Audio Journal of Oncology Podcast

Audio Journal of Oncology interview with: Bart Neyns MD PhD, Vrije Universiteit Brussel, Faculty of Medicine and Pharmacy, Medical Oncology Department, Brussels, Belgium  BARCELONA, Spain—Intracranial administration of autologous dendritic cells was combined with combination checkpoint inhibition in a phase 1 study of patients with recurrent glioblastoma that reported marked clinical responses to the European Society for Medical Oncology (ESMO) annual meeting in Barcelona. Cells harvested from each patient were injected directly into the brain tissue resection cavity lining after surgery. Patients also received intra-cranial injections of the checkpoint inhibitor combination: nivolumab plus ipilimumab. At the conference, Peter Goodwin discussed the research with lead author of the study, Bart Neyns MD PhD, Head of Medical Oncology at the Vrije Universiteit, Brussel, in the University Hospital Brussels Faculty of Medicine & Pharmacy, Brussels, Belgium. Audio Journal of Oncology interview with: Bart Neyns MD PhD, Vrije Universiteit Brussel, Faculty of Medicine and Pharmacy, Medical Oncology Department, Brussels, Belgium IN : “Patients with recurrent glioblastoma ….  OUT:…from me, Peter Goodwin, goodbye 10:54 secs SOURCE: ESMO 2024 Barcelona ESMO Abstract 441O Neyns , Medical Oncology Department, Vrije Universiteit Brussel – Faculty of Medicine & Pharmacy, Brussels, Belgium “A phase I clinical trial on the intracranial administration of autologous CD1c(BDCA-1)+/CD141(BDCA-3)+ myeloid dendritic cells (myDC) in combination with ipilimumab (IPI) and nivolumab (NIVO) in patients with recurrent high-grade glioma (rHGG)” Reference: CNS tumours Volume 35, Supplement 2S406-S407 September 2024Authors: Neyns1 ∙ I. Dirven1 ∙ L. Lescrauwaet2 ∙ M. Cammaert1 ∙ W. Geens2 ∙ X. Geeraerts1 ∙ L. Stevens1 ∙ S. Brock3 ∙ M. Kockx4 ∙ H. Everaert5 ∙ A-M. Van Binst6 ∙ S. Tuyaerts1 ∙ J. Duerinck7 1. Medical Oncology Department, Vrije Universiteit Brussel – Faculty of Medicine & Pharmacy, Brussels, Belgium 2. Neurosurgery, UZ Brussel – Universitair Ziekenhuis Brussel, Jette, Belgium 3. Pathology, UZ Brussel – Universitair Ziekenhuis Brussel, Jette, Belgium 4. Pathology Department, CellCarta, Antwerpen, Belgium 5. Nuclear Medicine, Vrije Universiteit Brussel – Faculty of Medicine & Pharmacy, Brussels, Belgium 6. Radiology Department, Vrije Universiteit Brussel – Faculty of Medicine & Pharmacy, Brussels, Belgium 7. Neurosurgery Department, Vrije Universiteit Brussel – Faculty of Medicine & Pharmacy, Brussels, Belgium https://www.audiomedica.com/wp-content/2025/09/241011-Bart-Neyns-ESMO-AJO-PRODUCTION-MASTER.mp3Background Intracranial admin of NIVO and IPI following the resection of rHGG is safe and has resulted in encouraging survival (J Duerinck et al. JITC 2021). myDC play a pivotal role in initiating an adaptive anti-tumor immune response and licensing of immune anti-tumor effector cells within the tumor microenvironment. Methods rHGG pts (after prior RT and TMZ, <8 mg methylprednisolone QD), underwent a leukapheresis followed by isolation/cryopreservation of myDC. NIVO (10 mg IV) was administered preoperatively. myDC (5-, 10-, or 20.106 cells) were injected into the brain tissue lining the resection cavity (iCer) following a maximal safe resection (MSR) or intratumorally (iTum) following a stereotactic biopsy (STX). IPI (5 mg) plus NIVO (10 mg) were co-injected iCer or iTum with the myDC. Postoperative NIVO was administered intracavitary (iCav, 10 mg) and intravenously (IV, 10 mg) Q2w (max 11x). Results 21 pts (13 M; med 49 y [range 20 -78]; IDHwt 17 pts, ECOG PS 0 or 1: 18-, 3 pts) underwent procurement of myDC; intraoperative administration of myDC was preceded by MSR in 19 pts, and STx in 2 pts. Respectively 6, 3, and 12 pts were treated at the 3 myDC dose levels. All pts received the peri-op iTum/iCer/IV-admin of IPI and NIVO as planned. The median postop iCav and IV NIVO-admin was 7 (range 0-11) and 8 (0-11). Study treatment was discontinued early for PD in 9- and AE in 3 pts. Most important TRAEs: bacterial colonization of the Ommaya reservoir (n=4), craniotomy wound dehiscence (n=2), and bacterial meningitis (n=1). At DBL (01MAY2024), 6 pts (29%) remain progression-free (incl. 3 pts with >2y PFS). PFS (med. 24w [95% CI 8- 39]) is superior when compared to the pts (n=70) with resectable rHGG treated in 4 other cohorts of the GlITIpNi trial (p=0.003). When including the durable benefit from bevacizumab at first PD in 3 pts, PFS compared favorably to a historical pooled cohort (n=469) of rHGG treated with VEGF(R)-inhibitors (p=0.007). The 1-year OS-rate was 50% [95% CI 24-76]. Conclusions Intracranial administration of myDC combined with IPI/NIVO is feasible, safe and associated with encouraging survival, deserving further investigation.          

