Dueck, Amylou C.

520 Background: Targeted therapy using trastuzumab (an anti-HER-2 receptor monoclonal antibody) has significantly improved survival in breast carcinoma patients (pts), but determining which pts will respond to this therapy remains a challenge. We previously reported (Miller DV, ASCO 2004 abstract #568) a subset of pts with breast cancers demonstrating focal HER-2 amplified clones (FHAC) amidst otherwise nonamplified tumor cells by fluorescence in-situ hybridization. These accounted for 21% of the HER-2 amplified but immunohistochemistry (IHC) negative cases and 30% of the HER-2 amplified but IHC equivocal cases. The clinical significance of this phenomenon was unclear at that time. We now report the disease-free survival (DFS) data on 91 FHAC pts with a comparison to the diffusely amplified (DA) cases in this trial group. Methods: Breast tumors were evaluated for HER-2 gene amplification using PathVysion™. FHAC cases demonstrated 2–40% of cells with >10 HER-2 signals and HER-2:CEP17 ratio >5.0, regardless of the overall HER-2:CEP17 ratio. Patient and disease characteristics were compared using chi-square tests. Cox regression models compared DFS between pts randomized to arms A (standard chemotherapy) and C (standard chemotherapy with concurrent trastuzumab) within 91 FHAC and 1571 DA cases. Median follow up was 4.0 years. Results: Age, race, menopausal status, surgical procedure, nodal status, histologic type and grade, and tumor size, were not significantly different between pateints with FHAC and DA. Pateints with FHAC had more frequent hormone receptor positivity compared to DA cases (66% vs 50%; p = 0.004). Hazard ratios between pts with FHAC and DA showed that both groups of pts had similar DFS (A: HR = 0.86, p = 0.65; C: HR = 0.72, p = 0.57). Hazard ratios between arms within FHAC and DA groups demonstrated similar benefit from trastuzumab in each group (FHAC: HR = 0.50, p = 0.30; DA: HR = 0.59, p < 0.0001). Results remained consistent when including hormone receptor status in the model. Conclusions: Based on a small number (n = 91) of pts with FHAC, benefit from trastuzumab appears to be similar whether the population of HER-2 amplified cells with breast carcinomas is focal or diffuse. [Table: see text]

e11527 Background: 118 Her2 positive invasive carcinomas were retested centrally at the Mayo Clinic for Her2 status confirmation prior to inclusion in Mayo Clinic Cancer Research Consortium study RC0639 phase II study of cardiac safety and tolerability of adjuvant chemotherapy plus trastuzumab with lapatinib for resected Her2+ breast cancer (MCCRC RC0639). Methods: Central confirmatory methods were immunohistochemical (IHC) Dako HercepTest on a Dako Autostainer using the manufacturer's recommendations and HercepTest kit epitrope retrieval kit and fluorescent in situ hybridization (FISH) using Vysis PathVysion probe kit. Test results are interpreted using ASCO/CAP guidelines (IHC >30%, Her2:CEP 17 ratio >2.2). Results: There is local and central test 3+ IHC concordance in 48 of 53 tumors (agreement 90.6%) and FISH amplification in 29 of 33 tumors (agreement 87.9%), improved or similar results using identical methods to results in NCCTG N9831 adjuvant trial (n=1063, 81.6% IHC; n=813, 88.1% FISH). Of 92 centrally tested 3+ IHC positive tumors, 88 (95.7%) were FISH amplified. 5 centrally tested patients interpreted as Her2 positive by pre-ASCO/CAP guidelines (IHC >10%; HER2:CEP17 ratio >2) are Her2 ineligible using ASCO/CAP guidelines. IHC not confirmed centrally was reviewed by a second pathologist in 16 of 118 specimens. IHC concordance between two central pathologists was 10/16 (62.5%) in negative or equivocal (≤30% IHC staining) specimens; 7/10 (70%) with two reader agreement were FISH amplified and 4/6 (66%) with disagreement were FISH amplified. Conclusions: Concordance in IHC and FISH results between local and central labs is similar or improved since N9831. New ASCO/CAP Her2 testing guidelines change eligibility based on Her2 status in 4.2 % of patients. Equivocal IHC results falling between pre- and post- ASCO/CAP IHC positive thresholds (>10% and <30% IHC strong staining) are only partially resolved by repeat IHC review and/or FISH testing. No significant financial relationships to disclose.

