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Background. Patient-reported outcomes (PROs) are increasingly recognized as a valuable component to understand treatment tolerability and toxicity among patients on clinical trials. We have implemented a system for monitoring patient reported outcomes (PROs), symptoms, and quality of life (QOL) using electronic PRO (ePRO) instruments for patients enrolled in the I-SPY2 trial. I-SPY2 is a phase II multi-site clinical trial evaluating the effect of novel neoadjuvant therapies for locally advanced breast cancer. We correlated patient demographic factors with symptoms, investigated the trajectory of symptoms throughout treatment, and sought to characterize symptoms associated with decline in physical function (PF). Methods. Our study population included 259 I-SPY2 patients that completed surveys on one of 9 study arms (including novel oral taxane/immunotherapy combinations, IV paclitaxel, checkpoint inhibitor+/- LAG3 inhibitor, and control IV paclitaxel +/- trastuzumab/pertuzumab). After the 12 week period of investigational agents, most patients received standard adriamycin and cyclophosphamide (AC). Symptom severity, frequency, and interference was assessed weekly using 33 items from the PRO-CTCAE item bank. PF was assessed using the NIH PROMIS instrument and was evaluated at baseline, inter-regimen (after 12 weeks of treatment), pre-surgery, and 1 and 6 months at follow-up. An odds ratio was used to assess univariate associations between age and race, and symptoms. Regularized multi-variate regression was used to evaluate early symptoms (prior to week 6) predictive of a clinically significant (>5 point T-score) decline in PF from baseline to post-treatment follow-up among all races and age groups. Results. Of 259 patients (mean age (SD) = 46.8 (13.6)), 160 (58%) were White, 13 (5%) were Asian, 26 (10%) were African American (AA), 25 (9.3%) were Hispanic, and 35 (13.5%) self-reported “Other”. At baseline, AA patients had a higher severity of joint pain than White patients (OR = 14.9, P < 0.05). During study treatment with paclitaxel and/or novel agent within the first 12 weeks of treatment, AA patients and non-white (NW) patients were more likely to report severe vomiting than White patients (OR =13.22 and 12.72, P< 0.05 and P< 0.03 respectively). During treatment with AC, NW patients were more likely to report higher severity of neuropathy than White patients (OR = 5.43, P< 0.03). Among all patients, in analysis of early symptoms predictive of a clinically significant decline in PF between baseline and 1 month post treatment, predictors included high frequency of diarrhea, severity of itching, and severity of joint pain. Further analysis of symptom trajectories revealed that frequency of diarrhea reported rose sharply between baseline and Cycle 2 with 9 patients (7%) reporting occasional or frequent diarrhea to 39 patients (28%) reporting occasional to almost constant diarrhea and remained stable at that proportion for the remainder of treatment. Frequency of diarrhea declined slightly during AC (17%) and dropped to baseline levels by follow-up. In contrast, severity of joint pain persisted post-treatment, rising consistently from baseline through follow- up with 3 patients (2%) reporting moderate to severe joint pain at baseline to 18 patients (35%) reporting moderate to severe joint pain at follow-up. Conclusion. Among I-SPY2 participants, when higher grade of diarrhea is persistent (or uncontrolled), it impacts physical function even after end of therapy. In some cases, race was also a determinant in symptom trajectory, although a higher enrollment of AA and NW patients will enable more robust estimates to be computed. While some of these early symptom predictors are transient and resolve by the time of follow-up, others persist long-term and contribute more directly towards impaired physical function at follow-up. Citation Format: Amrita Basu, Saumya Umashankar, Kaylee Blevins, Anna Northrop, Anika Christofferson, Ebunoluwa Olunuga, Jaeyoon Cha, Ananya Mittal, Julissa Molina-Vega, Laura Sit, Thelma Brown, Bev Parker, Diane Heditsian, Susie Brain, Carol Simmons, Alessandra Taboada, Tina J. Hieken, Kathryn Ruddy, Carolina Salvador, Candace Mainor, Anosheh Afghahi, Sarah Tevis, Anne Blaes, Irene M. Kang, Jane Perlmutter, Hope Rugo, Sai Kanaparthi, Garry Peterson, Lisa T. Weiss, Adam Asare, Laura J. Esserman, Michelle Melisko, Dawn Hershman. The Association Between Symptom Severity and Physical Function among Participants in I-SPY2 [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-07-03.