An interview with: Victor Velculescu MD PhD, Co-director, Cancer Genetics & Epigenetics Program, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. SAN DIEGO, USA—A blood test using an artificial intelligence DNA pattern recognition system that brings earlier, more certain detection of ovarian cancer was reported at the American Association for Cancer Research Annual Meeting held in San Diego. The test analyses patterns of fragments of circulating DNA (called DNA fragmentomes). When combined with analysis of circulating tumor protein markers these were found to be highly correlated with ovarian cancer. The test uses the DELFI (DNA Evaluation of Fragments for early Interception) system that has already been established for early detection of lung cancer. At the San Diego conference lead author of the research, Victor Velculescu MD PhD, Co-director, Cancer Genetics & Epigenetics Program, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland discussed the findings with Peter Goodwin. AUDIO JOURNAL OF ONCOLOGY with: Victor Velculescu MD PhD. IN: “Hello, Peter Goodwin here …..OUT:  ……..for the Audio Journal of Oncology, I’m Peter Goodwin”   13:49secs 2024 AACR ABSTRACT: Abstract 773: Early detection of ovarian cancer using cell-free DNA fragmentomes  AUTHORS: Akshaya V. Annapragada; Jamie E. Medina; Victor E. Velculescu et al. https://aacrjournals.org/cancerres/article/83/7_Supplement/773/719566/Abstract-773-Early-detection-of-ovarian-cancer https://pubmed.ncbi.nlm.nih.gov/39345137/ Early Detection of Ovarian Cancer Using Cell-Free DNA Fragmentomes and Protein Biomarkers Jamie E Medina # 1, Akshaya V Annapragada # 1, Pien Lof 2, Sarah Short 1, Adrianna L Bartolomucci 1, Dimitrios Mathios 1, Shashikant Koul 1, Noushin Niknafs 1, Michaël Noë 1, Zachariah H Foda 1, Daniel C Bruhm 1, Carolyn Hruban 1, Nicholas A Vulpescu 1, Euihye Jung 3, Renu Dua 1, Jenna V Canzoniero 1, Stephen Cristiano 1, Vilmos Adleff 1, Heather Symecko 4, Daan van den Broek 5, Lori J Sokoll 1, Stephen B Baylin 1, Michael F Press 6, Dennis J Slamon 7, Gottfried E Konecny 7, Christina Therkildsen 8, Beatriz Carvalho 9, Gerrit A Meijer 9, Claus Lindbjerg Andersen 10 11, Susan M Domchek 3 4, Ronny Drapkin 3 4, Robert B Scharpf 1, Jillian Phallen 1, Christine A R Lok 2, Victor E Velculescu 1 Affiliations 1The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. 2Department of Gynecologic Oncology, Centre of Gynecologic Oncology Amsterdam, Antoni van Leeuwenhoek Hospital-The Netherlands Cancer Institute, Amsterdam, the Netherlands. 3Penn Ovarian Cancer Research Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania. 4Basser Center for BRCA, Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania. 5Department of Laboratory Medicine, Antoni van Leeuwenhoek Hospital-The Netherlands Cancer Institute, Amsterdam, the Netherlands. 6Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California. 7David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California. 8Department of Surgical Gastroenterology, Hvidovre Hospital, Hvidovre, Denmark. 9Department of Pathology, Antoni van Leeuwenhoek Hospital-The Netherlands Cancer Institute, Amsterdam, the Netherlands. 10Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark. 11Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.   Ovarian cancer is a leading cause of death for women worldwide, in part due to ineffective screening methods. In this study, we used whole-genome cell-free DNA (cfDNA) fragmentome and protein biomarker [cancer antigen 125 (CA-125) and human epididymis protein 4 (HE4)] analyses to evaluate 591 women with ovarian cancer, with benign adnexal masses, or without ovarian lesions. Using a machine learning model with the combined features, we detected ovarian cancer with specificity >99% and sensitivities of 72%, 69%, 87%, and 100% for stages I to IV, respectively. At the same specificity, CA-125 alone detected 34%, 62%, 63%, and 100%, and HE4 alone detected 28%, 27%, 67%, and 100% of ovarian cancers for stages I to IV, respectively. Our approach differentiated benign masses from ovarian cancers with high accuracy (AUC = 0.88, 95% confidence interval, 0.83–0.92). These results were validated in an independent population. These findings show that integrated cfDNA fragmentome and protein analyses detect ovarian cancers with high performance, enabling a new accessible approach for noninvasive ovarian cancer screening and diagnostic evaluation. Significance: There is an unmet need for effective ovarian cancer screening and diagnostic approaches that enable earlier-stage cancer detection and increased overall survival. We have developed a high-performing accessible approach that evaluates cfDNA fragmentomes and protein biomarkers to detect ovarian cancer. Introduction Ovarian cancer is a leading cause of death in women worldwide, with more than 300,000 new cases and nearly 200,000 deaths globally each year (1). In the United States during 2024, approximately 19,600 new cases will be diagnosed and 12,700 women will die from ovarian cancer (2). The most common form of ovarian cancer is epithelial ovarian cancer, which comprises four major subtypes: serous, clear cell, mucinous, and endometrioid carcinomas. According to the Surveillance, Epidemiology, and End Results database, for individuals with detected invasive epithelial ovarian cancer, the estimated 5-year survival is 93% and 75% for localized (stage I) or regional (stage II or stage IIIA1 with regional lymph node involvement) disease, respectively, compared with 31% for distant disease (remaining