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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.

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.

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.

Background: Breast cancer remains the most frequently diagnosed cancer among women worldwide, accounting for a quarter of all diagnoses. Despite advances in treatment and symptom management, the majority of women will experience some form of drug-related toxicity, psychosocial distress, and subsequent impairments in their quality of life (QoL). Distress and impairments in QoL can interfere with treatment adherence, while engagement in health promoting behaviors and effective management of symptoms has been associated with improved QoL, adherence and increased survival. The utilization of QoL or other Patient Reported Outcome (PRO) measures in clinical trials remains inconsistent, and no uniformly accepted measure exists to integrate QoL data into the assessment of therapeutic agents. There are two goals of the I-SPY 2 QoL Pilot Study: 1) To demonstrate the reporting of an integrated utility-based QOL score, the PROPr, within a novel longitudinal approach that provides a single numerical index of QoL; 2) Generate a Clinical Benefit Index (CBI), a single composite score that integrates the longitudinal PROPr score with a clinical efficacy score, RCB index, to provide a measure that could go beyond clinical efficacy in the evaluation of therapeutic agents in the I-SPY 2 TRIAL. Methods: Study participants were part of the I-SPY 2 TRIAL assessing novel neoadjuvant therapies added to standard chemotherapy in the treatment of Stage 2/3 breast cancer. Participants completed a validated QoL measure at three time points: baseline, prior to surgery, and 1-month post-surgery. QoL was assessed using the NIH PROMIS measure (physical function (four items), anxiety (eight items), depression (eight items), fatigue (eight items), applied cognition (eight items) and social roles (four items)) and results at each time point used to calculate the PROPr, a single utility-based index score to assess overall quality of life. PROPr index utility scores were used to generate a single longitudinal QoL score based on area under the curve modeling. Clinical efficacy was assessed based on the residual cancer burden (RCB) observed at the time of surgery. The CBI was generated by plotting RCB index against the longitudinal PROPr index for each participant and study arm. Results: Only a fraction (n=107) of all patients had complete data across study timepoints and were included in our analyses, and thus our data represent a proof of concept. Patients on the control arm were treated with Paclitaxel followed by anthracycline (AC). Patients in the pilot were assigned either the control arm or six experimental drug arms. The longitudinal PROPr utility index demonstrated a range of outcomes, with some arms more challenging to tolerate, and others much better, ranging from 0.67 to 1.16. The RCB index of the seven study arms ranged from 0.49 to 1.99. The CBI, an integration of the longitudinal PROPr and RCB indexes, also demonstrated a range from 0.43 to 1.60. Conclusion: We are reporting the development of a novel, valid and standardized QoL assessment that should be a routine part of clinical trials in oncology. This proof of concept study suggests that that calculation of the CBI is feasible and can reveal differences in the clinical profiles of therapeutic agents, both in terms of QoL and overall integration of clinical efficacy and QoL. The CBI represents a novel approach to providing summary data that can be easily interpreted as part of clinical trial outcome data. Ideally, these integrated assessments would provide a more comprehensive evaluation of investigational therapies, and ultimately help inform treatment decision discussions between patients and providers. Moving forward, electronic PRO data will be collected as part of routine care in the I-SPY 2 TRIAL, thus enabling the longitudinal PROPr and CBI scores to be generated for every agent evaluated. Citation Format: Amrita Basu, Errol J. Philip, Barry Dewitt, Janel Hanmer, Aheli Chattopadhyay, Christina Yau, Smita Asare, Karyn Digiorgio, Ruby Singhrao, Adam Asare, Jane Perlmutter, I-SPY 2 Consortium, Michelle Melisko, Laura Esserman. The clinical benefit index: A pilot study integrating treatment efficacy and quality of life in oncology clinical trials [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 P2-12-06.

Background: While the side effects of anthracycline and taxane based chemotherapy are well characterized, introduction of experimental agents and immunotherapy in the neoadjuvant and adjuvant setting may significantly alter the toxicity profiles of these regimens, resulting in short and long-term changes in patient quality of life (QOL). Trial Design: I-SPY 2 is a phase 2 trial investigating novel targeted therapies and immunotherapy in combination with standard chemotherapy in the neoadjuvant setting for Mammaprint high-risk stage 2 and 3 breast cancers. A QOL sub-study was introduced into the I-SPY 2 trial platform in 2012. All patients who consent to screen for the I-SPY 2 trial receive a baseline QOL questionnaire. Patients who consent to the treatment phase of I-SPY 2 also complete questionnaires on the first day of treatment, mid-way through neoadjuvant treatment, prior to surgery, and then 1, 6, 12 and 24 months post-surgery. Instruments have included the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC) QLQ C30 and BR23, as well as NCI Patient-Reported Outcomes Measurement Information System (PROMIS) measures, the National Comprehensive Cancer Network (NCCN) Distress Thermometer, and a Fear of Recurrence (FOR) instrument. We are currently implementing an electronic platform for survey collection and modifying the survey instruments to incorporate 31 items from the Patient Reported Outcomes-Common Terminology Criteria for Adverse Events (PRO-CTCAE) measurement system along with previously included PROMIS items in domains of physical, psychological, cognitive, and sexual function, the Distress Thermometer, and the FOR instrument. During neoadjuvant treatment, patients will also complete weekly abbreviated surveys containing PRO-CTCAE items only. We are using the data from these measures to generate a Clinical Benefit Index (CBI), a single composite score that integrates a PROMIS Preference (PROPr) score with a clinical efficacy assessment (residual cancer burden- RCB index) to provide new insight into the overall impact that therapeutic agents in I-SPY2 have on cancer recurrence risk, general health, and QOL. Specific Aims: The primary objective of the QOL study is to evaluate the short- and long-term impact on QOL of novel agents added to standard treatment in high-risk breast cancer patients receiving neoadjuvant therapy. Factors including patient age, hormone receptor and HER2 status, and response to treatment by residual cancer burden will be evaluated to understand their impact on a patients’ QOL trajectory over time. A secondary objective is to compare patient reported toxicities (using PRO-CTCAE measures) with clinician-reported adverse events. Accrual: The I-SPY 2 trial has registered 2729 patients to date and there are 18 sites open across the US. Since the initiation of the QOL study, at least one QOL survey has been collected from 1066 patients. Given the adaptive design, enrollment for each agent varies based on patient outcomes, but collection of PRO measures on all patients will continue as new agents enter the trial. Clinical trial information: NCT01042379. Citation Format: Hila Ghersin, Aheli Chattopadhyay, Anne Blaes, Tara Sanft, Dawn Hershman, Amrita Basu, Ruby Singhrao, Susie Brain, Diane Heditsian, Hope S Rugo, Laura Esserman, Michelle Melisko. Introducing an electronic platform to collect patient reported outcomes in the I-SPY 2 trial, a neoadjuvant clinical trial [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 OT3-19-02.