Glycosaminoglycans (GAGs) are long, linear polysaccharides that are ubiquitously expressed on the cell surface and in the extracellular matrix of all animal cells. These complex carbohydrates play important roles in many cellular processes and have been implicated in many disease states, including cancer, inflammation, and genetic disorders. GAGs are among the most complex molecules in biology with enormous information content and extensive structural and functional heterogeneity. GAG biosynthesis is a nontemplate-driven process facilitated by a large group of biosynthetic enzymes that have been extensively characterized over the past few decades. Interestingly, the expression of the enzymes and the consequent structure and function of the polysaccharide chains can vary temporally and spatially during development and under certain pathophysiological conditions, suggesting their assembly is tightly regulated in cells. Due to their many key roles in cell homeostasis and disease, there is much interest in targeting the assembly and function of GAGs as a therapeutic approach. Recent advances in genomics and GAG analytical techniques have pushed the field and generated new perspectives on the regulation of mammalian glycosylation. This review highlights the spatiotemporal diversity of GAGs and the mechanisms guiding their assembly and function in human biology and disease.

Supplementary Table 1

Ductal carcinoma in situ (DCIS) is a biologically heterogenous entity with uncertain risk for invasive ductal carcinoma (IDC) development. Standard treatment is surgical resection often followed by radiation. New approaches are needed to reduce overtreatment. This was an observational study that enrolled patients with DCIS who chose not to pursue surgical resection from 2002 to 2019 at a single academic medical center. All patients underwent breast MRI exams at 3- to 6-month intervals. Patients with hormone receptor–positive disease received endocrine therapy. Surgical resection was strongly recommended if clinical or radiographic evidence of disease progression developed. A recursive partitioning (R-PART) algorithm incorporating breast MRI features and endocrine responsiveness was used retrospectively to stratify risk of IDC. A total of 71 patients were enrolled, 2 with bilateral DCIS (73 lesions). A total of 34 (46.6%) were premenopausal, 68 (93.2%) were hormone-receptor positive, and 60 (82.1%) were intermediate- or high-grade lesions. Mean follow-up time was 8.5 years. Over half (52.1%) remained on active surveillance without evidence of IDC with mean duration of 7.4 years. Twenty patients developed IDC, of which 6 were HER2 positive. DCIS and subsequent IDC had highly concordant tumor biology. Risk of IDC was characterized by MRI features after 6 months of endocrine therapy exposure; low-, intermediate-, and high-risk groups were identified with respective IDC rates of 8.7%, 20.0%, and 68.2%. Thus, active surveillance consisting of neoadjuvant endocrine therapy and serial breast MRI may be an effective tool to risk-stratify patients with DCIS and optimally select medical or surgical management.Significance:A retrospective analysis of 71 patients with DCIS who did not undergo upfront surgery demonstrated that breast MRI features after short-term exposure to endocrine therapy identify those at high (68.2%), intermediate (20.0%), and low risk (8.7%) of IDC. With 7.4 years mean follow-up, 52.1% of patients remain on active surveillance. A period of active surveillance offers the opportunity to risk-stratify DCIS lesions and guide decisions for operative management.