e24176 Background: Decision aids for prostate cancer treatment can improve knowledge, but the relative effect of pre-consultation and within-consultation DAs is not known. Methods: We conducted a parallel design, 2-by-2 factorial, 4-arm, cluster-RCT in urology practices affiliated with the NCI’s Alliance research base. We compared patient knowledge immediately after consultation (%12-item% correct) intervention arms compared to usual care. We used mixed effects regression modeling to assess effect of interventions on knowledge adjusting for site-clustering, race/ethnicity (non-Hispanic White; Other), age (years), clinical stage (T1-3), PSA, and Gleason score. Results: 15 of 21 randomized centers accrued 158 pts from Nov 2017 to June 2019. The arm delivering both DAs (n = 3 sites) recruited 25 pts. The pre-consultation DA arm (n = 4 sites) recruited 39 pts. The within-consultation DA arm (n = 4 sites) recruited 44 pts. The no DA arm (n = 4 sites) accrued 50 pts. Overall, mean age was 64; 54% were AA; 73% had T1 stage; median Gleason = 7; and median PSA = 7. The combined DAs group, followed by pre-consultation reported higher median knowledge (75% and 67%, respectively). The within-consultation and no DA arms both reported median knowledge scores (58%). Within arm, inter-site standard deviations in mean knowledge scores ranged from 0.164 in in the pre-consultation arm to 0.232 in the usual care arm. Neither pre-consultation nor within-consultation DAs had statistically significant effects (p = .15 and p = .99, respectively). Pre-specified adjusted difference [97.5% CIs], comparing the pre-consultation DA and the within-consultation DA with the control was 9.4% [-7.3%, 26.2%] and -0.4% [-16.9%, 16.1%], respectively. Intra-cluster correlation (ICC) coefficient was high (.24). No interaction effects were identified (p = .98). A post-hoc analysis comparing any DA vs usual care found a mean adjusted difference [95% CI] of 5.6% [-8.5%, 19.8%] (p = 0.40), 63.9% for any DA and 58.3% for usual care. Conclusions: Possible knowledge gains associated with some DAs for early prostate cancer were obscured by larger-than-expected intra-cluster correlation effects associated with the primary outcome. How interventions were used was not measured. Support:UG1CA189823; https://acknowledgments.alliancefound.org ; R01 MD008934-06. Clinical trial information: NCT03103321 .

e19112 Background: We sought to study the longitudinal QOL, financial burden and perception of care (PoC) in patients with multiple myeloma (MM) or lymphoma (LYM) enrolled on CTs vs. those receiving standard care (Non-CT). Methods: QOL was evaluated using the FACT-G questionnaire (baseline, 1, 2, 3, 6 & 12 months). Financial burden was evaluated using 10 questions adapted from the MEPS survey and PoC was evaluated using 6 questions adapted from the CAHPS survey (baseline, 3, 6 & 12 months). Results: 35 (28%) of 123 enrolled patients were treated on CTs. Demographics, QOL and financial burden are shown in the Table. Baseline QOL scores were similar in CT vs non-CT groups. Age, gender and self-reported performance status were significantly associated with baseline QOL, while lines of therapy & cancer type were not. There were no significant differences in change in QOL vs. baseline in patients treated on CTs vs. non-CTs at 1, 2, 3, 6 and 12 months from baseline, including the total FACT-G score and the subdomains of functional, physical, emotional and social well-being. Within each group, there was a decline in QOL over the first 3 months, specifically physical WB, which gradually returned to baseline. Baseline answers to financial burden questions were similar, except patients on CTs reported less need for taking extended time-off from work (22% vs. 46%, p = 0.02). The only statistically significant difference in individual Qs over 1 year was ‘worry about having to pay large medical bills’ at the 6-month timepoint (CT: 0%, non-CT: 52%, p = 0.01). Using a composite score from 4 MEPS questions, financial burden over time was lower in the CT group, though the differences were not statistically significant. There were no significant differences in PoC at baseline, 3, 6 and 12 months in the two groups based on answers to each of the six questions adapted from the CAHPS survey. Conclusions: Over 1 year, patients on CTs experienced a similar QOL and perceived their care to be similar as non-CT patients. Financial burden was lower in the CT group, though differences were not statistically significant. [Table: see text]

