Heditsian, Diane

271 Background: Many studies have shown that fatigue is associated with poor outcomes such as quality of life and physical function in breast cancer survivors.Early treatment of symptoms that result in persistent fatigue may be a strategy to mitigate long-term fatigue.As a result, we studied symptoms and developed risk estimates for patients that are most likely to develop fatigue by pre-surgery and follow up among patients treated on the I-SPY 2 neoadjuvant trial. I-SPY 2 is a phase-II adaptive trial for high-risk early-stage breast cancer patients. Methods: In this retrospective cohort study of 306 women undergoing neoadjuvant chemotherapy +/- targeted therapy, patients complete electronic surveys of symptoms via 34 PRO-CTCAE items and QOL via 9 PROMIS instruments. Fatigue is collected as part of the PROMIS survey and scored using Health Measures. Study timepoints are screening (SC), weekly study treatment (ST), 12 weeks (12w), pre-surgery (PS) and at 1, 6, 12 and 24 months (FU1-FU4) following surgery. Correlation between symptoms and fatigue at equal timepoints was quantified using spearman correlations and BH-adjusted p-values. For symptom odds analysis, symptoms were binarized such that those that had an average grade of mild or above (severity), rarely or above (frequency) or a little bit or above (interference) between ST weeks 1-6 were considered present. Clinically significant (CS) increase in fatigue was defined as an increase >=0.5 standard deviation (SD) in mean from baseline. Logistic regression was used to determine odds ratios of factors associated with fatigue. Results: Baseline PROMIS fatigue mean score was 47.14 (SD 9.31) with a median of 47.45. A CS increase in fatigue from baseline was seen in 55% of patients at 12w, and 61% of patients pre-surgery. Of the patients that had a CS increase in fatigue at any point prior to surgery, 45.7% had persistent fatigue through FU1-4. Symptoms associated with Fatigue at 12w were shortness of breath, headache, and nausea (P< 0.03). At PS, fatigue was significantly correlated with GI symptoms, neuropathy, and shortness of breath (P< 0.03). Risk estimates for patients that filled out symptom surveys at early timepoints (weeks 1-6) and also had fatigue were evaluated. Patients with early GU (genitourinary) symptoms had higher risk of fatigue at IR (OR=9.33, p=0.02, 88.9% in cases vs 33.3% in controls). Patients with early GI symptoms at PS (OR=8.56, p=0.03, 90.1% vs 50%), or FU2-4 (OR= 5.88 and 7.36, p= 0.04 and 0.02, 80% vs 39.1% and 81.8% vs 36.3%) also had a higher risk of developing fatigue. Conclusions: A CS increase in fatigue during treatment and follow up is seen in the majority of patients and is associated with a large number of persistent symptoms.

Abstract Objectives We describe the development and implementation of a system for monitoring patient-reported adverse events and quality of life using electronic Patient Reported Outcome (ePRO) instruments in the I-SPY2 Trial, a phase II clinical trial for locally advanced breast cancer. We describe the administration of technological, workflow, and behavior change interventions and their associated impact on questionnaire completion. Materials and Methods Using the OpenClinica electronic data capture system, we developed rules-based logic to build automated ePRO surveys, customized to the I-SPY2 treatment schedule. We piloted ePROs at the University of California, San Francisco (UCSF) to optimize workflow in the context of trial treatment scenarios and staggered rollout of the ePRO system to 26 sites to ensure effective implementation of the technology. Results Increasing ePRO completion requires workflow solutions and research staff engagement. Over two years, we increased baseline survey completion from 25% to 80%. The majority of patients completed between 30% and 75% of the questionnaires they received, with no statistically significant variation in survey completion by age, race or ethnicity. Patients who completed the screening timepoint questionnaire were significantly more likely to complete more of the surveys they received at later timepoints (mean completion of 74.1% vs 35.5%, P &lt; .0001). Baseline PROMIS social functioning and grade 2 or more PRO-CTCAE interference of Abdominal Pain, Decreased Appetite, Dizziness and Shortness of Breath was associated with lower survey completion rates. Discussion and Conclusion By implementing ePROs, we have the potential to increase efficiency and accuracy of patient-reported clinical trial data collection, while improving quality of care, patient safety, and health outcomes. Our method is accessible across demographics and facilitates an ease of data collection and sharing across nationwide sites. We identify predictors of decreased completion that can optimize resource allocation by better targeting efforts such as in-person outreach, staff engagement, a robust technical workflow, and increased monitoring to improve overall completion rates. Trial Registration https://clinicaltrials.gov/study/NCT01042379.

