Breast Cancer Treatment Decisions Research Articles

Abstract PO2-10-12: The devil is in the details: Workflow analysis of breast cancer treatment decision making and implications for decision support design

Abstract While numerous decision aids have been developed to support treatment decision-making in breast cancer1, widespread implementation remains limited due to challenges integrating these tools in clinical workflows2. Given these persistent issues, we need to better understand the complex workflows and needs of decision aid users - patients, their family caregivers, and breast cancer clinicians. Previous studies have explored various aspects of breast cancer team workflows3,4. Despite this work, it is still unclear how these complex workflows support or hinder decision aid use. In this study, we conducted an in-depth analysis of breast cancer team workflow to elicit design requirements for informatics tools to support patient-centered decision-making. This study was part of a larger project aimed at designing a COMputeried PAtient-centered Collaborative Technology (COMPACT) to support personalized decision-making for breast cancer patients. We conducted observations of clinicians and patients at one breast center, using a tablet computer with smart pen to take notes on all aspects of clinic workflow. We uploaded all observation notes into a qualitative data analysis software, Dedoose. Two researchers coded the observations in an inductive, consensus-based process. We met to review our codes and identify key themes emerging in the data. We observed 95 hours and 127 patient encounters across 20 clinician-centered and 8 patient-centered observations. We identified 10 themes related to the design of decision support, which we grouped into the 4 components of workflow6 (see Table 1). We identified numerous patient-specific factors communicated from the patient to the clinical team that influenced treatment decision-making. These “decision factors” covered the broader scope of the patient’s life that was important in the decision-making process (e.g., upcoming family wedding, work). Patients were frequently “knowledge brokers” and were asked to remember and relay information across members of the care team. We identified 28 different tools and technologies used to support treatment decision-making. Patient family caregivers (e.g., aunt, husband) played an important role in treatment decision-making. Based on these findings, we developed design requirements for informatics tools to better support patients (and clinicians). Our study highlights the complexity and interdependence of breast cancer treatment decision-making. Patients frequently made treatment decisions that influenced subsequent decisions. Decision aids typically focus on one decision or one care specialty and do not support consideration of several treatment options at one time1. Future research is needed to determine if and how decision support tools could incorporate the broader scope and interdependence between decisions to support patient-centered care. We highlight the need for informatics tools to consider the diverse and unique decision factors (e.g., hobbies) that are crucial to patient-centered decision-making. Decision support could help to elicit and incorporate these factors during treatment decision-making. However, the variable nature of these patient-specific factors presents a challenge to decision support design. Further research is needed to determine how to optimally incorporate such factors into decision support tools. We found inadequate system support for clinicians’ tasks including limited feedback loops to notify clinicians of completed tasks (e.g., mammogram, genetic testing). As a result, patients were often responsible for relaying information to and between different members of the clinical team. Given that patients only remember 50% of what clinicians tell them during visits7, a better system is needed to improve the reliability of information transfer. Our design guidelines can be used to improve the design of decision support tools and ultimately improve patient-centered decision-making. Table 1. Workflow components, themes, and associated challenges to decision support design Citation Format: Megan Salwei, Carrie Reale. The devil is in the details: Workflow analysis of breast cancer treatment decision making and implications for decision support design [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-10-12.

Abstract PO4-23-06: Outcomes and experiences of women denied immediate breast REconstruction after maSTectOmy for bREast cancer during the COVID-19 pandemic - The RESTORE C19 Study

Abstract Introduction 40% of women diagnosed with breast cancer in the UK each year undergo mastectomy and immediate breast reconstruction (IBR) is routinely offered to improve quality of life. During COVID19, this offer was withdrawn to prioritise frontline and emergency services. The RESTORE C19 study aimed to use mixed methods to explore the outcomes, lived experiences and views of women denied IBR during the pandemic. Methods Women not offered IBR between March & October 2020, were identified via B-Map-C, a UK prospective multicentre cohort study documenting changes in breast cancer treatment decisions during the pandemic. All patients were followed up between December 2021 & July 2022 (21-28 months following mastectomy) to explore their ongoing management including whether they had undergone, were awaiting, or had decided against delayed breast reconstruction (DBR) and the procedures performed. Descriptive statistics were used to summarise results. Semi-structured qualitative interviews were undertaken to explore the experiences of this group in more depth. Women were purposively sampled based on treatment centre, age, decision regarding DBR, and procedure performed. A topic guide was developed to explore experiences of breast cancer care; feelings about not having been offered IBR and factors influencing subsequent surgical decision-making. Interviews were transcribed in full and analysed thematically, with data collection and analysis undertaken concurrently and iteratively until saturation was achieved. Full ethical approval was obtained: IRAS 302580, Wales REC 4 21/WA/0347. Results Some 366 women were identified as not having been offered IBR in the B-MaP-C study for whom follow up data was available for 311 (85.0%) from 55 centres. The median age was 50 (range 27-83 years). Most women presented with symptomatic breast cancer (n=239, 76.8%), were fit with no significant comorbidities, had T1 or 2 tumours (n=215, 69.1%) and were node negative (n=186, 59.6%). Almost a fifth (n=58, 18.6%) of women had decided against breast reconstruction completely. Of the remainder, just under 60% (n=149/253), had attended a surgical consultation to discuss DBR and only a third (n=91/253, 36%) had been referred to plastic surgical services to discuss autologous procedures. Only 21 women (6.8%) had received DBR; (16 free flaps, 4 implants, 1 pedicled flap+/-implant). Interviews were performed with 18 women from 5 centres with a median age of 49 years (range 34-67): n=5 women had either received/were awaiting DBR; n=4 had undergone/were awaiting contralateral symmetrising mastectomy and n=9 had decided against/were undecided about further surgery. Whilst all women reported feeling ‘grateful’ for their breast cancer treatment, some felt ‘abandoned’ by healthcare professionals, others that they needed to chase breast surgical teams for care, advice, and support. Partners were also impacted by their experiences with some women describing lasting effects on their relationships. Many women described how their desire for symmetry, either by breast reconstruction or symmetrising mastectomy, had “paled into insignificance” in the months and years following treatment. Conclusions The impact of COVID19 continues to be felt by women treated for breast cancer in the UK. Most women not offered IBR are either still awaiting DBR almost three years after their initial mastectomy or have decided against further surgery. The interviews highlight the trauma many women experienced receiving breast cancer treatment during the pandemic and ongoing issues that, for some, are yet to be fully addressed. There is a need for individualised support to provide women with equitable and timely access to DBR and/or symmetrising mastectomy depending on patient preference to help them move on with their lives. Citation Format: Katherine Fairhurst, Rajiv Dave, Baek Kim, Rachel O'Connell, Raghavan Vidya, P.G. Roy, Stuart McIntosh, Patricia Fairbrother, Jo Skillman, Leila Rooshenas, Shelley Potter. Outcomes and experiences of women denied immediate breast REconstruction after maSTectOmy for bREast cancer during the COVID-19 pandemic - The RESTORE C19 Study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-23-06.

