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 .

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 .

AbstractBackgroundPatient‐reported outcomes (PROs) are a better tool for evaluating the experiences of patients who have symptomatic, treatment‐associated adverse events (AEs) compared with clinician‐rated AEs. The authors present PROs assessing health‐related quality of life (HRQoL) and treatment‐related neurotoxicity for adjuvant capecitabine versus platinum on the Eastern Cooperative Oncology Group‐American College of Radiology Imaging Network (ECOG‐ACRIN) EA1131 trial (ClinicalTrials.gov identifier NCT02445391).MethodsParticipants completed the National Comprehensive Cancer Network Functional Assessment of Cancer Therapy–Breast Cancer Symptom Index (NFBSI‐16) and the Functional Assessment of Cancer Therapy–Gynecologic Oncology Group neurotoxicity subscale (platinum arm only) at baseline, cycle 3 day 1 (C3D1), 6 months, and 15 months. Because of early termination, power was insufficient to test the hypothesis that HRQoL, as assessed by the NFBSI‐16 treatment side‐effect (TSE) subscale, would be better at 6 and 15 months in the capecitabine arm; all analyses were exploratory. Means were compared by using t‐tests or the Wilcoxon rank‐sum test, and proportions were compared by using the χ2 test.ResultsTwo hundred ninety‐six of 330 eligible patients provided PROs. The mean NFBSI‐16 TSE subscale score was lower for the platinum arm at baseline (p = .02; absolute difference, 0.6 points) and for the capecitabine arm at C3D1 (p = .04; absolute difference, 0.5 points), but it did not differ at other times. The mean change in TSE subscale scores differed between the arms from baseline to C3D1 (platinum arm, 0.15; capecitabine arm, −0.72; p = .03), but not from baseline to later time points. The mean decline in Functional Assessment of Cancer Therapy–Gynecologic Oncology Group neurotoxicity subscale scores exceeded the minimal meaningful change (1.38 points) from baseline to each subsequent time point (all p < .05).ConclusionsDespite the similar frequency of clinician‐rated AEs, PROs identified greater on‐treatment symptom burden with capecitabine and complemented clinician‐rated AEs by characterizing patients’ experiences during chemotherapy.

PURPOSETissue-based next-generation sequencing (NGS) in metastatic breast cancer (mBC) is limited by the inability to noninvasively track tumor evolution. Cell-free DNA (cfDNA) NGS has made sequential testing feasible; however, the relationship between cfDNA and tissue-based testing in mBC is not well understood. Here, we evaluate concordance between tissue and cfDNA NGS relative to cfDNA sampling frequency in a large, clinically annotated mBC data set.METHODSTempus LENS was used to analyze deidentified records of mBC cases with Tempus xT (tissue) and xF (cfDNA) sequencing results. Then, various metrics of concordance were assessed within overlapping probe regions of the tissue and cfDNA assays (104 genes), focusing on pathogenic variants. Variant allele frequencies of discordant and concordant pathogenic variants were also compared. Analyses were stratified by mBC subtype and time between tests.RESULTSRecords from 300 paired tissue and liquid biopsies were analyzed. Median time between tissue and blood collection was 78.5 days (standard deviation = 642.99). The median number of pathogenic variants/patient was one for cfDNA and two for tissue. Across the cohort, 77.8% of pathogenic tissue variants were found in cfDNA and 75.7% of pathogenic cfDNA variants were found in tissue when tests were ≤ 7 days apart, which decreased to 50.3% and 51.8%, respectively, for > 365 days. Furthermore, the median patient-level variant concordance was 67% when tests were ≤7 days apart and 30%-37% when > 30 days. The median variant allele frequencies of discordant variants were generally lower than those of concordant variants within the same time frame.CONCLUSIONWe observed high concordances between tissue and cfDNA results that generally decreased with longer durations between tests. Thus, cfDNA NGS reliably measures tissue genomics and is likely beneficial for longitudinal monitoring of molecular changes in mBC.

