Treatment Of Breast Cancer Research Articles

Abstract GS02-05: Overview of Axillary Treatment in Early Breast Cancer: patient-level meta-analysis of long-term outcomes among 20,273 women in 29 randomised trials

Abstract Background: In early breast cancer, the optimal management of the axilla is uncertain. To better understand the long-term benefits and risks of different approaches, we undertook an individual patient data meta-analysis of randomised trials comparing varying types of axillary treatment. Methods: Information was available on 20,273 women in 29 trials of axillary surgery or axillary radiotherapy. The trial comparisons included in this overview are summarised in Table 1. Randomisation took place during 1958–2009. Median follow-up was 10.0 years (IQR 7.4–11.5). Findings: In the trials of more extensive versus less extensive axillary treatment, the rate ratios (RR) for locoregional recurrence varied by site (p=0.003), however, 82% of these locoregional recurrences (552/670) occurred either in the breast or were of unspecified location (Table 2). Considering locoregional recurrence at any site, there was little difference in the risk from more versus less axillary treatment (10-year risk 4.3% vs 4.7%; RR 0.90 95% CI 0.77–1.05; p = 0.20), even in women treated for node-positive disease (3.7% vs 3.6%; RR 1.01, 95% CI 0.74–1.36, p=0.97). There was, however, a substantial difference in lymphoedema for trials of more versus less axillary surgery (odds ratio (OR) 2.35, 95% CI 2.05–2.70; p< 0.00001) and for trials of axillary treatment (surgery or radiotherapy) compared with no further axillary treatment (OR 3.08, 95% CI 2.01–4.71; p< 0.00001). In the four trials comparing axillary node clearance to axillary radiotherapy, the risk of locoregional recurrence appeared to be somewhat reduced in women allocated to clearance (43 vs. 56 events, 10-year risk 4.4% vs. 6.9%; RR 0.64, 95% CI 0.43-0.96, p=0.03) whilst their risk of lymphoedema was increased (OR 1.79, 95% CI 1.42–2.27; p< 0.00001). The risks of distant recurrence, breast cancer, non-breast-cancer, or all-cause mortality did not differ significantly by extent of axillary treatment or when comparing axillary clearance to radiotherapy. Interpretation: This is the most comprehensive overview of axillary treatment to date. Less extensive surgery, such as sentinel lymph node biopsy, or using axillary radiotherapy, resulted in a substantial reduction in lymphoedema compared to axillary node clearance. While there was no evidence of a difference in locoregional recurrence, a moderate effect cannot be excluded. Funding: Cancer Research UK, British Heart Foundation, Medical Research Council Table 1: Summary of the trials of treatment of the axilla in early breast cancer that began prior to 2012. Table 2: Numbers of locoregional recurrences as first event and rate ratios in the trials of more versus less axillary treatment. Citation Format: Gurdeep Mannu, Graham Beake, Richard Berry, David Dodwell, Robert Hills, Paul McGale, Stewart Anderson, Ian Campbell, Armando E. Giuliano, Reshma Jagsi, Thorsten Kuehn, Rebecca Llewellyn-Bennett, Eleftherios Mamounas, Robert Mansel, Pascal Roy, Emiel Rutgers, Nisha Sharma, Sandra Swain, Jonas Bergh, On behalf of the EBCTCG. Overview of Axillary Treatment in Early Breast Cancer: patient-level meta-analysis of long-term outcomes among 20,273 women in 29 randomised trials [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 GS02-05.

Abstract PO1-16-04: Targeting PKMYT1 Kinase as a Therapeutic Strategy for Treatment of Triple Negative Breast Cancer with Low Molecular Weight Cyclin E (LMW-E) Expression

Abstract Purpose: Low molecular weight isoforms of cyclin E (LMW-E) have been implicated in various human cancers, including triple negative breast cancer (TNBC), and are associated with a poor prognosis. However, targeted therapies for TNBC based on biomarkers are currently lacking. This study aims to investigate LMW-E as a potential therapeutic target in TNBC and evaluate the efficacy of RP-6306, a selective inhibitor of the Protein Kinase, Membrane Associated Tyrosine/Threonine 1 (PKMYT1), in LMW-E-positive breast tumors. Experimental Design: Immunohistochemical (IHC) analysis was performed on pre-treatment tumor specimens from TNBC patients (n=36) to assess the correlation between LMW-E expression, CDK1 phosphorylation at Threonine 14 (pT14), and pathologic complete response to neoadjuvant chemotherapy. LMW-E inducible human mammary epithelial cells (hMEC) and breast cancer cell lines were used to investigate the regulatory effect of LMW-E on PKMYT1, the kinase responsible for CDK1 phosphorylation at T14, and the response to RP-6306, a first in-class and selective inhibitor of PKMYT1. Patient-derived xenograft (PDX) models and transgenic mouse mammary tumor virus (MMTV) models of TNBC expressing human LMW-E (hLMW-E) were also utilized to assess LMW-E as a biomarker for predicting response to RP-6306. Results. Analysis of TNBC tumor biopsies revealed a significant positive correlation between LMW-E expression and CDK1 pT14, and both biomarkers were associated with a lack of pathological complete response to neoadjuvant chemotherapy. In vitro results using LMW-E inducible hMECs and breast cancer cell lines demonstrated that LMW-E up-regulates PKMYT1 and CDK1 pT14, acting as a PKMYT1 binding protein and enhancing PKMYT1 protein stability. High LMW-E protein levels predicted a favorable response to RP-6306, resulting in the accumulation of sub-G1 and polyploid cells, decreased tolerance to replication stress, increased DNA damage, chromosomal breakage, and apoptosis. In vivo treatment of TNBC PDX models and hLMW-E transgenic tumors with RP-6306 resulted in a significant reduction in tumor volume only in mice harboring high LMW-E tumors, while low cyclin E models showed no response. Immunohistochemical analysis confirmed increased γ-H2AX and decreased CDK1-pT14 and Ki67 levels, indicating the efficacy of RP-6306 in both PDX and transgenic models. Conclusion: This study highlights the regulatory axis from LMW-E to PKMYT1 and its predictive value for pathological complete response in TNBC patients receiving neoadjuvant chemotherapy. The selective PKMYT1 kinase inhibitor RP-6306 consistently induced DNA damage and inhibited tumor growth in in vitro and in vivo pre-clinical breast tumor models. Co-expression of LMW-E and CDK1-pT14 in TNBC can be used to stratify patients whose tumors are likely to respond to RP-6306, emphasizing its therapeutic significance. Citation Format: Mi Li, Amriti Lulla, Cansu Karakas, Spiridon Tsavaschidis, Yan Wang, Tuyen Nguyun, Tuyen Bui, Gary Marshall, Kelly Hunt, Khandan Keyomarsi. Targeting PKMYT1 Kinase as a Therapeutic Strategy for Treatment of Triple Negative Breast Cancer with Low Molecular Weight Cyclin E (LMW-E) Expression [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 PO1-16-04.