Abstract PO1-01-01: ECOG-ACRIN EA1211: Interim FDG-PET/CT for predicting response of HER2-positive breast cancer to neoadjuvant therapy (DIRECT Trial)

Abstract Background: Strategies to optimize treatment decision-making in early stage HER2-positive breast cancer are a current priority for the oncology and patient advocacy community. Recent studies suggest that early metabolic changes on FDG-PET/CT (imaging biomarker) 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%]. The ECOG-ACRIN EA1211/DIRECT 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). 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. 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%, in patients treated with neoadjuvant HER2-directed therapy. NPV is defined as the probability that pCR will not be achieved by participants with ΔSULmaxD15 < 40%. Secondary endpoints include evaluating the sensitivity, specificity, and positive predictive value of ΔSULmaxD15 of the primary breast cancer at a threshold of 40% and the 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 accrual is anticipated to complete in March 2025. Those interested in the clinical trial can email ea1211team@ecog-acrin.org. Conclusion: 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, and thus hoping to change practice. Citation Format: Heather Jacene, Constantine Gatsonis, Roisin Connolly, Brian Burnette, Erica Stringer-Reasor, Maeve Hennessy, Justin Romanoff, Alexander Taurone, Ciara O'Sullivan, H. T. Carisa Le-Petross, Courtney Lawhn Heath, Vered Stearns, Amy Fowler, Shou-Ching Tang, Karla A Sepulveda, Angela DeMichele, David Mankoff, Antonio Wolff. ECOG-ACRIN EA1211: Interim FDG-PET/CT for predicting response of HER2-positive breast cancer to neoadjuvant therapy (DIRECT Trial) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-01-01.

Abstract PO5-04-04: Development of a method to detect very low levels of HER2 expression in Circulating Tumor Cells (CTCs) by liquid biopsy in patients with metastatic breast cancer

Abstract Introduction Blood-based liquid biopsies are a non-invasive diagnostic approach for detecting circulating tumor cells (CTCs) or circulating tumor DNA (ctDNA) that may provide clinically actionable information for treatment decisions for metastatic breast cancer (MBC) patients when a conventional tissue biopsy is not feasible. Recently, the novel anti-HER2 antibody-drug conjugate, Trastuzumab Deruxtecan (T-DXd), has shown effectiveness against MBC with low HER2 expression detected by tissue biopsy characterized as HER2-low (immunohistochemically 1+ or 2+ and ERBB2 amplification-negative via in situ hybridization) and is being explored in an ultra-low population. Here we report on the application of a liquid biopsy platform designed to sensitively detect low levels of HER2 protein expression in CTCs from MBC patients. Methods Blood samples from 704 metastatic breast cancer patients as well as control cells lines were collected for cell-based and cell-free DNA analysis. After plasma isolation, nucleated cells deposited on glass slides went through immunofluorescent staining and imaging. CTCs were identified using Epic Sciences’ digital imaging and machine learning algorithms, and a subset of CTCs were isolated and sequenced for genomic quantification of large scale-state transitions (LSTs) as well as copy number variants (CNVs). The HER2 status was based upon on ASCO-CAP guidelines and the previous tissue biopsy results from the ordering healthcare provider, as documented on the DefineMBC™ test requisition form. Results Within a DefineMBC early-access program (EAP), 93% of patients with MBC had detectable CTCs. Among ERBB2-non-amp patients tested with the DefineMBC assay, 25% of patients with MBC had findings that were reported as consistent with HER2-low in the CAP-CLIA setting. To explore the lower boundaries of HER2 protein expression, we created and validated an MCF-7 HER2-negative ERBB2 knock-out cell line and utilized its 95% confidence level threshold (271 MFI) as a negative fluorescence cutoff for very low HER2 expression. Based upon publicly available CCLE datasets, MDA-MB-453, MCF7, and MCF7 ERBB2 KO breast cancer cell lines were selected for their high and low HER2 RNA expression levels and were corroborated via observed HER2 immunofluorescence median levels of 15740, 381, and 188 MFI respectively. In an exploratory analysis, among ERBB2-non-amp patients, we retrospectively applied the 271 MFI HER2 cutoff to the EAP cohort and identified 38% of patients with very low HER2 expression. We examined the impact of the HER2 ultra-low cutoff in patients not eligible for T-DXd treatment. Among patients reported as IHC=0 or with unknown IHC status from the most recent tissue biopsy, 44% and 42%, respectively, may qualify for treatment with T-DXd. Conclusion Using our higher sensitivity assay that combines CTC immunofluorescence and single-cell genomic analysis, we examined the lower boundary of HER2 protein expression. Feasibility data support further characterization of a very low HER2 expression phenotype, for the eventual inclusion into our comprehensive cancer profiling solution. To date, studies with biomarker expression have been limited to tissue biopsy, which may not always yield contemporaneous sampling in the metastatic setting. These results offer a liquid biopsy test that might identify patients potentially responsive to HER2-directed therapies. Citation Format: Giuseppe Di Caro, David Bourdon, Andrew Kunihiro, Alessandra Cunsolo, Ernest Lam, Megan Slade, Martin Blankfard, Lee Schwartzberg. Development of a method to detect very low levels of HER2 expression in Circulating Tumor Cells (CTCs) by liquid biopsy in patients with metastatic breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-04-04.