Background: There is no clinical equipoise on the best upfront management of patients with early-stage hormone receptor-positive (HR+)/HER2-negative (HER2-) breast cancer (BC) that is high-risk by clinicopathologic criteria, and low-risk based on molecular profiling. These patients are unlikely to respond to chemotherapy. However, these patients still have risk, often risk of late recurrence, despite standard adjuvant endocrine therapy. Novel endocrine-based strategies that are more effective and tolerable than current standard therapies are needed for this population. Next-generation orally-bioavailable selective estrogen receptor degraders (oSERDs) with improved pharmacokinetic (PK) properties are promising potential therapies for HR+ BC. The oSERD amcenestrant has demonstrated a favorable safety profile and encouraging efficacy in a phase I/II dose escalation and expansion trial for heavily pre-treated patients with HR+ metastatic BC and is an attractive agent for assessment in the neoadjuvant BC setting. The neoadjuvant setting offers a unique opportunity to study novel agents and to assess early biological endpoints. However, one of the challenges in studying endocrine-based strategies in the neoadjuvant setting is the lack of a robust surrogate endpoint to reliably predict response and benefit. The I-SPY2 Endocrine Optimization Protocol (EOP) is a pilot sub-study within the main I-SPY2 TRIAL that will test amcenestrant alone or in combination with abemaciclib or letrozole. EOP will test the feasibility of using the I-SPY2 platform to test novel endocrine-based strategies in the neoadjuvant setting in patients with clinical high-risk, molecular low-risk, HR+/HER2- tumors, and will generate a rich database of imaging, molecular, and pathologic correlative endpoints that may potentially inform the improved assessment of response to neoadjuvant endocrine therapy. Trial Design/Eligibility/Accrual: The I-SPY2 EOP is a prospective, randomized, open-label trial specifically for patients with HR+/HER2-negative MammaPrint (MP) low-risk tumors that are at least 2.5 cm in size. Eligible patients are identified during the screening process for the parent I-SPY2 trial. The planned total accrual for the EOP is 120 patients. Patients are randomized 1:1:1 to one of 3 oral treatment arms: 1) amcenestrant 200 mg daily; 2) amcenestrant 200 mg daily + abemaciclib 150 mg bid; 3) amcenestrant 200 mg daily + letrozole 2.5 mg daily. Patients are treated for 6 months prior to surgery. Premenopausal women must receive concomitant monthly ovarian suppression. Serial breast MRIs, breast biopsies, blood, and patient reported outcomes (PROs) are being collected, and patients will be followed for 10 years for recurrence and survival. Serial dedicated breast PET (dbPET) scans and PKs will be assessed in a subset of patients. Objectives/Statistics: The primary objective of the EOP is to investigate the feasibility of enrolling and treating molecularly-selected patients with early stage HR+/HER2- MP low-risk BC in a randomized neoadjuvant trial using an oral-SERD backbone. Treatment will be determined to be feasible if ≥75% of enrolled patients complete ≥75% of assigned study therapy. Secondary objectives include the safety, tolerability, PROs, and PKs related to amcenestrant +/- abemacilcib and letrozole, as well as the assessment of imaging, pathologic, and molecular correlative endpoints as potential biomarkers of response to neoadjuvant endocrine therapy. Status: This study opened in May 2021. Accrual is ongoing. Citation Format: A. Jo Chien, Kevin M Kalinsky, Julissa Molina-Vega, Rita Mukhtar, Karthik Giridhar, Olufunmilayo I Olopade, Amrita Basu, Smita M Asare, Paul Henderson, Gillian Hirst, Ruixiao Lu, Ella Jones, Nola Hylton, Lamorna Brown-Swigart, Laura J van 't Veer, Douglas Yee, Ingrid Mayer, Laura J Esserman. I-SPY2 endocrine optimization protocol (EOP): A pilot neoadjuvant endocrine therapy study with amcenestrant as monotherapy or in combination with abemacicilib or letrozole in molecularly selected HR+/HER2- clinical stage 2/3 breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT1-10-02.