Background: The Athena Breast Health Network is a multi-site effort aimed at integrating cutting-edge research and clinical care for breast cancer screening and treatment. At the University of California, San Francisco (UCSF) Breast Care Center (BCC), an Athena-based electronic Health Questionnaire System (eHQS) is distributed to all new patients. This questionnaire assesses self-reported personal and familial health history, comorbidities, and Patient-Reported Outcome Measurement and Information System (PROMIS) quality of life domains. Based on these responses, patients are proactively triaged to genetic counseling, psycho-oncology, onco-fertility, smoking cessation, peer support, nutritional counseling, behavioral sleep, and social work. These referrals are based on pre-defined thresholds, such as Ashkenazi Jewish Ancestry (referral to Genetic Counseling), or PROMIS Depression and Anxiety scores greater than or equal to 9 and 11, respectively. This analysis aims to assess the eHQS as a means to refer patients to supportive care services and assess if high-need patients (those with the highest symptom burden as assessed by quality of life PROMIS scores) are referred to services more frequently. Patients and Methods: Since Athena’s launch in 2013, over 6,000 patients have completed the online intake questionnaire at the UCSF BCC, 4,984 of whom have consented to research. 3,627 patients completed all relevant data to this study and were used in our analysis. A review of patient referrals was conducted to assess the number of referrals as a result of eHQS completion. PROMIS T-Scores in 8 domains (depression, anxiety, fatigue, sleep-related impairment and disturbance, cognitive function, applied cognition and physical function) were calculated with the Health Measures system and compared across patients stratified by age and cancer type and against the US general population. Results: When compared to the US population as a whole, PROMIS scores indicate that UCSF BCC patients have impaired quality of life in every assessed PROMIS domain except for depression. As age increases, PROMIS scores across multiple domains (depression, anxiety, sleep disturbance, cognitive function) increase, signifying lower symptom burden. Importantly, high symptom burden in the anxiety PROMIS domain was suggestive of lower quality of life scores in 6 out of the other 7 assessed PROMIS domains. 39% (1408 patients) of all analyzed BCC patients received at least one referral to a supportive care service. 721 of 1450 (50%) patients with an Invasive Breast Cancer (IBC) diagnosis and 246 of 571 (43%) patients with a DCIS diagnosis triggered at least one referral. 31% of all patients received a referral to genetic counseling, 16.3% to psycho-oncology, 11% to behavioral sleep, 8% to nutritional counseling, 7.6% to social work, 2.4% to smoking cessation, and 1.6% to onco-fertility. When compared to patients with DCIS or without a cancer diagnosis, patients with IBC are most likely to receive a referral to genetic counseling and psychosocial services. Referrals to supportive care services are less frequent as age increases. Conclusion: The Athena online intake form at the UCSF BCC effectively triages patients with high levels of anxiety (PROMIS > 8) and depression (PROMIS >10) to supportive care services. Preliminary results regarding the correlation between anxiety and overall poor quality of life suggest that referrals to psycho-oncology may be most efficacious in decreasing symptom burden. Using these analyses, we aim to refine our use of the eHQS to tailor the most relevant and effective referrals to the highest-need patients. Citation Format: Madeline Matthys, André Dempsey, Amrita Basu, Emily Wong, Nickolas Dreher, Irene Acerbi, Suzanne Ackerson, Laura Esserman, Athena Breast Health Network Investigators and Advocate Partners, Michelle Melisko, Laura van 't Veer. Triaging breast care center patients to supportive care services based on the Athena Breast Health Network online intake form and the patient-reported outcomes measurement information system (PROMIS) [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 P2-12-08.