stage III or stage IV; refs. 3, 4). Unfortunately, ovarian cancer is usually detected in advanced stages (stages III and IV) due to nonspecific clinical symptoms at earlier stages and the lack of an effective screening approach (3). Consequently, there is a clear unmet clinical need for the development of highly specific and sensitive assays to detect ovarian cancer in its earliest stages. Ovarian cancer screening trials such as the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (5), the U.K. Collaborative Trial of Ovarian Cancer Screening (UKCTOCS; ref. 6), and the Normal Risk Ovarian Screening Study (ref. 7) have shown that existing biomarkers, including cancer antigen 125 (CA-125), may provide a shift toward detection of earlier stages of cancer but not a survival benefit, likely because of suboptimal detection of ovarian cancers. These analyses open the door to new and more effective approaches aimed at identifying combinations of biomarkers with improved performance for early ovarian cancer detection. Such approaches would need to be affordable, accessible, and have high performance for high-grade serous ovarian carcinoma (HGSOC), which is more aggressive, typically detected in late stages, and responsible for the majority of ovarian cancer deaths (8). A secondary clinical need also exists in determining whether women presenting with ovarian masses have benign or malignant lesions. In this setting, preoperative malignancy classification is challenging and may lead to unnecessary procedures. A number of biomarkers have been proposed in this setting, including CA-125 and human epididymis protein 4 (HE4; refs. 9–11). Prediction models using a combination of multiple protein biomarkers as well as age and menopausal status (12), the risk of malignancy index (ref. 13), and other ultrasound classifications (International Ovarian Tumor Analysis; ref. 14) have been developed, but these vary in accuracy, performance, and ease of use in a clinical setting. Analyses of circulating cell-free DNA (cfDNA) provide another approach for early cancer detection in the screening or diagnostic settings. Approaches for ovarian cancer have included identification of tumor-specific mutations (15, 16), or alterations in DNA methylation (17), or specific repeat sequences (18, 19); however, these approaches have had limited sensitivities for early-stage disease, may be confounded by alterations in white blood cells (20), and have not been validated for clinical use. An emerging approach of cfDNA analyses have focused on the “cfDNA fragmentome,” defined as the genome-wide compendium of cfDNA fragments in the circulation, providing an integrated view of the chromatin, genome, epigenome, and transcriptome states of normal and cancer cells of an individual. Recent cfDNA fragmentome analyses using low-coverage whole-genome sequencing (WGS) combined with machine learning using DNA evaluation of fragments for early interception (DELFI) have demonstrated high sensitivity for early detection across lung (21), liver (22), and other cancer types (23–26) using an accessible, cost-efficient approach (27) that is not confounded by clonal hematopoiesis (20, 28). In this study, we present a method to detect ovarian cancer using cfDNA fragmentomes combined with protein biomarkers. This multianalyte combination has the benefit of utilizing genome-wide multifeature fragmentation analyses together with complementary protein biomarkers CA-125 and HE4 from the same blood draw that may have utility in both the screening and diagnostic settings. Results Clinical Cohorts Blood samples in the discovery cohort were collected from women with ovarian cancer (n = 94), with benign adnexal masses (n = 203), or without any known ovarian lesions (n = 182), who were part of previously reported prospective diagnostic or screening efforts at hospitals in the Netherlands and Denmark (Table 1; Supplementary Table S1; refs. 9, 21, 23, 29). For the validation cohort, we analyzed samples from patients prospectively collected at the University of Pennsylvania or t

Audio Journal of Oncology: Sept 23rd, 2025 An interview with: Timothy Yap MD PhD MBBS, Professor of Investigational Cancer Therapeutics, Head of Clinical Development, Therapeutics Discovery Division, University of Texas MD Anderson Cancer Center, Houston, USA SAN DIEGO, USA—Breast, ovarian, pancreatic, prostate and other solid tumors with mutations sensitizing them to poly ADP ribose polymerase (PARP) inhibition, could potentially be controlled better and with less toxicity with the new selective PARP-1 inhibitor saruparib than with existing licensed agents which inhibit both PARP 1 and PARP 2. That’s according to early results from the PETRA study reported to the San Diego meeting of the American Association for Cancer Research (AACR). Timothy Yap MD PhD MBBS, Professor of Investigational Cancer Therapeutics and Head of Clinical Development in the Therapeutics Discovery Division of the University of Texas MD Anderson Cancer Center in Houston, reported early clinical data from the PETRA study.  