Melin, Susan A.

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.

Abstract Purpose: Low-dose tamoxifen reduces breast cancer risk, but remains untested in chest-irradiated cancer survivors—a population with breast cancer risk comparable with BRCA mutation carriers. We hypothesized that low-dose tamoxifen would be safe and efficacious in reducing radiation-related breast cancer risk. Patients and Methods: We conducted an investigator-initiated, randomized, phase IIb, double-blinded, placebo-controlled trial (FDA IND107367) between 2010 and 2016 at 15 U.S. sites. Eligibility included ≥12 Gy of chest radiation by age 40 years and age at enrollment ≥25 years. Patients were randomized 1:1 to low-dose tamoxifen (5 mg/day) or identical placebo tablets for 2 years. The primary endpoint was mammographic dense area at baseline, 1 and 2 years. IGF-1 plays a role in breast carcinogenesis; circulating IGF-1 and IGF-BP3 levels at baseline, 1 and 2 years served as secondary endpoints. Results: Seventy-two participants (low-dose tamoxifen: n = 34, placebo: n = 38) enrolled at a median age of 43.8 years (35–49) were evaluable. They had received chest radiation at a median dose of 30.3 Gy. Compared with the placebo arm, the low-dose tamoxifen arm participants had significantly lower mammographic dense area (P = 0.02) and IGF1 levels (P < 0.0001), and higher IGFBP-3 levels (P = 0.02). There was no difference in toxicity biomarkers (serum bone-specific alkaline phosphatase, lipids, and antithrombin III; urine N-telopeptide cross-links) between the treatment arms. We did not identify any grade 3–4 adverse events related to low-dose tamoxifen. Conclusions: In this randomized trial in chest-irradiated cancer survivors, we find that low-dose tamoxifen is effective in reducing established biomarkers of breast cancer risk and could serve as a risk-reduction strategy.

Background: Lymphoma patients exposed to chest RT during adolescence/young adulthood are at increased risk for BC; the cumulative incidence exceeds 20% by age 45 and the BC risk is comparable to that in women with BRCA1 mutations. These findings present an urgent yet unmet need to reduce the risk of BC in RT-exposed lymphoma survivors. The risk of BC is 50% lower in chest RT-exposed survivors who also receive ovarian radiation, suggesting a critical role of endogenous estrogens in RT-related breast carcinogenesis, making tamoxifen (a selective estrogen receptor modulator) an attractive risk-reducing option. Tamoxifen administered at 20 mg/d is effective in BC prevention in other high risk populations, but severe adverse events (SAE: venous thromboembolism, endometrial cancer) have limited its broad use. Previous biomarker trials in the general population have shown that LDTam (5mg/d) is not inferior to tamoxifen at 20 mg/d in reducing BC risk, and is associated with a safer AE profile. Mammographic breast density (MBD) is an established biomarker of BC risk; high MBD is associated with a 4-fold higher risk of BC. We hypothesized that LDTam would be effective in reducing BC risk (using MBD as a primary endpoint) in chest RT-exposed lymphoma survivors. We used an investigator-initiated, multi-institutional, randomized phase IIb, double blind, placebo controlled trial (FDA IND 107367) to test this hypothesis. Methods: Female patients from 13 sites were ≥25y at enrollment, with a history of exposure to chest RT at ≥12 Gy by age 40 for their primary cancer, and were off therapy for ≥6 mo. Subjects with a prior history of BC/DCIS, B/L mastectomy, or baseline MBD <25% in both breasts were excluded. Tamoxifen 5mg or identical placebo tablets were provided by Sharp Clinical Services (Allentown, PA) under good manufacturing practice. Subjects were randomized 1:1 in a double-blinded fashion by a Web-based system to receive LDTam or placebo daily for 2y. MBD (in both breasts) was measured centrally on digital scans independently by 3 radiologists at baseline, 1y and 2y. Using an intention-to-treat analysis, the efficacy of LDTam in reducing MBD was compared between the LDTam and placebo arms by applying a linear mixed effects model for bivariate normally distributed data with random intercept and time*treatment arm effects. Correlations between the left and right breasts and within radiologists were accounted for in the model. Treating clinicians and all research staff were blinded to the treatment arm. Results: A total of 72 patients (LDTam: n=34; placebo: n=38) participated in the trial; primary diagnosis: Hodgkin lymphoma (86%); non-Hodgkin lymphoma (10%); other (3%); median age at diagnosis of primary cancer: 21.5y (IQR, 16-28), and at trial enrollment: 43.8y (35-49); median time from diagnosis of primary cancer to study: 17.0y (12-26). Median chest RT dose: 30.3 Gy (21-37.3); 11% had received pelvic radiation; 39% were post-menopausal at study. Participant characteristics were comparable between the two treatment arms, as was the mean baseline MBD (LDTam: 52.6% vs. placebo: 50.4%, p=0.6). The time*treatment arm effect was statistically significant (LDTam vs. placebo: estimate = -1.7, SE = 0.5, p = 0.001), indicating a significantly lower mean fitted MBD for LDTam (43.9%) vs. placebo (47.3%) at 2y (Figure). This represented a 16.5% relative reduction in MBD on the LDTam arm, corresponding to an estimated 33% lower risk of BC (assuming that reductions in MBD have the same benefit in lymphoma survivors as they do in the general population). There were no grade 3 or 4 AEs related to LDTam. Grade 2 AEs did not differ between treatment arms (LDTam: 44.1% vs. placebo: 36.8%, p=0.6). There was no difference in the prevalence of moderate-to-severe patient-reported outcomes between the treatment arms (Table). Conclusion: Low-dose tamoxifen was associated with a significantly steeper decline in MBD in chest RT-exposed lymphoma survivors, when compared with placebo, and was safe and well-tolerated. This is the first trial demonstrating efficacy of a pharmacologic intervention in reducing a biomarker strongly associated with breast cancer risk in lymphoma survivors with a past history of chest radiation. Disclosures Palomares: Covance: Other: Medical monitoring. Henderson:Seattle Genetics: Research Funding. OffLabel Disclosure: The drug is a low-dose tamoxifen, a selective estrogen receptor modulator. Tamoxifen in standard doses is used to reduce the risk of breast cancer in high risk populations. Tamoxifen in standard or low doses have not been tested before for chest-irradiated cancer survivors to reduce the risk of radiation-related breast cancer.