Abstract PO4-01-04: Clinical significance of Circulating tumor DNA (ctDNA) analysis in predicting pathologic complete remission in HER2-positive Breast Cancer Patients Undergoing Neoadjuvant Chemotherapy

Abstract Background: Neoadjuvant chemotherapy (NACT) combined with dual anti-HER2 agents followed by surgical resection is the standard treatment for stage II-III HER2-positive breast cancer. Despite the availability of effective therapies as an adjuvant treatment such as ado-trastuzumab emtansine (T-DM1) and neratinib, pathologic complete remission (pCR) strongly predicts survival. This study aimed to investigate the role of ctDNA analysis in predicting pCR and clinical outcome using comprehensive ctDNA analysis. Methods: A total of 34 HER2-positive breast cancer patients who underwent NACT combined with dual anti-HER2 agents and surgical resection were enrolled, including 22 clinical stage II and 12 III patients. Plasma samples were collected at four-time points: before neoadjuvant chemotherapy, after 3 cycles, at the completion of neoadjuvant chemotherapy, and after surgery. low-pass whole-genome sequencing (lpWGS) and whole exome sequencing (WES) in evaluating blood copy-number burden (bCNB), genomic alterations, mutational signatures, blood tumor mutational burden (bTMB). Mutations selected from the baseline sample were monitored for Molecular residual disease (MRD) monitoring. lpWGS yielded negative results, targeted NGS sequencing was conducted. Results: Among the enrolled patients (N=34), 21 patients (61.8%) had nodal metastasis and 22 patients (64.7%) were hormone receptor-positive. A total 26 patients (76.5%) achieved pCR. Positive ctDNA was detected in 20 patients (58.8%) at baseline. Higher nodal stage was significantly associated with ctDNA positivity at baseline. After surgery, MRD positivity was observed in 3 patients (8.8%). Among the 26 patents who acheived pCR, only 1 patient (3.8%) showed MRD positivity, while 2 non-pCR patients (25%) demonstrated MRD positivity. Conclusion: The presence of MRD was significantly associated with non-pCR status. The presence of ctDNA at baseline was associated with a higher nodal stage, suggesting its potential as a prognostic marker. Further studies with larger cohorts are warranted to validate these findings and explore the utility of ctDNA analysis for personalized treatment decisions in HER2-positive breast cancer. Citation Format: Byeongju Kang, Soo Jung Lee, Jeeyeon Lee, In Hee Lee, Jee-Young Park, Ho Yong Park, Tiantian Zheng, Lu Tan, Liam Il-Young Chung, Shidong Jia, Pan Du, Young Kwang Chae, Yee Soo Chae. Clinical significance of Circulating tumor DNA (ctDNA) analysis in predicting pathologic complete remission in HER2-positive Breast Cancer Patients Undergoing Neoadjuvant Chemotherapy [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-01-04.

Abstract PO4-05-03: Cell-free tumor DNA analysis in advanced or metastatic breast cancer patients enrolled in the German registry study PRAEGNANT

Abstract Background Accurate molecular profiling is crucial for optimal treatment decisions in advanced or metastatic breast cancer. Liquid biopsies, such as circulating cell-free tumor DNA (cfDNA, cftDNA or ctDNA), provide a non-invasive approach to monitor molecular alterations in the tumor. The German PRAEGNANT registry study aims to investigate such molecular biomarkers for precision medicine and their practical integration into clinical practice. In this context, cftDNA testing was performed as part of a PRAEGNANT research subproject, with the objectives of understanding the physician's rationale for initiating cftDNA testing, identifying detected alterations, and assessing the clinical impact of the associated findings Methods Patients with advanced or metastatic breast cancer were prospectively enrolled in the PRAEGNANT registry study (NCT02338167). The decision to undergo cftDNA testing was based on the physician's discretion. Blood samples were collected using Streck cfDNA BCT tubes and sent to the GUARDANT Health central laboratory for cftDNA extraction and subsequent next-generation sequencing analysis, employing the FDA-approved GUARDANT360 CDx test, a 74 gene panel including all guideline-recommended biomarkers, including single nucleotide variants (SNVs), indels, fusions and amplifications. Recruitment of patients occurred at four PRAEGNANT study centers between April 2022 and July 2023. The GUARDANT360 CDx report, along with a questionnaire regarding the testing intent and clinical impact of the results, was provided to the treating physician. Results 46 patients were eligible for analysis as per clinical characteristics. CftDNA analysis was successfully performed for all 46 cases. 38 (83%) harbored at least one somatic alteration in the analyzed genes. Fifteen patients (33%) harbored alterations in TP53, thirteen (28%) in PIK3CA. Five patients (11%) harbored mutations in ESR1. Somatic mutations in BRCA1 or BRCA2 were detected for five (11%) and six (13%) patients, respectively. One BRCA2 mutation was categorized as synonymous and one BRCA2 and three BRCA1 alterations as variants of uncertain significance. Eight patients (17%) harbored mutations in ATM. Most patients included were HR+HER2- (N=27, 58%). In this subgroup, eight (30%) patients had a PIK3CA alteration, five (19%) with an indication for treatment with alpelisib, eight (30%) a mutation in ATM, BRCA1 or BRCA2 and four (15%) in ESR1. Questionnaires regarding intention of testing and clinical impact were completed by 43 treating physicians (93%). Among them, 33% of patients had current indications for PARP inhibitor treatment, and 61% would consider it at the next change of therapy if a BRCA1 or BRCA2 mutation was detected. Additionally, 21% of patients had a current indication for alpelisib treatment if a relevant PIK3CA mutation was found, and 58% would consider it in the next line of treatment. Overall, cfDNA testing influenced the current or future treatment decisions in 35% of patients. Discussion The high prevalence of somatic alterations in TP53, PIK3CA, ESR1, and BRCA1/2 genes, identified through cftDNA testing with GUARDANT360 CDx, highlights their potential as biomarkers for targeted therapies in advanced/metastatic breast cancer. Detection of specific mutations influenced treatment decisions, such as eligibility for alpelisib or PARP inhibitors and might further facilitate treatment with elacestrant in future treatment lines after its approval in Germany. These findings demonstrate the clinical impact of cftDNA testing in guiding personalized treatment selection. Additionally, the identification of such somatic alterations within a registry study like PRAEGNANT presents a unique opportunity to consider enrolling these patients into biomarker-guided clinical trials. Citation Format: Hanna Hübner, Pauline Wimberger, Elena Laakmann, Eugen Ruckhäberle, Matthias Ruebner, Theresa Link, Erik Belleville, Iris Faull, Marcus Hausch, Diethelm Wallwiener, Andreas Schneeweiss, Hans Tesch, Sara Brucker, Peter A. Fasching, Volkmar Müller, Tanja Fehm. Cell-free tumor DNA analysis in advanced or metastatic breast cancer patients enrolled in the German registry study PRAEGNANT [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-05-03.

