Isopp 2023

The proceedings contain 109 papers. The topics discussed include: dose intensity of palbociclib and initial body weight dosage: implications on progression free survival in 220 patients with ER+/HER2-negative metastatic breast cancer;characteristics of Nirmatrelvir/Ritonavir (Paxlovid) recipients and clinical interventions by oncology pharmacists at a tertiary outpatient cancer center;safe handling of non-carcinogenic drugs in the Ghent University Hospital: development, implementation and communication of hospital-specific guidelines;case series: use of olaparib in uncommon locations in patients with impaired homologous recombination;real-world data evaluation of medicines used in special situations in oncohematology: a retrospective study from a comprehensive cancer institution;Dostarlimab in the treatment of recurrent endometrial cancer: real life experience;medication-related osteonecrosis of the jaws and CDK4/6 inhibitors in breast cancer;and efficacy and safety outcomes of generic imatinib in adults with chronic myeloid leukemia (CML) following the switch from branded imatinib.

Sensitizing breast cancers to immune checkpoint inhibitors through CD27 agonism and vaccination against tumor-associated antigen

Project objective: Despite the recent revolution in immune checkpoint inhibitors (ICIs), only modest improvement in overall survival and likely caused by not enough potent cellular immunity among BC patients. Our lab has been focus on inducing cellular immunity against HER2+ BC through vaccination against the tumor-associated antigen HER2. Approximately 20 years ago, we performed an experimental pilot study by administrating HER2 peptide and recombinant protein pulsed dendritic cells (DC vaccine) to six patients with refractory HER2+ advanced or metastatic (stage II (>= 6 +LN), III, or stage IV) BC. We followed the patients on 2019 found that all of the six patients were still alive, 18 years after vaccination. Their blood sample were analyzed with cytometry by time-offlight (CyTOF) and found there is a significantly increased presence of CD27 expressing memory T cells in response to HER2 peptide stimulation. Recent report on the SARS-CoV2 mRNA vaccine also suggested that CD27 expressing memory T cells plays a critical role in long-lasting cellular immunity against SARS-CoV2 infection. Therefore, we hypothesized that CD27 plays a critical role in cellular immunity against BC, and the stimulation of CD27 expressing T cells with mAb targeting CD27 significantly increase the cellular immunity triggered by vaccination against tumor-associated antigen. Result(s): We recapitulate the rise of CD27+ antigen specific T cells among the vaccinated patients using a transgenic mouse model expressing human CD27. When combined the adenoviral-vector based HER2 (Ad-HER2) vaccination with a single dose of human aCD27 antibody (Varlilumab), we found there is a robust increase in the HER2 specific T cells compared to vaccination alone, especially CD27+CD44+ memory CD4 T cells, even after 120 days post vaccination. Using an ICIinsensitive syngeneic HER2+ BC models, we found 50% of mice in the combination group of aCD27 antibody plus Ad-HER2 showed total tumor regression by the end of study. When combined with anti-PD1 antibody, the combination of AdHER2 and Varlilumab leads to total tumor regression in 90% of tumor bearing mice with syngeneic HER2+ BC, indicating that the vaccination against tumor associated antigen HER2 plus anti-CD27 antibody sensitized ICI-insensitive HER2+ BC toward ICI. Conclusion(s): Our data demonstrates that the administration of anti-CD27 antibody significantly increase the long term presence of CD27+ antigen specific memory T cells after vaccination against tumor associated antigen HER2. As consequence, combination of anti-CD27 with HER2 sensitized the immune unresponsive breast cancer toward anti-PD1 antibody. Our study suggests that the vaccination against tumor-associated antigen with mAb targeting CD27 leads to the robust cellular immunity, which is required for successful ICIs against breast cancer.

Liquid biopsy testing in metastatic or advanced breast cancer patients during the COVID-19 pandemic

Objective: During the COVID-19 pandemic, cancer patients had restricted access to standard of care tissue biopsy. Liquid biopsy assays using next generation sequencing technology provides a less invasive method for determining circulating tumour mutations (ctDNA) associated with targeted treatments or prognosis. As part of deploying technology to help cancer patients obtain molecular testing, a clinical program was initiated to offer liquid biopsy testing for Canadian patients with advanced or metastatic breast cancer. Method(s): Blood was drawn in two 10 mL StreckTM DNA BCTs and sent to the CAP/CLIA/DAP accredited Imagia Canexia Health laboratory for testing using the clinically validated Follow ItTM liquid biopsy assay. Plasma was isolated using a double spin protocol and plasma cell-free DNA (cfDNA) extracted using an optimized Promega Maxwell RSC method. Extracted cfDNA was amplified using the multiplex amplicon-based hotspot 30 or 38 gene panel and sequenced. An inhouse developed bioinformatics pipeline and reporting platform were used to identify pathogenic single nucleotide variants (SNVs), indels (insertions and deletions), and gene amplification. Included in the panel are genes associated with metastatic breast cancer: AKT1, BRAF, ERBB2, ESR1, KRAS, PIK3CA, TP53. Result(s): To identify biomarkers, 1214 metastatic or advanced breast cancer patient cfDNA samples were tested. There were 15 cases sent for repeat testing. We reported 48% of samples harboring pathogenic ctDNA mutations in TP53 (22%), PIK3CA (19%), ESR1 (18%), AKT1 (2%), ERBB2 (1.5%). Co-occurring variants were identified in samples with ESR1/PIK3CA as well as TP53/PIK3CA (both p-values <0.001). Interestingly, 29% of samples with mutated ESR1 harbored >= 2 ESR1 ctDNA mutations. In 56% of cases, previous molecular testing indicated the cancer subtype as hormone receptor (ER, PR) positive with/without HER2 negative status. In this specific subgroup, 49% harbored ctDNA mutations with 63% of those being PIK3CA and/or ESR1 mutations. Conclusion(s): A population of Canadian women with metastatic breast cancer were tested using a liquid biopsy gene panel during the COVID-19 pandemic for identification of biomarkers for targeted therapeutic options. Over 50% of the samples were identified as hormone positive, with greater than 60% harboring PIK3CA and ESR1 ctDNA mutations. Studies have shown that metastatic PIK3CA mutated ER-positive/HER2-negative tumors are predictive to respond to alpelisib therapy and have FDA and Health Canada approval. Additionally, ESR1 mutations are associated with acquired resistance to antiestrogen therapies, and interestingly we identified 29% of ESR1 mutated samples with multiple mutations possibly indicating resistance subclones. In future studies, longitudinal monitoring for presence of multiple targetable and resistance mutations could be utilized to predict or improve clinical management.