After his talk at the AACR conference he discussed the findings with Peter Goodwin. Timothy Yap MD PhD MBBS: AUDIO JOURNAL OF ONCOLOGY: IN (SARAH M AXWELL):  A new class of PARP inhibitor … ….OUT:  from me, Sarah Maxwell, Good-bye. 18:45 secs WHAT IS SARUPARIB? : “Saruparib is an investigational new drug that is being evaluated for the treatment of cancer. It is a first-in-class selective inhibitor of poly-ADP ribose polymerase 1, designed to treat cancers with homologous recombination repair deficiencies as a result of mutations in BRCA1, BRCA2, PALB2, RAD51C, or RAD51D genes.” AACR ABSTRACT: Next-generation PARP Inhibitor Demonstrates Clinical Benefit in Patients with Homologous Recombination Repair-deficient Breast Cancer PETRA: first-in-human Phase 1/2a trial of the first-in-class new generation poly-ADP-ribose polymerase-1 selective inhibitor (PARP1i) saruparib (AZD5305) in patients (pts) with advanced solid tumors with BRCA1/2, PALB2 or RAD51C/D mutations https://aacrjournals.org/cancerres/article/82/12_Supplement/CT007/701955/Abstract-CT007-PETRA-First-in-class-first-in-human AACR Abstract CT007: PETRA: First in class, first in human trial of the next generation PARP1-selective inhibitor AZD5305 in patients (pts) with BRCA1/2, PALB2 or RAD51C/D mutations Abstract Background: AZD5305 is a potent, highly selective PARP1 inhibitor and trapper with superior preclinical tolerability, target engagement and efficacy vs 1st generation dual PARP1/2 inhibitors (PARPi). This is the first report of the ongoing Phase 1/2a PETRA (NCT04644068) trial. Citation Format: Timothy A. Yap, Seock-Ah Im, Alison M. Schram, Adam Sharp, Judith Balmana, Richard D. Baird, Jessica S. Brown, Maria Schwaederle, Elizabeth A. Pilling, Ganesh Moorthy, Spiros Linardopoulos, Adam Dowson, Carol Pound, Edit Lukacs, Sabina Cosulich, Stephen J. Luen. PETRA: First in class, first in human trial of the next generation PARP1-selective inhibitor AZD5305 in patients (pts) with BRCA1/2, PALB2 or RAD51C/D mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT007. Methods: Pts with advanced breast, ovarian, prostate or pancreatic cancer bearing germline or somatic BRCA1/2, PALB2 or RAD51C/D mutations received AZD5305 QD PO until disease progression. ECOG PS 0-2 and Hb ≥9.0 g/dL were required. Prior PARPi and platinum therapy were permitted. The primary objective was safety; secondary objectives included pharmacokinetics (PK) and pharmacodynamics in tumor and/or blood samples and response by RECIST v1.1, CA125 or PSA. Exploratory genomic analyses included zygosity evaluation and ctDNA response monitoring. Results: At data cutoff (Nov 17, 2021), 46 pts received AZD5305 10-90 mg QD (43.5% had prior PARPi; median 3.5 prior lines of therapy). AZD5305 was well tolerated across all doses without DLTs. PK exposures were dose-proportional. Steady-state Ctrough was higher than 1st generation PARPi: specificaly 6.3 and 31.9 fold above target effective concentration at 10 and 90 mg, respectively. PARylation inhibition was ≥90% at 10-40 mg QD (PBMCs) confirming target engagement. 7/25 (28%) pts had objective responses: 5 RECIST PRs (3 confirmed) and 2 additional pts with PSA50 responses (1 confirmed), including platinum- and PARPi-resistant pts. 13/22 (59%) RECIST-measurable pts had SD or PR up to 51+ weeks. ctDNA declined on treatment in 7/13 (54%) evaluable pts (3 complete, 4 >50% reductions) across doses. Conclusions: AZD5305 is a highly selective PARP1 inhibitor and trapper with excellent physiochemical properties and a wide therapeutic index. It led to maximal target engagement and showed promising clinical activity with favorable tolerability at exposures surpassing those of 1st generation PARPi. MORE: (AACR RELEASE): Next-generation PARP Inhibitor Demonstrates Clinical Benefit in Patients with Homologous Recombination Repair-deficient Breast Cancer Drug has higher selectivity for PARP1, improving safety and tolerability SAN DIEGO – Saruparib, a selective inhibitor of poly-ADP ribose polymerase 1 (PARP1), demonstrated a promising objective response rate and progression-free survival in patients with certain homologous recombination repair (HRR)-deficient breast cancers, according to results from the phase I/II PETRA trial, presented at the American Association for Cancer Researc 2024 Annual Meeting in San Diego. Although blocking the enzyme PARP1 may be sufficient to prevent DNA repair in HRR-deficient tumors, all PARP inhibitors currently approved by the U.S. Food and Drug Administration (FDA) block both PARP1 and PARP2, which can limit utility because of toxicity, explained Timothy A. Yap, MBBS, PhD, professor of Investigational Cancer Therapeutics and vice president and head of clinical development in the Therapeutics Discovery Division at The University of Texas MD Anderson Cancer Center, who presented the study. “When we were developing first-generation PARP inhibitors, we weren’t able to increase the doses above a certain threshold because of toxicity,” Yap said. “By designing selective PARP1 inhibitors, we have a great opportunity to improve safety, tolerability, pharmacokinetics, pharmacodynamics, efficacy, and combinability with other therapies.” Saruparib, a PARP1-specific inhibitor, showed promising tumor growth inhibition in preclinical models of breast ovarian pancreatic and prostate cancer harboring HRR deficiency mutations. Because saruparib was less toxic than other PARP inhibitors, it could be given at higher doses. “The properties of saruparib enable patients to reach high drug pharmacokinetic exposure levels and pharmacodynamic target engagement,” Yap said. “This means that patients may be able to stay on the optimal dose for a longer duration due to fewer dose interruptions and reductions, which may ultimately improve efficacy.” PETRA is a multicenter phase I/II clinical trial evaluating the safety, tolerability, and efficacy of saruparib in 306 patients with previously treated (including ≤1 prior PARP inhibitor in the dose escalation phase and PARP inhibitor-naive breast cancer patients