Breast cancer risk prediction models have been developed. Independent prospective validation however was needed before broad clinical applications. The Department of Veterans Affairs (VA) Million Veteran Program (MVP) is one of the largest biobanks in the world. Important attributes include: large sample size (>830,000, April 20), national coverage, multi-ethnic representation, access to bio-specimens from which multi-omics measurements have been conducted, thousands of biomedical phenotypes derived from our baseline and life style surveys and electronic health records (EHR). About 9% of MVP registrants are women. Breast cancer risk prediction models were evaluated in a prospective cohort of women in MVP. MethodologyMore than 350000 MVP participants completed genotyping to date. Breast cancer diagnoses were captured from the EHR. Ethnicity was determined by a supervised learning algorithm, Harmonized Ancestry and Race/Ethnicity (HARE), that used genetically inferred ancestry to refine self-identified race/ethnicity. Clinical breast cancer risk prediction instruments were based on personal health, lifestyle, demographics, family history, and environmental exposure. Polygenic Risk Score used in this study is comprised of 313 single nucleotide polymorphisms (PRS313). Clinical risk models tested were: BPC3, Lit and Breast Cancer Risk Assessment Tool (BCRAT, a version of the Gail’s model). The BPC3 and Lit models were tested by deploying the iCARE (Individualized Cancer Absolute Risk Estimator) with or without incorporation of PRS313. The BCRAT was deployed in the R package “BCRA” (Breast Cancer Risk Assessment v. 2.1 by F. Zhang). The performance of the risk prediction models was assessed by Area under the Receiver Operating Characteristic Curve (AUC-ROC). The observed absolute risk over expected absolute risk was compared for each decile. Results35133 genetic females were identified without a prior breast cancer diagnosis. By HARE definition, 10717 were African Americans (AA), 317 non-Hispanic Asians (ASIAN), 19941 non-Hispanic whites (EU), 1803 Hispanic (HIS) and 1355 unassigned. The median age of this cohort at MVP entry was 55. 369 subjects developed incident breast cancers with a median follow up of 4 years. These new cases were identified from Cancer Registry (292 cases) and EHR search for compatible ICD plus CPT codes (77 cases). The breast cancer incidence rate was 2.6/1000/year. iCARE-lit model was tested in 2731 AA women (38 incident breast cancers), 9027 EU women (111 incident breast cancers), and 10254 non-AA women (122 incident breast cancers) that had comprehensive risk factor evaluation (20%. The iCARE-BPC3 had similar performance as iCARE-lit. The AUC of BCRAT alone was 0.648 for EU (20550 with 179 incident breast cancers) and 0.661 for AA (10462 with 96 incident breast cancers). Incorporation of PRS313 to BCRAT improved the AUC to 0.682 (EU) and 0.658 (AA). BCRAT plus PRS313 estimated that 5.6% (AA) and 4.4% (EU) of the women would have a lifetime risk of >20%. DiscussionWe prospectively evaluated and validated the performance of breast cancer risk prediction models as reported from case control studies. Longer follow up of more women in MVP will provide better assessment esp. for AA women. Prospective validation of these risk prediction models provides strong rationale for further development of these models in the clinical setting. Citation Format: Shiuh-Wen Luoh, Cynthia Brandt, Sally Haskell, Lina Gao, Byung Park, Paul Spellman, Saiju Pyarajan, Million Veteran Program, Nallakkandi Rajeevan, Jessica Minnier. Predicting breast cancer risk for women veterans [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS7-07.

Women with cancer are more likely to fall than women without cancer placing them at high risk of fall-related fractures, other injuries and disabilities. Determining the efficacy of fall prevention programs depends upon reliable self-reporting of falls. The purpose of this paper is to describe the approach used to collect falls as a primary endpoint of a 12-month fall prevention exercise trial in older women cancer survivors. GET FIT (Group Exercise Training for Functional Improvement after Treatment) was a randomized controlled trial of women cancer survivors aged 50–75 years who had completed chemotherapy and were randomized into one of three exercise groups: strength training, tai chi, or seated stretching (control). We captured falls and injurious falls through monthly and quarterly self-report. Women with an e-mail address received surveys electronically via REDCap and women without one completed the survey by phone, postcard, or in exercise class. Out of 442 randomized women, 96% (n=422) reported having an e-mail. Women with an email address were more likely to be white race (p

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.