Abstract PO1-05-13: Drop-out rates from line to line of treatment in metastatic breast cancer (MBC): Results from the Austrian AGMT_MBC-Registry

Abstract Background: In metastatic breast cancer (MBC) continuous treatment with sequentially administered cancer drugs is the standard of care. Lines of treatment (LoT) consisting of single drugs or drug combinations are usually administered until disease progression or unacceptable toxicity. To provide as many patients as possible access to the most effective therapies, the “best treatment first” strategy has been established as a subset of patients will be lost from LoT to LoT. To investigate drop-out rates in all subsequent LoT, high-quality real-world data are needed. Here, we present data from the Austrian Study Group of Medical Tumor Therapy (AGMT) MBC-Registry, a multicenter nationwide ongoing retrospective and prospective registry for MBC patients in Austria. Patients and methods: Patients with known hormone-receptor (HR) and HER2 status, available survival data and at least one LoT were included. Therapies administered between diagnosis or disease progression and subsequent disease progression were counted as one LoT. All types of antitumor drugs (endocrine therapy, targeted therapy, chemotherapy, immunotherapy) were considered. Results: As of 16-May-2023, 2,484 patients were included in the registry. Out of 2,044 evaluable patients, 1,330 (65.1%) were HR+/HER2-, 251 (12.3%) were HR+/HER2+, 146 (7.1%) were HR-/HER2+ and 317 (15.5%) were triple-negative, respectively. The median number of treatment-lines in the overall cohort was 3 (range 1-14; 95%CI 3-3). In patients with HR+/HER2-, HR+/HER2+, HR-/HER2+ and triple-negative tumors the median LoT were 3 (range 1-14; 95%CI 3-4), 4 (range 1-13; 95%CI 3-4), 3 (range 1-10; 95%CI 3-4) and 2 (range 1-9; 95%CI 2-3), respectively. Overall, 641 patients were still on treatment at data cut off. The estimated percentage of patients being treated in each LoT and the corresponding drop-out rates from 1st- to 5th-line are provided in Table 1. Conclusion: Relevant drop-out rates even in the early treatment lines support a “best treatment first” strategy. An accelerated investigation of promising cancer drugs in early treatment lines in patients with MBC is warranted. Drop-out-Rate 1st-line 2nd-line 3rd-line 4th-line 5th-line All n 2044 1281 869 558 344 Drop-out-Rate / 23.8% 24.8% 30.9% 34.0% HR+/HER2- n 1,330 854 586 380 244 Drop-out-Rate / 19.6% 23.0% 29.6% 30.7% HR+/HER2+ n 251 157 109 72 48 Drop-out-Rate / 23.4% 20.4% 25.0% 28.4% HR-/HER2+ n 146 78 59 37 24 Drop-out-Rate / 36.6% 16.9% 36.2% 33.3% Triple-negative n 317 192 115 69 28 Drop-out-Rate / 34.0% 38.2% 39.5% 57.6% Citation Format: Simon Gampenrieder, Gabriel Rinnerthaler, Angelika Pichler, Walter Herz, Andreas Petzer, Clemens Dormann, Marija Balic, Christoph Suppan, Sonja Heibl, Lukas Scagnetti, Margit Sandholzer, Clemens Schmitt, August Zabernigg, Daniel Egle, Petra Pichler, Christopher Hager, Florian Roitner, Johannes Andel, Kathrin Strasser-Weippl, Rupert Bartsch, Michael Hubalek, Michael Knauer, Christian F. Singer, Richard Greil. Drop-out rates from line to line of treatment in metastatic breast cancer (MBC): Results from the Austrian AGMT_MBC-Registry [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 PO1-05-13.

Abstract PO3-18-03: Preoperative single-dose camrelizumab and/or microwave ablation in women with early-stage breast cancer: A randomized window-of-opportunity trial

Abstract Immune checkpoint blockade (ICB) has shown low response rates for advanced breast cancer, and combinatorial strategies are needed to improve the effect of ICB. As an effective local therapy, microwave ablation (MWA) may be a trigger of antitumor immunity. This window-of-opportunity trial was conducted to determine the safety and feasibility of camrelizumab (anti-PD-1 antibody) combined with MWA in the treatment of early-stage breast cancer preoperatively. The peripheral immune response was also investigated. 60 participants were randomized to receive single-dose camrelizumab alone (n=20), microwave ablation (n=20), or both camrelizumab and microwave ablation (n=20), preoperatively. Camrelizumab and MWA were well tolerated alone and in combination. Different from that in single-dose camrelizumab or MWA group, participants showed stable quantity of blood cells after the combination therapy. After the combination therapy, peripheral CD8+T cells showed enhanced cytotoxic and effect-memory functions. Clonal expansional CD8+T cells showed different functions from emergent clones after the combination therapy, suggesting that the expansional clones may play a vital role in the enhanced biological functions of CD8+T cells. Enhanced interactions between clonal expansional CD8+T cells and monocytes was observed, suggesting monocytes contributed to enhanced functions of clonal expansional CD8+T cells. MHC I related pathways and interferon signaling pathways were activated in monocytes by the combination therapy. In conclusion, camrelizumab combined with MWA was feasible for the treatment of early-stage breast cancer. The peripheral CD8+T cells were activated after the combination therapy, dependent on monocytes with activated MHC I pathways. Citation Format: Wenbin Zhou, Hui Xie, Qiang Ding, Shui Wang. Preoperative single-dose camrelizumab and/or microwave ablation in women with early-stage breast cancer: A randomized window-of-opportunity 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 PO3-18-03.

Abstract PO5-27-05: Computational design and validation of a novel peptide-drug conjugate for treatment of triple negative breast cancer

Abstract Sortilin (SORT1) is a member of the vacuolar protein sorting 10 protein (Vps10p) family that functions as a receptor regulating peptide and protein trafficking between the plasma membrane, lysosomes, and trans-golgi network. As a cell surface receptor, SORT1 is able to mediate efficient endocytosis of extracellular ligands to the lysosomal compartment. Numerous reports have identified enriched SORT1 expression in a variety of tumor types, including triple-negative breast cancer (TNBC), a subtype of breast cancer associated with aggressive clinical behavior and poor disease outcomes. We sought to exploit SORT1-dependent internalization of peptides as a platform for rapid and specific chemotherapy delivery into TNBC cells. Using ProteinStudio (our proprietary computation-enabled design capabilities), we generated high-affinity SORT1 targeting peptides that exhibit efficient receptor dependent internalization and lysosomal localization. Alternative computational approaches such as AlphaFold2 failed to recapitulate the peptide design. Peptide drug conjugates (PDCs) were generated via a linkage strategy that combines our designed peptides to the antimitotic agent monomethyl auristatin E (MMAE). Our PDC molecules exhibit potent tumor regression in a MDA-MB-231 TNBC cell derived xenograft model, thereby highlighting the potential of SORT1-engaging PDCs as an efficacious targeted chemotherapeutic delivery strategy. Citation Format: Francine Liu, Andrew Zhai, Ozge Yoluk, Aron Broom, Tracy Stone, Glenn Butterfoss, Serban Popa, Tianyu Li, Lucas Siow, Christopher Ing, David White. Computational design and validation of a novel peptide-drug conjugate for treatment of triple negative 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 PO5-27-05.

Abstract PO1-27-07: Is HER2-low a biologically distinct breast cancer (BC) subtype? Prognosis and pathological complete response rate after neoadjuvant treatment (NAT) in early breast cancer (BC) HER2 negative

