Citations

1037 Background: TBCRC041, a randomized phase 2 trial of alisertib (A) ± fulvestrant (F) in women with HR+/HER2- MBC demonstrated promising clinical activity for alisertib (1). Interrogation of baseline (PreC1) and end of cycle 1 (EOC1) cfDNA and CTCs may identify biomarkers associated with response to A±F. Methods: Plasma cfDNA was sequenced using the Guardant INFINITY platform, which includes genomic and methylated tumor fraction (mTF) analysis. Pathogenic variants were determined using publicly available databases and Mayo Clinic annotation pipelines. CTCs were identified as nucleated, EpCAM+/ cytokeratin+/ CD45- cells and assessed for ER/HER2 staining (RareCyte, Seattle). PFS was defined as the time from randomization to progression or death. EOC1-PFS differs from PFS as time starts at C2D1. Stratified log-rank tests and conditional Cox modeling were used to assess whether PFS or EOC1-PFS differed by mutations in ESR1 or PIK3CA, pre-CTC ≥ 5, or mTF>1%. Results: Of the 91 eligible pts, 84 progressed, and 73 were deceased. In the 86 pts with PreC1-cfDNA results, variants were identified in ESR1 (42; 48.8%), PIK3CA (36; 41.9%), AKT1 (7; 8.1%), PTEN(7; 8.1%), BRCA1 (4; 4.7%), and BRCA2 (7; 8.1%). Pts with a PIK3CAmut had significantly decreased PFS (HR 1.8; 95%CI: 1.1 -2.9, p=0.014) but not by ESR1mut status (p=0.583). PreC1 and EOC1-mTF were determined for 78 and 76 pts, respectively. PreC1-mTF was 0-1% in 21; 1.1-10.0% in 27; and 10.1-100% in 30. mTF levels remained between 0-1% in 17 pts fell to 0-1% in 11 pts, and was 0-1% in 5 pts without a preC1-mTF determination. PFS did not differ with respect to PreC1-mTF (p=0.210), but EOC1-PFS was worse in pts with mTF >1% (HR 3.0; 95%CI: 1.6 -5.2, p<0.001). PreC1 and EOC1-CTC were determined for 78 and 76 pts. 36 (46.2%) pts had a PreC1 CTC count ≥ 5. EOC1-CTC levels remained at (n=17) or increased to (n=1) ≥ 5 and was ≥ 5 in 2 pts without a preC1-CTC determination. EOC1-PFS was not significantly different for EOC1-CTC ≥ 5 (p=0.065), but was significantly decreased in pts with PreC1-CTC≥5 (HR=1.8; 95%CI: 1.1-3.0; p=0.018). Broader cfDNA NGS panel and CTC-derived ER/HER2 staining results will be presented at the meeting. Conclusions: Among patients receiving A±F, PFS varied based on the PIK3CAmutation status. cfDNA and CTC assessment PreC1 and EOC1 provided complementary information. Further validation in larger datasets is needed. 1. JAMA Oncol 2023;9:815. Clinical trial information: NCT02860000 .