BACKGROUND: ExteNET showed that 1 year of neratinib, an irreversible pan-HER tyrosine kinase inhibitor, significantly improves 2-year invasive disease-free survival after trastuzumab-based adjuvant therapy in women with HER2-positive breast cancer. We report updated efficacy outcomes from a protocol-defined 5-year follow-up sensitivity analysis and long-term toxicity findings. METHODS: In this ongoing randomised, double-blind, placebo-controlled, phase 3 trial, eligible women aged 18 years or older (≥20 years in Japan) with stage 1-3c (modified to stage 2-3c in February, 2010) operable breast cancer, who had completed neoadjuvant and adjuvant chemotherapy plus trastuzumab with no evidence of disease recurrence or metastatic disease at study entry. Patients who were eligible patients were randomly assigned (1:1) via permuted blocks stratified according to hormone receptor status (hormone receptor-positive vs hormone receptor-negative), nodal status (0 vs 1-3 vs or ≥4 positive nodes), and trastuzumab adjuvant regimen (given sequentially vs concurrently with chemotherapy), then implemented centrally via an interactive voice and web-response system, to receive 1 year of oral neratinib 240 mg/day or matching placebo. Treatment was given continuously for 1 year, unless disease recurrence or new breast cancer, intolerable adverse events, or consent withdrawal occurred. Patients, investigators, and trial funder were masked to treatment allocation. The predefined endpoint of the 5-year analysis was invasive disease-free survival, analysed by intention to treat. ExteNET is registered with ClinicalTrials.gov, number NCT00878709, and is closed to new participants. FINDINGS: Between July 9, 2009, and Oct 24, 2011, 2840 eligible women with early HER2-positive breast cancer were recruited from community-based and academic institutions in 40 countries and randomly assigned to receive neratinib (n=1420) or placebo (n=1420). After a median follow-up of 5·2 years (IQR 2·1-5·3), patients in the neratinib group had significantly fewer invasive disease-free survival events than those in the placebo group (116 vs 163 events; stratified hazard ratio 0·73, 95% CI 0·57-0·92, p=0·0083). The 5-year invasive disease-free survival was 90·2% (95% CI 88·3-91·8) in the neratinib group and 87·7% (85·7-89·4) in the placebo group. Without diarrhoea prophylaxis, the most common grade 3-4 adverse events in the neratinib group, compared with the placebo group, were diarrhoea (561 [40%] grade 3 and one [BACKGROUND: ExteNET showed that 1 year of neratinib, an irreversible pan-HER tyrosine kinase inhibitor, significantly improves 2-year invasive disease-free survival after trastuzumab-based adjuvant therapy in women with HER2-positive breast cancer. We report updated efficacy outcomes from a protocol-defined 5-year follow-up sensitivity analysis and long-term toxicity findings.METHODS: In this ongoing randomised, double-blind, placebo-controlled, phase 3 trial, eligible women aged 18 years or older (≥20 years in Japan) with stage 1-3c (modified to stage 2-3c in February, 2010) operable breast cancer, who had completed neoadjuvant and adjuvant chemotherapy plus trastuzumab with no evidence of disease recurrence or metastatic disease at study entry. Patients who were eligible patients were randomly assigned (1:1) via permuted blocks stratified according to hormone receptor status (hormone receptor-positive vs hormone receptor-negative), nodal status (0 vs 1-3 vs or ≥4 positive nodes), and trastuzumab adjuvant regimen (given sequentially vs concurrently with chemotherapy), then implemented centrally via an interactive voice and web-response system, to receive 1 year of oral neratinib 240 mg/day or matching placebo. Treatment was given continuously for 1 year, unless disease recurrence or new breast cancer, intolerable adverse events, or consent withdrawal occurred. Patients, investigators, and trial funder were masked to treatment allocation. The predefined endpoint of the 5-year analysis was invasive disease-free survival, analysed by intention to treat. ExteNET is registered with ClinicalTrials.gov, number NCT00878709, and is closed to new participants.FINDINGS: Between July 9, 2009, and Oct 24, 2011, 2840 eligible women with early HER2-positive breast cancer were recruited from community-based and academic institutions in 40 countries and randomly assigned to receive neratinib (n=1420) or placebo (n=1420). After a median follow-up of 5·2 years (IQR 2·1-5·3), patients in the neratinib group had significantly fewer invasive disease-free survival events than those in the placebo group (116 vs 163 events; stratified hazard ratio 0·73, 95% CI 0·57-0·92, p=0·0083). The 5-year invasive disease-free survival was 90·2% (95% CI 88·3-91·8) in the neratinib group and 87·7% (85·7-89·4) in the placebo group. Without diarrhoea prophylaxis, the most common grade 3-4 adverse events in the neratinib group, compared with the placebo group, were diarrhoea (561 [40%] grade 3 and one [INTERPRETATION: At the 5-year follow-up, 1 year of extended adjuvant therapy with neratinib, administered after chemotherapy and trastuzumab, significantly reduced the proportion of clinically relevant breast cancer relapses-ie, those that might lead to death, such as distant and locoregional relapses outside the preserved breast-without increasing the risk of long-term toxicity. An analysis of overall survival is planned after 248 events.FUNDING: Wyeth, Pfizer, and Puma Biotechnology.