Abstract Background: Overexpression of HER2 is a significant prognostic and predictive factor in early breast cancer. HER2 positive tumors are those scored by immunohistochemistry (IHC) 3+ or 2+ with amplification by in situ hybridization (ISH). These tumors may benefit from HER2-targeted treatment and additionally, in early HER2-positive BC, achieving a complete pathological response after neoadjuvant treatment improves patient survival. In recent years, new anti-HER2 antibody-drug conjugates have proven effective for HER2 low BC (defined as IHC score 1+ or 2+ not amplified) in the metastatic disease setting; however, in HER2-low early BC, studies testing novel anti-HER2 antibody-drug conjugates as neoadjuvant therapy (NAT) are ongoing. Currently, we don´t know exactly whether HER2 expression can influence the pathological response rate after NAT or disease-free survival (DFS) in these patients compared to HER2-zero (IHC 0). The aim of our study is to determine the impact on response rate to NAT and survival outcomes in early HER2-negative BC. Methods: We conducted a retrospective study in two hospitals in Andalucia, Spain. Patients with early HER2 negative BC treated with NAT from January 2015 to June 2022 were included. Patients were divided into HER2 low patients (IHC 1+ or 2+ not amplified) and HER2 0 (IHC 0). We collected clinical and pathological characteristics, pathological response rate using the Residual Cancer Burden (RCB) system where a complete pathological response (pCR) was defined as ypT0/ypTis and ypN0, and survival outcomes. The primary objective of the study was to analyze the pCR rate after NAT according to HER2 score, and secondary objectives were to assess disease-free survival and overall survival (DFS and OS rates). Results: 574 patients were included (100% women). 397 patients had hormone receptors (luminal BC) on these tumors, and 177 did not have them, i.e., triple-negative BC (TNBC). 225 patients were HER2-zero, and 312 patients were HER2-low (253/312 patients had luminal BC and 59/312 patients were TNBC). The pCR in HER2-low patients was 17.3% and 23.1% in HER2-zero patients (p=0.047). For luminal BC patients, the pCR was 16.7% in HER2-low tumors and 13.7% in HER2-zero tumors (p=0.29). Similarly, there was no difference in pCR rates in TNBC patients (45.8% in HER2-low and 53.8% in HER2-zero tumors, respectively, (p=0.958). The overall survival (OS) at 96 months was 88.7% (95% CI 85.6%-92%). Regarding survival outcomes, neither HER2 expression level was associated with higher 8-year DFS: 81.1% in HER2-low patients (95% CI 75.7%-86.8%) and 74.9% in HER2-zero patients (95% CI 62.3%-90.1%) p=0.64. There was no difference between histological subtypes at 8-years regarding DFS rate: 80.5% (95% CI 74.3%-87.2%) in luminal HER2-low patients and 76.3% (95% CI 60.8%-95.7%) in luminal HER2-zero patients, p=0.22; 83.8% in TNBC HER2-low (95% CI 74.5%-94.2%) and 77.5% in TNBC HER2-zero patients (95% CI 69.4%-86.6%) p=0.26. We also didn´t find significant differences in terms of OS. For HER2-low patients, the 8-year OS was 90.9% (95% CI 87%-94.9%) and for HER2-zero patients, it was 86.4% (95% CI 80.8%- 92.5%) p=0.46. There were also no differences in OS for different histological subgroups with an 8-year OS in luminal HER2-low breast cancer patients of 92.5% (95% CI 88%-96.7%) and 87% in HER2-zero (95% CI 78.9%-96.1%) p=0.91. In patients with triple-negative breast cancer phenotype, the OS was 84.2% for HER2-low (95% CI 74.5%-95.2%) and 85.3% for HER2-zero (95% CI 77.9%-93.4%) p=1. Conclusions: We found no difference in survival outcomes and response rate to conventional NAT between HER2-low and HER2-zero expression levels. Therefore, our data do not support the hypothesis of HER2-low as a biologically specific breast cancer subtype. Further research on this approach with HER2 antibody-drug conjugate schemes as an alternative to traditional NAT schemes is warranted. Citation Format: Ana Gil-Torralvo, Yeray Rodriguez, Alejandro Falcon, David Morales, Mónica Cejuela, Isabel Miras, Marta Amérigo, Manuel Ruíz - Borrego, Juan Bayo, Francisco Javier Salvador Bofill. Is HER2-low a biologically distinct breast cancer (BC) subtype? Prognosis and pathological complete response rate after neoadjuvant treatment (NAT) in early breast cancer (BC) HER2 negative [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 PO1-27-07.

Abstract PO4-04-04: A Multicenter, Retrospective, Real World Study of Inetetamab Combined with Pyrotinib and Vinorelbine as Treatment for HER2-positive Metastatic Breast Cancer

Abstract Background Inetetamab, a new human epidermal growth factor receptor 2 (HER2) targeted antibody to optimize the ADCC effect, has shown great effectiveness in treating HER2-positive metastatic breast cancer. Pyrotinib, another HER2 targeted drug, is a typical representative of TKI drugs, which not only has a strong HER2 antagonistic effect but also can synergize with monoclonal antibodies to amplify the ADCC effect. Here, we investigated the efficacy and safety of inetetamb combined with pyrotinib and vinorelbine as treatment or HER2-positive metastatic breast cancer. Methods From Jan 2020 to July 2023, 77 HER2-positive metastatic breast cancer patients received inetetamb combined with pyrotinib and vinorelbine were enrolled in this study. Progression-free survival (PFS), overall survival (OS), objective response rate (ORR), clinical benefit rate (CBR), and safety profiles were reported. Results The patients’ median age at enrollment was 53 years, 35 patients (45.5%) had hormone receptor-positive disease and 54 patients (70.1%) had visceral metastasis. The median PFS was 10.03 months (95% confidence interval [CI] 6.66 to 13.41 months). ORR was 62.3% (48/77) and CBR reached 77.9% (60/77). The most common adverse event (AE) was diarrhea, occurring in 36 patients (46.8%). While the most common grade III/IV AEs included neutropenia (9[11.7%]), leukopenia (8[10.4%]) and diarrhea (5[6.5%]). No treatment-related serious adverse events or treatment-related deaths occurred. Conclusion The combination regimen of inetetamab combined with pyrotinib and vinorelbine showed an encouraging efficacy and favorable safety in patients with HER2 positive metastatic breast cancer. Citation Format: Yongmei Yin, Wei Li, Xiang Huang, Nan Jin, Xinyu Wu, Chunxiao Sun, Yijia Hua. A Multicenter, Retrospective, Real World Study of Inetetamab Combined with Pyrotinib and Vinorelbine as Treatment for HER2-positive 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 PO4-04-04.

Abstract PO3-16-06: Perceptions and experiences of patients and healthcare providers on genetic testing and treatment of early breast cancer: qualitative findings

Abstract Background: Olaparib is approved as adjuvant therapy for high-risk HER2-negative early breast cancer (eBC) patients with germline BRCA mutations (BRCAm). Understanding patients’ preferences for genetic testing and treatment in the context of shared decision-making is needed to support optimal care in eBC. This study elicited the perspectives of patients with eBC and healthcare providers (HCP) treating eBC regarding treatment decision-making, and drivers and barriers to BRCA testing. Methods: Semi-structured interviews were conducted in the United States from Jan-Feb 2023 with women (n=12) diagnosed with eBC from 2017-2021. Community and academic oncologists treating eBC (n=12) and genetic counselors (GCs; n=8) were also interviewed. Patients who were tested (n=7) and untested (n=5) for BRCAm were included. A content and thematic analysis was performed which identified key factors from the data; these analyses provided both a range and common responses that may influence BRCA testing and treatment decisions. Results: BRCA-tested patients considered testing beneficial. In choosing to receive testing, >50% of patients reported HCP recommendation (n=7) and the opportunity to have “all of the information” about their eBC (n=7) as strong influencers. Patients declined genetic testing noting fear around negative impact to their insurance coverage (n=2) or mental health (n=3), or if they did not have family who would benefit from the information. Cost did not strongly influence testing choice. In choosing a treatment, patients sought to maintain their quality of life (QoL) with fewer side effects while minimizing chance of recurrence. They expressed the dual goals of normalcy during treatment, including curtailing side effects that impact QoL, and returning to normalcy after treatment (n=7). Patients were willing to accept unpleasant side effects to have a more effective treatment if those side effects do not severely impact their QoL and the treatment is highly effective (n=9). Side effects that may lead to hospitalization were the least accepted as they disrupt normalcy. HCPs reported that patients eagerly accept testing and face minimal familial or access barriers to testing. HCPs observed that among their non-Medicare patients, testing is usually covered by insurance with minimal out-of-pocket costs, thus alleviating financial constraints observed in previous years. HCPs believe BRCA testing is driven by updated hereditary cancer testing guidelines (e.g., NCCN), lower testing costs, closer collaborations of physicians and genetic counselors, and greater awareness among patients. HCPs reported that they embrace patient-led decision-making in eBC, especially as it relates to patients with BRCAm considering additional prophylactic surgery, and GCs further emphasized patient autonomy. Oncologists mentioned that they discuss risk status starting at diagnosis and these conversations evolve over the patient journey as new information emerges. In HR+ eBC, oncologists offered most patients with BRCAm adjuvant olaparib, which they perceive as well tolerated. In triple-negative eBC, oncologists opted for neoadjuvant Keytruda regimen prior to considering adjuvant olaparib for gBRCAm patients. Conclusions: Patients value information that empowers them to achieve their goals of normalcy and remission that can be achieved by addressing QoL, side effects, and patients' goals of living “normally”. Though prior research highlighted insurance coverage and costs as significant barriers to BRCA testing, results from this study suggest that cost was not a major factor in testing decisions. Prior barriers to testing access have been mitigated making it more available and affordable than in the past, which could be broadly communicated to patients and HCPs to minimize misperception. Citation Format: Jagadeswara Earla, Emily Mulvihill, Josh Lankin, Lauren Howell, Alex Kissling, Weiyan Li, Jaime Mejia. Perceptions and experiences of patients and healthcare providers on genetic testing and treatment of early breast cancer: qualitative findings [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 PO3-16-06.