Introduction: Standard treatment for ductal carcinoma in situ (DCIS) involves surgical excision with radiation and often endocrine therapy. However, not all DCIS progresses to invasive ductal carcinoma (IDC); thus, surgical intervention may constitute overtreatment for DCIS that has low risk for progressing to IDC. A period of active surveillance (AS) with magnetic resonance imaging (MRI) monitoring may offer the opportunity to stratify lesions with high and low risk for invasion and to avoid overtreatment of DCIS. The purpose of this study was to characterize the outcomes of a cohort of women who elected to go on AS to avoid surgical intervention and to identify whether clinical and imaging features would identify patients who should convert to operative management. Methods: The clinicopathologic variables and outcomes of patients with DCIS who prospectively enrolled in MRI monitoring studies between 2002 and 2019 were retrospectively analyzed with IRB approval. We included 64 cases among 63 women who declined standard operative management for DCIS and had at least two breast MRIs. Clinicopathologic data and physician recommendations regarding continuing surveillance versus converting to operative management were recorded from the medical record. Those who had surgical excision showing IDC were considered to have progressed; those with only DCIS at excision or no operative intervention were considered to have stable disease. Results: Women in the cohort were an average of 53.6 years (29.8 - 78.9) old, and nearly all cases of DCIS with estrogen receptor (ER) status were ER+ (98.3%). Of the 64 cases in the cohort, 57 received endocrine therapy (89.1%). Average length of time on AS was 2.7 years (.2 – 11.9) with a median of 3 (2 – 18) MRIs performed and mean follow-up time 5.6 years (0.9 – 15.3). A total of 31 cases (48.4%) eventually had surgical excision while 33 (51.6%) remained on AS. There were 17 cases with IDC at surgery (26.6%). The IDC was an average of 1.5 cm (0.1 – 9.0) and most commonly ER + (88.2%), HER2 + (53.3%), grade 2 (58.9%), and node negative (82.4%). Only 7 women did not take endocrine therapy, but 3 of those women had IDC (42.9%). In 15 of the 17 cases with IDC (88.2%), the physician noted concern for progression in their clinic note and recommended surgical excision. This occurred a mean of 1.9 years (0.2 – 6.5) from the start of AS, with 47%, 67%, and 87% of cases identified within 1, 2 and 3 years from the start of AS. Suspicion of progression was based on an increase in lesion size or prominence on MRI and/or increase in calcifications on mammography. Of those that were identified as good candidates to continue AS with no concern for progression (n = 49), 16 chose to undergo surgical excision (32.7%) and 2 had IDC (4.1%). Conclusion: After over a decade of following women who seek alternatives to surgery for DCIS, we have identified clinicopathologic and imaging features that discriminate good candidates for AS and endocrine risk reducing therapy from those best treated with surgical excision. In our cohort of mostly ER+ patients receiving endocrine therapy on AS, over half of the cohort (51.6%) avoided surgical intervention. Her2 status, Oncotype DCIS, and Mammaprint scores of IDC is in process and will be presented. Our data support the study of AS as a method to stratify the risk of IDC and avoid overtreatment. We will present a personalized AS algorithm (based on biology and imaging) that we intend to prospectively test in the ATHENA network and NCI funded MCL consortium. Table 1: Cohort CharacteristicsFull Cohort (n=64)No evidence of IDC (n=47)IDC at surgery (n=17)Age at Diagnosis (years)53.6 (29.8 - 78.9)52.9 (29.8 - 74.5)55.5 (41.9 - 78.9)Time on AS (years)2.7 (.2 - 11.9)2.8 (.2 - 11.9)2.2 (.3 -5.9)Follow-Up (years)5.6 (0.9 - 15.3)Menopausal StatusPremenopausal26 (40.6%)22 (46.8%)4 (23.5%)Postmenopausal35 (54.7%)24 (51.1%)11 (64.7%)Unknown3 (4.7%)1 (2.1%)2 (11.8%)Breast CompositionFatty4 (6.3%)3 (6.4%)1 (5.9%)Scattered14 (21.9%)9 (19.1%)5 (29.4%)Heterogeneous27 (42.2%)19 (40.4%)8 (47.1%)Extreme17 (26.5%)14 (29.8%)3 (17.6%)Unknown2 (3.1%)2 (4.3%)0 (0.0%)ER StatusPositive57 (89.1%)41 (87.2%)16 (94.1%)Negative1 (1.6%)0 (0.0%)1 (5.9%)Unknown6 (9.3%)6 (12.8%)0 (0.0%)PR StatusPositive50 (78.1%)36 (76.6%)14 (82.3%)Negative5 (7.8%)3 (6.4%)2 (11.8%)Unknown9 (14.1%)8 (17.0%)1 (5.9%)GradeHigh20 (31.3%)15 (31.8%)5 (29.4%)Intermediate32 (50.0%)21 (44.6%)11 (64.7%)Low10 (15.6%)9 (19.1%)1 (5.9%)Unknown2 (3.1%)2 (28.5%)0 (0.0%Hormone TherapyYes57 (89.1%)43 (91.5%)14 (82.4%)No7 (10.9%)4 (8.5%)3 (17.6%) Citation Format: Case Brabham, Rita Mukhtar, April Liang, Paul Kim, Gillian Hirst, Amrita Basu, Heather Greenwood, Rita Freimanis, Alexander Borowsky, Shelley Hwang, Rick Baehner, Gregor Krings, Nola Hylton, Laura Esserman. Active surveillance for DCIS: Clinical outcomes at 5.6 years mean follow-up [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 PS1-03.

