Saphner, Thomas J.

Abstract Background Breast cancer chemoprevention is underutilized among high-risk women. We examined whether decision support could increase informed decision making. Methods We conducted a cluster randomized controlled trial to evaluate the effect of a patient-facing decision aid (RealRisks) and provider tool (BNAV) compared with standard education on the number of women with high-risk breast lesions making informed choices. Questionnaires were administered at baseline and 6 and 12 months. The primary outcome was chemoprevention informed choice (defined as adequate knowledge and attitudes congruent with decision) at 6 months. Secondary endpoints included breast cancer risk perceptions, worry, chemoprevention knowledge, decision conflict, and chemoprevention decision. Results Across 31 randomized sites, we enrolled 210 providers, who were primarily breast health specialists. Of these, 24 sites (14 intervention, 10 control) enrolled 412 patients. Among 287 patients evaluable for the primary outcome, there were no statistically significant differences in informed choice between the intervention and control arms at 6 months (35% vs 27%, respectively; P = .20) and 12 months (37% vs 25%, respectively; P = .05). At 6 months, women in the intervention compared with control arm were more likely to have accurate breast cancer risk perceptions (31% vs 21%, respectively; P = .03) and adequate chemoprevention knowledge (33% vs 23%, respectively; P = .04). At 12 months, 52% of women in the control and 50% in the intervention arm self-reported initiating chemoprevention. Conclusion Decision support led to modest improvements in accurate risk perceptions and chemoprevention knowledge but not informed choice. Relatively high chemoprevention uptake was achieved among women with high-risk breast lesions managed mainly by breast health specialists. Trial Registration NCT04496739, https://clinicaltrials.gov/study/NCT04496739?cond=NCT04496739&viewType=Card&rank=1

Abstract Background: Breast cancer (BC) chemoprevention with selective estrogen receptor modulators (SERMs) and aromatase inhibitors (AIs) remains underutilized among high-risk women. Improving knowledge about BC risk and chemoprevention among high-risk patients and their healthcare providers may enhance informed decision-making about this BC risk reduction strategy. Methods: We conducted a cluster randomized controlled trial to evaluate the effectiveness of web-based patient and provider decision support, RealRisks and BNAV, to improve chemoprevention informed choice among women with atypical hyperplasia (AH) or lobular carcinoma in situ (LCIS). Thirty-one sites, including academic and community practices across the U.S., were randomized to standard patient educational materials alone or combined with RealRisks and BNAV. A total of 412 patients and 210 healthcare providers were enrolled. Patient surveys were administered at baseline, 6 and 12 months. The primary outcome at 6 months was chemoprevention informed choice, defined as adequate chemoprevention knowledge and attitudes congruent with decision. Secondary endpoints included BC risk perceptions, worry, chemoprevention knowledge, decision conflict and chemoprevention decision. Assuming 10% loss to follow up (LTFU), roughly equal accrual across sites, and an intraclass coefficient (ICC) of 0.02, we had 90% power to detect a 15% absolute difference in informed choice if the event rate in the control arm was 10%. Results: Among 24 evaluable sites, 14 were randomized to the intervention arm and 10 to the control arm. Among 210 enrolled providers, median age was 46 (range, 28-83) and 78% were female; 75% physicians and 25% advanced practice providers/nurses; 53% medical oncologists, 29% surgeons, and 10% gynecologists/family practitioners/internists; and 83% had previously prescribed chemoprevention. Among 412 enrolled patients, median age was 53 (range, 35-74), including 77% White, 8% Black, and 10% Asian race, and 14% Hispanic ethnicity. In terms of BC risk factors, 77% had AH and 23% LCIS, 34% had a first-degree family history of BC, and 65% had heterogeneously or extremely dense breasts on mammography. Thirty percent were unevaluable for the primary endpoint (1% ineligible, 26% LTFU, 3% missing data). Among 288 evaluable patients (148 at intervention sites, 140 at control sites), the proportion of patients exercising informed choice at 6 months in the intervention and control arms was 35% vs. 27%, respectively (odds ratio [OR]=1.44, 95% confidence interval [CI]=0.84-2.46, p=0.19; observed ICC=0.006). Compared to patients in the control arm at 6 months, those in the intervention arm were more likely to have accurate BC risk perceptions (OR=1.80, 95% CI=1.11-2.91) and adequate chemoprevention knowledge (OR=1.62, 95% CI=1.00-2.61). We observed no significant differences in BC worry, decision conflict, or chemoprevention decision between study arms. At 6 months, 49% of women in the control arm and 51% in the intervention arm decided to take a SERM or AI for BC chemoprevention (p=0.58), a rate higher than anticipated. Conclusions: We did not observe a significant increase in informed choice among patients and providers assigned to chemoprevention decision support compared to standard educational materials alone. Among women with AH or LCIS seen mainly by breast specialists who prescribed chemoprevention, about half decided to take a SERM or AI. Therefore, relatively high chemoprevention uptake may be achieved among women with high-risk breast lesions managed by breast specialists. Chemoprevention decision support may improve decision antecedents, such as accurate BC risk perceptions and chemoprevention knowledge, but may have a limited role in changing health behaviors. Citation Format: K. D. Crew, G. L. Anderson, K. B. Arnold, A. Michel, M. T. DeLucie, C. W. Law, S. Pruthi, A. C. Sandoval Leon, R. Shirley, M. T. Grosse Perdekamp, S. V. Colonna, S. L. Krisher, T. King, L. D. Yee, T. J. Ballinger, C. Braun-Inglis, D. A. Mangino, K. B. Wisinski, C. A. DeYoung, M. Ross, J. D. Floyd, A. Kaster, L. VanderWalde, T. Saphner, C. Zarwan, S. Lo, C. Graham, A. K. Conlin, K. J. Yost, D. M. Agnese, C. Jernigan, D. L. Hershman, M. L. Neuhouser, J. A. Zell, B. Arun, R. Kukafka. Making informed choices on incorporating chemoprevention into care (MiCHOICE): Cluster randomized controlled trial of decision support for breast cancer chemoprevention, SWOG 1904 [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-01-15.