Abstract PO2-11-11: 'Who’s gonna take care of my babies?' The Impact of Children on Treatment Decisions for Women with Metastatic Breast Cancer: A qualitative analysis

Abstract Background: Many treatment options exist for metastatic breast cancer and decisions may be based on pathology, oncology clinician preference, performance status, financial considerations, patient values, or a combination of these factors. Some studies have characterized the importance that family and a strong support system can have on treatment decisions, but few have explicitly examined the impact that children—and grandchildren—have on treatment decisions in metastatic breast cancer (mBC). This qualitative study examined how being a parent or grandparent influences treatment decisions for women with metastatic breast cancer. Methods: A qualitative sub-analysis was conducted with a purposive diverse sample of thirteen women with metastatic breast cancer in the Eastern United States. Women of color were specifically oversampled relative to the regional population. Semi-structured interviews were conducted to explore treatment decision making, clinician-patient communication, and patient values relevant to their treatment decisions. Interviews were recorded, professionally transcribed, and coded by three independent coders. Any coding discrepancies were resolved through discussion. Thematic analysis identified recurrent themes important to women diagnosed with mBC. Results: Nearly 50% of the participants were women of color and of the 13 participants, 12 had children. When asked about what factors were important to them when making treatment decisions, a list of more than 10 themes emerged. Five participants said that children and grandchildren impacted their treatment decisions and were a crucial part of their cancer care. Other significant themes that emerged were side effects (54% of participants) and quality of life (46% of participants). Women who expressed that children were their top priority were also concerned about “looking sick” in front of their children. For women who said their grandchildren were the most important factor, being able to watch their grandchildren grow up was the primary motivator for their treatment decisions. Among the women who identified that side effects and quality of life were important, children either provided supportive care, helped with activities of daily living, or were too young to provide support. Conclusions: The presence of children and the relationships women with mBC have with their children was primary in making treatment decisions for their cancer. Of the participants in our study, having children—and grandchildren—rivaled other important factors such as quality of life and side effects of treatment, indicating the need to explore the impact that children have on cancer care as it is currently a poorly understood phenomenon. However, it is important not to make assumptions about patient treatment preferences based on whether women with mBC have children, instead, shared decision-making conversations should determine what is most important when deciding on a treatment plan. Future tools should integrate questions about family and children, and how these considerations may impact treatment decisions. Citation Format: Katherine Tomczik, Lorinda Coombs. 'Who’s gonna take care of my babies?' The Impact of Children on Treatment Decisions for Women with Metastatic Breast Cancer: A qualitative analysis [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-11-11.

Abstract PO5-04-05: Clinical validation of the concordance performance of ERBB2 status by single-cells genomics ERBB2 (HER2) amplification Assay in Circulating Tumor Cells (CTCs) from patients with matched HER2 status from metastatic tissue biopsies

Abstract Background Liquid biopsies are a non-invasive diagnostic approach for detecting CTCs that may provide clinically actionable information for treatment decisions for metastatic breast cancer (MBC) patients when a conventional biopsy is infeasible. Blood-based liquid biopsy has the potential advantage that it allows broad sampling of metastatic tumor clones because it is capable of and likely to obtain cellular and genomic contributions from more than one metastatic site. Here we report the concordance performance of HER2 positivity by single-cell CTC genomics ERBB2 (HER2) amplification in patients with matched HER2 status from metastatic tissue biopsies. Methods A prospective Clinical Experience Program for CTC ERBB2 (HER2) Assay across 25 different United States-based cancer centers, was used to recruit 128 MBC patients with documented standard-of-care metastatic tissue biopsies performed within the last 5 years (Days from tissue biopsy to liquid biopsy, Median: 19.5; interquartile range: 40.75) CTCs from blood collection at each respective clinical site were isolated from plasma, nucleated cells were plated, & slides were bio-banked for Immunofluorescent staining & subsequent imaging in a CAP CLIA lab. CTCs were identified using Epic Sciences digital imaging & machine learning algorithms. Individual CTCs were sequenced for genomic quantification of chromosomal instability (LSTs) and ERBB2 (HER2) amplification. Results Within the clinical validation cohort of 128 MBC patients, 30% (38/128) were HER2-positive by standard pathologic criteria (IHC 3+ or IHC2+/ISH+) in metastatic tissue biopsies. Among the 64 out of 128 cases with reportable results by the CTC ERBB2 (HER2) amplification on chromosomally unstable CTCs, 31% (20/64) of patients had ERBB2 amplification. Concordance between CTC single cell genomics and available tissue results for HER2 positivity showed a sensitivity of 69% and specificity of 78%. We then addressed the effects of two known biological confounders to the use of tissue biopsy for HER2 status determination: 1) tissue biopsies performed on bone metastases, 2) tumor evolution driven by treatment pressure over time leading to potential HER2 conversion and tumor heterogeneity. Thus, we performed subgroup analysis including only validation set patients with tissue biopsies performed on non-bone tissues, which showed slightly improved concordance to the tissue comparator with a Sensitivity of 86%, and Specificity of 75%. Next, to exclude the possibility of tumor evolution we selected only patients with the HER2 status comparator performed on non-bone tissue biopsies contemporaneous (Days from tissue biopsy to liquid biopsy, Median: 14; interquartile range: 22) to the blood draw for the CTC ERBB2 (HER2) amplification assay. This showed dramatically improved concordance performance with a Sensitivity of 100%, and a Specificity of 75%. Conclusions Blood and tissue are two biologically distinct sample types where variations in HER2 and other biomarker results might be expected due to analytic, temporal and clinical differences. These data indicate that determination of HER2 status by single cell genomic ERBB2 (HER2) amplification assay can aid in the clinical assessment of ERBB2 status in patients with metastatic breast cancer (MBC) for whom tissue biopsy for HER2 status is not available, or infeasible. Additionally, these results provide evidence of the contribution of site differences (bone) of metastatic biopsies and also tumor evolution to discordance between the CTC ERBB2 (HER2) Assay and tumor biopsy. Citation Format: Giuseppe Di Caro, Ernest Lam, Megan Slade, Shuguang Huang, Rick Wenstrup, Lee Schwartzberg. Clinical validation of the concordance performance of ERBB2 status by single-cells genomics ERBB2 (HER2) amplification Assay in Circulating Tumor Cells (CTCs) from patients with matched HER2 status from metastatic tissue biopsies [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-04-05.