Abstract PO2-01-07: Real-world efficacy of dual HER2-blockade in combination with anthracycline-containing and anthracycline-free neoadjuvant treatment in early breast cancer (BC)

Abstract BACKGROUND: Neoadjuvant therapy with antiHER-2 blockade is the standard of care for HER-2 positive early BC. The objective of this treatment is tumor downstaging to increase resectability and pathological complete response (pCR), a reliable surrogate endpoint for survival. Adding Trastuzumab (T) to chemotherapy resulted in an improvement in pCR, however, resistance to this agent is common and the incorporation of Pertuzumab (P) to the neoadjuvant scene demonstrated an increase in pCR in the Peony (39.3% vs 21.8%) and Neosphere trials (45.8% vs 29%). Across all studies, pCR is even higher in patients (pts) with negative hormonal receptor (HR) status (50%-63%) (3, 4). Tryphaena and Berenice found low rates of cardiotoxicity with T-P combination. Recently, TRAIN-2 data showed that anthracyclines and platinum have a similar pCR (67% vs 68%), but febrile neutropenia and cardiotoxicity is higher in the anthracycline group, concluding that omitting this therapy might be a preferred approach in the presence of dual HER2 blockade. Our study investigated the pCR benefit of dual HER2 blockade with anthracyclines and platinum in HER2 positive early BC. METHODS: We conducted a retrospective, unicenter, observational study of pts, treated with neoadjuvant T-P plus chemotherapy, in HER-2 positive early BC, between April 2015 and December 2022 at University Hospital A Coruña (Spain). The primary endpoint was total pCR in breast and axila (tpCR: ypT0/is ypN0). Secondary endpoints were: association between clinicopatological characteristics and pCR; and between cardiotoxicity and treatment pattern. Statistical analyses were conducted with Statistical Package for the Social Science (SPSS). RESULTS: During the study period, from April 2015 to May 2022, 154 pts were enrrolled. The median age was 51,3 years [range 26 – 799 years], all patients were female. Infiltrating ductal carcinoma was present in 92.2% pts, and 5.8% were inflammatory BC. At diagnosis, 11.7%, 61.7% and 26.6% had stages I, II and III, respectively, and 51.3% revealed axillary node involvement. Among observed cases, 94 (61%) were positive HR; 68 (45%) had histological grade 2 and 83 (53.9%) histological grade 3 tumors; and 151 pts (99.3%) presented a ki-67 level >20%. HER2 by immunohistochemistry (IHC) resulted in 3+ for 133 pts (86.9%) and in 2+ for 20 pts (13.1%), all of them with positive result by in situ hybridation (ISH). P-T were mostly combined with anthracyclines (64.9%). tpCR rate was 50.6%, and it was not significantly different according chemotherapy approach. tpCR was significantly higher among HR negative tumours (73.3%) compared with HR positive (36.2%) (p= 0.001), and in HER2 positive 3+ (55.6%) compared with HER2 positive 2+ (15%) tumours (p= 0.001). Achievement of tpCR was not significantly associated with tumor size, stage, histological grade and ki-67 level. Breast pCR was higher than tpCR (54.2%). 13 pts (8.4%) presented recurrence disease, in 76.9% of cases was a metastatic relapse. Cardiotoxicity was low during all stages of treatment and was not significantly associated with chemotherapy pattern. CONCLUSIONS: Neoadjuvant T-P plus chemotherapy with either anthracyclines or platinum therapy, demonstrated same efficacy and cardiac safety in our real-world study. pCR rates are lower in positive HR and HER2 positive 2+, needing more investigation with combination strategies including hormonotherapy, Our results are similar to data from randomized trials and other real-world efficacy studies, but we need more follow-up to identify late cardiotoxicity by anthracyclines and recurrences in positive HR tumors. Citation Format: Beatriz Alonso de Castro, Cristina Reboredo, Lourdes Calvo, Maria-Eva Perez-Lopez, Martin Igor Gomez Randulfe Rodriguez, Sofia silva diaz, Iria Parajo Vazquez, Silvia Antolin Novoa. Real-world efficacy of dual HER2-blockade in combination with anthracycline-containing and anthracycline-free neoadjuvant treatment in early breast cancer (BC) [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 PO2-01-07.

Abstract PO3-03-10: Race and neoadjuvant treatment of triple negative breast cancer (TNBC) in the US community oncology setting

Abstract Background: TNBC is an aggressive subtype of breast cancer with limited targeted therapies. Black women have twice the incidence of TNBC compared to White women and within TNBC, Black women have worse outcomes than White women. Differences in both tumor biology of TNBC and social determinants of health (SDOH) play a role in observed disparities. The focus of this study is to evaluate SDOH factors associated to differences in the use of neoadjuvant chemotherapy (NC) in Black and White women in the US community oncology setting. Methods: This study was a retrospective, observational, cross-sectional design and used iKnowMed SM EHR data from the The US Oncology Network. Patients diagnosed with TNBC between 03/31/2017 and 09/30/2021 with stages II-III disease of tumor size ≥ 2cm (T2 or higher) were included. The index date was date of TNBC diagnosis and records were assessed from 6 months pre- to 6 months post-diagnosis for NC initiation. Univariable and multivariable logistic regression was conducted to evaluate impact of self-reported race on NC. Age, stage, BMI, insurance, area deprivation index (ADI), size of practice represented by physician count and geographical region, were studied in their mediating and moderating effects1 on the relationship between race and NC treatment. Results: Of the 3321 patients with TNBC identified in this study, 1969 self-reported white and 494 self-reported black (80% and 20% respectively). In multivariable regression accounting for all variables, Black race (OR = 1.57, 95% CI [ 1.02, 2.44], p=0.04), younger age, more advanced stage, obesity, non-Medicaid insurance, and West region, were all found to be positively associated with use of NC. Higher physician count was nominally associated, (p = 0.07). ADI was not found to be associated to NC. Mediator and moderator analysis for the relationship between race and NC showed that only stage and ADI variable inclusion in the model are required for the positive association between black race and NC. This is driven by a significant interaction between ADI and stage (p = 0.027) which differed for Black and White women. Mainly, for Black women ADI is positively associated to NC treatment in stage IIA, but negatively associated in all other stages (interaction term, p = 0.033). For White women, ADI is negatively associated to NC treatment in all stages. Only Black women with stage IIA tend to be treated more instead of less with NC in areas of greater deprivation (greater ADI). BMI presents nominal interactions with both race and stage, where obesity was more strongly associated with NC treatment in Black women (p = 0.088) and in stage IIA (p = 0.086). All other variables presented association to NC treatment without mediation or moderation of the race effect and without detectable differences across stages. Conclusions: Black women with stage IIA appear to be a special subgroup of TNBC patients for whom treatment with NC increases with ADI. Increased ADI generally results in less standard of care treatment; this is observed in this study for White women overall and for Black women in stages > IIA. Black women in areas of greater deprivation with stage IIA disease, may be perceived to be presenting with more aggressive disease and thus offered NC preferentially. This result lends support to the hypothesis that young black women present with a distinct, more aggressive subtype of TNBC in the early stages. Mediator and moderator analyses are important tools in elucidating the relationships between factors underlying racial disparities in both care and outcomes. 1. Hayes AF, Rockwood NJ. Regression-based statistical mediation and moderation analysis in clinical research: Observations, recommendations, and implementation. Behav Res Ther. 2017 Nov;98:39-57. Odds ratios for multivariable analysis –insert figure image– Race, stage and ADI –insert figure image– Race and BMI in stage IIA –insert figure image– Citation Format: Paola Raska, Joseph Dye, Nicholas J Robert, Angel Kidd, Michael Danso. Race and neoadjuvant treatment of triple negative breast cancer (TNBC) in the US community oncology setting [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 PO3-03-10.