Abstract Background: TheTAILORx trial established that adjuvant endocrine therapy (ET) is non-inferiorto chemotherapy plus ET (CET) in T1-2N0 HR+/HER2-negative early breast cancer(EBC) with an Oncotype DX (ODX) 21-gene recurrence score (RS) of 11-25, RS 0-10is associated with low distant recurrence (DR) rates with ET alone, and RS26-100 is associated with higher DR rates despite CET. Although ODX isprognostic for 10-year DR, it has limited value for late DR >5 years. Inorder to develop improved DR risk prognostication, we developed multimodal AImodels integrating clinical, molecular, and histopathology features to provideprognostic information for early (<5years), late (>5 years), and overall DR at 15 years using primary tumorsamples and clinical data from volunteers who participated in TAILORx. Methods: DigitizedH&E slides were generated and nucleic acids extracted and sequenced from∼5000 primary tumor samples using Caris MI Tumor Seek-Hybrid, of which 2,808(56%) were used for model training and 5-fold nested cross validation (60/20/20split). Models included single-modality (clinical [C], image [I], molecular [M:ODX genes]), dual-modality (CM, IC), and multimodal (ICM). An expandedmolecular model (M+) model was also derived from expanded molecular inputsderived from whole transcriptome sequencing (WTS) data, including 5 commercialgene signatures (ODX, MammaPrint, Prosigna, EndoPredict, BCI) and 57 high-variancegenes; only EndoPredict, BCI, and ODX gene signatures were retained for model M+.Model-CM+ combined clinical plus expanded molecular features, while ICM/ICM+integrated image, clinical, and (expanded) molecular inputs. Risk scores were dichotomized into high vs. low risk groups usingthresholds chosen to yield risk group proportions closely matching thosedefined by the ODX RS cutoff of 25 for distinguishing high vs. low genomicrisk. Theprimary endpoint was distant recurrence (DR). Prognostic performance wasassessed using truncated concordance index (C-index, 90th percentile of eventtimes), hazard ratios (HRs), and log-rank tests. DNA-level whole exomesequencing (WES) features were also tested but did not provide additionalprognostic information and thus excluded from final models. Results: Theactual ODX continuous RS achieved a C-index of 0.625 for overall DR and 0.743early DR, but no prognostic value for late DR (0.52). Similar results for theC-index were observed for ODX+C for overall DR (0.619), early DR (0.724), andlate DR (0.514). Of all modelsevaluated, model-ICM+ gave the best overall prognostic accuracy for overall DR (C-index0.713; hazard ratio [HR] 3.56 for comparison of high vs. low risk, p<0.001)and late DR (C-index 0.655; HR 2.36, p<0.001), and ranked second for earlyDR (C-index 0.772; HR 6.59, p<0.001) behind the CM+ model (C-index 0.782). Amongsingle-modality models, Model-M+ improved early DR prognostication comparedwith a molecular model including only ODX genes(C-index 0.767 vs 0.744 for M),whereas Model-I was strongest for late DR prognostication (C-index 0.635). Conclusions: Molecularfeatures primarily drove prognostic accuracy for early DR within 5 years,whereas histopathology features strengthened the prognostic accuracy for lateDR after 5 years. Multimodal models captured these complementary signals, withICM+ giving the best overall accuracy for individualized prognostic assessment.Additional validation of the optimized ICM+ model and other models is beingperformed in an intendent validation sample of 2000 TAILORx volunteers, withresults to be presented at the meeting.Supported by the Breast CancerResearch Foundation and the U.S. NIH/NCI U10CA180820 and 5U24CA196172, and theU.S. Postal Service Breast Cancer Stamp Fund. Citation Format: J. A. Sparano, V. Wang, R. J. Gray, D. F. Makower, K. S. Albain, D. F. Hayes, C. E. Geyer, E. C. Dees, M. P. Goetz, J. A. Olson, S. S. Badve, T. J. Saphner, T. J. Whelan, M. Radovich, V. G. Kaklamani, G. W. Sledge. Multimodal artificial intelligence (AI) models integrating image, clinical, and molecular data for predicting early and late breast cancer recurrence in TAILORx [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr GS1-08.