in the dose expansion phase) HRR-deficient breast, ovarian, pancreatic, or prostate cancer. Patients had tumors with mutations in one of five HRR genes: BRCA1, BRCA2, PALB2, RAD51C, or RAD51D. Patients were treated at doses ranging from 10 to 140 mg saruparib daily; 60 mg daily was chosen as the recommended dose for further clinical development. Among the 31 breast cancer patients treated with 60 mg saruparib, the objective response rate was 48.4%, the median duration of response was 7.3 months, and the median progression-free survival was 9.1 months. In the cohort of 141 patients who received the 60 mg dose across all cancer types, adverse events were observed in 92.2% of patients and 12.1% of patients experienced a serious adverse event. Adverse events related to saruparib were observed in 76.6% of patients, and 2.1% of patients had a serious adverse event related to the drug; 3.5% of patients discontinued treatment due to adverse events related to saruparib. Yap noted that the adverse events profile from this phase I/II trial of heavily pretreated patients compared favorably to those from phase III trials testing other PARP inhibitors in treatment-naïve patients. “The low rate of dose reductions observed with saruparib suggests a very manageable safety profile that we believe will enable patients to stay longer at the optimal dose and therefore maximize the opportunity for long-term benefit,” Yap said. Pharmacokinetic analyses showed that, at all dose levels, patients maintained higher blood concentrations of saruparib than typically observed with other PARP inhibitors. At the molecular level, saruparib inhibited around 90% of PARP activity in tumor tissue collected from biopsies. “The excellent safety and tolerability profile, along with the favorable pharmacokinetic and pharmacodynamic properties, may enable patients to remain on saruparib treatment with sustained maximal target engagement and limited dose reductions or discontinuation,” Yap said. Limitations of this study include its single-arm design and small sample size. This study was funded by AstraZeneca. Yap is head of clinical development in the Therapeutics Discovery Division at The University of Texas MD Anderson Cancer Center, which has licensed therapeutics to Artios Pharma. He serves or has served as a consultant for 858 Therapeutics, Inc., AbbVie, Acrivon Therapeutics, Adagene, Aduro Biotech, Inc., Almac,  Amgen, Amphista Therapeutics, Artios Pharma, Astex Pharmaceuticals, AstraZeneca, Athena Therapeutics, Atrin Pharmaceuticals, Avenzo Therapeutics, Avoro Capital Advisors, Axiom Real-Time Metrics, Baptist Health System, Bayer, BeiGene, BioCity Biopharma, Blueprint Medicines, Boxer Capital, BridGene Biosciences, Bristol Myers Squibb, C4 Therapeutics, Inc., Cal

Interviews with: Stacey A.  Kenfield ScD, Epidemiologist, Professor of Urology, Epidemiology and Biostatistics, and June Chan ScD, Cancer Epidemiologist, Department of Epibiostat and Urology, University of California San Francisco, California USA.  SAN DIEGO, USA—Physical exercise keeps patients with prostate cancer alive longer, according to a combination of epidemiological and clinical study evidence emerging from research in San Francisco, California. Intervention study findings reported at the American Association for Cancer Research (AACR) Annual Meeting in San Diego are consistent with mounting epidemiological evidence showing that regular physical exercise can help patients with advanced or metastatic prostate cancer live longer, have slower disease progression and improve their quality of life. Stacey A. Kenfield ScD, Professor of Urology, Epidemiology and Biostatistics at the University of California San Francisco (UCSF) reported from the INTERVAL-GAP4 trial. Together with her colleague, June Chan ScD, Cancer Epidemiologist in the Department of Epibiostat and Urology at UCSF (who chaired the session on exercise for cancer patients at the AACR) she talked with the Audio Journal of Oncology about the findings and recommendations for using physical exercise as an adjunct to standard management for patients with prostate cancer. Audio Journal of Onclogy Episode: Stacey A. Kenfield ScD and June Chan ScD, University of California San Francisco IN (Sarah Maxwell): There’s new evidence that exercise….. OUT:  From me, Sarah Maxwell, Bye bye!”  10:28 secs AACR ABSTRACT TITLE: Intense exercise for survival among men with metastatic prostate cancer: 12-month feasibility results from the INTERVAL-GAP4 trial pilot site at Edith Cowan University, Australia First Author: Stacey A. Kenfield, UCSF – University of California San Francisco, San Francisco, CA, Authors: A. Kenfield1, N. H. Hart2, J. Sison1, J. M. Chan1, K. S. Courneya3, F. Saad4, R. U. Newton5; Institutions: 1UCSF – University of California San Francisco, San Francisco, CA, 2University of Technology Sydney, Sydney, Australia, 3University of Alberta, Edmonton, AB, Canada, 4Université de Montréal, Montréal, QC, Canada, 5Edith Cowan University,  Perth, Australia Stacey A. Kenfield, Departments of Urology and Epidemiology & Biostatistics, University of San Francisco California, San Francisco, CA ABSTRACT Introduction: Men with prostate cancer undertaking moderate-to-vigorous exercise have a marked reduction of 30-60% in all-cause and cancer-related mortality based on observational studies. In 2016, the Intense Exercise for Survival among Men with Metastatic Prostate Cancer (INTERVAL-GAP4) was launched to determine if supervised exercise improves overall survival in men with metastatic prostate