Abstract PO1-04-05: Effectiveness and safety of inetetamab + pyrotinib + vinorelbine in ≥second-line treatment of HER2-positive metastatic breast cancer

Abstract Background: In real-world settings, Patients with HER2-positive metastatic breast cancer (MBC) who cannot receive antibody-drug conjugates (ADCs) as standard second-line therapy due to cost–benefit ratios and who have no preferred options as ≥third-line regimen by NCCN guidelines, require new regimens to meet their clinical needs. This study aims to explore the effectiveness and safety of inetetamab + pyrotinib + vinorelbine for ≥second-line treatment of HER2-positive MBC. Methods: Patients with HER2-positive MBC who received ≥second-line treatment at our hospital from June 2020 to December 2022 were enrolled. Progression-free survival (PFS), objective response rate (ORR), clinical benefit rate (CBR) and adverse reactions were assessed. Patients received inetetamab + pyrotinib + vinorelbine until disease progression or unacceptable toxicity were evaluated every two cycles according to the RECIST 1.1 criteria. Results: 89 patients were included based on the inclusion and exclusion criteria. Among them, 45 patients received second-line treatment who couldn't use T-DM1 or T-DXd, and 44 patients received ≥third-line treatment. The median PFS of the second-line treatment subgroup was 17months, the ORR and CBR were 60.0% and 86.7%, respectively, which were significantly higher than those in the ≥third-line treatment subgroup and numerically superior to T-DM1 as a second-line treatment option. Additionally, the ORR and CBR of patients with baseline brain metastasis who did not receive radiotherapy were 27.3% and 72.7%, respectively. The most common adverse events observed were leukopenia (37.1%), neutropenia (42.7%), anemia (34.8%) and diarrhea (67.4%). The incidence of grade 3-4 leukopenia, neutropenia, anemia and diarrhea were 11.2%, 15.7%, 55.6% and 27.0%, respectively. A total of 8 patients (8.9%) discontinued medication due to adverse reactions. Conclusions: Inetetamab + pyrotinib + vinorelbine demonstrates good efficacy and controllable toxicity as a second-line treatment for HER2-positive MBC. This therapeutic regimen provides a viable alternative option for patients who are unable to receive ADCs as the second-line treatment. Citation Format: Fan Wu, Mulan Chen, Weiwei Huang, Lili Wang, Nani Li, Xiufeng Wu, Xinhua Chen, Yi Hong, Lin Lin, Kan Chen, Jian liu. Effectiveness and safety of inetetamab + pyrotinib + vinorelbine in ≥second-line treatment of HER2-positive 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 PO1-04-05.

Abstract PO2-22-04: Median Five-Year Follow-Up Results from the Multi-Institution Trial for the Treatment of Early-Stage Breast Cancer Using Intra-Operative Electronic Brachytherapy

Abstract Background: An IRB-approved single arm prospective multi-institution trial was designed to determine the efficacy and outcome of single fraction 20 Gy intra-operative radiation therapy (IORT) using disposable balloon electronic brachytherapy at the time of breast conserving surgery for early-stage breast cancer (women at least 40 years old, infiltrating ductal carcinoma [IDC] or ductal carcinoma in situ [DCIS], single lesion no larger than 3 cm, pN0). Ipsilateral breast tumor recurrences (IBTR) at median 5-year follow-up, the primary protocol endpoint of the trial, would be analyzed with outcomes compared to reported whole breast radiation therapy (WBRT) results. Methods: Between May 2012–July 2018,1199 enrolled breast cancer patients at twenty-six national and international institutions were successfully treated per protocol with lumpectomy plus single 20 Gy fraction IORT using disposable balloon electronic brachytherapy. Data collection and retrospective chart review included demographics, treatment, histopathology, toxicity, IBTR (defined as recurrence in the lumpectomy cavity/index quadrant), and survival. Results: All subjects were successfully treated with a single 20 Gy fraction of IORT. IORT cohort characteristics of the treated subjects are summarized in Table 1. Sixty-six (5.5%) patients received subsequent unplanned risk-adjusted WBRT. At median 5.0-year follow-up (range 0.5 – 9 years), there were 42 (3.50%) IBTR. The original mean tumor size of patients with IBTR was 13.6mm (range 0.03 - 30mm). The mean time to IBTR was 47.6 months (range 12 – 98 months). There were 30 IBTR in patients originally diagnosed with IDC, and 12 IBTR among patients originally diagnosed with DCIS. Three patients originally diagnosed with IDC recurred as DCIS, while 4 patients with DCIS recurred as IDC. The remainder recurred with the same pathology as their original diagnoses. Sorting by 2017 ASTRO accelerated partial breast irradiation (APBI) criteria, there were 25 IBTR in patients categorized immediately following lumpectomy plus IORT as Suitable, 12 IBTR among patients categorized immediately following lumpectomy plus IORT as Cautionary, and 5 IBTR in patients categorized immediately following lumpectomy plus IORT as Unsuitable. Nine (0.75%) patients experienced new ipsilateral primary breast cancers, with 8 classified as Suitable and one as Cautionary using post-lumpectomy plus IORT ASTRO APBI criteria. Seventeen (1.4%) patients experienced acute serious adverse events (SAEs). These included 5 wound infections, 4 hematomas, 2 skin ulcerations, 2 cellulitis, 2 seromas, 1 skin necrosis, and 1 wound dehiscence. All SAEs resolved within 6 months of IORT. One patient died of breast cancer metastases at 3-year follow-up. One patient who was diagnosed with IBTR at 3-year follow-up died 3 years later from dementia. There were 45 unrelated patient deaths. Conclusions: At median 5.0-year follow-up, the 1199 early-stage breast cancer patients successfully treated in this multi-institution trial with a single 20 Gy fraction of IORT to the lumpectomy cavity at the time of partial mastectomy experienced an IBTR of 3.50%. This recurrence rate is acceptable when compared to the 0.9% - 2.5% IBTR reported for WBRT, given the benefits of IORT (convenience, decreased exposure to XRT, better cosmetic outcome, patient preference). Table 1. IORT cohort characteristics Citation Format: Barbara Schwartzberg, AM Nisar Syed, Ajay Bhatnagar, Sophia Rahman, Veronica Jones, Albert Chang, Todd Cockerham, Virginia Osborn, Robert Cohen, Charles Hodge, Christina Lopez-Penalver, Bapsi Chakravarthy, William Dooley, Chika Madu, Atsuko Okabe, Maen Farha, Andrea Madrigrano, Christopher Morrison, Geoffrey Neuner, Craig Wengler, Steven David, Katayoon Toosie, Bryon Stephens. Median Five-Year Follow-Up Results from the Multi-Institution Trial for the Treatment of Early-Stage Breast Cancer Using Intra-Operative Electronic Brachytherapy [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 PO2-22-04.

Abstract PS09-07: SPAG5 as a companion prognostic and predictive test for management of early stage HER2 positive breast cancer (BCs)