Abstract PO4-16-10: Overall survival in sentinel node biopsy and axillary dissection: a real-world data

Abstract Background: Information about the status of the axilla (presence or absence of lymph node disease) is important for breast cancer (BC) treatment decision-making. Axillary dissection (AD) has been gradually substituted by sentinel node biopsy (SLNB) in clinical node negative patients and intraoperative evaluation became a routine. Most of the patients with a positive node in an intraoperative evaluation were submitted to AD, and when a negative intraoperative evaluation but a positive paraffin evaluation was found a new axillary surgery was a routine. Both approaches were gradually abandoned with the publication of the ACOSOG Z011 study showing no difference in local recurrence or overall survival (OS). Objective: To evaluate the number of patients with BC who meet the criteria of Z011 trial and could be spared of AD and compare the outcomes of the SLNB only and those that had AD. Methods: Patients with BC that were submitted to upfront surgery and had at least one positive node in SLNB were included in these retrospective analyses at Pérola Byington Hospital database, diagnosed between 1992 and 2019. Clinical and pathological characteristics were extracted from the database and patient medical records. T-test or chi-square test was used to individually analyze the association of each variable between the groups. Multivariate analysis was used to calculate odds ratio (OR) and 95% confidence intervals (CI) for independent variables correlated with positive AD. Cox regression was used for survival analysis, and survival curves were plotted using the Kaplan-Meier method, analyzing the difference between curves using the Log-rank test. R software version 4.1.1 was used for all analyses, with a p-value < 0.05 considered statistically significant. Results: A total of 729 patients were analyzed, with a mean age of 54.1 (±11.6) years at diagnosis. Most patients (n=633, 86.8%) underwent AD after a positive SLNB and 40,3% of the patients that were submitted to AD the only positive node was the sentinel node. After AD, 63,3% of these patients had 1 or 2 lymph nodes positive and met the Z011 criteria trial. The mean number of lymph node in AD was 12.2. Most patients (72.7%) were diagnosed at clinical stage II, 62% had nuclear grade 2 tumors, 52.9% had Luminal B subtype, and 63% were postmenopausal. Furthermore, 58.5% of patients underwent breast-conserving surgery, and 5.2% of patients experienced recurrence. The chance of AD was observed 2,2 times for the luminal B (OR 2.163, 95% CI 1.104-4.239, p=0.025), 2,1 times HER2-positive with receptor positive (OR 2.125, 95% CI 1.160-3.893, p=0.015), and 2,8 times for triple-negative (OR 2.806, 95% CI 1.013-7.757, p=0.047) compared to Luminal A. Patients that were submitted to AD had worse outcome when compared to SLNB, the overall survival showed a 94.4% higher risk of death with a median survival of 11 years (HR 1.944, 95% CI 1.20-3.14, p=0.006). Conclusion: These retrospective analyses showed 63,3% of the patients that had a positive node in a SLNB could be spared from AD (based on Z011 trial). Patients submitted to AD had worse outcome and these findings needs to be clarified. Citation Format: Renata Pares, Andre Mattar, Juliana de Lima, Marcelo Antonini, Francisco Pimentel Cavalcante, Luiz Henrique Gebrim. Overall survival in sentinel node biopsy and axillary dissection: a real-world data [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-16-10.

Abstract PO1-10-06: Understanding clinical meaningfulness in metastatic breast cancer treatment decision-making: experiences and perspectives of patients, caregivers, and clinicians

Abstract Background: While many clinical and non-clinical factors inform metastatic breast cancer (mBC) treatment recommendations; patient preferences, values, and care goals also influence how treatment options are weighed, deliberated, and decided upon. Additionally, in the mBC care setting, clinical meaningfulness and clinically meaningful outcomes (e.g., survival, quality-of-life) are important factors to consider along the care continuum. However, the extent to which patients and their oncology care team align on the interpretation and use of these concepts during treatment decision-making has not been well elucidated. This study examined perspectives on the concepts of (i) clinical meaningfulness and (ii) clinically meaningful outcomes associated with mBC treatment among five key stakeholder groups: patients, caregivers, oncologists, advanced practice providers (APPs), and oncology nurses. Methods: Qualitative semi-structured in-person and web-based focus groups were conducted between March and June 2023 among: (i) people living with mBC; (ii) unpaid or informal caregivers to people with mBC; and providers involved in the care of patients with mBC, including (iii) oncologists, (iv) APPs (i.e., physician assistants and nurse practitioners), and (v) oncology nurses. Discussion guides were developed to elicit stakeholder perspectives on clinical meaningfulness and clinically meaningful outcomes to help identify areas of convergence and divergence between and within stakeholder groups. All discussions were audio recorded and transcribed. The constant comparative approach was used to identify key themes. Results: Twenty-two focus groups were conducted with 50 patients, 24 caregivers, 8 oncologists, 13 APPs, and 17 oncology nurses. Overall, patients and caregivers were unfamiliar with the concepts of clinical meaningfulness and clinically meaningful outcomes, underscoring the critical need for using accessible and patient-friendly terminology in treatment decision-making discussions. While some providers were familiar with these concepts, they reported not using these terms when discussing treatment recommendations with patients. Although some provider participants thought clinical meaningfulness described quantitative endpoints (e.g., additional months of survival), participants across all stakeholder groups described patients’ abilities to achieve life goals (e.g., participation in milestone events and social activities, ability to travel) as paramount. Recommendations for improving treatment decision-making discussions included taking a patient-centered approach, with inclusive, dynamic patient-provider discussions and continuous evaluation of patient priorities across the care continuum, not just at diagnosis. Meaningful outcomes beyond overall survival need to be considered, including quality of life, progression-free survival, minimal or manageable side effects, and improvement in symptom burden and functioning. Across all stakeholders, participants stressed that outcomes considered meaningful are highly individualized and dynamic, evolving over time as patients move through the treatment journey and life stages. Conclusions: Clinical meaningfulness is poorly understood and not often considered in the clinical setting when making mBC treatment decisions, highlighting a need for accessible and patient-friendly terminology in mBC treatment decision-making conversations. While participants valued overall survival, the importance of meaningful outcomes that support patients’ quality of life was emphasized. Study findings can be used to inform both practice and clinical research to better capture meaningful outcomes for patients. Citation Format: Stephanie Graff, Emily Freeman, Meaghan Roach, Rozanne Wilson, Ricki Fairley, Mary Gullatte, Jeanne Stemland, Becky Chan, Paulina Wochal, Julie Katz, Suepattra May-Slater. Understanding clinical meaningfulness in metastatic breast cancer treatment decision-making: experiences and perspectives of patients, caregivers, and clinicians [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-10-06.