cancer. Here, we describe the demographic characteristics, completion rates, exercise adherence, and safety of the first 12 months of the intervention at the pilot site, Edith Cowan University in Perth, Australia. Methods: INTERVAL-GAP4 is a multi-center global randomized controlled phase III trial. Patients are randomly allocated (1:1) to: (intervention) a high intensity combined resistance and aerobic exercise supervised program for 1 year tapering to self-management in year 2; or (control) self-directed unsupervised exercise with print materials. Patients were stratified by site and by disease/treatment status (metastatic hormone-sensitive prostate cancer [mHSPC] or metastatic castration-resistant prostate cancer [mCRPC] and if the latter, treatment modality). The study did not meet recruitment goals and closed to further enrollment in February 2023. Results: 240 participants were evaluated between April 2016-Feb 2023, 60 patients were consented, 52 participants were randomized, and two patients did not receive the allocation, resulting in 50 participants (27 intervention and 23 control). Main reasons for exclusion were not meeting clinical criteria (N=81), time commitment (N=24), unable to contact (N=22), not interested (N=19), and poor physical function (N=13). Median age at randomization was 72 years (IQR: 68, 77), median body mass index (BMI) was 31.7 kg/m2 (IQR: 27.5, 35.7), 94% identified as white, and time since diagnosis was 5 years (IQR: 1, 9). 13 participants (26%) had mHSPC and 37 (74%) had mCRPC. Completion rates were the following at 6 months: 84% completed surveys, 62% exercise testing, and 66% biological samples. Of 42 alive at 12 months: 85% completed surveys, 73% testing, and 73% biological samples. Median exercise adherence was 90% (IQR: 78, 97) for the first 12 months of the study. Adherence was not significantly different for those with mCRPC vs. mHSPC status. There were 10 SAEs in first 12 months; all (100%) were unrelated to the intervention. Conclusions: Exercise training was feasible and safe in men with metastatic prostate cancer with no difference observed in exercise session adherence by disease status. Survey completion was high, while in-person completion rates were affected by the COVID-19 pandemic. Additional analysis of the entire study population (N=145) is ongoing and will be compared with the pilot site. ALSO: https://ascopubs.org/doi/10.1200/GO.2023.9.Supplement_1.81 Intense exercise for survival among men with metastatic prostate cancer: 12 months feasibility results from the INTERVAL-GAP4 trial. Background: Exercise is now considered an important therapy to ameliorate treatment side effects, improve quality of life and physical function however, causation of survival benefit and the underlying mechanisms is not yet established. In 2015, the Intense Exercise for Survival among Men with Metastatic Castrate-Resistant Prostate Cancer (INTERVAL-GAP4) – a worldwide multicentre phase III trial – was launched to determine if high-intensity combined resistance and aerobic exercise plus psychosocial support improves overall survival in men with metastatic prostate cancer. Here, while exercise delivery and follow-up assessments are still taking place in 6 different countries, we aim to examine the feasibility, exercise compliance and safety of a 12-month exercise medicine program in patients with mCRPC. Methods: Experimental design was a longitudinal analysis of attrition rates, exercise attendance and compliance metrics and programme safety over the initial 12 months of patients participating in the INTERVAL-GAP4 trial at the Edith Cowan University site in Perth, Australia. Results: 201 patients were screened for participation and 46 patients (22.9%) were randomly assigned to the two study arms. Median time since prostate cancer diagnosis was 72.0 (interquartile range (IQR): 19.5-118.5) months. Most patients were previously treated with radiotherapy (53.3%). Metastases present mostly in the lymph nodes (53.3%), followed by bones (51.1%), lungs (2.2%) and bladder (2.2%). Participants attended a total of 2,907 out of 3,744 exercise sessions scheduled, with a median exercise attendance of 78.8% (IQR: 71.6%-82.7%) per participant. Majority of sessions were performed at an RPE of 7-8 indicating “vigorous intensity” or at an RPE of 5-6 indicating “moderate intensity” (67.2%). Tolerance was moderate-to-high in most sessions (83.0%). 191 adverse events (AEs) were observed throughout the study period. A total of 136 adverse events were reported by 19 participants from the exercise group, and these were mainly disease related (n= 69, 50.7%). Most AEs were grade 1 and 2 (n= 126, 92.7%). In the control group, 55 AEs were observed, and these were mainly disease related (n= 22, 40.0%) and grade 1 and 2 (n= 51, 92.7%). The most common intervention-related adverse events experienced in the exercise group were pain (n= 6, 50.0%; i.e., back pain, bone pain, lymph node pain, and general pain). Conclusions: Patients with mCPRC can participate in high-intensity aerobic and resistance training with moderate to high attendance and tolerance. The exercise intervention appears safe with limited intervention-related adverse events experienced and mostly minor and expected. However, with only 22.9% of screened patients deemed suitable and willing, this aspect of feasibility requires attention. Clinical trial information: NCT02730338. Robert Usher Newton: Exercise Medicine Research Institute, Edith Cowan University, Joondalup, Western Australia, Australia Pedro Lopez Nicolas H. Hart Daniel Abido Galvao Dennis R Taaffe Timothy Dudley Clay Charles M Ryan Stacey A. Kenfield Fred Saad: Division of Urology, Centre Hospitalier de l’Université de Montréal (CHUM/CRCHUM), Montreal, QC, Canada  