Abstract Background In 2008, bevacizumab received accelerated Food and Drug Administration (FDA) approval for use in human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC). Based on the preclinical and preliminary clinical activity of the trastuzumab and bevacizumab combination, ECOG-ACRIN E1105 trial was developed to determine if the addition of bevacizumab to a chemotherapy and trastuzumab combination for first-line therapy would improve progression-free survival (PFS) in patients with HER2-positive MBC. Findings: 96 patients were randomized to receive standard first-line chemotherapy and trastuzumab with or without bevacizumab between November 2007 and October 2009, and 93 began protocol therapy. Induction therapy was given for 24 weeks, followed by maintenance trastuzumab with or without bevacizumab. 60% (56/93) began carboplatin and 74% (69/93) completed 6 cycles of induction therapy. Primary endpoint was PFS. Median PFS was 11.1 and 13.8 months for placebo and bevacizumab arms, respectively (hazard ratio [HR] 95%, Confidence Interval [Cl] for bevacizumab vs. placebo: 0.73 [0.43–1.23], p = 0.24), and at a median follow-up of 70.7 months, median survival was 49.1 and 63 months (HR [95% Cl] for OS: 1.09 [0.61–1.97], p = 0.75). The most common toxicities across both arms were neutropenia and hypertension, with left ventricular systolic dysfunction, fatigue, and sensory neuropathy reported more frequently with bevacizumab. Conclusions In this trial, the addition of bevacizumab did not improve outcomes in patients with metastatic HER2-positive breast cancer. Although the trial was underpowered due to smaller than anticipated sample size, these findings corroborated other clinical trials during this time.

Abstract Purpose A protocol was developed to evaluate the value of an NK-1 receptor antagonist for preventing nausea and vomiting resulting from highly emetogenic chemotherapy when an olanzapine-based antiemetogenic regimen was used. Materials and Methods A221602, a prospective double-blind, placebo-controlled clinical trial, was developed to compare 2 ­olanzapine-containing antiemetic regimens, one with an NK-1 receptor antagonist (aprepitant or fosaprepitant) and one without. Trial patients had a malignant disease for which they received intravenous highly emetogenic chemotherapy (single day cisplatin ≥ 70 mg/m2 or doxorubicin plus cyclophosphamide on 1 day). Patients on both arms received commonly administered doses of a 5-HT3 receptor antagonist, dexamethasone, and olanzapine. Additionally, patients were randomized to receive an NK-1 receptor antagonist (fosaprepitant 150 mg IV or aprepitant 130 mg IV) or a corresponding placebo. The primary objective was to compare the proportion of patients with no nausea for 5 days following chemotherapy between the 2 study arms. This trial was designed to test for the noninferiority of deleting the NK-1 receptor antagonist, with noninferiority defined as a decrease in freedom from nausea by less than 10%. Results A total of 690 patients were entered on this trial, 50% on each arm. The proportion of patients without nausea for the complete 5-day study period was 7.4% lower (upper limit of the one-sided 95% confidence interval was 13.5%) in the arm without an NK-1 receptor antagonist compared with the arm with an NK-1 receptor antagonist. Conclusion This trial did not provide sufficient evidence to support that deletion of the NK-1 receptor antagonist was as good as keeping it, as a part of a 4-drug antiemetic regimen for highly emetogenic chemotherapy (ClinicalTrials.gov Identifier: NCT03578081).