Competitive cause of death in elderly breast cancer survivors

Background: Breats cancer is a major health problem in elderly ( >= 70 years) women. Increase incidence with age and the progressive increase in life expectancy mean that the numbers in elderly breast cancer diagnosis are increasing. These patients do not always receive the proper treatment and despite this the survival of this population is not always depends on cancer, there are other competing causes of death typical of the aging population. Method(s): A retrospective observational analysis of women >= age 70 diagnosed with breast carcinoma in HUPHM between 2014 and 2020 was made. Clinical, pathological data and stages at diagnosis were analyzed. We checked our patients with the national death center (official national registry) thus obtaining an exact date of death and the cause of death. Data updated in January 2023 , ensuring a minimum follow-up of 24 months. We excluded deaths from Covid or of unknown cause to avoid bias. Result(s): A total of 421 patients were analyzed, mean age of 78.6 years and median follow-up of 48 months. 28% of patients had died at the time of analysis, 11% due to cancer and 17% from other causes. If we analyze the population deceased by cancer, no deaths are detected in patients diagnosed with carcinoma in situ (4% of the population), in stage I (30% of the population) the cumulative incidence of cancer death at 5 years is 3%, 7% In stage II (30% of the population), 15% in stage III (16%) and 70% in stage IV (12%). Death by other causes are more frequent in early breast cancer, the cumulative incidence at 5 years are 10% in stage I, 22% in stage II, 44% in satge III and just 10% in stage IV. The most frequent causes of death in this population were caridovascular events and infections. There are no differences in 5-year mortality according to histological subtypes 20%, 12%, 25% and 12% for triple negative, Rh+/HER2-, RH+/her2+ and RH-/HER2+ respectively. Conclusion(s): Although elderly patients do not receive optical treatments, mortality from cancer in early stages is incidental at 5 years, a different scenario is seen in metastatic disease in which the patient's prognosis depends mainly on the oncological disease, Therefore, an effort should be made in the treatment of these patients with metastatic breast cancer since adequate treatments can have a clearly positive impact on the survival of patients. Legal entity responsible for the study: The authors. Funding(s): Has not received any funding. Disclosure: All authors have declared no conflicts of interest.Copyright © 2023

EMERALD trial analysis of patient-reported outcomes (PROs) in patients with ER+/HER2- advanced or metastatic breast cancer (mBC) comparing oral elacestrant vs standard of care (SoC) endocrine therapy

Background: The phase III EMERALD trial (NCT03778931) reported significantly prolonged progression-free survival (PFS) and a manageable safety profile with elacestrant vs SoC endocrine therapy (ET) in patients (N=478) with ER+/HER2- advanced or mBC following progression on prior CDK4/6i plus ET. PROs measuring quality of life (QoL) are reported here. Method(s): EMERALD patients (pts) completed 3 PRO tools at prespecified time points: the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30), the PRO version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE), and the EuroQoL 5 Dimension 5 Level (EQ-5D-5L). Result(s): The ratio of PROs tools completed vs. PROs tools expected was 80-90% through cycle 4 and approximately 70% at cycle 6;likely due to clinical study period overlapping with COVID-19 period. Overall, the EORTC QLQ-C30 scores were similar for elacestrant and SoC, with no differences across all time points for both functional and symptom scales. However, PRO-CTCAE results showed that fewer pts who received elacestrant reported very severe nausea (4.0% vs 14.3% by cycle 6) or very severe vomiting (9.1% vs 50% by cycle 6) compared with SoC. There were no clinically meaningful differences across all time points in adverse events typically observed with pts with cancer on ET, such as fatigue, nausea, vomiting, joint and muscle pain and hot flashes. EQ-5D-5L scores were generally comparable throughout treatment for both study arms, with elacestrant showing numerically better outcomes vs SoC for mobility, self-care and usual activities. Similar trends were observed for the full intent-to-treat population and in pts with detectable estrogen receptor 1 mutations (ESR1m). Conclusion(s): This analysis confirmed that QoL was maintained between treatment groups in the EMERALD trial. Together with the previously described statistically significant prolonged PFS and manageable safety profile, these PRO results provide additional evidence that oral elacestrant is clinically meaningful in this patient population with limited therapeutic options. Clinical trial identification: NCT03778931. Editorial acknowledgement: Jeffrey Walter, IQVIA. Legal entity responsible for the study: Stemline Therapeutics/Menarini Group. Funding(s): Stemline Therapeutics/Menarini Group. Disclosure: J. Cortes: Financial Interests, Personal, Advisory Board: Roche, Celgene, Cellestia, AstraZeneca, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Lilly, MERCK SHARP& DOHME, GSK, LEUKO, Bioasis, Clovis oncology, Boehringer Ingelheim, Ellipses, Hibercell, BioInvent, Gemoab, Gilead, Menarini, Zymeworks, Reveal Genomics;Financial Interests, Personal, Invited Speaker: Roche, Novartis, Celgene, Eisai, Pfizer, Samsung Bioepis, Lilly, MERCK SHARP& DOHME, Daiichi Sankyo;Financial Interests, Personal, Other, Consulting/advisor: Expres2ion Biotechnologies;Financial Interests, Personal, Stocks/Shares: MedSIR, Nektar Therapeutics;Financial Interests, Institutional, Research Grant: Roche, Ariad Pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer healthcare, Eisai, Guardant Health, Merck Sharp & Dohme, Pfizer, Piqur Therapeutics, Puma B, Queen Mary University of London;Other, Travel cost and expenses: Roche, Novartis, Eisai, Daiichi Sankyo, Pfizer, Gilead, AstraZeneca. F.C. Bidard: Financial Interests, Personal, Advisory Role: Pfizer, AstraZeneca, Lilly, Novartis, Radius Health, Menarini;Financial Interests, Institutional, Advisory Role: Menarini;Financial Interests, Personal, Speaker's Bureau: Pfizer, Novartis, AstraZeneca, Roche, Lilly, Rain Therapeutics;Financial Interests, Institutional, Research Grant: Novartis, Pfizer, Menarini Silicon Biosystems, Prolynx;Financial Interests, Institutional, Other, patents: ESR1 & MSI detection techniques;Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Roche, Pfizer, AstraZeneca, Novartis. A. Bardia: Financial Interests, Personal, Advisory Board: Pfizer, Novartis, Genentech, Merck, Sanofi, Eisa , Lilly, Mersana, AstraZeneca/Daiichi, Menarini, Gilead;Financial Interests, Personal, Royalties: UpToDate;Financial Interests, Institutional, Invited Speaker: Genentech, Novartis, Pfizer, Merck, Sanofi, Radius Health, Immunomedics/Gilead, Daiichi Pharma/AstraZeneca, Eli Lilly.;Non-Financial Interests, Principal Investigator: Gilead, Mersana, AstraZeneca/Daiichi, Novartis, Pfizer, Genentech, Lilly, Merck, Sanofi. V.G. Kaklamani: Financial Interests, Personal, Other, Honoraria: Genentech, Novartis, Pfizer, Genomic Health, Puma Biotechnology, AstraZeneca, Seattle Genetics, Daichi, Gilead Sciences;Financial Interests, Personal, Advisory Role: Amgen, Eisai, Puma Biotechnology, Celldex, AstraZeneca, Athenex, bioTheranostics;Financial Interests, Personal, Speaker's Bureau: Genentech, Novartis, Genomic Health, Puma Biotechnology, Pfizer, AstraZeneca/Daiichi Sankyo;Financial Interests, Personal, Research Grant: Eisai. I. Vlachaki: Financial Interests, Personal, Full or part-time Employment: Menarini Hellas A.E. G. Tonini: Financial Interests, Personal, Full or part-time Employment: Menarini Ricerche S.p.A. N. Habboubi: Financial Interests, Personal, Full or part-time Employment: Stemline Therapeutics;Financial Interests, Personal, Leadership Role: Stemline Therapeutics. P.G. Aftimos: Financial Interests, Personal, Advisory Board: Boehringer Ingelheim, Macrogenics, Roche, Novartis, Amcure, Servier, G1 Therapeutics, Radius, Deloitte, Menarini, Gilead, Novartis, Eisai, Lilly;Financial Interests, Personal, Invited Speaker: Synthon, Amgen;Financial Interests, Institutional, Research Grant: Roche.Copyright © 2023