TPS622 Background: Approximately 50% of newly diagnosed invasive breast cancers are stage 1, with the majority being ER/PR-positive, HER2-negative. Genomic assays such as the Oncotype DX have identified patients (pts) with reduced risk of distant metastasis and without benefit from chemotherapy added to endocrine therapy, freeing them from excess toxicity. Genomic assays are also recognized as prognostic for in-breast recurrence (IBR) after BCS and could similarly allow de-escalation of adjuvant radiotherapy (RT). Reducing overtreatment is of interest to pts, providers, and payers. Methods: We hypothesize that breast-conserving surgery (BCS) alone is non-inferior to BCS plus RT for IBR and breast preservation in women intending endocrine therapy (ET) for stage 1 invasive breast cancer (ER and/or PR-positive, HER2-negative with an Oncotype DX Recurrence Score [RS] of ≤18). Stratification is by age (<60; ≥60), tumor size (≤1 cm; >1-2cm), and RS (≤11, >11-18/MammaPrint Low). Pts are randomized post-BCS to Arm 1 with breast RT using standard methods (moderate or ultra hypo- or conventional-fractionated whole breast RT with/without boost, or APBI) with ≥5 yrs of ET (tamoxifen or AI) or Arm 2 with ≥5 yrs of ET (tamoxifen or AI) alone. The specific regimen of ET in both arms is at the treating physician’s discretion. Eligible pts are stage 1: pT1 (≤2 cm), pN0, age ≥50 to <70 yrs, s/p BCS with negative margins (no ink on tumor), s/p axillary nodal staging (SNB or ALND), ER and/or PR-positive (ASCO/CAP), HER2-negative (ASCO/CAP), and Oncotype DX RS ≤18 (diagnostic core biopsy or resected specimen); (a “low risk” MammaPrint is permissible if completed as part of usual care prior to screening). Primary endpoint is IBR (invasive breast cancer or DCIS). Secondary endpoints are breast conservation rate, invasive in-breast recurrence, relapse-free interval, distant disease-free survival, overall survival, patient-reported breast pain, patient-reported worry about recurrence, and adherence to ET. We assume a clinically acceptable difference in IBR of 4% at 10 yrs to judge omission of RT as non-inferior (10-yr event-free survival for RT group is 95.6% v 91.6% for the omission-of-RT group). BR007 is powered to detect non-inferiority with 80% power and a one-sided α=0.025, assuming that there would be a ramp-up in accrual in the first two years (leveling off in yrs 3-5); 1,670 pts (835 per arm) are required for randomization. Conservative loss to follow-up is 1%/yr. Some T1a pts screened may have Oncotype DX scores >18, making them ineligible for the study. In the accrual process, 1,714 pts will be required to register to ensure that our final randomized cohort is 1,670 pts. Current accrual (02-05-2024) is 805 screened and 716 randomly assigned. Clinical trial information: NCT04852887 .

TPS614 Background: Strategies to optimize treatment decision-making in early stage HER2-positive breast cancer are a priority. Recent studies suggest that early metabolic changes on FDG-PET/CT predict response to HER2-directed therapy. The TBCRC026 trial showed that participants not obtaining a 40% reduction in SULmax by cycle 1 day 15 (C1D15) following neoadjuvant trastuzumab/pertuzumab (HP) were unlikely to obtain pCR [negative predictive value (NPV) 91%]. This trial aims to validate FDG-PET/CT as a neoadjuvant interim (niFDG-PET/CT) imaging integral biomarker in patients treated with standard HER2-directed regimens (NCT05710328). Methods: Trial design: EA1211/DIRECT is a multicenter, single-arm, primary imaging phase 2 study enrolling patients with stage II/III HER2-positive breast cancer. Patients undergo standard skull base-thigh FDG-PET/CT at baseline and C1D15 and receive standard of care pertuzumab-based neoadjuvant therapy followed by surgery. Eligibility: Age ≥18 years, ECOG performance status 0-2, stage IIa-IIIc, untreated HER2-positive breast cancer with known hormone receptor status, suitable to undergo FDG-PET/CT imaging and neoadjuvant therapy. Statistical methods: ΔSULmaxD15 will be computed as: (D15 SULmax – baseline SULmax)/baseline SULmax. The primary objective is to estimate the NPV of niFDG-PET/CT for pCR using ΔSULmaxD15 of the primary breast cancer at a threshold of 40%. NPV is defined as the probability that pCR will not be achieved by participants with ΔSULmaxD15 <40%. Secondary endpoints include evaluating sensitivity, specificity, and positive predictive value of ΔSULmaxD15 of the primary breast cancer at a threshold of 40% and ability of the niFDG-PET/CT biomarker to predict 3-year event free survival (EFS). Sample size: We expect that 50% of patients will not reach the ΔSULmax threshold of 40% and a pCR rate of 40-60%. The proposed sample size is 210 participants, adjusted to 235 to account for missing data in 10% of cases. Computation of exact, two-sided 95% confidence intervals (CI) for NPV determined the lower limit of the CI is at least 80% when the true NPV is at least 88%. The lower limit is 84% when the true NPV has the value of 91%, which was estimated in the TBCRC026 study. Current status: EA1211/DIRECT was activated in May 2023 across the NCI National Clinical Trials Network (NCTN) and is anticipated to complete in March 2025. Those interested in the clinical trial can email ea1211team@ecog-acrin.org. The EA1211/DIRECT trial is the first step in implementing a Response-Guided Treatment Strategy by validating the ΔSULmax threshold of 40% as the optimum cut point across standard of care HER2-directed neoadjuvant regimens. If EA1211/DIRECT meets its objectives, the results will be used to design clinical utility studies, thus hoping to change practice. Clinical trial information: NCT05710328 .