An interview with Jonathan T. Yang MD PhD, Washington University, Seattle, USA, (Formerly of Memorial Sloan Kettering Cancer Center, New York.) SAN DIEGO, USA—An international phase one clinical study has found that a drug known to inhibit DNA damage repair was able to boost the efficacy of radiotherapy in patients being treated for their glioblastoma. The radiosensitizer, AZD1390, an inhibitor of ataxia telangiectasia mutated (ATM) kinase, was tested as adjunctive therapy (combined with standard radiation plus temozolomide) among 115 patients who had recurrent or newly diagnosed glioblastoma.  First author Jonathan T. Yang MD PhD, of Memorial Sloan Kettering Cancer Center in New York, reported promising efficacy to the American Association for Cancer Research Annual Meeting in San Diego, where Audio Journal of Oncology correspondent Peter Goodwin caught up with him. Audio Journal of Oncology: IN: [Sarah MAXWELL] “A radio sensitizer drug has shown …….OUT:…..from me, Sarah Maxwell, goodbye” 10:59secs https://www.aacr.org/about-the-aacr/newsroom/news-releases/azd1390-with-radiotherapy-shows-manageable-safety-profile-and-preliminary-efficacy-for-patients-with-glioblastoma-in-phase-i-trial/ https://clinicaltrials.gov/study/NCT03423628 Abstract: “AZD1390 With Radiotherapy Shows Manageable Safety Profile and Preliminary Efficacy for Patients with Glioblastoma in Phase I Trial” Journal ABSTRACT: https://www.sciencedirect.com/science/article/pii/S0360301624009799 Safety and preliminary efficacy of AZD1390 + radiation therapy (RT) for glioblastoma.) (IMRT) with glioblastoma (GBM), the most common primary brain malignancy in adults, is an aggressive cancer with limited life expectancy. The standard of care backbone for newly diagnosed GBM is intensity-modulated radiation therapy Glioblastoma (GBM), the most common primary brain malignancy in adults, is an aggressive cancer with limited life expectancy. The standard of care backbone for newly diagnosed GBM is intensity-modulated radiation therapy (IMRT) with concomitant and adjuvant temozolomide. AZD1390, an oral, highly potent, and selective ataxia telangiectasia mutated kinase inhibitor, is designed to augment the efficacy of IMRT without exacerbating neurotoxicity. AZD1390 is optimized for blood brain barrier penetration, confirmed in a human healthy volunteer PET study (NCT03215381) and a Phase 0 study in patients (pts) with GBM (NCT05182905). This global, Phase 1, open-label study (NCT03423628) evaluates the safety and preliminary efficacy of escalating doses of AZD1390 and radiation therapy (RT) in pts with GBM and brain metastases. Materials/Methods Eligible adult pts received escalating once-daily AZD1390 doses following a Bayesian continual reassessment method, with IMRT 35 Gy in 10 fractions over 2 weeks (Arm A, recurrent GBM) or IMRT 60 Gy in 30 fractions over 6 weeks (Arm C, newly diagnosed, O-6-methylguanine-DNA methyltransferase unmethylated GBM). Pts in both Arms received 2 additional weeks of adjuvant AZD1390 post-IMRT. Arm B included pts with brain metastases but was closed due to low recruitment and is not reported. Primary objective was safety; secondary objectives included clinical efficacy and pharmacokinetics (PK). Results As of Feb 6, 2024, 115 pts have received AZD1390 (75 in Arm A; 40 in Arm C) at doses of 10–900 mg/day. PK was linear with a slightly more than dose-proportional increase and a mean terminal elimination half-life around 9–11 hours. Most patients had ≥1 treatment-emergent adverse event (AE); the most common were fatigue (51.3%), nausea (39.1%) and headache (38.3%). Grade ≥3 AZD1390-related AEs occurred in 18/115 pts (15.7%). The maximum tolerated dose was identified as 400 mg in Arm A and 300 mg in Arm C. Dose limiting toxicities included, but were not limited to, creatinine kinase elevation in Arm A and radiation skin injury in Arm C. Treatment was well tolerated, with the majority of reported AEs being low-grade. AEs led to discontinuation of AZD1390 in 13.0% of pts. The safety profile was consistent across Arms despite the different RT schedules; the most notable difference was in radiation skin injury, a reversible event, with higher frequency and severity in Arm C. At doses demonstrating target engagement in the Phase 0 study, median overall survival was 12.7 months (95% CI = 10.7, 18.9, n = 21) for Arm A and is still maturing for Arm C. Conclusion Concurrent AZD1390 and IMRT administration is tolerated with a manageable safety profile, at doses shown to achieve clear target engagement in the Phase 0 study. Preliminary efficacy is encouraging in Arm A. These data suggest the potential for AZD1390 to act as a radiosensitizer for the treatment of GBM. Clinical investigation is ongoing. Previous article in issue Next article in issue Author Disclosure: J.T. Yang: Grant/research funding; AstraZeneca, Kazia Therapeutics, Debiopharm, Cantex Therapeutics. Compensation/Payment; Plus Therapeutics, Nanocan Therapeutics, Kazia Therapeutics. Stock options; Nanocan Therapeutics. P.Y. Wen: Independent Contractor; Anheart, AstraZeneca, Black Diamond, Celularity, Chimerix, Day One Bio, Genenta, GlaxoSmithKline, Kintara, Merck, Mundipharma, Novartis, Novocure, Prelude Therapeutics, Sagimet, Sapience, Servier, Symbio, Tango, Telix, VBI Vaccines. Grant/research funding; AstraZeneca, Black Diamond, Bristol