Introduction: Advances in technology and internet capability have provided an opportunity for efficient collection of Patient Reported Outcomes (PRO) during medical treatment. Here we describe the development and implementation of a system for monitoring patient reported adverse events (AEs) and quality of life (QoL) using electronic PRO (ePRO) instruments for patients enrolled on the Investigation of Serial studies to Predict Your Therapeutic Response with Imaging And moLecular analysis (I-SPY 2 TRIAL), a phase II adaptive platform clinical trial for locally advanced breast cancer. Methods: We designed an ePRO system to increase the accuracy of patient-reported QoL and AE data collection with the intent to act on symptoms in real time. Using the OpenClinica electronic data capture system, we developed rules-based logic to build automated ePRO surveys, customized to the I-SPY 2 treatment schedule. Weekly surveys contained a maximum of 126 validated, branching logic questions from the Patient Reported Outcomes Measurement Information System (PROMIS®) Health Measures and the National Cancer Institute’s Patient Reported Outcomes - Common Terminology Criteria for Adverse Events (PRO-CTCAE™) instruments. We piloted ePROs at the University of California, San Francisco (UCSF) to evaluate compatibility with a variety of I-SPY 2 patient scenarios (e.g., dose delays). We then staggered rollout of the ePRO system to 22 I-SPY 2 sites to ensure technological feasibility. In order to improve accuracy of data collection, we utilized real-time tracking and developed a Clinical Research Coordinator (CRC) training manual, which integrated workflow diagrams with technical solutions. CRCs were trained using remote video sessions. Results: The UCSF ePRO pilot began in September of 2020. Over 9-months, we accrued 43 I-SPY 2 patients (average age of 43.8 years), whose interactions with the ePRO system informed design improvements. Of the patients who received a baseline ePRO survey, the completion rate was 75.9% (average age of 44.2 years). This represents an increase from the 15-20% baseline completion rate for the 360 UCSF I-SPY 2 patients who received paper-based PRO surveys between May 2012 - January 2019. As of June 2021, the ePRO system was operational at all 22 I-SPY 2 sites. The UCSF pilot revealed that engagement with patients at critical timepoints improved survey completion. CRCs facilitated patient participation by sending instructional emails and communicating with patients weekly. We tracked data completeness using a Patient Tracking report, which displayed each patient’s survey completion history. This real-time tool enabled CRCs to identify patients who had not completed ePRO surveys prior to their visit, so they could be provided a tablet computer to complete the survey in the clinic. After introducing tablets into the workflow at UCSF, patient completion of the baseline survey increased from 75.9% to 80%. Conclusion: The transition from paper to electronic QOL and AE data collection improves the ability of patients to complete PRO surveys, but the process must also be optimized and integrated into clinical workflow and trial conduct. In the future, we will present additional results highlighting the feasibility of multilingual ePRO integration into I-SPY 2. ePRO also provides a new opportunity for data analysis, as well as the potential to reduce high grade toxicity through early intervention. It will allow us to assess QoL and AE data by drug regimen, site, provider, and study treatment. The creation of clinician-facing reports also enables access to patient responses in real-time. By implementing ePRO within I-SPY 2, we not only increase efficiency and accuracy of patient-reported data collection, but also improve quality of care and patient safety. Citation Format: Anna Northrop, Anika Christofferson, Michelle Melisko, Laura Sit, Ebunoluwa Olunuga, Ananya Mittal, Adi Goldman, Thelma Brown, Diane Heditsian, Bev Parker, Susie Brain, Carol Simmons, Alessandra Taboada, Kathryn J Ruddy, Tina Hieken, Mara Piltin, Kiri Cook, Carolina Salvador, Candace Mainor, Anosheh Afghahi, Sarah Tevis, Anne Blaes, Irene Kang, Susan Melin, Laura Esserman, Adam Asare, Dawn L Hershman, Amrita Basu. Improving patient-reported outcome data capture for clinical research: ePRO in ISPY 2, a phase 2 breast cancer study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-12-02.

The HER3/ERBB3 receptor is an oncogenic receptor tyrosine kinase that forms heterodimers with EGFR family members and is overexpressed in numerous cancers. HER3 overexpression associates with reduced survival and acquired resistance to targeted therapies, making it a potential therapeutic target in multiple cancer types. Here, we report on immunogenic, promiscuous MHC class II–binding HER3 peptides, which can generate HER3-specific CD4+ Th1 antitumor immune responses. Using an overlapping peptide screening methodology, we identified nine MHC class II–binding HER3 epitopes that elicited specific Th1 immune response in both healthy donors and breast cancer patients. Most of these peptides were not identified by current binding algorithms. Homology assessment of amino acid sequence BLAST showed >90% sequence similarity between human and murine HER3/ERBB3 peptide sequences. HER3 peptide–pulsed dendritic cell vaccination resulted in anti-HER3 CD4+ Th1 responses that prevented tumor development, significantly delayed tumor growth in prevention models, and caused regression in multiple therapeutic models of HER3-expressing murine tumors, including mammary carcinoma and melanoma. Tumors were robustly infiltrated with CD4+ T cells, suggesting their key role in tumor rejection. Our data demonstrate that class II HER3 promiscuous peptides are effective at inducing HER3-specific CD4+ Th1 responses and suggest their applicability in immunotherapies for human HER3-overexpressing tumors.