TPS612 Background: The TAILORx and RxPONDER trials demonstrated that RS identifies many postmenopausal pts with node-neg and node-pos BC and RS ≤25, who do not benefit from addition of ACT to endocrine therapy (ET). Both trials also showed that certain subsets of premenopausal pts (node-neg/high clinical risk/RS 16-20, node-neg/RS 21-25, and node-pos/RS ≤25) benefited from adding ACT to ET. Most premenopausal pts in these trials did not receive ovarian function suppression (OFS) as part of their ET regimen. Given the observed benefit from OFS in high-risk premenopausal pts with HR+/HER2- BC in the SOFT/TEXT trials, many questioned whether all or part of the observed ACT benefit in the TAILORx/RxPONDER trials may have been the result of chemotherapy-induced OFS. To address this question, we developed OFSET, a phase III, multicenter clinical trial comparing OFS+ET v ACT+OFS+ET. Methods: We hypothesize that addition of ACT to OFS+ET is superior to OFS+ET in improving invasive breast cancer-free survival (IBCFS) among premenopausal, early-stage BC pts with HR+/HER2- tumors, and a 21-gene RS between 16-25 (for pN0 pts) and 0-25 (for pN1 pts). Secondary objectives include invasive disease-free survival, overall survival, distant recurrence-free interval, breast cancer-free interval, and health-related quality of life (HRQOL). Pts must be node-neg with RS 16-20 (plus high clinical risk), or RS 21-25, or have 1-3 positive nodes with RS ≤25. Stratification is by nodal status/RS status (pN0 RS 16-25 v pN1 RS 0-15 and pN1 RS 16-25), intent to receive CDK4/6 inhibitor (yes; no), and age (18-39 v ≥40). Pts are randomized after surgery to either OFS+ET or ACT+OFS+ET. ET is an aromatase inhibitor (AI). Choice is per investigator discretion; tamoxifen is allowed if AI is not tolerated or if OFS is incomplete. Radiotherapy will be administered per investigator discretion per protocol guidelines. The HRQOL substudy will assess differences in severe menopausal symptoms, measured by the FACT ESS-19 score between arms, as well as increased pain severity (PROMIS). Blood and tumor specimens will be collected for future research. Accrual of 3,960 pts is anticipated to be completed in 7 yrs, 7 mos. Per NSABP B-28 and RxPONDER data, 5yr IBCFS of pN1 pts on the ACT+OFS+ET arm is estimated at 92.3%. Based on TAILORx data, 5yr IBCFS of pN0 pts on the ACT arm is ~95%. Assuming 56% of pts to be pN0 and 44% pN1, and a 0.5% annual loss-to-follow-up rate, the definitive analyses to detect a hazard ratio: 0.75 with ACT+OFS+ET v OFS+ET, with one-sided α of 0.025 and 80% power, will require 380 IBCFS events, expected to occur~11 yrs after study initiation. OFSET was activated Aug 2023. Clinical trial information: NCT05879926 .