Home-based treatment with subcutaneous (SC) trastuzumab -only a pandemic solution? Real world evidence (RWE) analysis

Background The pandemic has accelerated the introduction of more flexible and cost-effective treatment forms. The efficacy of trastuzumab in the intravenous (IV) and SC forms is similar both in early and advanced HER2-positive breast cancer (BC) patients. Compared to IV administration, SC enables reduction of treatment costs and time, and saves equipment and human resources. SC formulation is more convenient for both patients and healthcare providers and may be implemented as a home-based therapy. Recently, systemic anticancer treatment (including chemotherapy) has been increasingly performed at home, improving patient comfort and reducing the burden on the healthcare system. Poland has already implemented home-based treatment with some biologic compounds;however, they have not included trastuzumab in BC patients. Objectives This RWE analysis aims to evaluate the organizational and therapeutic procedures related to the home-based treatment with SC trastuzumab and the attitudes of patients and healthcare providers to this approach. Material and methods The study enrolled early HER2(+) BC patients treated with trastuzumab during the COVID-19 pandemic. Monitoring and treatment duration were consistent with SmPC and reimbursement regulations in Poland. The first 3-6 doses of SC trastuzumab (alone or in combination with CHT) were administered at a cancer center in outpatient and inpatient settings. Subsequent doses were administered at home by 3 qualified breast nurses. Post-injection follow-up was used for educational purposes. Data were analyzed with descriptive statistics. The study was reviewed and approved by the local Bioethics Committee. Results The analysis included 20 patients treated in two comprehensive cancer centers in Poland with a median age of 59 years (range, 36-72 years). Seven patients (35%) were professionally active. The average distance from the place of residence to the cancer center was 24 km (range, 2-65 km). A total of 232 doses were administered (mean 11.6 doses per patient;range 6-14), 133 doses at home and 99 at the cancer center. The overall tolerance of trastuzumab was good and consistent with the known safety profile described in Summary of Product Characteristics. Only 1 patient (5%) discontinued treatment prematurely due to decreased LVEF;another 19 patients completed treatment as planned. For 19 patients (95%), the benefits of SC treatment included time savings, the ability to continue working, and avoiding crowded places and infection risk. 2 patients (10%) considered the nurse's visit privacy disturbing, while 18 (90%) would recommend home-based drug administration. The average duration of a nurse's stay at home was 60 minutes (range 30 to 130 minutes). No logistical or technical problems were reported, except for occasional patient lateness. Nurses positively assessed the treatment provided in the nursing office, which was a source of additional knowledge, and experience. The overall impression of home-based therapy was positive for both patients and nurses. The limitation of the study is the declarative nature of the data. Conclusions Home-based treatment with SC trastuzumab should be pursued due to its safety, ease of organization, positive perception by patients and nurses, and reducing healthcare system resources. It can be particularly valuable for disabled patients who have difficulty reaching the hospital and professionally active patients. Specialized, trained nurses can self-sufficiently carry out part of the prolonged trastuzumab treatment, reducing physician involvement.

PD11-04 Primary results of SOLTI-1503 PROMETEO phase 2 trial of Combination of Talimogene Laherparepvec (T-VEC) with Atezolizumab in patients with residual breast cancer after standard neoadjuvant multi-agent chemotherapy

Background: Residual disease (RD) following neoadjuvant chemotherapy (NAC) in early HER2- negative breast cancer (BC) remains an unmet medical need. However, no therapies to date have tested their activity directly in chemo-resistant RD. Here, we hypothesized that combining an oncolytic virus such as T-VEC with atezolizumab may offer clinical benefit in patients (pts) with RD after standard NAC. To our knowledge, PROMETEO is the first trial that examines the activity of immunotherapy in pts with RD prior to surgery. Method(s): PROMETEO (NCT03802604) is a singlearm, open-label, multicenter phase II trial. Women with triple-negative BC (TNBC) or hormone receptor-positive/HER2-negative (HR+/HER2-) BC with baseline (i.e., before NAC) ki67 >= 20% were eligible. RD was confirmed with a magnetic resonance imaging (MRI) showing a tumor diameter >= 10 mm and a core-biopsy detecting the presence of invasive cells. Before surgery, T-VEC was administered intratumorally on week 1 (106 pfu/mL), then in week 4 and every 2 weeks thereafter (108 pfu/mL) for 4 injections. Atezolizumab (840 mg) was administered intravenously every 2 weeks for 4 infusions, starting at week 4. Surgery was performed in < 3 weeks after completing the treatment. The primary objective was to evaluate the efficacy of the combination, measured by the rate of residual cancer burden (RCB) class 0/1 at surgery. Tumor samples collected at 5 timepoints (before NAC, during screening period, after first dose of T-VEC, after first dose of T-VEC and atezolizumab and at surgery) were mandatory to assess gene expression, tumor-infiltrating lymphocytes (TILs), immune cells PD-L1 IHC (SP142), tumor mutational burden (TMB) by FoundationOne and other translational endpoints. Result(s): Between Dec 2018 to Feb 2022, 28 pts were enrolled: 20 pts with HR+/HER2- disease and 8 pts with TNBC. Median age was 47 (range 31-71) and 71% of pts were premenopausal. At diagnosis before NAC, clinical stage II disease represented 60.7%, cN+ 60.7%, median Ki-67 was 37.5% (range 20%-95%), high TILs (>=10%) 37%, median TMB was 3 (0-19) and only 1 of 27 pts (3.7%) had a PD-L1-positive tumor. After NAC, mean tumor size by MRI was 28.3 mm (10-93). Two pts discontinued from the trial (1 withdrawal of consent and 1 COVID infection). The completion of 5 cycles of treatment was achieved by 73% of pts. The overall RCB-0/1 rate was 25% (7 of 28, 95% IC 10.7 - 44.9%), all with RCB 0 (pathologic complete response [pCR]). The pCR rate was 30% in HR+/HER2- disease and 12.5 % in TNBC. Radiological response by MRI was achieved by 3 of 28 pts (10.7%). Interestingly, none of the 7 pts with a pCR had radiological response (stable disease n=5, progressive disease [PD] n=2). Six pts (21.4%) had radiological PD and had RCB 2/3. Overall, 27 (96%) patients had at least one treatment-emergent adverse event (TEAE) of any grade. Most common grade 1 or 2 AEs were fever (11 pts, 39.3%), ALT increased (9 pts, 32.1%), AST increased (8 pts, 28.6%), arthralgia (6 pts, 21.4%) and anemia (6 pts, 21.4%). Grade 3 reversible neutropenia occurred in 1 patient. Across all pts, significant increases (p< 0.001) in TILs, immune genes and immune PDL1+ cells were observed after 1 dose of TVEC, 1 dose of the combination and at surgery. Intrinsic subtype changes at surgery occurred in 73.1% of cases, mostly (46.1%) Luminal A/B converting to Normal-like. At surgery, 19 of 26 (73.1%) of tumors were PDL1+. Conclusion(s): Two months of T-VEC in combination with atezolizumab induced a pCR in a subgroup of pts with chemoresistant HER2- breast cancer. This effect is probably related to the immune activation provoked by the combined treatment. Interestingly, a high discrepancy was observed between the presurgical radiological imaging and the actual surgical pathological report. Pre-operative window-ofopportunity trials in this context might provide important clues regarding the activity of novel treatment strategies.