Background: The I-SPY2 TRIAL has shown that the addition of pembrolizumab to standard neoadjuvant chemotherapy results in improved rates of estimated pathologic complete response (pCR) for hormone-receptor positive (HR+) as well as triple negative breast cancer (TNBC). I-SPY2 has tested a number of novel immunotherapy combinations including the combination of pembrolizumab and SD-101, a synthetic oligonucleotide with cytidine-phospho-guanosine (CpG) motifs that stimulates plasmacytoid dendritic cells (pDC) through engagement of toll-like receptor 9 (TLR9). Biomarkers of response to immunotherapy may be different than chemotherapy, and pathologic response may not fully reflect the benefit from checkpoint inhibitors. Early markers of response to immunotherapy are needed to minimize the risk of immune-related toxicity in patients who are unlikely to benefit. The objective of this study is to assess the change in regional lymph nodes (LNs) by breast MRI in I-SPY2 patients receiving neoadjuvant chemotherapy +/- immunotherapy, and to explore if changes in regional LNs correlate with pCR and residual cancer burden (RCB). Methods: This is a retrospective study of the prospective multicenter I-SPY2 adaptive neoadjuvant trial investigating all patients enrolled at UCSF in 3 study arms between Dec 2015 and April 2021: 1) Control (weekly paclitaxel 80 mg/m2 x 12 weeks followed by AC x 4); 2) weekly paclitaxel + pembrolizumab 200 mg IV every 3 weeks, followed by AC x 4; 3) weekly paclitaxel + every 3 week pembrolizumab + intra-tumoral SD-101 weekly x 4 then every 3 weeks x 2 followed by AC x 4. Serial pre-operative breast MRIs were performed in all patients at baseline, 3 weeks, 12 weeks, and 20 weeks. A single breast radiologist blinded to treatment arm reviewed all MRIs for all patients included in this study and assessed longest diameter and cortical thickness of the largest ipsilateral axillary LN, number and location of abnormal LNs, and development of new abnormal LNs over time. Rates of pCR and RCB were evaluated in patients who showed evidence of LN growth and/or development of new lymphadenopathy (LAD) compared to those who did not. A two-sample test for equality of proportions to measure the statistical significance at alpha=.5 between control and immunotherapy arms and LN change was used. Results: A total of 43 patients were included, of whom 16 were in the control group, 11 received pembrolizumab, and 16 received pembrolizumab + SD-101. Median age was 45 years, mean tumor size was 4.8 cm, and 60% of tumors were HR+HER2-negative with the remaining 40% being TNBC. Baseline patient and tumor characteristics were similar between the 3 study arms. LN enlargement and/or development of new LAD over time was significantly more common in patients receiving immunotherapy than patients in the control arm (48.1% versus 6.3%, p=0.006). This was seen in both HR+ and TN subtypes. While there was a numerically higher rate of pCR/RCB-1 pathology in patients with increased and/or new LAD compared to those without (64% vs 51%), this difference was not statistically significant. The association of LN change and immune-related toxicities will be reported. Conclusion: The addition of immunotherapy to standard neoadjuvant chemotherapy in the I-SPY2 trial was associated with an increase in size of ipsilateral axillary LN and/or development of new LAD on serial breast MRI imaging during the course of neoadjuvant treatment. These changes were not associated with worse pathologic response at surgery and should not be assumed to be due to disease progression. Whether these changes could reflect immunotherapy benefit needs to be investigated in a larger trial with longer follow-up. Citation Format: Anika Christofferson, Elissa Price, Rita A Mukhtar, Amrita Basu, Laura Esserman, A Jo Chien. Single-institution retrospective analysis of lymph node (LN) change on breast MRI in patients with high risk early-stage breast cancer receiving neoadjuvant chemotherapy with and without immunotherapy on the ISPY-2 TRIAL [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 P3-03-07.

Purpose: Standard treatment for ductal carcinoma in situ (DCIS) involves surgical excision usually with radiation therapy or mastectomy and often endocrine therapy, treatments that are the same as for invasive cancer (IDC). It is clear, however that not all patients with DCIS will develop IDC and so the question is who benefits from early surgical intervention? Active Surveillance (AS) with endocrine risk reduction presents an opportunity to improve outcomes by identifying those lesions that can be managed with endocrine therapy alone without immediate surgical intervention. An active surveillance cohort of women who chose not to have surgery at diagnosis were followed with serial MRIs to identify the imaging features associated with successful AS and those with IDC. Methods: Patients with DCIS were enrolled in MRI surveillance studies between 2002 and 2019 and analyzed retrospectively with IRB approval. Per medical record review, these patients sought to avoid surgical intervention. Inclusion criteria included at least two breast MRIs performed for purposes of surveillance. The final cohort of patients included 64 cases with at least two breast MRIs, with 27 patients having more than 4 MRIs. All breast MRIs consisted of routine sequences, including both pre and post IV contrast images with at least 2 post-contrast time points. Lesion conspicuity, change in lesion, background parenchymal enhancement (BPE), change in BPE, and likelihood of invasive cancer at each MRI timepoint, were subjectively measured independently by two breast radiologists. A Likert scale was used to grade each imaging feature. Radiologists were blinded to the clinical outcome of whether the patient had IDC at surgery or not. Input variables included all imaging features collected and classification trees were trained and bootstrapped on 90% of the data using recursive partitioning to distinguish imaging features predictive of clinical outcome. Proportionality tests were conducted to test whether IDC was associated with age, menopausal status, and breast composition among other clinical variables.Results: Women in the cohort had a mean age of 53.6 years (range 29.8 to 78.9). 98.3% were HR+. Of the 64 cases in the cohort, 57 received endocrine therapy (89.1%). A total of 31 cases (48.4%) eventually had surgical excision and 33 (51.6%) remained on AS. At surgery, 17 patients had IDC (26.6%). Classification trees revealed that the most distinguishing features in the model correlating with IDC were if the lesion was distinct from background at MRI timepoint 1, an increase in BPE between MRI timepoints 1 and 2, and an increase in the lesion size or conspicuity between MRI timepoints 1 and 2. At diagnosis, 56.3% demonstrated a more diffuse pattern of enhancement where the DCIS lesion was not distinguishable above background. Of those with lesions that did not stand out above background at diagnosis and whose BPE did not increase, only 1 of 31 patients developed IDC (3%) with mean follow up of 4.62 years. Patients with IDC were proportionately older (>60) and post-menopausal (73% with IDC were postmenopausal), although only 57% were postmenopausal at diagnosis. Other variables such as breast composition were not enriched in either the IDC versus the non-IDC population. Conclusion: Our study suggests that imaging markers such as BPE and conspicuity of lesion enhancement may provide information to better understand and stratify the risk of DCIS and avoid overtreatment. Importantly, MRI may provide insight as to when a diagnosis of DCIS is more likely to be a global risk factor amenable to endocrine risk reduction, versus a lesion best treated with surgical excision. Pathology correlation is underway. We are currently developing methods to improve reproducibility and harmonization between radiologists, and performance on a validation set will be presented. Citation Format: Heather Greenwood, Rita Freimanis, Case Brabham, Rita Mukhtar, Gillian Hirst, Paul Kim, April Liang, Laura Esserman, Nola Hylton, Amrita Basu. Magnetic resonance imaging insights from an active surveillance cohort of women with DCIS [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 PD5-01.