Abstract Background: SPAG5 is a novel oncogene that is amplified in 40% of HER2+BC. Herein, we evaluated the prognostic and predictive significance of SPAG5 in HER2+ BC Methods: This retrospective cohort study included 2454 patients with HER2+BC derived from 6 cohorts in adjuvant (Adj) and neoadjuvant (NACT) settings. Adj cohorts: The association between SPAG5 and survivals were evaluated in 1354 HER2+ BC who received Adj therapy: 1) HER2+ Adj transcript cohort (n=448): 31% (137/448) did not receive Anthracycline (AC), Taxane (TX), Trastuzumab (TZ) or Pertuzuman (PZ) whereas 20% (89/448) had received AC alone and 35% (155/448) received TZ + AC +/- TX (Median follow- up (MFU): 60 months (m). 2) HER2+ Adj Molecular Taxonomy of BC International Consortium cohort (n=240): patients with ER- and lymph node (LN) + received Adj chemotherapy but none received TZ (MFU: 109 m). 3) HER2+ Adj Historical cohort (n=206): no TZ, AC or TX was received (MFU: 143 m). 4) HER2+/ER- cohort (n=101): AC alone was received; MFU: 62 m. 5) HER+ Adj TZ cohort (n=359): patients received TZ +TX+/-AC (MFU: 90 m). Neo-Adjuvant cohort: the associations of SPAG5 protein expression with pathological complete response (pCR) was evaluated in 1100 BCs (MFUT: 67 m) including 200 local cases participated in ROSCO trial. In this cohort; 73% (803/1100) received AC+TX. AC alone was given to 187/1100 (17%) whereas 88/1100 (8%) received TX alone. Of HER2+ BC, 14% (54/399) received AC +/- TX and 63% received TZ + TX +/-AC and 23% (92/399) received TZ + PZ + TX +/- AC. Sections were IHC profiled for HER2, ER, PR, Ki67 and SPAG5 and stained for Fluorescent in situ hybridisation (FISH) using a novel triple colour probe (HER2/SPAG5/Ch17). ASCO guidelines recommendations were followed. Results: In univariate survival analysis, High SPAG5 (+) transcript was associated with shorter 5- year distant metastases free survival (5-y DRFS); p< 0.0001, compared to SPAG5 low (-) in HER2+ patients who did not receive TZ or AC whereas in those who received AC alone, SPAG5+ was associated with lower risk of 5-y DRFS than SPAG5- (p < 0.001). Multivariable Cox regression analysis showed that SPAG5+ transcript ; as well as LN status, was independently associated with poor prognosis (HR (95% CI): 4.9 (2.0-12.0), p< 0.001). The interaction term between SPAG5 and AC was significantly associated with lower risk of DR. Multivariable Cox regression analysis for 10-year relapse free survival (10y-RFS) in HER2+ patients who did not receive AC or TZ confirmed that SPAG5+ protein expression ; as well as LN status and tumour size, were independently associated with poor prognosis (HR (95% CI): 2.1 (1.3, 3.5), p=0.002). SPAG5+ predicted response for NACT +/- HER2 targeting agents. For instance; None of HER2 IHC 2+ with SPAG5- expression/(0/191) either with HER2 FISH- (0/121) or HER2 FISH+ (0/70) achieved pCR whereas 51% (48/95) of those of HER2 IHC 2+/SPAG5+ achieved pCR (p < 0.0001). Similarly patients with HER2+ IHC 3+/SPAG5+ achieved higher pCR rate compared to those with SPAG5- expression [73% (107/146) vs., 10% (14/135); respectively]; p< 0.0001. Noteworthy, after receiving TZ+ PZ +Texans +/- AC, patients with SPAG5+ achieved higher pCR rate compared to those with SPAG5- expression [85% (50/59) vs., 0% (0/51); respectively, p< 0.001]. Similarly in HER2 + BC patients who received TZ + TX +/- AC, SPAG5+ expression was associated with higher pCR [67% (67/101)] compared to those with SPAG5- [10% (11/107)]; p< 0.001. In HER2+ who received AC alone, SPAG5+ cases achieved higher pCR compared to those with SPAG5- [56% (20/36) vs., 6% (3/47); p< 0.001; respectively]. Multivariable logistic regression analysis showed that SPAG5+ expression as well as ER, HER2 IHC, grade, clinical TNM and HER2 targeting agents were independent predictors for pCR (OR (95% CI: 13.74 (5.76-32.79; p< 0.001). Conclusions SPAG5 is an independent poor prognostic factor in HER2+ BC and could help in distinguishing those who would and would not benefit from NACT and HER2 targeting agents. Citation Format: TAREK ABDEL-Fatah, Graham Ball, Daniel Yeo, Graham Hickman, Arlene Chan, Ian Ellis, Stephen Chan. SPAG5 as a companion prognostic and predictive test for management of early stage HER2 positive breast cancer (BCs) [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 PS09-07.

Abstract PO4-04-06: Exploring the use of tyrosine kinase inhibitors (TKIs) in the management of HER2-positive metastatic breast cancer post trastuzumab emtansine (T-DM1) therapy failure: Insights from a real-world study

Abstract Background Trastuzumab emtansine (T-DM1) is the established standard second-line treatment for HER2-positive metastatic breast cancer (MBC) patients who have previously received trastuzumab. However, there is ongoing debate regarding the subsequent therapeutic options following T-DM1 failure. This study aimed to evaluate the efficacy and safety of tyrosine kinase inhibitors (TKIs)-based therapy in HER2-positive MBC patients with resistance to T-DM1. Methods During the period from September 2018 to October 2021, a multicenter real-world study was conducted, enrolling a total of 53 patients diagnosed with HER2-positive metastatic breast cancer (MBC). These patients underwent TKIs-based therapy following the failure of T-DM1 treatment. The primary focus of the study was on evaluating progression-free survival (PFS) as the main endpoint. Secondary endpoints encompassed objective response rate (ORR), overall survival (OS), clinical benefit rate (CBR), and safety assessments. Results A total of 53 patients received TKIs-based therapy as a second-line or later treatment. The median progression-free survival (PFS) for TKIs-based therapy was 11.9 months (95% CI 7.9-15.9). The objective response rate (ORR) and clinical benefit rate (CBR) were found to be 19.6% and 72.5%, respectively. Among patients with brain metastasis (n=12), a median PFS of 10.5 months (95% CI 7.5-13.5) and an intracranial ORR of 33.3% were observed. Patients treated with pyrotinib (n=21) showed improved PFS compared to those treated with lapatinib (n=30), as well as patients who had derived favorable benefit from T-DM1 (PFS ≥ 6 months). Hormone receptor status (HR) and response to T-DM1 were identified as independent factors affecting the effectiveness of TKIs-based therapy. The most frequently reported adverse events included thrombocytopenia (23.6%), diarrhea (15.7%), leucopenia (15.7%), and hand-foot syndrome (15.7%). Conclusion TKIs-based therapy demonstrated favorable effectiveness and safety in HER2-positive metastatic breast cancer (MBC) patients who had previously received T-DM1 but experienced treatment failure. This includes patients with brain metastases. Notably, individuals who derived favorable benefits from prior T-DM1 treatment displayed significantly prolonged progression-free survival (PFS) when undergoing subsequent TKIs-based therapy. Citation Format: Yongmei Yin, Chunxiao Sun, Yijia Hua, Nan Jin, Wei Li, Xiang Huang. Exploring the use of tyrosine kinase inhibitors (TKIs) in the management of HER2-positive metastatic breast cancer post trastuzumab emtansine (T-DM1) therapy failure: Insights from a real-world 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 PO4-04-06.

Abstract PO3-20-05: Phase II Study of Genomically Guided Radiation Dose Personalization in the Management of Triple Negative Breast Cancer

Abstract Background: Our group has previously developed the radiosensitivity index (RSI) using a multigene expression model that is directly proportional to tumor radioresistance (high RSI = increased radioresistance). RSI has been previously validated in two datasets of patients with triple negative breast cancer (TNBC). In this study, we will run a selective dose personalization study in TNBC patients undergoing breast conservation therapy (BCT). Based on patients RSI scores, they will either receive a radiation therapy (RT) boost of 10 Gy to the tumor cavity or not. Given our data in two independent datasets, the current study will reveal the feasibility and benefit of selective genomic dose personalization in TNBC following BCT. Trial Design: The study is designed as a prospective, nonrandomized, phase II trial of genomically guided RT in the management of TNBC undergoing BCT. Patients will be allocated to one of two groups based on their RSI determination from fresh frozen tissue collected by biopsy or at the time of BCT. These groups will be Group A, RSI optimized whole breast radiotherapy alone or with a 10 Gy boost or Group B, RSI not optimized whole breast radiotherapy with a boost of 10 Gy to tumor cavity. Patients will receive standard of care chemotherapy, neoadjuvant or adjuvant. Eligibility: TNBC patients undergoing BCT. Specific Aims: To determine the three-year local control following genomically guided dose personalization in the management of TNBC following BCT. Secondary objectives include determination of overall survival (OS), progression free survival (PFS), and quality of life (QOL) following genomically guided dose personalization. Statistical Methods: The primary hypothesis is the three-year local control rates differ for groups A and B, against the null hypothesis that the two rates are identical. Patients will allocate approximately 78% in group A and 22% in group B and local control rates are expected to be 96% and 75%, respectively. Assuming 80% power and 10% type I error for a log-rank test, 86 patients are needed. An interim analysis will be completed when 4 disease progression events are observed. There will be approximately 43 patients at the time of interim analysis. Patient Accrual: This study is open with 1 patient enrolled at the time of submission. A total of 86 patients will be enrolled. Contact Information: Kamran A. Ahmed MD, Moffitt Cancer Center, email: kamran.ahmed@moffitt.org, Clinical trial information: NCT05115474. Funding: Moffitt and Morton Plant Mease Foundations. Citation Format: Kamran Ahmed, Iman Washington, Matthew Mills, Michelle DeJesus, Youngchul Kim, Ronica Nanda, Javier Torres-Roca, Steven Eschrich, Janis De La Iglesia, John Puskas, Marilin Rosa, Jason Wilson, Paula Lundgren, Negar Golesorkhi, Nazanin Khakpour, Susan Hoover, Marie Lee, John Kiluk, Melissa Mallory, Christine Laronga, Laura Kruper, Brian Czerniecki, Roberto Diaz. Phase II Study of Genomically Guided Radiation Dose Personalization in the Management of Triple Negative 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 PO3-20-05.