PD13-08 Phase 1 TROPION-PanTumor01 Study Evaluating Datopotamab Deruxtecan (Dato-DXd) in Unresectable or Metastatic Hormone Receptor-Positive/HER2-Negative Breast Cancer (BC)

Background: Datopotamab deruxtecan (Dato-DXd) is an antibody-drug conjugate (ADC) consisting of a humanized anti-TROP2 IgG1 monoclonal antibody covalently linked to a highly potent topoisomerase I (Topo I) inhibitor payload via a stable, tumor-selective, tetrapeptide-based cleavable linker. Dato-DXd demonstrated compelling single-agent antitumor activity in heavily pretreated patients (pts) with metastatic triple-negative BC (Krop, SABCS 2021). This is the first report of results from the TROPION-PanTumor01 study in pts with unresectable or metastatic hormone receptor- positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-;including HER2-low and HER2-zero) BC. Method(s): TROPION-PanTumor01 (NCT03401385) is a phase 1, multicenter, open-label, 2-part doseescalation/expansion study evaluating Dato-DXd in previously treated pts with solid tumors. Based on previous clinical findings and exposure-response results from pts with NSCLC, Dato-DXd 6 mg/kg IV Q3W is being evaluated in pts with unresectable or metastatic HR+/HER2- BC that progressed on standard therapies. The primary objectives were safety and tolerability. Tumor responses, including ORR (complete response [CR] + partial response [PR]) and DCR (CR + PR + stable disease [SD]), were assessed per RECIST version 1.1 by blinded independent central review. Result(s): As of the April 29, 2022, data cutoff, 41 pts had received Dato-DXd (median follow-up, 10.9 mo [range, 7-13]);9 pts were ongoing. The primary cause of treatment discontinuation was disease progression (63% progressive disease [PD] or clinical progression). Median age was 57 y (range, 33- 75);54% had de novo metastatic disease. Pts were heavily pretreated (Table) with a median of 5 (range, 3-10) prior regimens in the advanced setting;95% had prior CDK4/6i (adjuvant/metastatic). Median time from initial treatment for metastatic disease to the first dose of Dato-DXd was 42.7 mo (range, 10.2-131.1). Treatment-emergent adverse events (TEAEs;all cause) were observed in 98% (any grade) and 41% (grade >=3) of pts. Most common TEAEs (any grade, grade >=3) were stomatitis (80%, 10%), nausea (56%, 0%), fatigue (46%, 2%), and alopecia (37%, 0%). Serious TEAEs were observed in 6 pts (15%);1 pt died due to dyspnea, which was not considered to be treatment related. Dose reductions occurred in 5 pts due to stomatitis (n=3), fatigue (n=2), keratitis (n=1), and decreased appetite (n=1) (>1 AE per pt);14 pts had treatment delayed due to stomatitis (n=8), retinopathy (n=1), dysphagia (n=1), fatigue (n=1), malaise (n=1), COVID-19 (n=1), cellulitis (n=1), urinary tract infection (n=1), decreased lymphocyte count (n=1), and nasal congestion (n=1;>1 AE per pt). Three pts discontinued treatment due to keratitis (n=1) and pneumonitis (n=2);1 case of pneumonitis was adjudicated as grade 2 drug-related interstitial lung disease. The ORR was 29% (11 confirmed PRs;1 pending confirmation), the DCR was 85% (35/41), and the clinical benefit rate (CR + PR + SD >=6 mo) was 41% (17/41). Conclusion(s): Dato-DXd demonstrated a manageable safety profile and encouraging antitumor activity, with high disease control in heavily pretreated pts, the majority having received prior CDK4/6i. Based on these findings, the TROPION-Breast01 (NCT05104866) randomized phase 3 study comparing 2L+ Dato-DXd vs investigator's choice chemotherapy is currently enrolling pts with HR+/HER2- BC.

SMALL: Open Surgery versus Minimally invasive vacuum-Assisted excision for smaLL screendetected breast cancer - a UK phase III randomised multicentre trial

Background: Mammographic screening programmes reduce breast cancer mortality, but detect many small tumours with favourable biological features which may not progress during a woman's lifetime. Screen-detected cancers are treated with standard surgery and adjuvant therapies, with associated morbidities. There is a need to reduce overtreatment of good prognosis tumours and numerous studies have evaluated the omission of radiotherapy in this context. However, there is little evidence to support surgical de-escalation, although percutaneous minimally invasive treatment approaches have been described. Vacuum-assisted excision (VAE) is in widespread use for management of benign lesions and lesions of uncertain malignant potential. SMALL (ISRCTN 12240119) is designed to determine the feasibility of using this approach for treatment of small invasive tumours detected within the UK NHS Breast Screening Programme (BSP). Method(s): SMALL is a phase III multicentre randomised trial comparing standard surgery with VAE for screendetected good prognosis cancers. The main eligibility criteria are age >=47 years, unifocal grade 1 tumours with maximum diameter 15mm, which are strongly ER/PR+ve and HER2-ve, with negative clinical/radiological axillary staging. Patients are randomised 2:1 in favour of VAE or surgery;with no axillary surgery in the VAE arm. Completeness of excision is assessed radiologically, and if excision is incomplete, patients undergo open surgery. Adjuvant radiotherapy and endocrine therapy are mandated in the VAE arm but may be omitted following surgery. Co-primary end-points are: 1. Noninferiority comparison of the requirement for a second procedure following excision 2. Single arm analysis of local recurrence (LR) at 5 years following VAE Recruitment of 800 patients will permit demonstration of 10% non-inferiority of VAE for requirement of a second procedure. This ensures sufficient patients for single arm analysis of LR rates, where expected LR free survival is 99% at 5 years, with an undesirable survival probability after VAE of 97%. To ensure that the trial as a whole only has 5% alpha, the significance level for each co-primary outcome is set at 2.5% with 90% power. The Data Monitoring Committee will monitor LR events to ensure these do not exceed 3% per year. Secondary outcome measures include time to ipsilateral recurrence, overall survival, complications, quality of life and health economic analysis. A novel feature of SMALL is the integration of a QuinteT Recruitment Intervention (QRI), which aims to optimise recruitment to the study. Recruitment challenges are identified by analysing recruiter/patient interviews and audiorecordings of trial discussions, and by review of trial screening logs, eligibility and recruitment data and study documentation. Solutions to address these are developed collaboratively, including individual/group recruiter feedback and recruitment tips documents. Result(s): SMALL opened in December 2019, but recruitment halted in 2020 for 5 months due to COVID-19. At 7st July 2022, 142 patients had been randomised from 26 centres, with a randomisation rate of approximately 45%, and a per site recruitment rate of 0.4-0.5 patients/month, approaching the feasibility recruitment target of 144 patients. Drawing from preliminary QRI findings and insights from patient representatives, a recruitment tips document has been circulated (on providing balanced information about treatments, encouraging recruiters to engage with patient preferences, and explaining randomisation). Individual recruiter feedback has commenced, with wider feedback delivered across sites via recruitment training workshops. Conclusion(s): Despite pandemic-related challenges, SMALL has an excellent recruitment rate to date and is expected to have a global impact on treatment of breast cancer within mammographic screening programmes.

Neurovirulence of SARS CoV2: From Clinical Data to Preclinical Neu-ropsychological Exploration

Introduction: COVID-19 pandemic represents a major health issue caused by SARS CoV2, a human coronavirus. Since the outbreak of this pandemic, the literature on SARS CoV-2 has grown differentially, with increased awareness of extra-respiratory symptoms, including neurological symptoms. Method(s): Review based on studies published from December 2019 to June 2020. Results and Discussion: This review discusses the neurological aspect of SARS CoV2, including the suggested mechanism involved. Neurological disorders are cited in addition to emerging experimental models with viral involvement. Conclusion(s): There is a need for further investigation to clarify how it can lead to the onset of acute and chronic neurological disorders, mentioning the importance of experimental studies in neuropsy-chopharmacology.Copyright © 2022 Bentham Science Publishers.