Ductal carcinoma in situ (DCIS) is a biologically heterogenous entity with uncertain risk for invasive ductal carcinoma (IDC) development. Standard treatment is surgical resection often followed by radiation. New approaches are needed to reduce overtreatment. This was an observational study that enrolled patients with DCIS who chose not to pursue surgical resection from 2002 to 2019 at a single academic medical center. All patients underwent breast MRI exams at 3- to 6-month intervals. Patients with hormone receptor–positive disease received endocrine therapy. Surgical resection was strongly recommended if clinical or radiographic evidence of disease progression developed. A recursive partitioning (R-PART) algorithm incorporating breast MRI features and endocrine responsiveness was used retrospectively to stratify risk of IDC. A total of 71 patients were enrolled, 2 with bilateral DCIS (73 lesions). A total of 34 (46.6%) were premenopausal, 68 (93.2%) were hormone-receptor positive, and 60 (82.1%) were intermediate- or high-grade lesions. Mean follow-up time was 8.5 years. Over half (52.1%) remained on active surveillance without evidence of IDC with mean duration of 7.4 years. Twenty patients developed IDC, of which 6 were HER2 positive. DCIS and subsequent IDC had highly concordant tumor biology. Risk of IDC was characterized by MRI features after 6 months of endocrine therapy exposure; low-, intermediate-, and high-risk groups were identified with respective IDC rates of 8.7%, 20.0%, and 68.2%. Thus, active surveillance consisting of neoadjuvant endocrine therapy and serial breast MRI may be an effective tool to risk-stratify patients with DCIS and optimally select medical or surgical management. Significance: A retrospective analysis of 71 patients with DCIS who did not undergo upfront surgery demonstrated that breast MRI features after short-term exposure to endocrine therapy identify those at high (68.2%), intermediate (20.0%), and low risk (8.7%) of IDC. With 7.4 years mean follow-up, 52.1% of patients remain on active surveillance. A period of active surveillance offers the opportunity to risk-stratify DCIS lesions and guide decisions for operative management.

Glycosaminoglycans (GAGs) are long, linear polysaccharides that are ubiquitously expressed on the cell surface and in the extracellular matrix of all animal cells. These complex carbohydrates are composed of alternating glucosamine and uronic acids that can be heterogeneously N- and O-sulfated. The arrangement and orientation of the sulfated sugar residues specify the location of distinct ligand binding sites on the cell surface, and their capacity to bind ligands impacts cell growth and development, the ability to form tissues and organs, and normal physiology. The heterogeneous nature of GAGs and their inherent structural diversity across different tissues, cell types, and disease states creates challenges to characterizing their structure and function. Here, we describe detailed methods to investigate GAG-protein interactions in vitro and evaluate the structural composition of two classes of sulfated GAGs, heparan sulfate and chondroitin/dermatan sulfate, using liquid chromatography, mass spectrometry, and radiolabeling techniques. Overall, these methods facilitate the evaluation of GAG structure and function to uncover the unique roles these molecules play in cell biology and human disease.

ATRX is a tumor suppressor that has been associated with protection from DNA replication stress, purportedly through resolution of difficult-to-replicate G-quadruplex (G4) DNA structures. While several studies demonstrate that loss of ATRX sensitizes cells to chemical stabilizers of G4 structures, the molecular function of ATRX at G4 regions during replication remains unknown. Here, we demonstrate that ATRX associates with a number of the MCM replication complex subunits and that loss of ATRX leads to G4 structure accumulation at newly synthesized DNA. We show that both the helicase domain of ATRX and its H3.3 chaperone function are required to protect cells from G4-induced replicative stress. Furthermore, these activities are upstream of heterochromatin formation mediated by the histone methyltransferase, ESET, which is the critical molecular event that protects cells from G4-mediated stress. In support, tumors carrying mutations in either ATRX or ESET show increased mutation burden at G4-enriched DNA sequences. Overall, our study provides new insights into mechanisms by which ATRX promotes genome stability with important implications for understanding impacts of its loss on human disease., ATRX is a chromatin remodeling protein, which loss has been associated to replication stress, DNA damage, and DNA repair failures that drive genome instability. Here the authors reveal that ATRX protects genomic integrity at G4-containing regions by maintaining these regions in a closed heterochromatic state.