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.

Winters-Stone KM, Torgrimson B, Horak F, Eisner A, Nail L, Leo MC, Chui S, Luoh S-W. Identifying factors associated with falls in postmenopausal breast cancer survivors: a multi-disciplinary approach. 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 P 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.

The GET FIT (Group Exercise Training for Functional Improvement after Treatment) trial is the first randomized controlled trial to test the efficacy of two specific and separate types of exercise training, tai chi and strength training, to reduce falls in older female cancer survivors. The purpose of the present study is to: 1) report on the feasibility of recruitment into the trial and 2) report on retention and adherence to the exercise trial. Women were recruited through cancer registries, clinician referral, letters to past research participants, self-referral and screening of electronic health records (EHR). Interested and eligible women were consented and randomized to participate in a strength training, tai chi, or flexibility (placebo control) exercise class two times a week for 6 months. Out of 1490 screened women, 442 began the study intervention and 52 withdrew before the 6 month intervention was complete resulting in an 88% retention rate. Women who withdrew from the study reported more worry about falls compared to those who did not withdraw (p

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.

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 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

100Background: The NCI-MATCH is the largest national signal-finding trial incorporating centralized genomic testing to direct pts to molecularly targeted phase 2 treatment arms. HER2 gene amp is ob...

Amplification of a portion of 17q11∼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∼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.

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, comparative 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 Hpa II and Msp I 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.

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

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.

130 Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a side effect of cancer treatment that may persist and impact physical function. Studies that quantify functional consequences associated with CIPN in post-treatment cancer survivors are rare, based on self-report, or use small samples. The purpose of this study was to compare objective and self-report measures of physical function, gait patterns, and falls between women cancer survivors with or without symptoms of CIPN. Methods: Baseline assessments from 678 women cancer survivors enrolled in exercise trials were available for analysis. Women who self-reported symptoms of CIPN (CIPN+) were compared to asymptomatic women (CIPN-) on the following: maximal leg press strength (LPmax); timed chair stand (CS), physical performance battery (PPB), gait patterns (speed (SP), step number (SN), stride length (SL), base of support (BOS), % time in double support (%DS)), self-report physical function (PF) and disability (DIS), and falls in the past year (% fallers). Group comparisons were made using analysis of covariance, adjusting for time since diagnosis and cancer site (breast or other). Results: After excluding women who had diabetes, were premenopausal at cancer diagnosis or had not received chemotherapy, 462 cases were analyzed (age: 62±6yrs; time since diagnosis: 5.8±4.1yrs). CIPN+ (N = 210) and CIPN- (N = 252) groups significantly differed on all measures (*p < 0.05; **p < 0.01), except maximal leg strength and base of support during a usual walk, with worse performance for CIPN+. Conclusions: In our sample of women cancer survivors, 45% had symptoms of CIPN an average of 6 years post treatment and significantly worse physical function, altered gait patterns and more falls than asymptomatic women. CIPN should be addressed early in treatment and strategies to improve function and mobility and prevent falls need to be tested. [Table: see text]

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.