Anastrozole dose escalation for optimal estrogen suppression in postmenopausal early stage breast cancer: A prospective trial

Introduction: We performed matched case-control studies utilizing cohorts of postmenopausal women with ER+ breast cancer receiving adjuvant aromatase inhibitors (AI) on MA.27 [anastrozole, exemestane] or PreFace [letrozole] to assess the association between estrogen suppression after 6 months of treatment and an early breast cancer (EBC) event within 5 years of AI initiation (Clin Cancer Res 2020;26:2986-98). We found a significant 3.0-fold increase in risk of an EBC event for those taking anastrozole with levels of estrone (E1) >=1.3 pg/mL and estradiol (E2) >=0.5 pg/mL, but not for exemestane or letrozole. Given these findings we designed a prospective pharmacodynamic (PD) study to evaluate the impact of anastrozole (1 mg/day: ANA1) on E1 and E2 levels, and among those with inadequate estrogen suppression (IES: E1 >=1.3 pg/mL and E2 >=0.5 pg/mL), to evaluate the safety and PD efficacy of high-dose anastrozole (10 mg/day: ANA10), which has been found to be safe in prior clinical trials (Cancer 1998;83:1142-52). Method(s): Post-menopausal women with stage I-III, ER >=1% positive/HER2-negative breast cancer who were candidates for anastrozole were eligible after completion of locoregional therapy and chemotherapy, as clinically indicated. Women who were pre-menopausal at diagnosis were not eligible. All patients received 8-10 weeks of ANA1, after which those with adequate estrogen suppression (AES: E1< 1.3 pg/mL or E2< 0.5 pg/mL) came off study. Those with IES went on to receive ANA10 for 8-10 weeks, followed by letrozole (2.5 mg/day: LET) for 8-10 weeks. All patients were managed at their treating oncologist's discretion following study discontinuation. E1 and E2 blood levels were measured pre-treatment and after completion of each treatment cycle by a CLIA-approved liquid chromatography with tandem mass spectrometry in the Immunochemical Core Laboratory at Mayo Clinic. With a sample size of 29 patients with IES after ANA1, a one-sided binomial test of proportions with a significance level of 0.05 will have an 87% chance of rejecting the proportion with AES after ANA10 is at most 25% (Ho) when the true proportion is at least 50%. Specifically, the null hypothesis is rejected if the number of women with AES after ANA10 is 12 or more. Data lock was July 6, 2022. Result(s): Of the 161 women enrolled from April 2020 through May 2022, 3 withdrew consent prior to start of ANA1 and 2 were ineligible;thus, 156 women comprised the study cohort. Median patient age was 64 years (range 44-86), 10% of patients were of Hispanic ethnicity and/or non-white race, and 15% received chemotherapy. Six patients remain on ANA1, and 10 discontinued ANA1 due to refusal (7), adverse event (AE) (2), or COVID-19 (1). Forty-one of the remaining 140 patients (29.3% 95%CI: 21.9- 37.6%) had IES with ANA1. Nine of these 41 patients did not go on to ANA10 due to refusal (6) or AE (3). Of the 32 patients who started ANA10, 8 remain on treatment, 5 discontinued due to refusal (3) or AE (1-grade 2 urinary tract infection;1-grade 1 palpitations), and 19 had a blood draw 45 days or more after starting ANA10. No grade 3-5 AEs or grade 2 hot flashes or arthralgias were reported. Of these 19 patients, 14 achieved AES with ANA10 (73.7% 95%CI: 48.8-90.9%). All 19 patients switched to LET of which 3 remain on treatment, 1 is missing E1/E2 data, and 15 had a blood draw 45 days or more after starting LET. Of these 15 patients, 10 maintained AES, 2 acquired AES with LET, and 3 no longer had AES. Anastrozole and letrozole drug levels will be reported at the meeting. Conclusion(s): Approximately 29% of postmenopausal women with ER+/HER2- BC receiving adjuvant anastrozole 1 mg/daily had IES. A majority of these patients achieved AES with dose escalation to ANA10 without tolerability issues. E1 and E2 levels are logical biomarkers given the mechanism of action of anastrozole, and further study utilizing them to determine the optimal dose of anastrozole for a given patient should be performed.

Cyclin-dependent kinase 4/6 inhibitor in advanced breast cancer during the COVID pandemic period: efficacy in relation to vaccination for SARS-COV 19

Introduction: More than 2 years after the WHO declaration of a pandemic, SARS-Cov-2 still represents a public health problem The pandemic has increased the complexity of cancer treatments including breast cancer. These difficulties were highlighted in adjuvant treatments but above all in metastatic disease. Vaccination has been one of the most important public health factors that has reduced deaths, hospitalizations and the severity of symptoms related to infection. In metastatic breast cancer hormone receptor positive and HER2/neu negative currently the first line of treatment is given by the association between cyclin 4/6 inhibitors and hormone therapy (aromatase inhibitors or fulvestrant) A well-known and frequent side effect of this therapy is the reduction of white blood cell values and neutrophils. The hypothesis that this study is to evaluate whether treatment with cyclin inhibitors initiated before the period of vaccinations may have influenced, due to the reduction in white blood cell values, an increased risk of infection in these patients. Material(s) and Method(s): In our study, we selected patients who had started treatment with cyclin inhibitors before starting the vaccination cycle (in Italy up to the fourth dose in cancer patients) and continue it without evidence of disease progression. All patients were offered a vaccination cycle with mRNA COVID vaccines and were followed during their cancer treatments. All patients, at least 90 days after the last dose of vaccine, have been tested for antibodies against SARS CoV-2 (trimeric spike protein) with a value expressed in binding antibodies unit (BAU) according to international standard WHO During the observation period (starting from the first dose of vaccine administered) the patients were clinically checked and in case of suspicion of infectious pathology with symptoms suggestive of SARS-COV-19 infection, they were tested with molecular swab Results: We evaluated 52 patients who started cyclin treatment before the vaccination course and who are currently without signs of disease recurrence During the study period we found 14 SARSCOV19 infections (28% of patients) and one patient with two infectious episodes. No patients needed treatment in a hospital or resuscitation setting. All patients have fully recovered from the infection and at most after 21 days have resumed the treatment still in place Statistically, a linear regression calculation was applied to evaluate a functional relationship between variables measured on the basis of sample data. We did not find a relationship between spikes or infections compared to the start date of the vaccination cycle;instead we observed a relationship between the value of the spike and the date of last immunization (considered as an active infection or fourth dose of vaccine) with a reduction in the values the further you go away Conclusion(s): The data of the study show that there is a correlation between the time elapsed between the last vaccination and the risk of getting sick. For this reason, the fourth recall represents a strong help to reduce this risk. We did not find any ranges we could refer to regarding the dosage of trimeric spike protein. Considering the positivity rate of infections that does not exceed the general vaccinated population and the absence of serious infectious symptoms with hospitalization, treatment with cyclin inhibitors appears to be a safe treatment even in a pandemic period. (Table Presented).