7044 Background: There is growing interest to implement electronic patient-reported outcomes in oncology practices for symptom monitoring. It is not well known what nurse, physician, and patient impressions of benefits, acceptability, and challenges are in routine care use. Methods: PRO-TECT is an ongoing U.S. national trial including 26 community oncology practices across 15 states that implemented PRO symptom monitoring [NCT03249090]. Patients complete weekly PROs between visits, nurses receive alerts for severe/worsening symptoms, and oncologists review PROs at office visits. Interviews were conducted with 147 stakeholders including nurses (N = 46), oncologists (N = 27), data managers (N = 15), and patients (N = 59). Each stakeholder group had different interview guides with overlapping topics to explore experiences with the PRO system. Interviews lasted 15-60 minutes, were digitally recorded, transcribed, and entered into a qualitative analysis software program. A codebook was developed from the research questions, interview guides, and discussions with the project team. Standardized coding methods were applied, with transcripts double coded for thematic analysis. Feedback surveys were also completed by nurses (N = 57), oncologists (N = 38), and patients (N = 435). Results: Key benefits perceived across stakeholder groups included increased patient self-awareness of symptoms; improved direct communication of patients with care teams; more open and honest conveying of symptom experiences; ability to track symptoms over time; and increased involvement of patients in their own care. Most stakeholders felt PRO symptom monitoring had a positive impact on quality of care delivery, and believed benefits of PROs outweighed necessary staff efforts. Challenges included additional work by nurses to review and respond to alerts, staff turnover requiring retraining, and limited time of oncologists. In the survey, 39/56 (70%) nurses felt the PRO system improved quality of care; 27/33 (82%) oncologists noted PROs were useful for team discussions and care delivery; and 320/434 (74%) patients agreed that weekly PRO reporting improved discussions with their care team. Conclusions: Clinicians and patients perceived weekly PRO symptom monitoring between visits to be valuable despite added staff effort. Results of additional analyses are forthcoming. Clinical trial information: NCT03249090 .

7018 Background: Standard reporting of symptomatic adverse events (AEs) in oncology relies on clinicians to rate patient (pt) experience using CTCAE; each symptom is represented by a single graded item. To capture direct pt experience, NCI developed PRO-CTCAE to supplement CTCAE. In PRO-CTCAE, the pt answers up to 3 questions per AE about a symptom’s frequency, severity and interference with daily activities. To align PRO-CTCAE with CTCAE, we developed an algorithm for mapping sets of questions for an AE to a single composite numerical grade. Methods: We used a 5-step process. (1) All 187 possible PRO-CTCAE score permutations were presented to clinical investigators to subjectively map permutations to single numerical grades (range 0-3). (2) Permutations with < 75% agreement were presented to investigator committees at a National Clinical Trials Network meeting to gain majority consensus via anonymous voting. (3) The resulting algorithm was refined via graphical and tabular approaches to assure directional consistency. (4) Validity, reliability and sensitivity were assessed in a national study dataset. (5) Accuracy for delineating AEs between study arms was measured in 2 phase III clinical trials (Alliance for Clinical Trials in Oncology A091105 and Exelixis COMET-2). Results: (1) 12/187 score permutations had < 75% initial agreement. (2) Majority consensus was reached for all permutations. (3) 5 mappings were adjusted to assure directional consistency. (4) Composite grades for 46/59 (78%) AEs were higher in pts with ECOG performance status 2-4 vs 0-1 (median effect size 0.23 [range -0.49-0.73]; 32/59 effect size ≥0.2; 25/59 p< 0.05), similar to when conducting analysis on individual unmapped items. The test-retest reliability for 24 selected composite grades ranged from 0.57-0.96 (median intraclass correlation coefficient [ICC] 0.77) with 18/24 (75%) grades having ICC ≥0.7. Median (range) standardized response means in pts reporting worsening, no change, and improvement were 0.20 (0.03-0.34), -0.06 (-0.20-0.03) and -0.12 (-0.32-0.06). (5) Pattern, directionality and statistical significance of between-arm differences in both trials were preserved with composite grades as compared to individual unmapped items. Conclusions: A composite grading algorithm for PRO-CTCAE was rigorously developed and validated. PRO-CTCAE composite grades may be useful in analyses to provide a single metric for each pt-reported AE for trial and real-world reporting. Support: UG1CA189823; U01CA233046; HHSN261200800043C; Bayer (A091105); https://acknowledgments.alliancefound.org .