TPS632 Background: Male breast cancer is a rare disease, and most cases are hormone receptor-positive (HR+). Due to a lack of clinical trials, male breast cancer has historically been treated based on data extrapolated from women. However, there are substantial knowledge gaps in the comparative efficacy, safety, and patient-reported outcomes of endocrine therapies for male breast cancer. While tamoxifen is the current standard of care, additional data are warranted for aromatase inhibitors (AI), gonadal suppression, and cyclin-dependent kinase 4/6 (CDK4/6) inhibitors. Methods: This is an open-label, multicenter, randomized, phase II trial designed to evaluate different endocrine therapies in men with HR+ and human epidermal growth factor receptor 2 (HER2)-negative breast cancer. A total of 60 men will be enrolled across nine (9) sites within the Translational Breast Cancer Research Consortium (TBCRC). Key eligibility criteria include male sex and stage I, II, or III HR+/HER2- breast cancer before surgical resection of the primary tumor and axillary nodes. Key exclusion criteria include prior anti-cancer therapy for the current breast cancer or any other malignancy within the past 12 months, and inflammatory breast cancer. The trial has two phases. The first phase is a window of opportunity component in which newly diagnosed men are randomized 1:1:1 to either tamoxifen (Arm A), anastrozole (Arm B), or anastrozole plus degarelix (Arm C) given for three weeks. The primary endpoint for the window phase is Ki-67 reduction from the baseline diagnostic biopsy to the research biopsy at the end of the window phase. The second phase consists of neoadjuvant treatment, in which the tamoxifen group is randomized 1:1 to tamoxifen (Arm D) versus tamoxifen plus abemaciclib (Arm E), and the anastrozole alone (Arm B) and anastrozole plus degarelix (Arm C) groups are merged and then randomized 1:1 to anastrozole plus degarelix (Arm F) versus anastrozole plus degarelix plus abemaciclib (Arm G). The duration of the neoadjuvant phase is four (4) months, and the primary endpoint of this phase is residual cancer burden (RCB) index at time of surgery. The trial is powered for the RCB endpoint in a 2 x 2 factorial design to detect a 0.6 unit decrease in RCB index with 80% power and alpha=10%. For the Ki-67 endpoint, we assume an approximately 50% reduction in Arms A and B; Arm C will be of interest if it leads to ≥80% reduction in Ki-67. Secondary endpoints include: estradiol and testosterone levels at baseline, end of window, and during neoadjuvant phase; preoperative endocrine prognostic index (PEPI) score at surgery; adverse events; and patient-reported outcomes (including quality of life). Tumor tissue will be collected for correlative analyses. The study opened to enrollment at Dana-Farber in October 2023, and additional sites will open in 2024. Clinical trial information: NCT05501704 .

594 Background: Recent analyses in HER2+ and triple negative (TN) breast cancer (BC) treated with neoadjuvant systemic therapy (NAST) suggest that extent of disease at presentation (tumor [T] size and nodal [N] involvement) influences outcomes independently of response to NAST, even in the context of pathologic complete response (pCR). Given this, we evaluated the association of clinical T and N status prior to NAST with long-term outcomes in I-SPY2. Methods: We identified patients (pts) with TN and HER2+ BC who received NAST on the I-SPY2 trial with available clinical T size and N status prior to NAST, pathologic response after NAST, and follow up for recurrence and survival. We conducted univariable and multivariable (MV) Cox proportional models for Event Free (EFS), Distant Recurrence Free (DRFS), and Overall Survival (OS) in TN and HER2+ BC according to response after NAST, adjusting for residual cancer burden (RCB) category. Results: Of 1,170 pts with TN or HER2+ BC, 1,013 were eligible (TN: 623 and HER2+: 390), after 157 pts were excluded due to missing critical variables. Median follow up was 4.4 years (range 0.3-10.2). Median age was 48 for TN and 49 for HER2+ BC. Following NAST, pCR was achieved in 277 (45%) pts with TN and 197 (51%) pts with HER2+ BC. Among pts with pCR, separate MV analyses for TN and HER2+ BC showed no independent association between clinical T and N category with EFS, DRFS or OS (p values all > 0.05). However, among pts with residual disease, clinical T category (but not clinical N status) prior to NAST retained