Women's Knowledge of Genomic Testing and Precision Medicine in Breast Cancer Treatment Decision-Making.

To understand awareness of genetic and genomic testing, as well as decision-making, in women diagnosed with breast cancer. 29 African American/Black and Latina/Hispanic women diagnosed with breast cancer. A semistructured interview guide was used in focus groups conducted via videoconference. Transcripts were analyzed using thematic analysis. Many of the women understood the concept of genetic testing to identify the BRCA1/BRCA2 variant, but none of them were aware of genomic testing and its implications for personalized medicine. Participants discussed provider and patient roles in treatment decision-making, identifying roles that the physician might play in treatment planning, from primary decision-maker to collaborator. As the number of precision cancer treatments expands, patients must be able to comprehend the information provided to make informed decisions about their treatment. Providers should do a better job of explaining potential treatments so that patients feel they are part of the decision-making process. Addressing gaps in treatment access and uptake requires providers to prioritize patient engagement and understanding.

A scoping review of web-based, interactive, personalized decision-making tools available to support breast cancer treatment and survivorship care.

We reviewed existing personalized, web-based, interactive decision-making tools available to guide breast cancer treatment and survivorship care decisions in clinical settings. The study was conducted using the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews(PRISMA-ScR). We searched PubMed and related databases for interactive web-based decision-making tools developed to support breast cancer treatment and survivorship care from 2013 to 2023. Information on each tool's purpose, target population, data sources, individual and contextual characteristics, outcomes, validation, and usability testing were extracted. We completed a quality assessment for each tool using the International Patient Decision Aid Standard (IPDAS)instrument. We found 54 tools providing personalized breast cancer outcomes (e.g., recurrence) and treatment recommendations (e.g., chemotherapy) based on individual clinical (e.g., stage), genomic (e.g., 21-gene-recurrence score), behavioral (e.g., smoking), and contextual (e.g., insurance) characteristics. Forty-five tools were validated, and nine had undergone usability testing. However, validation and usability testing included mostly White, educated, and/or insured individuals. The average quality assessment score of the tools was 16 (range: 6-46; potential maximum: 63). There was wide variation in the characteristics, quality, validity, and usability of the tools. Future studies should consider diverse populations for tool development and testing. There are tools available to support personalized breast cancer treatment and survivorship care decisions in clinical settings. It is important for both cancer survivors and physicians to carefully consider the quality, validity, and usability of these tools before using them to guide care decisions.

Abstract 2407: Detection of hotspot PIK3CA mutations in primary tumors and plasma-cfDNA of breast cancer patients using a novel highly sensitive CE-IVD kit

Abstract Introduction: Detection of PIK3CA mutations in primary tumors (FFPEs) and liquid biopsy samples is of increasing importance for treatment decisions in breast cancer. Oncolipsy PIK3CA kit (Pharmassist Ltd, Greece) is based on the combination of allele-specific priming, asymmetric PCR, and melting curve analysis. The CE-IVD kit can detect the presence of four PIK3CA hotspot mutations (E542K, E545K, E545Q, H1047R). The aim of the present study was to: a) evaluate the performance of this novel CE-IVD kit both in FFPEs and plasma-cfDNA samples from patients with metastatic breast cancer (MBC) and b) directly compare the derived results using the Oncolipsy PIK3CA kit with the cobas® PIK3CA mutation test (CE-IVD, Roche Diagnostics, Germany) in identical gDNAs isolated from FFPEs samples. Patients and methods: We analyzed 42 primary tumors (FFPEs) and 29 plasma-cfDNA samples from patients with estrogen receptor (ER) positive metastatic breast cancer. Genomic DNA was isolated from FFPEs using the QIAamp DNA FFPE Tissue Kit (Qiagen, Hilden, Germany), while cfDNA was extracted from 2.00 mL of plasma using the QIAamp DSP cNA Kit (Qiagen, Hilden, Germany). PIK3CA hotspot mutations were detected in the LightCycler® 2.0 (IVD instrument, Roche Diagnostics, Germany) using the highly sensitive Oncolipsy PIK3CA kit (analytical sensitivity 0.05%). A direct comparison study was performed using the cobas® PIK3CA Mutation Test on the cobas z 480 analyzer (IVD instrument, Roche Diagnostics, Germany). Results: In primary tumors the E545K mutation was detected in 22/42 (52.4%), the E542K and H1047R mutations were detected in 11/42 (26.2%) and 4/42 (9.5%) of primary tumor samples, respectively, while the E545Q mutation was not detected in any FFPE sample tested. At least one PIK3CA mutation was detected in 14/29 (48.3%) plasma-cfDNA samples. More specifically the E545K mutation was detected in 11/29 (38%), the H1047R mutation in 3/29 (10.4%) and the E542K mutation in 2/29 (6.9%) while the E545Q mutation was not detected in any plasma-cfDNA sample tested. In FFPEs, as expected, PIK3CA mutation frequency was higher compared to plasma-cfDNA. Direct comparison of the results derived using these two commercially available kits, the Oncolipsy CE-IVD kit and the cobas PIK3CA mutation test, using the same gDNA isolated from 42 FFPEs revealed a concordance of 34/42 (81%). Conclusions: The commercially available Oncolipsy PIK3CA CE-IVD kit is highly sensitive and specific for the detection of four PIK3CA hotspot mutations in primary tumors and plasma-cfDNA. Acknowledgement: This study has been financially supported by the European Union and Greek national funds through the Operational Program Competitiveness, Entrepreneurship and Innovation, under the call RESEARCH - CREATE - INNOVATE (project code: T1RCI-02935). Citation Format: Stavroula Smilkou, Dimitra Stergiopoulou, Eleni Tzanikou, Loukas Kaklamanis, Ioanna Balgkouranidou, Helena Linardou, Flora Zagouri, Evangelia Razi, Stylianos Kakolyris, Amanda Psyrri, Christos Papadimitriou, Ioanna Koukli, Athina Markou, Evi Lianidou. Detection of hotspot PIK3CA mutations in primary tumors and plasma-cfDNA of breast cancer patients using a novel highly sensitive CE-IVD kit [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2407.