Emerging Toxicities of Antibody-Drug Conjugates for Breast Cancer: Clinical Prioritization of Adverse Events from the FDA Adverse Event Reporting System.

Antibody-drug conjugates (ADCs) are gaining widespread use in the treatment of breast cancer, although toxicity remains an underexplored issue in the real-world clinical setting. Individual case safety reports collected in large pharmacovigilance databases can advance our knowledge on their safety profile in routine clinical practice. We prioritized adverse events (AEs) reported with ADCs approved for breast cancer using the Food andDrugAdministration Adverse Event Reporting System (FAERS). We assessed clinical priority of AEs reported in FAERS (February 2013-March 2022) for trastuzumab emtansine (T-DM1), trastuzumab deruxtecan (T-DXd), and sacituzumab govitecan (SG) by attributing a score to each AE disproportionally reported with ADCs. Four criteria were assessed: clinical relevance, reporting rate, reported case fatality rate, and stability of disproportionality signals (consistency of the reporting odds ratio across multiple analyses using three different comparators). We retained 6589 reports (77.4% referring to T-DM1 as suspect), and 572 AEs generated a disproportionality signal in at least one analysis. The majority of these AEs (62%) were classified as moderate clinical priorities (e.g., interstitial lung disease with T-DXd, thrombocytopenia, peripheral neuropathy with T-DM1, febrile neutropenia, and large intestine perforation with SG). Three AEs emerged as high clinical priorities (6 points): septic shock and neutropenic colitis with SG (N = 8 and 13, with median onset 13 and 10 days, respectively), without co-reported immunosuppressive agents; and pulmonary embolism with T-DM1 (N = 31, median onset 109 days, 52% with reported metastasis). The heterogeneous spectrum of post-marketing toxicities for ADCs used in breast cancer, as emerging from the FAERS, is largely in line with preapproval evidence. Although causality cannot be proved, we call for increased awareness by oncologists on potential serious unexpected reactions, including early onset of septic shock and neutropenic colitis with SG, and late emergence of pulmonary embolism with T-DM1.

Abstract PO1-09-11: Racial Differences in Pathologic Complete Response Rate and Overall Survival Following Neoadjuvant Chemotherapy for Breast Cancer

Abstract Background: Neoadjuvant chemotherapy (NAC) is increasingly used in the treatment of breast cancer and has been utilized in multiple clinical trials assessing the efficacy of novel therapies. Pathologic complete response (pCR) following NAC is associated with improved survival outcomes in breast cancer and pCR is a commonly used endpoint in clinical trials. Despite improvements in breast cancer survival using modern treatment regimens, Black women continue to experience worse survival outcomes as compared to White women. The objective of this study was to evaluate the association between race and clinical outcomes, specifically pCR rate, recurrence free survival and overall survival, in patients undergoing neoadjuvant chemotherapy at our institution. Methods: We conducted a retrospective review of patients who completed at least 75% of the recommended cycles of neoadjuvant chemotherapy for breast cancer between 2010 and 2016 and underwent surgery. Receptor subtypes were defined as HR+/HER2-negative, HER2+ or triple-negative. The association between race and pCR, defined as ypT0/ypTis ypN0, and survival endpoints of overall survival and recurrence free survival were analyzed using multivariable logistic regression and Cox proportional hazard models. Results: A total of 532 women met the inclusion criteria, 323 (60.7%) were White, 188 (35.3%) were Black and 21 (3.9%) were other/unknown. Median follow-up was 65 months. The receptor subgroups consisted of 195 (36.7%) HR+/HER2-negative cancers, 193 (36.3%) HER2+ cancers and 144 (27.1%) triple-negative cancers. No significant association between race and receptor subtype (p=0.55) or pre-treatment clinical stage (p=0.96) was observed. The overall observed pCR rate was 19% for Black patients and 27% for White patients, demonstrating a significantly different pCR rate by race in multivariate analysis (odds ratio of pCR White vs Black of 1.75; p=0.02). The largest discrepancy in pCR rate between White and Black patients was within subjects with triple-negative disease (pCR rate 44% White patients vs 27% Black patients, p=0.03). There was no association between recurrence free survival and race in univariate analysis (p=0.15). A significant difference in overall survival by race was observed using multivariable Cox proportions hazard model (hazard ratio Black vs White 1.77; p=0.03). Conclusions: In this retrospective analysis of patients receiving neoadjuvant chemotherapy, Black patients experienced a significantly lower pCR rate compared to White patients, with the biggest gap identified within triple-negative breast cancers. During the study period, Black patients also experienced a lower overall survival rate compared to White patients. Differences in the ability to achieve a pCR may be a contributing factor to the worse survival outcomes of Black patients. Citation Format: Chad Livasy, Erin Donahue, Brittany Neelands, Lejla Hadzikadic-Gusic, Terry Sarantou, Mckenzie Needham, Alicia Patrick, Arielle Heeke, Antoinette Tan, Richard White. Racial Differences in Pathologic Complete Response Rate and Overall Survival Following Neoadjuvant Chemotherapy for 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 PO1-09-11.

Abstract PO4-20-06: Impact of iatrogenic menopause on vaginal health and sexuality