Twitterchats as a means to educate patients with CRC and caregivers and stimulate collaborations

Background: During the COVID-19 pandemic, Twitter has been instrumental in accelerating knowledge dissemination and forging collaborations within the medical community and amongst patient advocates. Tweetchats within Twitter are scheduled conversations on a specific topic. In oncology, Tweetchats have been used by cancer advocates to spread awareness and for patient and caregiver education. A colorectal cancer (CRC) specific tweetchat did not previously exist. This describes the creation, and experiences with a CRC specific tweetchat. Method(s): The #CRCTrialsChat tweetchat was created by a patient advocate for colorectal cancer patients, caregivers and clinicians to meet and exchange clinical trial-related information. Two gastrointestinal (GI) medical oncologists and two radiation oncologists were enlisted as moderators. The topic for each session is chosen by the patient advocate, who creates an outline and divides the content, which is designed to last a one hour session. The idea is to create engaging, technical, but easy to understand content. Each moderator then works on the answers to their assigned section, which is edited to fit tweet character limit. Sessions may also have guest moderators with expertise on a specific topic. Through tweeting, moderators answer specific questions that come up during the session and later. Result(s): To date, we have had four sessions covering the following topics: Clinical trial basics, CRC Updates from ASCO22, ClinicalTrialFinders and BRAF-mutated tumors. The content created has been simple and engaging, the format has functioned smoothly, and the reach of #CRCTrialsChat has been steadily increasing. After the most recent session on BRAF in September 2022, the @CRCTrialsChat has 281 followers, 17K impressions and 14.6K profile visits, a reflection of its excellent content. From a clinician perspective, this is a great format to interact with colleagues, discuss enrolling trials and also become familiar with using Twitter. Conclusion(s): A CRC clinical trial focused tweetchat is an engaging way to deliver trial-related content to an audience of clinicians, patients and caregivers. The current format appears to be an effective way to create and disseminate information. Future sessions will focus on ctDNA, molecular markers such as KRAS and HER2, and rectal cancer trials. Our hope is that #CRCTrialsChat will stimulate continued patient and clinician engagement, increase awareness of clinical trials, enhance trial participation and initiate patient-centric research and collaborations.

Treatment of HER2-positive (HER2+) hormonereceptor positive (HR+) metastatic breast cancer (mBC) with the novel combination of zanidatamab, palbociclib, and fulvestrant

Background: HER2+ mBC remains incurable, with a need for new HER2-directed therapies and regimens, including chemotherapy-free options. Zanidatamab (zani) is a novel HER2-targeted bispecific antibody that binds HER2 in a unique trans configuration, driving multiple mechanisms of antitumor activity, including complement-dependent cytotoxicity. A CDK4/6 inhibitor combined with endocrine therapy is an approved treatment for HER2-negative/HR+ mBC and this combination has also demonstrated encouraging antitumor activity when paired with HER2-targeted therapy(ies) in HER2+/HR+ mBC. Here, we report results from ZWI-ZW25-202 (NCT04224272), an ongoing singlearm phase 2 study of zani combined with palbociclib (palbo) and fulvestrant (fulv) in pts with HER2+/HR+ mBC. Method(s): Eligibility requirements include: HER2+/HR+ unresectable, locally advanced BC or mBC;ECOG PS of 0 or 1;prior treatment with trastuzumab, pertuzumab and T DM1 (additional prior HER2-targeting agents are permitted);and no prior treatment with CDK4/6 inhibitors. Part 1 of the study evaluated the safety and tolerability of the zani/palbo/fulv combination and determined the recommended doses for use in Part 2, where the antitumor activity of the combination is being evaluated. Endpoints include safety outcomes, progression-free survival at 6 months (PFS6), confirmed objective response rate (cORR) per RECIST v1.1;disease control rate (DCR=complete response [CR] plus partial response [PR] plus stable disease [SD]);duration of response (DOR);PFS;and overall survival. Result(s): As of 24 Feb 2022, 34 pts (33 HER2+/HR+ per central analysis) with a median age of 52 (range 36-77) have been treated. In the metastatic setting, pts had received a median (range) of 4 (1-10) prior systemic regimens, including 3 (1-8) different prior HER2 targeted therapies, and 1 (0-4) endocrine therapy. Seven pts (20%) had prior T DXd treatment and 7 pts had prior fulv treatment. All pts received zani (20 mg/kg Q2W) and standard doses of palbo and fulv. Eighteen pts (53%) remained on treatment;median duration of zani treatment was 6.9 mo (range 0.5- 16.3). A dose-limiting toxicity (DLT) of neutropenia occurred in 1 of 7 DLT-evaluable pts in Part 1. Among all pts (n=34), the most common (>20%) treatment (zani, palbo and/or fulv)-related adverse events (TRAEs) were diarrhea (74%), neutrophil count decreased/neutropenia (62%), stomatitis (41%), asthenia (26%), nausea (24%), and anemia (21%). Grade (Gr) >=3 TRAEs in 2 or more pts included neutrophil count decreased/neutropenia (50%), anemia (6%), diarrhea (6%), and thrombocytopenia (6%). AEs of special interest were all Gr <=2 and included 4 pts with cardiac events (LVEF decrease of >=10% from baseline) and 1 pt with infusion-related reaction. There were no treatment-related serious AEs. Palbo was discontinued for 1 pt due to an AE (AST increase);no pt discontinued zani treatment as a result of AEs. Two deaths occurred: 1 due to disease progression and 1 due to an unrelated AE of pneumonia caused by COVID-19. In 29 pts with measurable disease, the cORR was 34.5% (95% CI: 17.9, 54.3), all responses were cPRs, of which 1 is pending CR confirmation. DOR ranged from 2.3 to 14.9+ mo, with 8 confirmed responses ongoing, and the DCR was 93.1% (95% CI: 77.2, 99.2). Interim median PFS was 11.3 mo (range 0.03-16.7;95% CI: 5.6, not estimable). PFS6 analysis is planned following the completion of enrollment. Conclusion(s): Zani in combination with palbo and fulv shows encouraging antitumor activity with durable responses in heavily pretreated pts and a manageable safety profile. This regimen has the potential to be a chemotherapy-free treatment option in pts with HER2+/HR+ mBC. Enrollment in the study is continuing.