Background Symptom burden and reduced quality of life (QOL) are considerable hurdles in oncology. The authors used the Patient-Reported Outcomes Measurement Information System (PROMIS), which assesses physical and psychosocial health, to establish a mean symptom burden, examine potential drivers, and characterize severe symptom burden in breast cancer patient subgroups with the goal of characterizing stage IV patient QOL and triaging patients to individualized supportive care services. Methods New patients at the University of California San Francisco Breast Care Center received questionnaires with 8 PROMIS domains: depression, anxiety, fatigue, sleep-related impairment, sleep disturbance, cognitive function, cognitive abilities, and physical function. PROMIS values were scored with the HealthMeasures service and were compared by age, cancer stage, and educational status. Results Stage IV patients with breast cancer (n = 169) reported higher depression and fatigue and worse cognitive function, cognitive abilities, and physical function than patients with stage 0 to III disease (n = 2577). As age increased, cognitive function impairment, depression, anxiety, and sleep-related symptoms decreased. More educated patients showed better physical function and less severe sleep disturbance and fatigue. Across all subgroups, patients with high anxiety had the greatest probability of worse symptom burden and function in other domains. Conclusions This study provides an additional set of PROMIS population estimates across breast cancer demographic groups. The analysis of a large stage IV population reinforces that metastatic patients have impaired QOL across multiple domains. Because anxiety emerged as a potential driver of impaired QOL in other domains, earlier interventions to reduce anxiety could improve QOL overall. These analyses will help to determine appropriate thresholds of intervention. Lay summary Patients receiving treatment for breast cancer can experience decreased quality of life. This study characterized differences in self-reported quality of life among patients of different ages, with different stages of cancer, and with different educational backgrounds. This study also examined the effect of decreased quality of life in one area (eg, anxiety) on another area (eg, difficulty in sleeping). Patients who were younger, had not attended college or technical school, or had stage IV cancer tended to have worse quality of life. Patients who had high levels of anxiety also tended to have high levels of impairment in other areas.

The volume explores elements of change and continuity in Hindu extremist nationalism over the last two decades. Sarkar deploys fieldwork and closely reads and analyzes Hindutva's cultural, social, pedagogical, ritual, and visual messages to understand their ideological purpose, political movements, organizational networks and techniques of mobilization. She particularly focuses on their social ideas and women's work, the particularities in their notions of Hindu faith and Indian nationalism, their remaking of Indian history and their modes of disseminating their ideological literature.

HER2 breast cancer (BC) remains a significant problem in patients with locally advanced or metastatic BC. We investigated the relationship between T helper 1 (Th1) immune response and the proteasomal degradation pathway (PDP), in HER2-sensitive and -resistant cells. HER2 overexpression is partially maintained because E3 ubiquitin ligase Cullin5 (CUL5), which degrades HER2, is frequently mutated or underexpressed, while the client-protective co-chaperones cell division cycle 37 (Cdc37) and heat shock protein 90 (Hsp90) are increased translating to diminished survival. The Th1 cytokine interferon (IFN)-γ caused increased CUL5 expression and marked dissociation of both Cdc37 and Hsp90 from HER2, causing significant surface loss of HER2, diminished growth, and induction of tumor senescence. In HER2-resistant mammary carcinoma, either IFN-γ or Th1-polarizing anti-HER2 vaccination, when administered with anti-HER2 antibodies, demonstrated increased intratumor CUL5 expression, decreased surface HER2, and tumor senescence with significant therapeutic activity. IFN-γ synergized with multiple HER2-targeted agents to decrease surface HER2 expression, resulting in decreased tumor growth. These data suggest a novel function of IFN-γ that regulates HER2 through the PDP pathway and provides an opportunity to impact HER2 responses through anti-tumor immunity.