11113 Background: Patient-reported outcomes (PROs) are valuable for understanding treatment tolerability and toxicity. I-SPY2 is a phase-II neoadjuvant clinical trial for breast cancer with electronic PROs and quality of life (QOL) assessments. We sought to understand how well the GP5 self-reported tolerability item reflected toxicity burden and QOL during treatment and follow-up in I-SPY 2 participants. Methods: Our study included 306 patients who completed the FACIT Item GP5 and answered PROMIS surveys at two or more timepoints. Analysis timepoints included screening (SC), inter-regimen (IR), pre-surgery (PS), 1-month post-surgery (FU1), and 6-months post-surgery (FU2). Symptoms were assessed weekly using PRO-CTCAE and CTCAEv4.0. QOL was evaluated using PROMIS. The GP5: “I am bothered by side effects of treatment,” was used to estimate tolerability, where worse tolerability is a higher score. Odds ratios, Spearman correlation, and regularized multi-variate regression were used to evaluate the associations between individual symptoms and adverse events with GP5 scores. Results: Demographic information was available for 243 of the 306 (70.2%) participants (median age=47,73.7% white). In the 306, tolerability scores worsened over study treatment, with a maximum mean score of 1.71 at Cycle 11. Tolerability improved after treatment cessation at FU1(1.09). Mean tolerability at week 6 was 1.53. The only clinical factor that was associated with early change in tolerability (week 6 to PS) was age >50 (mean score ranged from 1.55-1.70 vs 1.29-1.45 (age<50), p<0.05). PRO-CTCAE and GP5 correlative analysis suggested that higher grade abdominal pain, decreased appetite, dizziness and blurry vision significantly associated with higher GP5 scores at multiple timepoints (p<0.05). Symptoms not associated with tolerability were nail loss, acne, hair loss, and rash (p>0.05). Additionally, the total number of low-grade (mild to moderate) symptoms a patient experienced during study treatment was significantly correlated to poor tolerability (p<0.00001). Among patients with CTCAE data, 9% had adrenal insufficiency, and higher GP5 was found across all study timepoints in those with (compared to without) adrenal insufficiency (mean GP5 = [1.7-1.9] vs [1.3-1.5] respectively). Similarly, among patients with neuropathy (14%), higher GP5 scores were reported across all study timepoints (mean GP5 = [1.8-2.3] vs [1.3-1.5] respectively). Higher GP5 scores during treatment were correlated with higher fatigue scores at PS and FU1 (p<0.02 and p<0.001) and lower physical functioning at PS (p<0.01). Conclusions: TheGP5 measure is associated with self-reported symptoms, higher grade adverse events and quality of life scores. Furthermore, greater accumulation of lower grade symptoms can lead to poor tolerability. The single measure GP5 composite score reflects multiple components of treatment toxicity.

369 Background: Patient-reported outcomes (PROs) are a valuable component to understand treatment tolerability and toxicity. We have implemented an electronic system for monitoring PROs and quality of life (QOL) for patients enrolled in the I-SPY2 trial, a phase II trial evaluating the effect of novel neoadjuvant therapies for breast cancer. We associated patient demographic factors with symptoms, decline in physical function (PF), and tolerability to treatment. Methods: Study population for this analysis includes 259 enrolled patients receiving combinations of experimental immunotherapy and chemotherapy. Patients completed PRO-CTCAE/PROMIS/FACT surveys reflecting symptom severity, symptom frequency, tolerability of drug, and physical function at baseline through follow up (12 months). CTCAE 5.0 was collected weekly at these timepoints to assess adverse events (AE). Odds ratio and regularized multi-variate regression was used to evaluate early symptoms predictive of a clinically significant decline in PF from baseline to post-treatment follow-up. Results: Of 259 patients, 160 (58%) were White, 13 (5%) were Asian, 26 (10%) were African American (AA), and 25 (9.3%) were Hispanic. 25% of all patients had a clinically significant decline in PF between baseline and pre-surgery/follow-up. Symptom predictors of decline included high frequency of diarrhea and severity of joint pain. African American (AA) patients had higher severity of joint pain than White patients (OR = 14.9, P < 0.05). 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). Overall, patients that reported lower tolerance to therapy had higher grade of AE. While patients with low-grade adverse events were less bothered by their side effects at follow-up, higher grade adverse events such as hypothyroidism impacted distress levels by more than double. Conclusions: Among I-SPY2 participants, when higher grade of symptoms is persistent through follow up, it impacts physical function and tolerability even after end of therapy. Our study can allow physicians to be more diligent in active and post treatment monitoring. Clinical trial information: NCT01042379 .

Abstract 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 (&gt;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 &lt; 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&lt; 0.05 and P&lt; 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&lt; 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.

Abstract 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.