The Psychological Impacts of COVID-19 on Breast Cancer Patients in China

Background: Approximately 30% to 50% of breast cancer patients experienced mental distress prior to the advent of COVID.The delayed access to cancer treatment due to the outbreak of COVID -19 pandemic posed a unique challenge to breast cancer patients and caused a significant level of mental distress among them. In the current research, we examined the psychological impacts of COVID on breast cancer patients in China using Symptom Checklist-90-R (SCL-90-R). Method(s): Participants were breast cancer patients at the outpatient clinic of Xijing hospital. The study was conducted virtually, and the questionnaires were distributed via Wenjuanxing, the Chinese alternative of Qualtrics. The researchers were healthcare workers affiliated with Xijing hospital, and the survey was sent to a breast cancer patient support group which included 1399 cancer patients and 6 healthcare workers. The initial sample consisted of 199 participants who signed an informed consent form to participate in the study. The inclusion criteria were as follows: 1) diagnosed with breast cancer, 2) aged 18 years or above, and 3) had no history of cognitive impairment or previous diagnosis of psychiatric disorders. The validated Mandarin version of the SCL-90-R (Wang, 1984) was then given to the participants to evaluate their psychological status.Categorical variables were summarized as numbers and percentages;continuous variables were described as mean (M) +/- standard deviation (SD). Data were analyzed using IBM SPSS Statistics Version 26. Result(s): Participants (N = 195) filled out the SCL-90 questionnaire in February, 2020. All participants were female breast cancer patients treated at Xijing hospital, among which 16.41%, 36.41%, 19.49%, and 28.21% had respectively received treatment for less than a year, 1-3 years, 3-5 years, and 5 years or more. 64.62% of the patients were at stage I;0.77% were at stage II and III;4.62% were at stage IV according to TNM classification. The molecular type of participants is as follows: 47.2% of ER+ HER2-, 31.8% of HER2+, and 21.0% of Triple negative.Participants whose treatments continued to be delayed, on average, reported an elevated general psychopathology score (M = 1.48, SD = 0.47) compared to participants whose treatments were resumed (M = 1.30, SD = 0.34), and the difference was statistically significant, t(193) = 2.96, p = .003, d = 0.44, 95%Cl [0.06, 0.30]. The one-way ANOVA revealed a marginally significant effect of length of treatment delay on general psychopathology score, F(4, 190) = 2.09, p = .08, eta2 = .04. Follow-up multiple comparison analysis showed that participants who had their treatment delayed for 3 weeks to 1 month (M = 1.70, SD = 0.70) reported significantly higher general psychopathology scores than participants whose delay in treatment was less than 1 week (M = 1.34, SD = 0.40), p = .05. General health status (p < .001) and current treatment status (p = .02) are the only two variables that were statistically associated with general psychopathology score.Poorer perceived health status and current delay in treatment were associated with higher general psychopathology score, Additionally, younger age was associated with higher interpersonal sensitivity (p = .01) and hostility (p = .006). Conclusion(s): We found that breast cancer patients at an advanced stage were more likely to experience psychological symptoms with longer treatment delay, and whose treatments continued to be delayed reported elevated psychological symptoms than individuals whose treatment were resumed, regardless of treatment type. Additionally, a treatment delay of more than three weeks might have exacerbated breast cancer patients' psychological symptoms, whereas a short-term delay of less than three weeks was less likely to have a significant effect on one's mental wellbeing.

Evaluation of risk factors for barotrauma complications in COVID-19 patients treated with high flow nasal cannula (HFNC)

Aim: To evaluate risk factors for barotrauma development in COVID-19 patients treated with HFNC. Method(s): 34 COVID-19 patients are studied retrospectively, 24 males, mean age 61,74 years. Symptoms (dyspnoea, cough, fever, hemoptoe, fatigue), comorbidities (arterial hypertension (AH), COPD, asthma, diabetes, heart and kidney diseases, bronchiectasis), blood tests (total blood count, neutrophils to lymphocytes (Neu:Ly) ratio, lactate dehydrogenase (LDH), ferritin, interleukin-6, C-reactive protein), chest X-ray findings at admission are assessed. Need for oxygen therapy (ambient air, low flow therapy, HFNC) during the hospitalisation, barotrauma development (pneumothorax (PT), pneumomediastinum (PM), subcutaneous emphysema (SE)) and disease outcome are analysed. Result(s): Age decrease by 1 year leads to increased risk of SE by 17% (hazard ratio (HR)0.852,p=0.018). LDH increase by 1 U/l leads to 0.4% increased risk of SE (HR1.004,p=0.020). Age and LDH level are proved as risk factors for SE. AH increases the risk of PM by 27.5% (HR1.275,p=0.087). Ferritin increase by 1 ug/l leads to 0.2% higher risk of PT (HR1.002,p=0.019). Multivariate model reveals AH (HR1.777,p=0.057) and ferritin level (HR1.004,p=0.013) as risk factors for barotrauma. Multivariate model shows LDH (HR1,003,p=0,023), ferritin (HR1,004,p=0,007), and Neu:Ly (HR1,123,p=0,059) as main risk factors for PT,PM, SE. Dyspnoea increases the death risk 11 times (HR11.2,p=0.034) while LDH increase by 1 U/l leads to 0.1% increased death risk (HR1.001,p=0.087). Conclusion(s): AH, age, ferritin, LDH, Neu:Ly levels are proved as risk factors for PT, PM and SE. Dyspnoea is a risk factor for death outcome.

Effect of a 12 Week Virtual Supervised Exercise Program on Cardiorespiratory Fitness in Breast Cancer Patients Undergoing Chemotherapy: Results from the STRENGTH Trial

Background: Chemotherapy (CTX) for breast cancer (BC) can have a detrimental effect on cardiorespiratory fitness (CRF), as measured by VO2max. This decline may be attenuated by physical activity, which can also reduce mortality risk and improve quality of life (QoL) for patients (pts) with BC. During the COVID-19 pandemic, many have pivoted to home-based exercise routines, which have been shown to be safe and feasible for pts with BC receiving CTX. We conducted the STRENGTH Trial to evaluate the effect of a 12-week virtual supervised exercise program in BC pts receiving CTX on CRF. Method(s): This is a single-center, prospective, single-arm study designed to evaluate the effect of a 12-week virtual supervised exercise training program on CRF in BC pts receiving CTX. Participants aged >=18 years with stage I-IV BC who were planned to receive at least 12 weeks of CTX of investigator's choice were eligible for inclusion. Participants were asked to complete a total of 150 minutes (min) of moderate intensity physical activity/week, as a combination of a 45 min weekly virtual personal training session and workout classes streamed from the Peloton Digital platform (i.e. walking, running, cardio, yoga, strength training, and cycling). The primary endpoint was the distance walked on a Six-Minute Walk Test (6MWT), an accepted surrogate marker for VO2max, at the start and completion of the program. Secondary endpoints included assessment of QoL using the Functional Assessment of Cancer Therapy - General (FACT-G) and symptom assessment using the MD Anderson Symptom Inventory (MDASI) questionnaires at the beginning, middle and end of the study. Exploratory endpoints included treatment adherence, toxicities, completion and response. Result(s): 33 participants signed consent for the clinical trial and 2 withdrew voluntarily prior to beginning the program. 5 participants discontinued prematurely due to a diagnosis of COVID-19 (N=3) and pulmonary embolism (N=2) and were not included in the primary endpoint. One participant remains on study at this time. Median age 49 yrs;range 33-68. Mean BMI 29.55;range 18.1-46.5. 13 HR+/HER2-, 7 HR-/HER2-, 11 HER2+. 14 (45%) pts had Stage I, 11 (35%) pts had Stage 2, 5 (16%) pts had Stage 3, 1 (3%) pt had Stage 4. 23 pts (70%) received either an anthracycline or HER2-based therapy. 19 pts (61%) received neoadjuvant CTX on study, 11 pts (35%) received adjuvant CTX and 1 pt (3%) received treatment in metastatic setting. The average number of exercise min per week per participant was 123.2 min (95% CI, 104.1-142.2), with a relative dose intensity of 82%. In the pts that completed the study thus far (N=25), there was no statistically significant difference between the distance walked during the 6MWT at the start and end of the study (median difference= -10m, range: -129-150m, p= 0.67). There was no statistically significant difference in the FACT-G score at the start and end of the study (median difference= -1.0, range -17.83- 30.0, p=0.54). Pts scored higher on the MDASI (median difference= 0.33, range -1.55-4.62, p=0.04) at the end of the exercise program compared to the beginning. There were no new or unexpected treatment toxicities observed. Conclusion(s): Pts who participated in a 12-week virtual supervised exercise program during CTX for BC did not experience a statistically significant difference in the distance walked during the 6MWT between the beginning and end of the exercise program. Exercise may attenuate the decline in cardiorespiratory function that has historically been observed with CTX for BC. Some pts were not able to adhere to the recommended 150 min of exercise/week suggesting a potential need for modified exercise targets for pts with BC undergoing CTX. This study is limited by a small sample size and larger, randomized clinical trials are needed to further evaluate optimal exercise recommendations for patients with BC undergoing CTX in order to maintain and potentially, even improve, cardiorespiratory function.