Abstract Background: A significant number of patients with breast cancer may develop chest wall recurrence, which can be difficult to treat, and is associated with a poor prognosis. Given the inflammatory nature of chest wall disease, and the association of chest wall disease with lymphovascular invasion, we hypothesized that immunotherapy may be beneficial in this setting. Furthermore, combining immunotherapy and chemotherapy may have a synergistic effect; indeed, the combination of the anti-programmed cell death 1 (PD-1) antibody, pembrolizumab, with chemotherapy has been approved for metastatic triple negative breast cancer (TNBC). Consequently, in this study, we are evaluating the combination of pembrolizumab/carboplatin vs. carboplatin alone for chest wall recurrence. Trial design: This is a phase II study of patients with chest wall disease from breast cancer. Patients are randomized in a 2:1 manner to pembrolizumab/carboplatin x 6 cycles (Arm A) with the option to continue pembrolizumab +/- carboplatin after 6 cycles (Arm Ax) vs. carboplatin alone (Arm B) with the option to cross-over to pembrolizumab +/- carboplatin on progression (Arm Bx). Carboplatin is dosed at AUC 5 IV every 3 weeks, and pembrolizumab at 200 mg IV every 3 weeks. Trastuzumab may be continued with study treatment in patients with HER2 positive disease. Imaging scans (CT chest, abdomen, and pelvis, and bone scan) occur at baseline and every 3 cycles. Chest wall biopsies and peripheral blood is collected at baseline and after completing 2 cycles of treatment for correlative studies. Eligibility criteria: Patients must have chest wall disease from breast cancer. Distant metastases are allowed. TNBC, hormone receptor positive/HER2 negative disease (after 2 prior hormone therapies), and HER2 positive disease (progressed on standard HER2 directed treatment) are eligible. Any number of prior lines of chemotherapy are acceptable, including a prior platinum chemotherapy in the absence of disease progression on the platinum. Specific Aims: Primary aim is to determine disease control rate in the chest wall and other distant sites at 18 weeks of treatment with RECIST 1.1. Secondary aims including determining toxicity, progression-free survival, response based on irRECIST, and response based on tumor PD-L1 expression. Exploratory aims include studying changes in: 1) immune composition of tumor and peripheral blood, 2) peripheral blood cell-free DNA and circulating tumor cells, 3) soluble PD-L1 expression, and 4) association of MYC with PD-1 and immune markers, based on preclinical data demonstrating that MYC upregulates these markers. Statistical Methods: 84 patients (Arm A: 56, Arm B: 28) are being enrolled at 7 sites in the Translational Breast Cancer Research Consortium. The study is powered to identify a 20% difference in disease control rates between Arms A and B (HR 0.52, α= 0.10, ß=0.20). A futility analysis will occur for Arm B after 18 patients are enrolled to allow for early closure if lack of efficacy. Accrual: Present accrual is 57 patients (Arm A: 39, Arm B: 18). (NCT03095352). This trial is partly funded by grants from Merck and University of California San Francisco. Contact information: Neelima Vidula, MD, Massachusetts General Hospital, nvidula@mgh.harvard.edu Citation Format: Neelima Vidula, Rita Nanda, Kathy Miller, Leisha Emens, Vandana Abramson, Ben Park, Minetta C. Liu, Andrei Goga, Hope Rugo. Randomized phase II trial of pembrolizumab/carboplatin vs. carboplatin alone for breast cancer with chest wall recurrence: TBCRC044 [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 OT1-18-08.