Abstract Background: Late recurrence of breast cancer after 5 years accounts for about 50% of recurrences in hormone receptor (HR)-positive early breast cancer (EBC). TAILORx established non-inferiority of adjuvant endocrine therapy (ET) given for at least 5 years to chemotherapy plus ET (CET) in EBC and a 21-gene recurrence score (RS) of 11-25, although there was some chemotherapy benefit in women Methods: Eligibility criteria included women 18-75 years with HR-positive, HER2-negative, T1b-T2N0 EBC who agreed to have CT assigned or randomized based on the RS assay. The primary endpoint was invasive disease-free survival (iDFS) in the RS 11-25 group. The “primary analysis” refers to the original prespecified analysis for the primary IDFS endpoint (836 IDFS events at full information in the RS 11-25 group) after a median of 7.5 years. The “updated analysis” was performed after a median followup of 11.0 and 10.4 years in the randomized and overall populations, respectively. Results:10,253 eligible women enrolled between 4/7/06-10/6/10.The updated analysis includes substantially more events that the primary analysis, including IDFS events (1819 vs. 1210), distant recurrences (561 vs. 384), locoregional +/- distant recurrences (764 vs. 543), and deaths (910 vs. 499). The table provides 5 and 12-year event rates (and standard errors) for all arms, and comparisons of the randomized arms. The primary trial conclusions remain unchanged: ET was non-inferior to CET in the randomized group with a RS 11-25. Although recurrence occurred in < 10% by 12 years for a RS 0-25, late recurrence events beyond 5 years exceeded earlier recurrence. Non-recurrence events occurred in about 13% at 12 years (~1%/year), contributing substantially to the IDFS rates. For women Conclusions: The current updated analysis confirms findings from the original primary analysis that ET is non-inferior to CET in HR-positive, HER2-negative, node-negative EBC and a RS 11-25. As in the original primary analysis, the subgroup of women Citation Format: Joseph Sparano, Robert J. Gray, Della Makower, Kathy S. Albain, Daniel F. Hayes, Charles Geyer, Elizabeth Dees, Matthew P. Goetz, John A. Olson Jr, Tracy G. Lively, Sunil Badve, Thomas Saphner, Lynne I. Wagner, Timothy Whelan, Virginia Kaklamani, George Sledge. Trial Assigning Individualized Options for Treatment (TAILORx): An Update Including 12-Year Event Rates [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 GS1-05.

12107 Background: Chemotherapy-induced nausea and vomiting (CINV), a major adverse effect of cancer treatment, can attenuate life quality. Multiple international antiemetic guidelines have recommended a 4-drug regimen (corticosteroid, 5-HT3 receptor antagonist, NK-1 receptor antagonist, and the antipsychotic medication olanzapine) for decreasing highly emetogenic CINV. This raised a question regarding whether antiemetic therapy regimens for highly emetogenic chemotherapy could be de-intensified, decreasing cost and side effects from anti-emetogenic agents. Methods: Study A221602 was developed to compare two olanzapine-containing antiemetic regimens, one with the use of an NK-1 receptor antagonist (aprepitant or fosaprepitant) and one without. Patients (pts) received intravenous highly emetogenic chemotherapy as either 1) cisplatin, given on one day, at a dose of ≥ 70 mg/m2, with or without other chemotherapy agent(s) or 2) doxorubicin (60 mg/m2) plus cyclophosphamide (600 mg/m2) on one day. Pts in both arms received 1) a 5-HT3 receptor antagonist (palonosetron 0.25 mg IV or ondansetron 8-16 mg IV or 16-24 mg PO,) on day one, 2) dexamethasone (12 mg PO, day one followed by 8 mg PO, days 2-4), and 3) olanzapine (10 mg/day PO, days 1 to 4). On Day 1, all agents were given prior to chemotherapy, with the exception that olanzapine could be taken prior to chemotherapy or at bedtime. Additionally, pts were randomized to receive an NK-1 receptor antagonist (fosaprepitant 150 mg IV or aprepitant 130 mg IV; 346 pts) or a matching placebo (344 pts). The primary objective was to compare the proportion of patients with no nausea for 5 days following receipt of their chemotherapy between the two study arms. Results: While there was no suggestion of outcome differences on day 1 between the two study arms, fewer pts (7.4%; upper limit of the 95% confidence interval was 13.5%) without NK-1 receptor antagonists were without nausea for the complete 5-day study period. Conclusions: Per the study design, created to exclude a 10% benefit for NK-1 receptor antagonists, the results did not provide sufficient evidence to reject the hypothesis that the 4-drug regimen was superior to the protocol 3-drug regimen (p=0.24). Support: UG1CA189823; Clinical trial information: NCT03578081.