Digital PCR quantification of ultrahigh ERBB2 copy number identifies poor breast cancer survival after trastuzumab

HER2/ERBB2 evaluation is necessary for treatment decision-making in breast cancer (BC), however current methods have limitations and considerable variability exists. DNA copy number (CN) evaluation by droplet digital PCR (ddPCR) has complementary advantages for HER2/ERBB2 diagnostics. In this study, we developed a single-reaction multiplex ddPCR assay for determination of ERBB2 CN in reference to two control regions, CEP17 and a copy-number-stable region of chr. 2p13.1, validated CN estimations to clinical in situ hybridization (ISH) HER2 status, and investigated the association of ERBB2 CN with clinical outcomes. 909 primary BC tissues were evaluated and the area under the curve for concordance to HER2 status was 0.93 and 0.96 for ERBB2 CN using either CEP17 or 2p13.1 as reference, respectively. The accuracy of ddPCR ERBB2 CN was 93.7% and 94.1% in the training and validation groups, respectively. Positive and negative predictive value for the classic HER2 amplification and non-amplification groups was 97.2% and 94.8%, respectively. An identified biological “ultrahigh” ERBB2 ddPCR CN group had significantly worse survival within patients treated with adjuvant trastuzumab for both recurrence-free survival (hazard ratio, HR: 3.3; 95% CI 1.1–9.6; p = 0.031, multivariable Cox regression) and overall survival (HR: 3.6; 95% CI 1.1–12.6; p = 0.041). For validation using RNA-seq data as a surrogate, in a population-based SCAN-B cohort (NCT02306096) of 682 consecutive patients receiving adjuvant trastuzumab, the ultrahigh-ERBB2 mRNA group had significantly worse survival. Multiplex ddPCR is useful for ERBB2 CN estimation and ultrahigh ERBB2 may be a predictive factor for decreased long-term survival after trastuzumab treatment.

AI improves accuracy, agreement and efficiency of pathologists for Ki67 assessments in breast cancer

The Ki-67 proliferation index (PI) guides treatment decisions in breast cancer but suffers from poor inter-rater reproducibility. Although AI tools have been designed for Ki-67 assessment, their impact on pathologists' work remains understudied. 90 international pathologists were recruited to assess the Ki-67 PI of ten breast cancer tissue microarrays with and without AI. Accuracy, agreement, and turnaround time with and without AI were compared. Pathologists’ perspectives on AI were collected. Using AI led to a significant decrease in PI error (2.1% with AI vs. 5.9% without AI, p < 0.001), better inter-rater agreement (ICC: 0.70 vs. 0.92; Krippendorff’s α: 0.63 vs. 0.89; Fleiss’ Kappa: 0.40 vs. 0.86), and an 11.9% overall median reduction in turnaround time. Most pathologists (84%) found the AI reliable. For Ki-67 assessments, 76% of respondents believed AI enhances accuracy, 82% said it improves consistency, and 83% trust it will improve efficiency. This study highlights AI's potential to standardize Ki-67 scoring, especially between 5 and 30% PI—a range with low PI agreement. This could pave the way for a universally accepted PI score to guide treatment decisions, emphasizing the promising role of AI integration into pathologist workflows.

"How is it going to help?": Exploring Black breast cancer patients' questions about biomarker testing to predict chemotherapy-induced peripheral neuropathy.

Many Black breast cancer patients experience chemotherapy-induced peripheral neuropathy (CIPN). Our study assessed Black breast cancer patients' questions about a biomarker test that can predict likelihood of CIPN. Nineteen Black women who were previous/current breast cancer patients participated in focus groups. Researchers briefly explained CIPN and the biomarker test, and then participants were asked what questions they would have about the test and its use in treatment decisions. These participant-voiced questions composed the data for this study and were analyzed using thematic analysis. Participants' questions centered on six themes: reasons for the test, effect on timeline of breast cancer treatment, testing procedure, limits of test (including accuracy), research done to develop this test (including research participants), and concerns about personal information connected to the test (including DNA). This study provides an exploratory look at questions that Black breast cancer patients may have about toxicity biomarker testing use in breast cancer treatment decisions. These findings provide a starting point for developing patient-centered approaches for integrating this precision medicine tool into clinical care. The methodological choice to generate participants' questions (rather than answers to a question) led to robust, actionable data.

163P Impact of genomic sequencing data on treatment decisions in advanced breast cancer (ABC)

163P Impact of genomic sequencing data on treatment decisions in advanced breast cancer (ABC)

Using Life Cycle Assessment as a Tool to Evaluate the Environmental Impact of Radiation Oncology and Inform Treatment Decision-Making in Early-Stage Breast Cancer

The effects of climate change negatively impact patient health and healthcare delivery across the cancer care continuum. Environmental impacts arising from radiation therapy (RT), as measured with formal life cycle assessment (LCA) methods, have not been reported to date. LCA is a standardized approach to systematically analyze the effects a product or process has on the environment by accounting for all its components and their life cycle. Here, we used LCA to compare the footprint of RT delivery among several environmental impact categories, including carbon (CO2) emissions, in early-stage breast cancer (ESBC) regimens with clinical equivalency. We used LCA methods to estimate the environmental footprint of ESBC treatments across 9 standard impact categories including greenhouse gases, ozone depletion, smog, carcinogenics, and respiratory effects, in a cohort of 50 patients receiving moderate hypofractionation (mod-hEBRT) to 42.4 Gy in 16 fractions (n = 25) and ultra-hypofractionation (ultra-hEBRT) to 26 Gy in 5 fractions (n = 25). We analyzed life-cycle emissions associated with patient and staff commute, RT quality assurance and set-up equipment, linear accelerator (LINAC) requirements, clinic supplies, and linen use. Facility emission estimates are underway. All calculations were done in SimaPro 9.4 using the ecoinvent 3.8 database and TRACI 2.1 impact assessment methods. Confidence intervals were calculated using stochastic computations. Total emissions associated with delivering a full course of mod-hEBRT versus ultra-hEBRT averaged 502 kg CO2-eq (95% CI, 484 to 521) and 264 kg CO2-eq (95% CI, 252 to 277), respectively. The largest contributors to total emissions in each group were patient and staff transportation (301.8 vs 196.4 kg CO2-eq, respectively) and LINAC equipment and utilization (175 vs 55.2 kg CO2-eq, respectively). In addition, treatment with mod-hEBRT was found to have, on average, a larger environmental footprint over ultra-hEBRT across all impact categories. The leading contributor to these environmental impacts continued to be patient and staff transportation, which accounted for 91.1% of ozone depletion, 63.2% of smog, 55.3% of acidification, 86.4% of carcinogenics, 53.2% of respiratory effects, 79.7% of ecotoxicity, and 67.9% of fossil fuel depletion in mod-hEBRT. We present the first LCA estimating the environmental footprint of mod versus ultra-hEBRT in ESBC patients. Evaluation of emissions and environmental impacts demonstrate lower carbon and environmental footprints in shorter RT courses that are otherwise clinically equivalent. These data provide the opportunity to consider practice changes in RT delivery that utilize clinically appropriate and ecologically informed regimens in the treatment of ESBC patients.