independent prognostic information in both TN and HER2+ BC in a MV model adjusting for age, RCB class, and hormone receptor status (for HER2+ BC). Compared to cT1-2, cT3-4 stage at diagnosis was associated with worse EFS, DRFS, and OS in TNBC, and with worse EFS, DRFS (but not OS) in HER2+ BC (Table). Additionally, hormone receptor status was independently associated with outcomes in HER2+ BC with residual disease (data not shown). The 5y EFS for cT1-2 vs cT3-4 according to RCB class in TNBC were: RCB0: 94% vs 95%, RCB1: 90% vs 65%, RCB2: 74% vs 44% and RCB3: 45% vs 20%. The 5y EFS for cT1-2 vs cT3-4 according to RCB class in HER2+ were: RCB0: 95% vs 88%, RCB1: 89% vs 84%, RCB2: 85% vs 64% and RCB3: 56% vs 50%. Conclusions: Tumor size (but not N involvement) prior to NAST was independently associated with outcomes in TN and HER2+ BC with residual disease, independently of RCB class. TN and HER2+ BC achieving pCR exhibited favorable outcomes regardless of extent of disease prior to NAST. These data are consistent with prior findings of the Neobioscore contributing only in the context of residual disease. Clinical trial information: NCT01042379 . [Table: see text]

567 Background: We proposed adjunctive statistical standardization of quantitated ER and PgR to improve inter-laboratory comparability of biomarker results and therapeutic management of breast cancer. Methods: We utilized CCTG MA.27 (NCT00066573), an adjuvant phase III trial of exemestane versus anastrozole in postmenopausal women with ER+ and/or PgR+ tumours. IHC ER and PgR HSCORE and % positivity (%+) were centrally assessed by machine image quantitation, and each statistically standardized to mean of 0, standard deviation of 1 following Box-Cox variance stabilization transformations of square for ER; for PgR, 1.) natural logarithm (0.1 added to 0 HSCOREs and 0 %+), 2.) square root. The primary endpoint was STEEP distant disease-free survival (DDFS) at the longest trial follow-up of median 4.1 years; a secondary endpoint was event-free survival (EFS). Survival was described with Kaplan-Meier plots and tested with the univariate Wilcoxon (Peto-Prentice) test statistic. We examined cut-points at standard deviations about mean of 0 (<-1; (-1,0]; (0,1]; >1) and explored single cut-points. Cox multivariate regressions were adjusted for age, T and N stage, grade, lymphovascular invasion, treatment, and baseline patient demographics; 2-sided Wald tests had nominal significance if p<0.05. Results: Of the 7576 women accrued, 3048 women had machine-quantitated image analysis results: 2900 (95%) for ER; 2726 (89%) for PgR. Statistically standardized HSCORE and %+ units differentiated both univariate DDFS and EFS; DDFS was significantly different by ER levels (p<0.001) and PgR levels (p<0.001). In multivariable assessments, ER HSCORE and %+ were not significantly associated (p=0.52-0.88) with the DDFS primary endpoint in models with PgR, while higher PgR HSCORE and %+ had significantly better DDFS (p=.001, in all instances) in models with ER. Conclusions: DDFS was superior for patients with higher ER and PgR standardized units compared with those with HSCOREs and %+ <-1. The adjunctive statistical standardization of ER and PgR performed here is similar to that mandated for clinical practice by the World Health Organization for BMD. [Table: see text]

550 Background: Residual disease after neoadjuvant chemotherapy (NAC) in HER2-positive breast cancer (BC) confers poor outcomes. Despite additional trastuzumab emtansine (T-DM1) in the adjuvant setting, a significant number of patients with residual disease still develop recurrence. H2NVAC is a multi-epitope T helper cell-activating peptide vaccine that is composed of 4 degenerate HER2-derived HLA-DR epitopes admixed with GM-CSF. Our previous phase I trial showed that this vaccine was safe and generated robust, long-lasting T and B cell immune responses. Methods: Patients with stage II-III HER2+ BC with any amount of residual disease in the breast /axilla after NAC were enrolled in a safety run-in phase of H2NVAC in combination with T-DM1. Patients were treated with H2NVAC and T-DM1 for 6 cycles, followed by 2 boosters at 3 and 12 months. Dose-limiting toxicity (DLT) was defined as any grade (G) ≥ 3 adverse events (AE) occurring within 21 days after the first vaccination. Results: A total of20 patients were enrolled with a median age of 51 years (range 27-69), 80% were White and 15% were Black. Most patients had hormone receptor-positive disease (90%). 