Abstract Background Black race is associated with worse outcomes in early breast cancer. We evaluated clinicopathologic characteristics, the 21-gene recurrence score (RS), treatment delivered, and clinical outcomes by race and ethnicity among women who participated in the Trial Assigning Individualized Options for Treatment. Methods The association between clinical outcomes and race (White, Black, Asian, other or unknown) and ethnicity (Hispanic vs non-Hispanic) was examined using proportional hazards models. All P values are 2-sided. Results Of 9719 eligible women with hormone receptor–positive, HER2-negative, node-negative breast cancer, there were 8189 (84.3%) Whites, 693 (7.1%) Blacks, 405 (4.2%) Asians, and 432 (4.4%) with other or unknown race. Regarding ethnicity, 889 (9.1%) were Hispanic. There were no substantial differences in RS or ESR1, PGR, or HER2 RNA expression by race or ethnicity. After adjustment for other covariates, compared with White race, Black race was associated with higher distant recurrence rates (hazard ratio [HR] = 1.60, 95% confidence intervals [CI] = 1.07 to 2.41) and worse overall survival in the RS 11-25 cohort (HR = 1.51, 95% CI = 1.06 to 2.15) and entire population (HR = 1.41, 95% CI = 1.05 to 1.90). Hispanic ethnicity and Asian race were associated with better outcomes. There was no evidence of chemotherapy benefit for any racial or ethnic group in those with a RS of 11-25. Conclusions Black women had worse clinical outcomes despite similar 21-gene assay RS results and comparable systemic therapy in the Trial Assigning Individualized Options for Treatment. Similar to Whites, Black women did not benefit from adjuvant chemotherapy if the 21-gene RS was 11-25. Further research is required to elucidate the basis for this racial disparity in prognosis.

605 Background: Pre-clinical and nonrandomized clinical data support synergy of the combination of bevacizumab and trastuzumab. We conducted a randomized double-blinded phase III trial of chemotherapy/trastuzumab ± bevacizumab to evaluate efficacy (PFS after treatment initiation) of the addition of bevacizumab in first-line treatment of HER2+ MBC. Methods: Days 1, 8 and 15 paclitaxel ± carboplatin were administered with trastuzumab and either placebo or bevacizumab 10 mg/kg every 2 weeks for a total of 6 months. Antibody therapy was then continued without chemo every 3 weeks, until disease progression or unacceptable toxicity. Disease assessments were performed every 3 months. Results: Ninety-six of the planned 489 analyzable patients (pts) were accrued between 2007 and 2009, at which time the study terminated due to poor accrual. Seventy % of pts were post-menopausal, 60% had ER+/HER2+ BC. Median age was 55 years (28-80). Outcomes and toxicities are summarized on the tables below. Median follow-up was 30 months. Conclusions: The combination of chemotherapy, trastuzumab, and bevacizumab did not significantly increased toxicity, and was overall safe and well tolerated. No significant differences in clinical benefit were observed between both treatment arms. Data on CTCs and Quality of Life will be presented at the meeting. This study was conducted by the Eastern Cooperative Oncology Group (Robert L. Comis, MD, Chair) and supported in part by Public Health Service Grants CA23318, CA66636, CA21115, CA32291, CA31946, CA49957, CA27525, CA14548, CA17145, CA32102, CA25224, CA49. [Table: see text] [Table: see text]