Abstract Background Due to the lowering of circulating estrogens symptoms of genitourinary syndrome of menopause (GSM) may arise with premenopausal breast cancer patients who become menopausal due to breast cancer treatment. Clinical signs of GSM are i.a. vaginal dryness, dyspareunia, loss of libido, dysfunction of arousal and/or orgasm: this may negatively impact vaginal health, sexual activity and quality of life. The composition and function of the vaginal microbiome may also change due to changes of gonadal hormones during the menopausal transition. This change may contribute to vaginal discomfort and problems during sexual activity. With this prospective research we aim to uncover the relationship between vaginal health and sexuality, it gives an unique opportunity to investigate the vaginal changes and possible shift of vaginal microbiome when menopause occurs. This is a first in time study where longitudinal samples of the vaginal microbiome in one patient are investigated before and after menopause. The vaginal microbiome might be a future target to treat vaginal discomfort after treatment for breast cancer. Trial design This is a prospective minimal invasive study where participants are asked to undergo a baseline gynecologic examination, again 3 and 6 months after menopause. During this examination we measure vaginal pH, describe vaginal hydration and anatomy (using vaginal-, and vulvar assessment scale (VAS, VuAS)) and sample the vaginal microbiome (analyzed with 16S rRNA gene sequencing and quantitative real-time polymerase chain reaction (qPCR)). At the same time, a blood test is performed (Estradiol, FSH) and participants complete a survey (demographic information, medical history, current well-being using World Health Organisation- Five Well-Being Index (WHO-5), sexual functioning using the Female Sexual Functioning index (FSFI), Female Sexual Dysfunction Scale – revised (FSDS-R) and Short Sexual Functioning scale (SSFS)). Eligibility criteria - Patients (>18 years) with Stage I, IIA, IIB, IIIA, IIIB, IIIC breast cancer - Reproductive age or menopausal transition according to STRAW+10 criteria - Iatrogenic menopause caused by ovarian function suppression (OFS), bilateral salpingo-ovariectomy (BSO) or by starting chemotherapy - Any partner status - Latest cervical cytology is normal - No prior history of hysterectomy - Patients who take oral contraceptives or have a Levonorgestrel- containing IUD can participate. Oral contraceptives should be stopped or the Levonorgestrel-containing IUD should be removed before systemic breast cancer therapy Specific aims To accurately describe what vaginal changes occur during breast cancer treatment To evaluate if the onset of menopause is related to changes in vaginal microbiome To evaluate if there is a relation between the objective vaginal changes and the subjective complaints related to GSM To evaluate if there is a relation between the objective vaginal changes and a possible alteration in sexuality Statistical methods Using multiple comparison procedures in ANOVA (analysis of Variance) model, the clinical findings (VAS, VuAS, pH, composition of microbiome) and validated questionnaires (WHO-5, FSFI, FSDR-r, SSFS) are linked to analyze if vaginal changes are related to changes in sexual wellbeing. The interpretation of the results of this investigation should be interpreted with caution due to the explorative nature of the study. Present accrual/Target accrual 23/60 participants are included (JULY 2023) Citation Format: Nynke Willers, Sileny Han, Patrick Neven, Paul Enzlin, Sarah Lebeer, Sarah Ahannach. Impact of iatrogenic menopause on vaginal health and sexuality [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 PO4-20-06.

Abstract PO3-09-08: Using Social Determinants of Health to Improve Surgical Delays for Breast Cancer Patients at Rush University Cancer Center

Abstract Introduction Delays to surgery in the treatment of breast cancer can lead to worse disease specific mortality and overall survival. Previous work has shown a woman’s time to surgical treatment is influenced by income, which may be secondary to social determinants of health (SDOH) including health literacy, safety, stress, access to health care and transportation, housing, and ability to pay utilities. This study sought to evaluate a screening process for SDOH to assess and address barriers to care for women newly diagnosed with breast cancer. Methods A SDOH screening tool consisting of 7 yes/no questions was developed and used by trained breast oncology nurses via phone call made to all new patients prior to their first visit. Based on patient response, patients are provided with community resources or referred to the hospital social work team. Primary outcome included the SDOH screening results, and secondary outcome included time to surgery. Results 118 patients were screened, of which 60 patients had surgery as their first treatment and were included in this analysis. Twenty-seven patients screened positive for SDOH need. Ten patients reported >3 SDOH concerns and were referred to social work. The most common concerns were food insecurity and trouble paying utilities. Of the 27 patients who screened positively, 18 identified as Black or African American, 3 were Hispanic, 1 Asian and 5 White. The mean household income for these patients based on their reported zip codes was $55,615.78. Average time to surgery for patients with a positive SDOH screen was 37.7 days and negative SDOH screen was 42 days. For patients with a positive SDOH screen, those with 2 or fewer SDOH needs had an average time to surgery of 41.9 days and those with 3 or more SDOH needs had an average 30.6 days until surgery. Discussion Patients who screened positive for SDOH need and were provided resources had a faster time to surgery than patients who initially screened negative for SDOH. Patients referred to social work had the fastest time to surgery. Early identification of SDOH is necessary for all patients to improve equity and outcomes in breast cancer treatment. Citation Format: Hilary Tingley, Madeline McIntosh, McKenzie Klee, Margaret Gladman, Alison Coogan, Andrea Madrigrano. Using Social Determinants of Health to Improve Surgical Delays for Breast Cancer Patients at Rush University Cancer Center [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 PO3-09-08.

Abstract PO2-08-11: The MAGIC study: Universal whole genome tumour and germline sequencing of newly diagnosed breast cancer identifies a high proportion of ER+ BRCA-like tumours

Abstract Background: Identification of germline mutations in hereditary breast cancer (HBC) genes can have profound benefits in the treatment of breast cancer (BC) and manging risk for patient and the family. In addition, sequencing of the tumours can reveal clinically relevant somatic features, such as homologous recombination deficiency (HRD) and mutational signatures, that can guide treatment which are not discernible by germline sequencing alone. We hypothesised that current standard of care where women diagnosed with BC are not routinely offered tumour sequencing is suboptimal as fails to exploit all therapeutic vulnerabilities which can be exploited in the treatment of BC. The MAGIC study is the first prospective trial in Australia of unselected invasive BCs in general oncology practice combining both germline and tumour sequencing. Methods: The MAGIC study included a total of 651 consecutive consented patients presenting with non-metastatic BC between June 2020 to March 2023. It included invasive BC, high-grade DCIS and pleomorphic LCIS. The sequencing was conducted in two phases; for phase one, 157 cases underwent whole genome sequencing (WGS) on both germline and matched BC DNA while for phase two, 494 cases underwent only germline whole exome sequencing. Germline variants were interrogated for pathogenic variants in BRCA1, BRCA2, PALB2, ATM, CHEK2, BARD1, BRIP1, RAD51B, RAD51C, RAD51D, MLH1, MSH2, MSH6, PMS2, CDH1, PTEN, STK11, TP53 and NTHL1. Tumour homologous recombination (HR) repair deficiency was calculated using HRDetect (Nat Med 2017;23:517). For BCs showing a high HRDetect score ( >0.75) all HBC gene promoter CpG islands were assessed for hypermethylation using the Twist NGS Methylation system. Mutational signatures were calculated from somatic mutations identified from whole genome sequenced BCs using the DeconstructSig package in R (Genome Biol. 2016;17:31) and referenced against the COSMIC v2 signature catalogue. Results: Actionable germline variants in any HBC gene were identified in 7.7% of cases (7.8% of invasive and 6.1% of in situ BC) with 5.2% having an actionable mutation in an HR pathway gene (BRCA1, BRCA2, PALB2 and RAD51C). Most cases with pathogenic variants showed bi-allelic inactivation in the tumour. All BRCA1, BRCA2 and PALB2 tumours showed high HRDetect and/or HRD scores consistent with loss of HR repair function, indicating them to be the underlying hereditary driver of the BC. One BC with a pathogenic PMS2 variant showed retention of the wild-type allele with no evidence of a mismatch repair mutational signature suggesting PMS2 was not the driver of this BC. Of the 157 BC in phase one that underwent WGS and did not have a germline pathogenic HBC gene variant, 16% (18/117 invasive and 3/13 DCIS) had an HRDetect score of >0.7 indicative of a homologous recombination repair defect and therefore biologically a “BRCA-like” tumour. Of these 21 BRCA-like cases, only 3 invasive BCs had clear somatic bi-allelic inactivation of an HBC gene that could explain the high HRDetect score (2 BRCA1 and 1 BRCA2). One of the 21 BRCA-like cases had a germline variant of unknown significance (VUS) in an HBC gene (a BRCA2 missense variant in an ER+ tumour. The tumour showed loss of the wild-type allele). Of the BRCA-like cases, 71% were ER positive which included 3 invasive lobular cancers. Conclusion: Tumour sequencing identified three times as many cases that might be eligible for HR repair defect targeted therapy than germline testing alone (16% versus 5.2%). Unlike a previous study (Ann Oncol., 2019 30:1071-1079), the majority of the BRCA-like BCs were ER+ with no evidence of a VUS in a known HBC gene suggesting these are driven by novel germline or somatic mutations in genes involved in DNA HR repair. Citation Format: Ian Campbell, Lisa Devereux, Kirsten Hogg, Luxi Lal, Michelle Sinclair, Lesley Stafford, Magnus Zethoven, Anita Skandarajah, Paul James, Geoffrey Lindeman, Bruce Mann, Dilanka De Silva. The MAGIC study: Universal whole genome tumour and germline sequencing of newly diagnosed breast cancer identifies a high proportion of ER+ BRCA-like tumours [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 PO2-08-11.