Introduction: One of the principal limiting factors to achieving cures in patients with cancer is drug resistance. Drug repositioning is the application of FDA-approved drug compounds for novel indications beyond the scope of the drug’s original intended use. This approach offers advantages over traditional drug development by reducing development costs and providing shorter paths to approval, as drug safety has already been established during the drug’s original regulatory process. One approach for computational drug repositioning involves generating a disease gene expression signature and then identifying a drug that can reverse this disease signature. In this study, we extracted drug resistance signatures from the I-SPY 2 TRIAL by comparing gene expression profiles of responder and non-responder patients stratified by treatment and molecular subtype. We then applied our drug repositioning pipeline to predict compounds that can reverse the gene expression profiles of these drug resistance signatures. We hypothesize that reversing these drug resistance signatures will resensitize tumors to treatment and improve patient outcome. Methods: We first generated the drug resistance signatures by performing differential expression between responders (RCB 0/I) and non-responders (RCB III) within treatment arms and molecular subtypes. An optimal log fold-change cutoff was selected for each signature by identifying the cutoff that best separates the responder and non-responder samples using k-means clustering. We then applied our drug repositioning pipeline to identify compounds that significantly reverse these signatures using the drug perturbation profiles generated in a breast cancer cell line in the Connectivity Map v2 dataset. Briefly, the pipeline uses a non- parametric, rank-based pattern-matching strategy based on the Kolmogorov-Smirnov (KS) statistic to assess the enrichment of resistance genes in a ranked drug gene expression list. Significance of each prediction is estimated from a null distribution of scores generated from random gene signatures. Results: We found that few individual genes are shared among the resistance signatures across the treatment arms and molecular subtypes, with the most common genes present in only 5/17 of the treatment arm and molecular subtype groups. At the pathway-level, however, we found that immune-related pathways are generally enriched among the responders and estrogen-response pathways are generally enriched among the non-responders. Although most of our drug predictions are unique to treatment arms and molecular subtypes, our drug repositioning pipeline identified the selective estrogen receptor degrader (SERD) fulvestrant as a compound that can potentially reverse resistance across a majority of the treatment arms and molecular subtypes. Conclusion: We applied our drug repositioning pipeline to identify novel agents to sensitize drug-resistant tumors in the I-SPY 2+ clinical trial and identified a SERD, fulvestrant, as a potential candidate for multiple molecular subtypes and treatment arms. Citation Format: Katharine Yu, Amrita Basu, Christina Yau, Denise Wolf, Gillian Hirst, Laura Sit, Nicholas O’Grady, Thelma Brown, I-SPY 2 TRIAL Investigators, Angela DeMichele, Don Berry, Nola Hylton, Doug Yee, Laura Esserman, Laura van 't Veer, Marina Sirota. Computational drug repositioning for the identification of new agents to sensitize drug-resistant breast tumors across treatment arms and molecular subtypes [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 PS11-04.