Background Comorbidities in metastatic breast cancer patients (pts) impact treatment decisions, eligibility for clinical trials, and influence prognosis and quality of life (QoL). The aim of this study was to evaluate the concordance between pt-reported and physician-documented (PD) comorbidities in an electronic medical record to (1) reliably document pts’ health histories to establish eligibility for clinical trials and novel therapeutics, and, (2) identify comorbidities that may be more comprehensively reported by pts rather than physicians. Patients and Methods All new pts at UCSF’s Breast Care Center (BCC) are administered an electronic intake survey that includes an assessment of pt-reported health history, comorbidities and symptoms. Between November 2016 and March 2020, 305 pts self-reported metastatic breast cancer (described as “breast cancer spread to sites other than breast or axillary lymph nodes”), and 222 consented to use of their clinical data for research. Chart-reviews were conducted for PD comorbidities at their initial BCC clinic visit. Pt and physician concordance was summarized for 54 comorbidities. Cohen’s kappa (κ) was used to quantify level of agreement. Concordance was classified using Landis and Koch thresholds with agreement as poor or slight (κ Results Of the 222 pts, 37 pts (17%) incorrectly reported having metastatic breast cancer, 4 (2%) had duplicate surveys, 7 (3%) cancelled appointment and 5 (2%) had metastatic cancer from another primary. Thus, 168 pts with confirmed metastatic disease were included in the analysis (median age, 56 years; age range, 29-86 years; median time from diagnosis of metastatic breast cancer, 0.46 years). Highest PD comorbidities were obesity, hypertension (HTN) and thyroid disease, while highest reported comorbidities by pts were HTN, depression and arthritis. 23 of 54 comorbidities had a moderate to high level of agreement between physician and pt reports (κ≥0.40). As shown in Table 1, agreement was high for diabetes (type 1 or 2), HTN and thyroid disease, moderate for asthma/bronchitis and depression, and low for obesity, anxiety, stomach ulcers/gastroesophageal reflux disease (GERD) and arthritis. Conclusion In this review of data collected as part of routine care at an academic medical center, rates of comorbidities were relatively low, and there is substantial variance in the concordance of comorbidity reporting between pt and physicians. Pt-reported comorbidity data may help physicians more comprehensively document conditions such as depression, anxiety, arthritis and stomach ulcers/GERD, which in some cases may be subjective in nature but may significantly impact a pt’s quality of life and performance status. However, pts may underreport conditions such as obesity and heart disease, and inaccurately report other conditions such as non-insulin dependent diabetes. Recognition of depression, anxiety and GERD as comorbidities is important since some medications for these conditions may be contraindicated in some clinical trials. Understanding this concordance data may inform how we collect pt reported data to optimize understanding of a pt’s global health condition. Table 1: Concordance between physician-documented and patient-reported comorbiditiesComorbidityPhysician ReportedPatient ReportedConcordanceκDiabetes6%5%98%0.83Hypertension24%20%93%0.79Thyroid Disease20%18%92%0.74Insulin dependent Diabetes1%1%99%0.66Depression11%20%87%0.51Asthma/bronchitis12%15%89%0.51Stomach ulcers/ GERD11%18%84%0.36Obesity34%15%75%0.36Heart disease/heart valve disease7%4%93%0.32Anxiety10%18%83%0.30Non-insulin dependent diabetes3%1%97%0.27Arthritis9%20%78%0.14 Citation Format: Saumya Umashankar, Michelle E. Melisko, Madeline Matthys, Laura Van't Veer, Amrita Basu. Concordance between patient-reported and physician-documented comorbidities among stage 4 breast cancer patients [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS9-05.