OPTIMA, a prospective randomized trial to validate the clinical utility and cost-effectiveness of gene expression test-directed chemotherapy decisions in high clinical risk early breast cancer

Background: Multi-parameter tumor gene expression assays (MPAs) are used to estimate individual patient risk and guide chemotherapy use in hormone-sensitive, HER2-negative early breast cancer. The TAILORx trial supports MPA use in a node-negative population. Evidence for MPA use in postmenopausal node-positive breast cancer has been provided by the RxPONDER trial interim analysis but this relies on the absence of superiority in an analysis where >50% of events were unrelated to breast cancer. There is much uncertainty about MPA use for premenopausal patients. OPTIMA (Optimal Personalised Treatment of early breast cancer usIng Multi-parameter Analysis) (ISRCTN42400492) is a prospective international randomized controlled trial designed to validate MPAs as predictors of chemotherapy sensitivity in a largely node-positive breast cancer population. Method(s): OPTIMA is a partially blinded study with an adaptive two-stage design. The trial recruits women and men age 40 or older with resected ER-positive, HER2-negative invasive breast cancer and up to 9 involved axillary lymph nodes. Randomization is to standard management (chemotherapy and endocrine therapy) or to MPA-directed treatment using the Prosigna (PAM50) test. Those with a Prosigna tumor Score (ROR-PT) >60 receive standard management whilst those with a low score (<=60) tumor are treated with endocrine therapy alone. Endocrine therapy for premenopausal women includes ovarian suppression for all participants unless they experience a chemotherapy-induced menopause. Adjuvant abemaciclib is permitted. The trial will be analyzed for (1) non-inferiority of recurrence according to randomization and (2) cost-effectiveness. The key secondary outcome is non-inferiority of recurrence for patients with low ROR-PT score tumors. The efficacy analyses will be performed Per Protocol using Invasive Breast Cancer Free Survival (IBCFS) as the primary outcome measure to limit the risk of a false non-inferiority conclusion. Recruitment of 4500 patients over 8 years will permit demonstration of up to 3% non-inferiority of test-directed treatment with at least 83% power, assuming 5-year IBCFS is 87% with standard management. An integrated qualitative recruitment study addresses challenges to consent and recruitment, building on experience from the feasibility study which found that a multidisciplinary approach is important for recruitment success. OPTIMA is strongly supported by a patient group which has helped design all patient documents and which is represented on the TMG. Result(s): The OPTIMA main trial opened in January 2017 and has continued to recruit throughout the COVID-19 pandemic. Overall recruitment as of 1 July 2022 was 2814 (2593 from UK, 221 from Norway). Patient characteristics are well balanced between the trial arms. Currently 95% of randomized participants are eligible for inclusion in the PP analysis. 66% of the MPA-directed arm participants have been allocated to endocrine therapy only. The test failure rate is < 1%. Conclusion(s): OPTIMA will provide robust unbiased evidence on test-directed chemotherapy safety for both postmenopausal and premenopausal women with 1-3 involved nodes as well as for patients with 4-9 involved nodes and for patients treated with abemaciclib.

Trastuzumab deruxtecan (T-DXd) + durvalumab (D) as first-line (1L) treatment for unresectable locally advanced/metastatic hormone receptor-negative (HR-), HER2-low breast cancer: updated results from BEGONIA, a phase 1b/2 study

Background: Patients with HR- advanced/metastatic breast cancer (a/mBC) with a low level of HER2 (immunohistochemistry [IHC] score 1+ or IHC 2+ and negative in situ hybridization [ISH]) have poor prognosis. Combining 1L chemotherapy with immune checkpoint inhibitors can modestly improve outcomes vs chemotherapy alone, but treatment benefit is largely seen in patients with PD-L1+ disease. BEGONIA (NCT03742102) is an ongoing 2-part, open-label platform study, evaluating safety and efficacy of D, an anti-PD-L1 antibody, combined with other novel therapies in 1L triple-negative a/mBC, including HR-, HER2-low disease. T-DXd is a trastuzumab-topoisomerase I inhibitor antibody-drug conjugate that improves survival in patients with previously treated HR-, HER2-low mBC (NCT03734029;Modi NEJM 2022). Here, we report updated results of the T-DXd + D combination from BEGONIA. Method(s): Patients with unresectable HR-, HER2-low (per local testing, IHC 2+/ISH-, IHC 1+/ISH-, or IHC 1+/ISH untested) a/mBC were enrolled in the T-DXd + D arm. Patients eligible for 1L treatment, regardless of PD-L1 status, received intravenous T-DXd 5.4 mg/kg + D 1120 mg every 3 weeks until progression or unacceptable toxicity. PD-L1, assessed using the VENTANA PD-L1 (SP263) Assay, was defined as high if >= 5% of the tumor area was populated by PDL1-expressing tumor or immune cells. Primary endpoints were safety and tolerability. Secondary endpoints included investigator-assessed objective response rate (ORR;RECIST v1.1);progressionfree survival [PFS];and response duration. Patients included in the efficacy analysis had >= 2 ontreatment disease assessments, progressed, died, or withdrew from the study. Result(s): As of April 8, 2022, 56 patients received T-DXd + D (34 ongoing) and 46 were included in the efficacy analysis. Median (range) follow-up was 10.1 (0-22) months. Median age was 53.5 years, 71% had received prior treatment for early stage BC, and 64% had visceral metastases at baseline. Confirmed ORR was 26/46 (57% 95% CI, 41-71) and unconfirmed ORR was 33/54 (61% 95% CI, 47-74);1/46 patients (2%) had complete and 25/46 (54%) had partial responses. Confirmed response occurred irrespective of PD-L1 expression (PD-L1 high ORR, 5/7 [71%];PD-L1 low, 13/21 [62%];PD-L1 missing, 8/18 [44%]). Median duration of response was not reached;however, 64% of patients remained in response at 12 month follow-up and 73% had an ongoing response at data cutoff. Median PFS was 12.6 months (95% CI, 8-not reached). Adverse events (AEs) were consistent with the agents' known safety, with treatment-related AEs occurring in 49 patients (88%), any Grade 3/4 AEs in 18 patients (32%), and any serious AEs in 10 patients (18%). The most common all-Grade AEs were nausea (41 [73%]), fatigue (26 [46%]), and vomiting (17 [30%]). Adjudicated treatment-related interstitial lung disease/pneumonitis occurred for 5 patients (9%), which were mostly Grade 1 or 2 and 1 case of Grade 5 associated with COVID pneumonia. Seven patients (13%) and 21 patients (38%) had T-DXd dose reduction and dose delay, respectively;22 (39%) had D dose delay. Seven patients (13%) discontinued treatment due to AEs. Conclusion(s): For patients with HR-, HER2-low a/mBC, T-DXd in combination with D in the 1L setting shows manageable safety and promising efficacy including durable responses and an encouraging PFS. Although subgroups were small, responses were observed irrespective of PD-L1 expression. Analysis of additional translational data is ongoing. Funding(s): AstraZeneca/Daiichi Sankyo.