Background. Immunotherapy has emerged as an important component of neoadjuvant therapy for some patients with breast cancer (BC). As a result, immune-related adverse events (irAEs) are increasing and have effects on both short and long term symptoms significantly impacting patient quality of life. BC patients may develop new conditions including arthralgias, gastrointestinal issues, endocrinopathies, and fatigue during or after cancer therapy that may be acute or long-lasting in nature. Monitoring for early onset and severity of symptoms, and adjusting treatment and symptom management could optimize therapy for a particular patient, maximizing potential efficacy while mitigating toxicity. We sought to identify patient demographic characteristics and symptom patterns associated with risk for development of irAEs in the context of a randomized trial for patients with early-stage high-risk breast cancer. Methods. I-SPY2 is a multi-center, phase 2 trial using response-adaptive randomization for high-risk early-stage women with BC. The study population for this analysis includes enrolled patients receiving combinations of experimental immunotherapy and chemotherapy. Groups considered for statistical comparisons included those that developed an irAE versus those that did not develop an irAE up until the surgery timepoint. In I-SPY adverse events are documented through the Common Terminology Criteria for Adverse Events (CTCAEv5.0). Hypothyroidism, adrenal insufficiency, and pneumonitis were the irAEs considered in this study. A chi-square test was used to assess associations between race and ethnicity (White, Asian, Black, non-Hispanic) and irAEs. One-way ANOVA was used to evaluate the association between age (>50 vs < 50) and irAEs. 33 symptoms reported at CTCAE grade 2 or higher were included in the analyses and a symptom burden score was calculated using area under curve (AUC) which combined the duration of each symptom between baseline and week 6 of treatment, and grade of adverse event. Regularized regression using leave-one out cross validation was used to evaluate early symptoms (as quantified by the symptom burden score) as predictors, and irAEs as surrogate responses. Results. Out of 461 patients, percentages of patients wth irAEs of interest included hypothyroidism (13%), adrenal insufficiency (9%), and pneumonitis (4%). Demographic information was available for 333 patients, of which 270 (81%) were White, 23 (7%) were Asian, 37 (11%) were African American (AA) and 278 (17%) were non-Hispanic. There were proportionately higher number of white patients that developed hypothyroidism than non-white patients (35 of 265 (13%) vs 2 of 63 (3%), P < 0.04). Pneumonitis was more common in patients over 50 years old than under 50 years old (P < 0.02). Symptoms that were most commonly reported up to week 6 of treatment among patients who developed an irAE included: diarrhea (36%), fatigue (15%), dizziness (12%) and shortness of breath (SOB) (11%). Symptoms associated with the development of hypothyroidism included fatigue (15%, mean AUC=11.8 vs 5.8 for those that did not develop irAE), SOB (11%, 4.3 vs 2.8), and blurry vision (1%, 1.0 vs 0.12). Development of adrenal insufficiency was associated with early reports of diarrhea (36%, 19.0 vs 10.5), SOB (11%, 7.8 vs 2.6), joint pain (3%, 2.29 vs 0.58), decreased appetite (3%, 3.55 vs 0.91), and constipation (1%, 3.6 vs 0.02). No significant early symptoms emerged for pneumonitis due to a limited number of events. Conclusion. Our study utilizes an analysis framework that is aimed to determine symptom clusters that predict the development of irAEs. We describe specific symptoms presenting early with the development of hypothyroidism and adrenal insufficiency, in recognition of allowing physicians to be more diligent in active and post treatment monitoring. Citation Format: Amrita Basu, Saumya Umashankar, Michelle Melisko, Ruixiao Lu, Hongmei Yu, Christina Yau, Smita Asare, Maria Pitsouni, Rebecca A. Shatsky, Claudine Isaacs, Angela DeMichele, Dawn Hershman, Rita Nanda, Mi-Ok Kim, Laura J. Esserman, Hope Rugo. Identification of symptoms that are associated with irAEs in the I-SPY clinical trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS5-04.

The links among feminism, race, and transnationalism, which are key to the Meridians project, are also crucial to understanding the events of 9/11 and the war on Afghanistan. Some pieces in this archive provide feminist perspectives on the impact of war and fundamentalism on women’s lives in Afghanistan and Pakistan. Other pieces analyze the ways in which racist representations of Muslim women and of Islam have come to play a key part in colonial and neocolonial “great games” being played in South, West, and Central Asia. Yet others link the U.S.-sponsored war in Afghanistan to the repression of the media and the attacks on civil liberties within the U.S. itself. In constructing an archive of these courageous testimonies, Meridians honors the courage and integrity of women in the United States and around the world who aspire to a better, more just world.

The use of mechanical forces to chemically transform polymers dates back decades. In recent years, the use of mechanochemistry to direct constructive transformations in polymers has resulted in a range of engineered molecular responses that span optical, mechanical, electronic and thermal properties. The chemistry that has been developed is now well positioned for use in materials science, polymer physics, mechanics and additive manufacturing. Here, we review the historical backdrop of polymer mechanochemistry, give an overview of the existing toolbox of mechanophores and associated theoretical methods, and speculate as to emerging opportunities in materials science for which current capabilities are seemingly well suited. Non-linear mechanical responses and internal, amplifying stimulus–response feedback loops, including those enabled by, or coupled to, microstructured metamaterial architectures, are seen as particularly promising. Polymer mechanochemistry converts mechanical forces in materials to chemical reactions through the response of functional groups known as mechanophores. This Review discusses the colorimetric, mechanical, chemical and electronic responses of mechanophores that may be useful in materials for strain sensing and strengthening, soft devices and additive manufacturing.