Purpose In breast MRI, contrast enhancement of normal fibroglandular tissue is referred to as background parenchymal enhancement (BPE). Hormonal status significantly affects the degree of BPE, potentially due to the association with mammary vascularity and activity1-5. Studies have shown that BPE may be associated with breast cancer survival6, treatment response to neoadjuvant chemotherapy (NAC)7,8 and future breast cancer risk9. In most patients undergoing NAC, BPE is suppressed by the nonspecific anti-proliferative effects of chemotherapy on normal breast and/or ovary5,10. However, some patients exhibit equivalent or even stronger BPE post-NAC compared to pre-NAC. We hypothesized that non-suppressed BPE in post-NAC MRI may be associated with inferior treatment response. This study aimed to investigate the association between BPE suppression and treatment response as defined by pathologic complete response (pCR). Methods This study included patients with stage II/III breast cancer enrolled in the I-SPY 2 TRIAL being treated with standard NAC with or without investigational agents. The whole cohort was split into two subgroups based on hormone receptor status (HR+, n= 536; HR-, n=452). Patients underwent dynamic contrast enhanced MRIs at four time points during NAC: baseline (T0), after 3 weeks of the first regimen (T1), inter-regimen (T2), and pre-surgery (T3). Using in-house software, the contralateral breast parenchyma was automatically segmented for the entire breast volume. Quantitative BPE (qBPE) was calculated as the mean early (~150s post-contrast injection) percent enhancement of the central 50% of the axial slices. A breast radiologist reviewed all exams and excluded those where automated segmentation failed to accurately define tissue. For T1, T2 and T3, BPE was categorized based on the change from T0 as suppressed (qBPE < qBPE[T0]) or non-suppressed (qBPE ≥ qBPE[T0]). Chi-squared test was used to examine the association between BPE suppression and pCR, with p Results HR+ cohort: pCR rates were lower for patients with non-suppressed BPE than those with suppressed BPE at every visit (T1-T3) (Table 1). The difference was statistically significant at T2 (p=0.04) and T3 (p=0.01). Table 1: HR+ cohortpCR rate (%)No. of pCR patientsNo. of non-pCR patientsTotal number of patientsP valueOverall22.8122414536BPE at T1suppressed23.6822663480.45non-suppressed20.532124156BPE at T2suppressed25.7972803770.04*non-suppressed16.01789106BPE at T3suppressed25.7982833810.01*non-suppressed12.5128496 HR- cohort: pCR rates were slightly lower for the non-suppressed BPE group, but no statistically significant association was found (Table 2). Table 2: HR- cohortpCR rate (%)No. of pCR patientsNo. of non-pCR patientsTotal number of patientsP valueOverall44.7202250452BPE at T1suppressed46.81411603010.66non-suppressed44.45265117BPE at T2suppressed48.81441512950.79non-suppressed47.3434891BPE at T3suppressed49.31461502960.94non-suppressed48.9434588 Conclusion In HR+ breast cancer, lack of BPE suppression may indicate inferior treatment response. The contrasting results in HR+ and HR- cohorts are noteworthy in terms of the possible relationship between suppression of normal mammary and ovarian activity and treatment response in HR+ cancer. Reference Radiographics 2014; 34: 234-47. Radiology 1997; 203: 137-44. Radiology 1997; 203: 145-9. Breast J 2005; 11: 236-41. AJR Am J Roentgenol 2015; 204: 669-73. Eur Radiol 2018; 28: 4705-16. Eur Radiol 2016; 26: 1590-6. Transl Oncol 2015; 8: 204-9. J Clin Oncol 2019; : JCO1800378. Radiology 2015; 277: 687-96. Citation Format: Natsuko Onishi, Wen Li, David C. Newitt, Roy Harnish, Jessica Gibbs, Ella F. Jones, Alex Nguyen, Lisa Wilmes, Bonnie N. Joe, Michael J. Campbell, Amrita Basu, Laura J. van’t Veer, Angela DiMichele, Douglas Yee, Donald A. Berry, Kathy S. Albain, Judy C. Boughey, A. Jo Chien, Amy S. Clark, Kirsten K. Edmiston, Anthony D. Elias, Erin D. Ellis, David M. Euhus, Heather S. Han, Claudine Isaacs, Qamar J. Khan, Julie E. Lang, Janice Lu, Jane L. Meisel, Zaha Mitri, Rita Nanda, Donald W. Northfelt, Tara Sanft, Erica Stringer-Reasor, Rebecca K. Viscusi, Anne M. Wallace, Rachel Yung, Michelle E. Melisko, Jane Perlmutter, Hope S. Rugo, Richard Schwab, W. Fraser Symmans, Smita M. Asare, Julie E. Yau, Christina Yau, Laura J. Esserman, Nola M. Hylton. Lack of background parenchymal enhancement suppression in breast MRI during neoadjuvant chemotherapy may be associated with inferior treatment response in hormone receptor positive breast cancer [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 PD9-05.

Background: Ductal carcinoma in situ (DCIS) currently accounts for 20% of new breast cancer diagnoses. DCIS is typically treated with surgery and radiation therapy, despite having a much better prognosis than invasive disease. Previous studies have documented features and biomarkers in DCIS that are associated with a higher risk of invasion, and have shown that the tumor microenvironment plays a role in invasive progression of DCIS. In this study we leveraged publicly available gene expression datasets in a meta-analysis to identify biological processes underlying differences in invasive potential. We focused on studies using laser capture microdissection to elucidate these differences within both the epithelial and stromal compartments. Methods: All studies included in this analysis were publicly available datasets downloaded from the Gene Expression Omnibus. Studies were included if they reported gene expression of laser-capture microdissected human breast tissue processed on Affymetrix microarrays and included samples that had the histology of IDC or DCIS. We included 5 studies in our analysis, totaling 83 DCIS epithelial samples, 67 IDC epithelial samples, 26 normal epithelial samples, 22 DCIS stromal samples, 20 IDC stromal samples, and 14 normal stromal samples. The raw datasets were normalized using the Robust Multiarray Average algorithm, and batch effects associated with study and platform were corrected using ComBat. To assess differences in gene expression between DCIS and IDC, we conducted differential gene expression analysis using a t-test and Benjamini-Hochberg correction. Next, we used the DAVID Bioinformatics functional annotation tool to identify enriched pathways in the differentially expressed (DE) gene sets. Finally, hierarchical clustering was used to identify groups of samples within the epithelial and stromal groups based on the DE genes. Results: We found 422 and 118 genes that were differentially expressed (FDR < 0.05) between DCIS and IDC, in epithelium and stroma respectively. Interestingly, 102 of the 118 DE genes in the stroma were downregulated in IDC compared DCIS. Within the epithelial DE genes, pathways related to extracellular matrix reorganization, collagen catabolic processes, and cell-matrix adhesion were upregulated in IDC compared to DCIS. Within the stromal DE genes, cell-adhesion, leukocyte migration, and the Ras/MAPK pathways were downregulated in IDC compared to DCIS. When hierarchically clustered based on DE genes, we identify 6 clusters. Two sets of three clusters associated perfectly with histology (stromal vs epithelium). Within each set of histological clusters, two clusters were comprised entirely or nearly entirely (>97%) of specimens from patients with either IDC or DCIS, while the last cluster (mixed) was comprised of samples from both disease subtypes. Interestingly, only a minority (26%) of stromal samples were classified as mixed, in contrast to a majority of epithelial samples (53%). Conclusions: Our meta-analysis identified DE gene sets that were enriched in processes relating to the tumor microenvironment in both the epithelial and stromal components. Many of the DE genes between DCIS and IDC epithelia were related to collagen production, likely due to the inclusion of fibroblasts in the dissected IDC epithelia. Further analysis will seek to extricate underlying biological changes from differences occurring due to sample dissection and processing. The widespread downregulation of genes in the stroma of IDC supports prior theories that invasion may be related to the loss of a suppressive environment in the stroma. Our results suggest that evaluation of the stromal component of DCIS may be critical in understanding its invasive potential and could therefore guide treatment recommendations. Citation Format: Andre Dempsey, Christina Yau, Olivier Harismendy, Jonah Donnenfield, Amrita Basu, Michael Campbell, Alexander D Borowsky, Gillian Hirst, Laura J Esserman. Gene expression changes in the epithelium and stroma of invasive ductal carcinoma and ductal carcinoma in situ: A meta-analysis [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 P6-06-07.