40% were premenopausal, 40% were postmenopausal, and 20% were unknown. 14 patients had ypT1, 3 patients ypT2, 3 patients ypT3, 1 patient ypT4, 8 patients ypN0, 9 patients yp N1, 1 patient ypN1mi, and 2 patients ypN2. H2NVAC, in combination with T-DM1, was well tolerated, with no DLT being observed. Only grades 1 and 2 AEs were observed during the DLT period, with fatigue being the most common (G1 60%, G2 5%), followed by peripheral sensory neuropathy (G1 55%, G2 5%) and injection site reaction (G1 50%). Across all treatment cycles, the top 10 most common AEs that were at least possibly related to treatment include injection site reaction (G1 85%, G2 15%), AST increase (G1 65%), ALT increase (G1 45%), fatigue (G1 35%, G2 10%), peripheral sensory neuropathy (G1 35%, G-tube 10%), alk-phos increase (40% G1), nausea (G1 35%, G2 5%), arthralgia (G1 35%), myalgia (G1 25%, G2 5%), and platelet count decrease (G1 30%). There were four patients with G3 AEs at least possibly related to the vaccine observed after the DLT period, including allergic reaction, myositis/skin infection, urticaria, and pruritus/maculopapular rash. Conclusions: H2NVAC, in combination with T-DM1, was safe without DLT observed. The side effect profile was favorable, with the most common AE being the G1 injection site reaction. A multicenter, randomized, placebo-controlled, phase II trial of H2NVAC vs. placebo in combination with trastuzumab emtansine is currently ongoing through the ACCRU consortium. Clinical trial information: NCT04197687 .

538 Background: The phase 3 PALLAS trial compared 2 years of the CDK4/6 inhibitor palbociclib with endocrine therapy of provider choice, versus endocrine therapy alone, as adjuvant treatment for patients (pts) with Stage II-III hormone receptor-positive HER2-negative (HR+/HER2-) breast cancer. The SET2,3 index adjusts the measurement of SETER/PR index of endocrine receptor-related transcriptional activity with a baseline prognostic index (BPI) derived from tumor size (T), number of involved lymph nodes (N) and gene expression levels of ESR1, PGR, ERBB2 and AURKA (RNA4 subtype score). High SET2,3 (index ≥ 2.10) represents high endocrine sensitivity with favorable prognosis. Clinical outcome results from PALLAS were previously published, and the trial now has 5-year median follow-up. Methods: Participants in PALLAS provided a tumor tissue block prior to randomization. RNA was extracted from samples with sufficient tumor tissue and cellularity (>25mm2 with ≥20% cancer nuclei). SET2,3 index was measured from 300ng total RNA using the QuantiGene Plex platform (ThermoFisher, Waltham, MA) following the manufacturer’s protocol and using pre-defined quality control (QC) parameters and cut point. Results from primary tumor samples prior to systemic therapy were analyzed. Invasive disease-free survival (iDFS) was summarized with Kaplan-Meier plots using log-rank test. Cox models were adjusted for treatment arm assignment, with a treatment arm by SET index value interaction term to test for prediction of palbociclib benefit. The pre-defined level of significance was a two-sided 0.05. Results: There were 4075 pts from the total PALLAS population (N=5796) who provided a primary tumor sample that met pre-analytical requirements to perform the SET assay, from which 3388 (83%) results passed quality control, including 3093 from a sample obtained prior to receiving systemic therapy (1559 in palbociclib arm and 1534 in the control arm). SET2,3 index could not be calculated for 12 pts due to missing tumor or nodal information. There was no evidence of an interaction between treatment arm and SET indices (continuous) for iDFS: SET2,3 index interaction p=0.12 and SETER/PR index interaction p=0.92. Estimated 5-year iDFS was superior for those with high SET2,3: iDFS was 91.4% (95%CI 89.9–92.8) in 1719 (55.8%) pts with high SET2,3, versus 78.5% (95%CI 76.0–80.8) in 1362 (44.2%) pts with low SET2,3 (HR 0.38, 95%CI 0.31–0.47, p<0.0001). The SETER/PR index was also significantly associated with iDFS (HR 0.70 per 0.5 units, 95%CI 0.65–0.77, p<0.0001). Conclusions: There was no evidence that the SET2,3 or SETER/PR index of endocrine-related transcriptional activity predicts benefit from palbociclib treatment. SET2,3 index was strongly prognostic for pts with Stage II-III breast cancer, with excellent 5-year IDFS for pts classified as SET2,3 high. Clinical trial information: NCT02513394 .