Abstract Patients with metastatic breast cancer (MBC) typically have short survival times and their successful treatment represents one of most challenging aspects of patient care. This poor prognostic behavior is in part due to molecular features including increased tumor cell clonal heterogeneity, multiple drug resistance mechanisms, and alterations of the tumor microenvironment. The AURORA US Metastasis Project was established with the goal to identify molecular features specifically associated with metastasis. We therefore collected and molecularly characterized specimens from 55 metastatic breast cancer (BC) patients representing 51 primary cancers and 102 metastases. The 153 unique tumors were assayed using RNAseq, tumor/germline DNA exomes and low pass whole genome sequencing, and global DNA methylation microarrays. We found intrinsic molecular subtype differences between primary tumors and their matched metastases to be rare in triple negative breast cancer (TNBC)/Basal-like subtype tumors. Conversely, tumor subtype changes were relatively frequent in estrogen receptor positive (ER+) cancers where ~30% of Luminal A cases switched to Luminal B or HER2-enriched (HER2E) subtypes. Clonal evolution studies identified changes in expression subtype coincident with DNA clonality shifts, especially involving HER2 amplification and/or the HER2E expression subtype. We further found evidence for ER-mediated downregulation of genes involved in cell-cell adhesion in metastases. Microenvironment differences varied according to tumor subtype where ER+/Luminal metastases had lower fibroblast and endothelial cell content, while TNBC/Basal-like metastases showed a dramatic decrease in B cells and T cells. In 17% of metastatic tumors, we identified DNA hypermethylation and/or focal DNA deletions near HLA-A that were associated with its’ significantly reduced expression, and with lower immune cell infiltrates. We also identified low immune cell features in brain and liver metastases when compared to other metastatic sites, even within the same patient. These findings have direct implications for the treatment of metastatic breast cancer patients with immune- and HER2-targeting therapies and suggest potential novel therapeutic avenues for the improvement of outcomes for some patients with MBC.

TPS1111 Background: Chest wall recurrence is a subtype of breast cancer that is challenging to treat, and associated with a short duration of response to treatment and an increased risk of development of distant metastases. Given the inflammatory nature of this disease and the association of chest wall disease with lymphovascular invasion, which is correlated with higher programmed cell death 1 (PD-1) expression, we hypothesized that immunotherapy may be beneficial as treatment. Combinations of immunotherapy and chemotherapy have a synergistic effect and demonstrated efficacy in the treatment of metastatic triple negative breast cancer (TNBC). This study is evaluating the efficacy of pembrolizumab, an anti-PD-1 antibody, in combination with carboplatin, in patients with chest wall infiltration from breast cancer. This drug combination has shown efficacy in advanced lung cancer. Methods: This is a multicenter, 2:1 randomized phase II study of pembrolizumab/carboplatin (Arm A, 56 patients) vs. carboplatin (Arm B, 28 patients) in 84 patients with chest wall disease from breast cancer, with or without distant metastases. Patients may have TNBC, hormone receptor positive/HER2 negative (following receipt of 2 prior hormone therapies), or HER2 positive breast cancer (with option to continue trastuzumab on study). Pembrolizumab is administered as 200 mg IV every 3 weeks, and carboplatin as AUC 5 IV every 3 weeks. Patients on Arm A may continue pembrolizumab +/- carboplatin (Arm Ax) after completion of 6 cycles of treatment, while patients in Arm B can cross-over to pembrolizumab (+/- carboplatin) on progression (Arm Bx). Patients must have adequate organ function, performance status ≤ 2, and may have received any number of lines of prior chemotherapy. Patients undergo serial chest wall photography and imaging (CT chest, abdomen, and pelvis, and bone scan) at baseline and every 6 weeks, as well as blood collection for correlative studies and chest wall biopsies at baseline and after 2 cycles of treatment. The primary endpoint is disease control rate (RECIST 1.1) at 18 weeks of treatment, and the study is powered to determine a 20% difference in disease control rates between arms (HR 0.52, a = 0.10, ß = 0.20). An interim analysis will occur for Arm B after 18 patients are enrolled, with a stopping rule for futility. Secondary endpoints include progression-free survival, toxicity (NCI CTCAE), and response based on irRECIST and tumor programmed death ligand 1 (PD-L1) expression. Exploratory objectives include evaluating changes in soluble PD-L1, tumor and peripheral blood immune composition, circulating tumor cells and cell-free DNA, and MYC oncogene expression. This study (NCT03095352) is open at 7 sites in the Translational Breast Cancer Research Consortium (TBCRC). 52 patients are enrolled. Grant funding is provided by Merck and UCSF. Clinical trial information: NCT03095352 .