Triple Negative Breast Cancer (TNBC) is characterized by lack of hormone receptors and targeted therapies, resistance to existing treatment and poor survival outcome, highlighting the need for novel therapy development. Oncogene addiction in breast cancer (BC) cells to drive malignancy up presents oncodrivers as promising therapeutic candidates in BC. Our group has shown loss of anti-oncodriver CD4+-T-helper-type-1 (Th1) response in TNBC patients. Here, we studied effects of combination treatment with Th1 cytokines (IFN-γ+TNF-α) and oncodriver blockade in human and mouse TNBC cells (MDA-MB-231, MDA-MB-468, HCC1143, BT549, 4T1). We measured expression of 3 oncodriver proteins: EGFR, HER3 and cMET and observed multiple oncodrivers in majority of the cell lines, suggesting combined oncodriver inhibition may have stronger antitumor effects. Based on oncodriver status, we tested combination treatment with Th1 cytokines and a) monoclonal α-EGFR antibody cetuximab, b) cMET RTK inhibitor crizotinib and c) siRNA inhibition of three oncodrivers. No significant difference in proliferation after IFN-γ or IFN-γ+TNF-α treatment suggested IFN-γ is the primary effector cytokine. IFN-γ alone reduced proliferation >50% in majority of TNBC cells. In EGFRhigh/HER3pos/cMETlow MDA-MB-468, IFN-γ and cetuximab treatment significantly increased apoptosis compared to untreated cells. Combined EGFR and HER3 siRNA inhibition, followed by IFN-γ treatment, increased apoptosis in those cells. In EGFRpos/HER3low/cMEThigh MDA-MB-231 and EGFRlow/HER3high/cMEThigh 4T1, IFN-γ and crizotinib combination significantly decreased proliferation (p Citation Format: Amrita Basu, Yongsheng Jia, Krithika Kodumudi, Doris Wiener, Brian Czerniecki. Th1 cytokines and oncodriver inhibition: A combination treatment strategy in TNBC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4088.

The proto-oncogene HER2/ErbB2 overexpression occurs in 30% of invasive breast cancer patients and its critically associated with aggressive disease, metastasis and tumor recurrence. Despite advances in the treatment of HER2+ breast cancers, resistance and metastatic disease are potential obstacles. Cullin 5 (Cul 5), a scaffold protein mediates formation of the Cullin 5-RING E3 ubiquitin ligase functional complex. This complex acts on protective molecular chaperone heat shock protein (HSP90) complex and subsequently leads to polyubiquitination and proteasomal degradation of its client protein HER2/ErbB2. Reduced expression of Cul 5 in breast cancer patients can abrogates its inhibitory function and favor HSP90 mediated stabilization of HER2/ErbB2. More recently, we showed that Th1 cytokines (IFN-γ and TNF-α) decreased HER2 expression and induced senescence and apoptosis in HER2 overexpressing breast cancer cell lines. However, the role of Th1 cytokines on Cul 5 mediated regulation of HER2/ErbB2 remains unknown. In the present study, low level expression of Cul 5 was observed in various human (SKBR3, HCC1419 and JIMT1) and mouse (Tubo) HER2+/ER- breast cancer cell lines. Interestingly, treatment of HER2+/ER- breast cancer cells with Th1 cytokines increased the expression of Cul 5 and downregulated the expression of HER2. We knocked-down Cul 5 expression by specific siRNA found that treatment of Th1 cytokines failed to decrease HER2 expression in HER2+/ER- breast cancer cells. To investigate whether the mechanism of Th1 cytokines on Cul5 is via downstream signaling molecule STAT-1, we knock-down STAT-1. Silencing of STAT-1 expression prevented Th1 cytokines mediated activation of Cul 5. We also observed no effect on the inhibition of HER2 expression after Th1 cytokines treatment in HER2+/ER- breast cancer cells in which the expression of STAT-1 was knocked-down. Collectively, our findings demonstrate a novel mechanism that Th1 cytokines promote Cul 5 expression via STAT1 signaling and enhance Cul 5 mediated proteasomal degradation of HER2 in HER2+/ER- breast cancer. Enhancing Cul 5 levels may represent a new therapeutic avenue for the inhibition of HER2 overexpression and prevention of metastasis and tumor relapse. Citation Format: Yongsheng Jia, Ganesan Ramamoorthi, Krithika Kodumudi, Amrita Basu, Doris Wiener, Brian Czerniecki. Th1 cytokines promotes E3 ubiquitin ligase Cullin 5 expression via STAT1 signaling cascade and enhance cul5 mediated proteasomal degradation of HER2 in HER2+/ER- breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4434.