1016 Background: The ph III EMBRACE trial of E vs physician’s choice of tx led to FDA approval of E as ≥3rd-line tx for MBC pts with prior exposure to anthracyclines/taxanes. The ph III BOLD 301 trial of E vs capecitabine in advanced BC treated with anthracyclines/taxanes showed a nonsignificant trend to improved median OS for all pts; pre-planned analysis by HER2 status revealed a nominally significant benefit for HER2- pts. Methods: RU011201I is an investigator initiated ph III trial with 1:1 randomization to E (1.4 mg/m2 D1,8 q21days) vs P (90 mg/m2 D1,8,15 q28days) within strata defined by (neo)adjuvant taxanes (yes/no), HR status (+/-), and line of tx (1st/2nd). Pts had measurable or non-measurable disease by RECIST v1.1; new or progressive mets; peripheral neuropathy (PN) gr<2; ≤1 prior chemotx regimens for advanced or MBC. Asymptomatic brain mets with stable MRIs for >3 mos were allowed. (Neo)adjuvant taxanes were allowed if >12 mos between tx completion and disease recurrence. Radiographic studies occur q12wks. Survival data are collected q12wks after the Off-Tx Visit. Pts reported side effects weekly; post-baseline symptomatic AE rates worse than baseline were compared between arms using Fisher’s exact tests. We report clinical outcomes and the primary objective related to PRO-CTCAE use. Results: 201 pts enrolled 3/2014 - 5/2018 with 33.8 mos median f/u; 3 are on tx as of 2/20/20 (1E, 2P). Pt characteristics were the same between E vs P: median age 62 yrs (range 27-85); 42% prior taxane; 78% ER+; 70% starting 1st line tx. Baseline lesion distribution was similar except for lung mets (37E, 53P). No difference was seen between E vs P in PFS (5.7 vs 5.9 mos; P=0.72), OS (18.1 vs 16.4 mos; P=0.75), TTF (5.3 vs 4.9 mos; P=0.82), DOR (10.8 vs 12.3 mos; P=0.84), or number of metastatic events (55 vs 54). 37E and 36P pts required ≥1 dose reduction. Hematologic toxicities ≥ gr 3 were higher with E (40 vs 22%). PN events were similar: 56 vs 58 total, 4 vs 7 motor, 52 vs 51 sensory. Median duration of PN and median time to 1st PN event were 74 vs 140 and 56 vs 41 days. Worsened numbness/tingling severity and other pt-reported AE rates were similar, but worsened numbness/tingling interference (63% vs 78%, P=0.04) and vomiting frequency (35% vs 57%, P=0.005) were lower with E. Conclusions: Clinical outcomes were equivalent with E vs P as 1st/2nd line tx for HER2- advanced BC. The nature and severity of PN were similar between arms, but time of onset, duration, and interference with daily living favor E. E may be a suitable treatment option in this setting. Clinical trial information: NCT02037529 .