Liquid biopsy identification of ERBB2 amplified and HER2 expressing metastatic breast cancer: Comparison and combination of cell and cell-free platforms.

3061 Background: Liquid biopsies are a non-invasive diagnostic approach for detecting circulating tumor cells (CTCs) or circulating tumor DNA (ctDNA) that may provide clinically actionable information for treatment decisions for metastatic breast cancer (MBC) patients when a conventional biopsy is otherwise infeasible. Here we report a comprehensive liquid biopsy platform including: 1) quantitative immunofluorescent HER2 and ER protein expression in CTCs (ctcIF), 2) determination of ERBB2 amplification and the number of Large-scale State transitions (LST) by single-cells CTC genomics (ctcDNA) and 3) alterations in plasma ctDNA. Methods: Blood samples from 457 progressing metastatic breast cancer patients and 25 healthy donors (HDs) as controls were collected for cell &amp; cell-free DNA analysis. After plasma isolation, nucleated cells were plated, &amp; slides were bio-banked for Immunofluorescent staining &amp; subsequent imaging. CTCs were identified using Epic Sciences digital imaging &amp; machine learning algorithms, and individual CTCs were sequenced for genomic quantification of LSTs and Copy Number Variants (CNV). Bio-banked plasma was analyzed to detect ctDNA alterations with high clinical relevance (Class IA). Results: Within this cohort of 457 MBC patients, the presence of CTCs, ctcDNA (LST+) and ctDNA alterations were detected in 98%, 58%, and 42%, respectively, while no CTCs and no ctDNA alterations were detected in the HD cohort, suggesting high specificity. ctcDNA genomics was more sensitive than ctDNA in detecting ERBB2amp in MBC patients (16%, and 2%, respectively). A mean variant allele frequency (VAF) of &lt; 25%, which is the threshold for detecting a two-fold ERBB2 amplification by ctDNA, was present in 20% and 80% of ERBB2amp MBC detected by the ctDNA and ctcDNA platform, respectively, suggesting that the ctcDNA platform can identify the majority of ERBB2amp among patients with a low ctDNA fraction. HER2exp or ERexp expression by ctcIF were detected in 67% and 67% of MBC patients, respectively. A liquid biopsy classification of HER2 status by combining the three platforms (ctcIF, ctcDNA, and ctDNA) identified that in the tested population, 16% were ERBB2amp, 52% were HER2 expressing (HER2exp and ERBB2nonamp), and 27% were HER2neg (HER2- and ERBB2nonamp). To identify MBC patients that may potentially change treatment as a result of the test we identified a small cohort of MBC patients (n=46) with HER2- disease and tissue biopsy IHC=0, 74% of these patients had HER2exp CTC consistent with HER2 low expression which may aid therapeutic decisions in later line MBC. Conclusions: Here we report a comprehensive liquid biopsy profile combining ctcIF, ctcDNA, and ctDNA platforms with high sensitivity and specificity in determining clinically actionable HER2 and ER biomarker status that may impact therapeutic decision-making in MBC patients.

Impact of race and age on intrinsic subtype distribution and treatment decisions in metastatic breast cancer: Preliminary analysis of HARMONY (LCCC1829).

1055 Background: Gene expression profiling (GEP) is used to classify breast cancer (BC) into four intrinsic subtypes: Luminal A (LumA), Luminal B (LumB), HER2-Enriched, and Basal-like. Non-LumA subtypes are associated with poorer outcomes. Studies in early BC show that hormone receptor-positive (HR+)/HER2-negative (HER2-) tumors have a higher frequency of non-LumA subtypes in Black and younger (&lt;50) women. Similarly, triple negative BC, which carries the poorest prognosis and is mostly Basal-like, are overrepresented in Black and younger women. These variations in intrinsic subtype contribute to outcomes disparities. The extent to which these racial and age differences in subtypes and mortality occur in metastatic breast cancer (MBC) is unknown. Methods: HARMONY (NCT03769415) is a prospective clinical trial in patients with newly diagnosed MBC. Bulk tumor GEP (PAM50 intrinsic subtyping) is performed on primary and metastatic tumors. A primary objective is to determine the extent and treatment implications of molecular discordance (defined a priori as treatment differences by intrinsic subtype compared to clinical subtype); other endpoints to be reported later include GEP comparisons between primary and metastatic samples. Here we examine differences in a) intrinsic subtype and b) treatment patterns in MBC by race and age. Results: At the time of analysis, the study had accrued 220 participants. Mean age was 58, 24% were Black women. Sixty-five percent had HR+/HER2- MBC, 14% HER2-positive, and 21% triple negative. Unlike in early BC, LumB exceeded LumA (LumA 27%, LumB 35%, HER2-Enriched 12%, Basal-like 25%). Similar to early BC, subtype varied by race and age with more non-LumA subtypes in young and Black women. Discordance between intrinsic and clinical subtype was seen in 24% of Black, 20% of White women, in 29% of younger and 18% of older women. Treatment patterns also differed by race and age, where a higher percentage of younger Black women received first-line chemotherapy compared to younger White women overall (45% vs. 10%, p=0.0025), and in HR+/HER2- disease (33% vs 8.7%, p=&gt;0.05). No difference was seen in older women (24% vs 17%, p=0.44). Median progression free survival was worst in younger Black women compared to all other participants (5.4 vs 19.5 months, p=0.027), which may be driven by clinical subtype. Conclusions: Intrinsic subtype of tumors in a metastatic population has a different distribution by race and age than early BC, with more poor-prognosis non-LumA subtypes, and approximately 1 in 5 have discordance between clinical and molecular subtype, which may be therapeutically relevant. Clinical trial information: NCT03769415 . [Table: see text]