Oncodrivers are a promising target in novel breast cancer therapy development, owing to oncogene addiction of breast cancer cells to sustain their malignancy. We have previously shown progressive loss of CD4+ T-helper type 1 response to oncodrivers in triple negative breast cancer (TNBC) patients. TNBC is marked by lack of cell surface ER, PR and Her2 receptors and is the most aggressive subtype of breast cancer. Lack of therapeutic targets, resistance to existing hormone therapy, metastasis and poor survival in TNBC patients underline the need for novel TNBC therapy development. In this study, we investigated the effect of EGFR inhibitors (cetuximab, erlotinib and lapatinib) alone or combination with Th1 cytokines (IFN-γ and TNF-α) on growth and proliferation of MDA-MB-231 and MDA-MB-468 TNBC cells. We observed decrease in EGFR expression in TNBC cells when treated with IFN-γ alone and in combination with EGFR inhibitors. In addition, IFN-γ alone, in combination with TNF-α and all three EGFR inhibitors, markedly increased STAT1 phosphorylation, indicating suppression of growth and proliferation in TNBC cells. Decreased STAT3 phosphorylation by combination treatment in TNBC cells may induce apoptosis and inhibit proliferation further. Combination of cetuximab and IFN-γ increased cleaved caspase-3 expression in MDA-MB-231, but not in MDA-MB-468 TNBC cells. EGFR inhibition and Th1 cytokine treatment showed combination treatment resulted in severe cell loss and morphological alteration, while Th1 cytokines alone did not induce significant senescence in MDA-MB-231 cells in senescence associated β-galactosidase assay. We are currently investigating activation status of other signaling pathways in TNBC cells, following Th1 cytokines treatment with EGFR inhibition. Our data suggests a combinatorial treatment approach, including DC1 vaccination to elicit Th1 immune response and inhibition of EGFR oncodriver, may lead to an effective and novel therapeutic strategy for triple negative breast cancer. Citation Format: Amrita Basu, Krithika Kodumudi, Doris Wiener, Brian Czerniecki. Th1 cytokines and EGFR inhibition: A combinatorial therapeutic strategy in TNBC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 826.

Precision oncology requires predictive models for therapy selection using variety of biomarkers and clinical features as input. Building and validating these models requires analysis of large numbers of diverse cases in order to relate markers and treatments to positive outcomes. The -omics technologies provide a rich source of genetic and epigenetic markers but demand large compute and storage systems to process the data. Thus, there is an urgent need for scalable and reliable information systems to support nation-scale research and delivery of precision oncology. At Lockheed Martin, we deliver operational solutions to complex problems. Here, we present our vision for a precision oncology platform. This solution integrates best-in-class capabilities from multiple sources/vendors to support innovation, research and clinical care for a whole nation. We not only thought about the basic -omics based data collection, but also an infrastructure to collect and store data within a compliant privacy and security framework that also facilitates collaborative analytics and data sharing for deeper insight. Taking a systems engineering approach, we have examined some of the challenges to implement such a platform. For instance, running the basic genomic data processing pipelines to yield variant calls, which in turn will feed the variant store, should be a single scalable workflow. Accounting for multiple data sources, various use cases and selections of tools are at the core of an adaptable workflow. A variant store design that can scale and support a national cohort with an overlaying cohort selection tool are all part of this intricate design. It is our vision that a systems engineering and integration approach can deliver a unified solution for the national precision oncology roadmap. It is paramount that all the individual pieces should be well tuned to deliver scalability and reliability and simultaneously work in complete harmony. Only then we can process data at-scale needed for finding actionable mutations, designing effective treatments and implementing prevention strategies, affordably and reliably. Citation Format: Ogan Abaan, Amrita Basu, David Deal, Michael Hultner. Adaptive operations and technology platform for nation-scale precision oncology. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3632.

Our understanding of the genetic basis for cancer is advancing at a rapid rate due to the application of next generation sequencing (NGS) technologies. It is becoming common to sequence tumors and patients in an attempt to find actionable mutations that could offer the patient a more targeted and effective treatment. However, the genomics of cancer is very complex and only a handful of actionable mutations have been characterized. Larger-scale studies are needed to understand the pathogenic spectrum of cancer variants and deliver reliable clinical decision-making support to providers. Several large-scale sequencing projects are underway to collect NGS data on tumors (e.g. TCGA, ICGC, and TARGET) but a national platform for analysis, interpretation, and reporting does not exist. We propose that a consolidated informatics platform for the collection of outcomes data with genomics and clinical data would accelerate research and provide patients with the opportunity for personalized cancer treatment. In addition, with 1,665,540 new cancer cases predicted in the US for 2014, a national-scale genomics platform is needed, capable of sequencing 3 million genomes per year, storing exabytes of data, while supporting over 20,000 oncologists, researchers, and analysts. At Lockheed Martin, we deliver highly scalable and reliable information systems for a variety of missions and citizen services. Here, we will present our vision for a national cancer genomics platform to include NGS data collection, cost-efficient storage, scalable and modular processing pipelines, and collaborative analytics and data sharing capabilities, within a compliant privacy and security framework. In conclusion, by leveraging the scale of clinical cancer sequencing and capturing these data into a case management system for translational research, this platform provides data at-scale needed for finding actionable mutations, designing effective treatments and implementing prevention strategies, faster. Citation Format: Ogan Abaan, Amrita Basu, Noah Brown, Bret Light, David Deal, Michael Hultner. A population-based approach to address clinical cancer care: The national genomics platform. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4743. doi:10.1158/1538-7445.AM2015-4743