Abstract Background: Side effects of and adherence to aromatase inhibitors in women with ductal carcinoma in situ are not well described. Methods: Postmenopausal women in a prospective phase II study of neoadjuvant letrozole for estrogen receptor positive DCIS completed questionnaires on side effects [Menopause Specific Quality of Life Questionnaire (MENQOL), Brief Pain Inventory-short form (BPI-SF), Arthritis Impact Measurement Scales (AIMS2)], well-being (FACT-G), and adherence [Medication-Taking questionnaire] at baseline, 1, 3 and 6 months (mo), and study completion. We used descriptive statistics and paired t-tests to compare 1, 3 and 6 mo results to baseline. Hierarchical linear mixed modeling, controlling for baseline symptom or well-being level, was used to examine effect of symptoms and well-being on intentional and nonintentional nonadherence, based on the Medication-Taking Questionnaire. Results: Included were 84 women, mean age 63 (39-83) years. In univariate analyses, compared to baseline, menopausal symptoms increased [physical (p=0.001 at 3, p&lt;0.001 at 6 mo); vasomotor (p&lt;0.001 at 1, 3, 6 mo), psychosocial (p=0.006 at 6 mo) and sexual (p=0.01 at 6 mo)]. Joint pain and stiffness increased [BPI-SF pain subscale (p=0.048 at 3, p=0.01 at 6 mo); AIMS2 joint pain subscale (p=0.03 at 1, p&lt;0.001 at 3 and 6 mo); AIMS2 stiffness subscale (p=0.004 at 3, p=0.01 at 6 mo)]. Intentional and nonintentional adherence did not significantly change over time (p&gt;0.05). Lower emotional (p=0.049) and functional (p=0.002) well-being by FACT-G and higher joint pain (p=0.03) by AIMS2 were associated with higher nonintentional nonadherence; higher physical side effects of menopause (p=0.001) by MENQOL were associated with lower intentional nonadherence. Conclusions: Among women taking letrozole for DCIS, menopausal symptoms and joint pain/stiffness increased over time with most differences noted at 3 and 6 mo. Lower well-being and higher symptom levels were associated with higher nonintentional nonadherence. NCT01439711.U10CA180821, U10CA180882, UG1CA189823, Breast Cancer Research Foundation, https://acknowledgments.alliancefound.org. Citation Format: Gretchen Kimmick, Amylou C Dueck, Rebecca Shelby, Michelle Naughton, Abigail Caudle, Briant Fruth, E. Shelley Hwang. Musculoskeletal side effects over time and association with adherence in women taking neoadjuvant letrozole for estrogen receptor positive DCIS: CALGB 40903 (Alliance) [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 P5-14-17.

11553 Background: Little is known about the toxicity of trastuzumab (T) or of trastuzumab + lapatinib (T + L), approved in the advanced setting, in older pts. We have performed a sub-analysis of the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation (ALTTO) trial focused on treatment completion and toxicity of T and T+L in older pts (aged ≥65 years (yr)). Methods: The ALTTO trial (NCT00490139, NCCTG N063D) randomised 8381 pts with early HER2+ BC into 4 arms and we included the T and T+L arms in our analysis. Eligible pts for our study were those having received at least one dose of assigned treatment. Treatment completion was evaluated through the rate of temporary treatment interruptions (TTI), permanent treatment discontinuations (PTD) and lapatinib dose reductions (LDR). Toxicity was evaluated via a selected set of adverse events of interest (AEIs). Risk factors for TTI, PTD, LDR and AEIs were assessed, including comorbidities and polypharmacy at baseline (defined as use 5 or more co-medications) and AEIs during treatment. Results: A total of 430 pts≥65-year-old were identified for this sub-analysis, out of a total of 4190 pts with a median age of 68 yrs (range 65-80). Older pts were more likely to have comorbidities (70% vs 38%). Treatment completion was worse among older pts in the T+L arm but not in the T arm (Table). AEIs were more common in the T+L arm in all patients, with older patients having higher AEI rates (78.04% in older vs 63.38% in younger), particularly diarrhea (60.75% vs 38.0%). Identified risk factors (multivariate) for worse treatment completion in the T and T+ L arms included concomitant use of chemotherapy and the occurrence of grade 3 adverse events, among others. Conclusions: T + L has worse treatment completion and is more toxic in older patients, while T was well tolerated. Identifiable risk factors at baseline and during the course of treatment could be used to aid in regimen selection and management for both T and T + L in their respective indications. Support: UG1CA189823, Novartis;https://acknowledgments.alliancefound.org. [Table: see text]