PURPOSE Predictive biomarkers to identify patients with human epidermal growth factor receptor 2 (HER2)–positive breast cancer who may benefit from targeted therapy alone are required. We hypothesized that early measurements of tumor maximum standardized uptake value corrected for lean body mass (SULmax) on 18 F-labeled fluorodeoxyglucose positron emission tomography-computed tomography (PET-CT) would predict pathologic complete response (pCR) to pertuzumab and trastuzumab (PT). PATIENTS AND METHODS Patients with stage II or III, estrogen receptor–negative, HER2-positive breast cancer received four cycles of neoadjuvant PT. 18 F-labeled fluorodeoxyglucose positron emission tomography-computed tomography was performed at baseline and 15 days after PT initiation (C1D15). Eighty evaluable patients were required to test the null hypothesis that the area under the curve of percent change in SULmax by C1D15 predicting pCR is ≤ 0.65, with a one-sided type I error rate of 10%. RESULTS Eighty-eight women were enrolled (83 evaluable), and 85% (75 of 88) completed all four cycles of PT. pCR after PT alone was 22%. Receiver operator characteristic analysis of percent change in SULmax by C1D15 yielded an area under the curve of 0.72 (80% CI, 0.64 to 0.80; one-sided P = .12), which did not reject the null hypothesis. However, between patients who obtained pCR and who did not, a significant difference in median percent reduction in SULmax by C1D15 was observed (63.8% v 41.8%; P = .004) and SULmax reduction ≥ 40% was more prevalent (83% v 52%; P = .03; positive predictive value, 31%). Participants not obtaining a 40% reduction in SULmax by C1D15 were unlikely to obtain pCR (negative predictive value, 91%). CONCLUSION Although the primary objective was not met, early changes in SULmax predict response to PT in estrogen receptor–negative and HER2-positive breast cancer. Once optimized, this quantitative imaging strategy may facilitate tailoring of therapy in this setting.

Abstract Genomic testing has transformed clinical care in metastatic breast cancer. Cell-free DNA (cfDNA) has made sequential testing feasible, however, concordance between tissue and cfDNA, sensitivity of cfDNA, and optimal sampling frequency have not been examined on large data sets with clinical annotation. Of the 648 genes in the tissue NGS Tempus xT assay, 105 genes are also included in the Tempus xF cfDNA plasma-based test. Both platforms are run on Illumina and detect SNVs, indels, CNVs, and rearrangements/fusions with high sensitivity and specificity (&gt;90%). This study used the Tempus Labs LENS™ tool to identify the most recent ~3,300 metastatic breast cancer patients who underwent clinical testing and had either tissue-based testing, cfDNA testing or both. Of the 212 patients with xF and xT testing, 87 had xT before xF, 135 had xF before xT, and 7 had the testing performed at the same time. The most common pathogenic germline versus somatic alterations on tissue-based testing and their concordance will also be reported. In summary, this data suggests a variable amount of concordance between tissue-based and plasma-based assays. Timing of assay performance and inclusion of germline DNA might play an important role in contributing to these differences which need further exploration. Table: Count of Reported Variants and xT/xF Concordance by GeneSomatic GenesxF frequency (n)xT frequency(n)Concordance Between xF and xTTP5313911043%PIK3CA848058%ESR1584141%BRCA238217%ERBB2372629%NF1322113%RB1272416%ATM30165%GATA3213441%FGFR13353%PTEN193036%ARID1A251823% Citation Format: Minetta Liu, Jeff Schaffer, Aneta Piwowarczyk, Nike Beaubier, Kimberly Blackwell, Ben Park. Concordance and use patterns of tissue and cell-free based genomic testing in metastatic breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD9-12.