Myers Squibb, Chimerix. B.S. Imber: Grant/research funding; AstraZeneca. Honoraria; GT Medical Technologies, Telix Pharmaceuticals. J. Drappatz: Grant/research funding; Novocure, Servier, Novartis. Copyright/Patent/License/Royalty; Elsevier, Wolters Kluwer. Stock; Pfizer, GlaxoSmithKline, Gilead. R. Jena: None. D. Forst: Grant/research funding; American Society of Clinical Oncology. Stock; Eli Lilly. A. Zukas: None. S.C. Short: None. C. Fan: Stock; AstraZeneca. W. Trigg: Stock; AstraZeneca. A. Milner: None. U. Polanska: Stock; AstraZeneca. C. Glover: Stock; AstraZeneca. Stock options; AstraZeneca. C. Stavraka: Stock; AstraZeneca. D. Dalal: Stock; AstraZeneca. D. Karanovic: None. A. Chalmers: Grant/research funding; AstraZeneca. Honoraria; AstraZeneca. MORE: PRESS RELEASE: AZD1390 With Radiotherapy Shows Manageable Safety Profile and Preliminary Efficacy for Patients with Glioblastoma in Phase I Trial SAN DIEGO – AZD1390, an ataxia telangiectasia mutant (ATM) kinase inhibitor, demonstrated a manageable safety profile in both recurrent and newly diagnosed glioblastoma (GBM) patients when given in combination with standard-of-care radiotherapy and showed preliminary efficacy in recurrent GBM patients, according to results from a global phase I trial presented at the American Association for Cancer Research (AACR) Annual Meeting 2024, held April 5-10. “Glioblastoma is a lethal cancer with the majority of patients not surviving past two years from diagnosis,” said Jonathan T. Yang, MD, PhD of Memorial Sloan Kettering Cancer Center, who presented the results of the trial. “Despite efforts to improve survival, the current standard of care continues to be a backbone of radiotherapy with or without temozolomide [Temodar] without much innovation in the past two decades. This context highlights both the urgent need to develop new medicines and the historical challenges of developing novel therapeutics for this devastating disease.” Intensity-modulated radiation therapy (IMRT), which is the standard of care in newly diagnosed GBM patients, causes the death of cancer cells by damaging the DNA inside of the cell. But the ATM cell signaling pathway is activated to help repair the DNA double-strand breaks (DSBs) caused by radiation therapy, thus impeding its effectiveness. An ATM inhibitor prevents the repair of DSBs, thereby enhancing the cancer-killing effect of radiation therapy, Yang said. GBM accounts for approximately 50% of primary malignant brain tumors. One reason brain tumors have been difficult to treat is because the blood-brain barrier prevents some therapies from penetrating into the brain and reaching the cancers they aim to treat. Because of this challenge, AZD1390 was designed to penetrate the blood-brain barrier and a healthy volunteer study recently showed that AZD1390 crossed through an intact barrier. Other pre-clinical experiments demonstrated the potential antitumor effects of AZD1390 without exacerbating IMRT toxicity in surrounding areas by not causing harm to normal, healthy brain tissue. Yang and his colleagues assessed the safety, tolerability, early efficacy, and maximum tolerated dose of AZD1390 with IMRT in humans. As of February 2024, 115 patients were given AZD1390 in the phase I trial, including 75 patients with recurrent GBM in Arm A and 36 patients with newly diagnosed, MGMT unmethylated GBM in Arm C. In both Arms, patients received escalating once-daily doses of AZD1390; patients in Arm A were given 35 Gy of IMRT in 10 fractions over two weeks while those in Arm C were given 60 Gy of IMRT in 30 fractions over six weeks. Additionally, following the completion of IMRT, patients were given adjuvant AZD1390 for two weeks. Out of the 115 patients, 18 (15.7%) experienced an AZD1390-related adverse event (AE) of a grade 3 or 4; there were no grade 5 treatment-related AEs. Additionally, 4.3% of patients discontinued AZD1390 treatment due to an AE related to AZD1390 only. “Most adverse effects experienced by patients during the study were low grade, readily manageable, and reversible in nature,” Yang said. AZD1390 With Radiotherapy Shows Manageable Safety Profile and Preliminary Efficacy for Patients with Glioblastoma in Phase I Trial Page 2 of 3 Patients in Arm C experienced a higher frequency and severity of radiation-related skin injury due to longer exposure to radiation, and most instances were easily managed and fully reversed following treatment with topical steroids and moisturizers, Yang said. The researchers identified 400 mg in Arm A and 300 mg in Arm C as the maximum tolerated doses. While Yang said they are still col

An interview with: Heather McArthur MD MPH, Clinical Director Breast Cancer, Komen Distinguished Chair Clinical Breast Research, University of Texas Southwestern Medical Center, Dallas TX MILAN, Italy—Adjuvant therapy with a checkpoint inhibitor did not benefit patients with triple negative breast cancer in a big new study reported to the 14th European Breast Cancer Conference in Milan, Italy. Heather McArthur MD MPH, Clinical Director of Breast Cancer and Komen Distinguished Chair in Clinical Breast Research at the University of Texas Southwestern Medical Center, Dallas TX, told the conference that the ALEXANDRA/IMpassion030 phase 3 trial failed to show a survival benefit when adjuvant atezolizumab was added to standard therapy. In Milan, she discussed the findings with Audio Journal of Oncology reporter Peter Goodwin. Heather McArthur MD MPH: IN: [SARAH MAXWELL] Patients with triple negative ,,OUT:     …from me, Sarah Maxwell, good-bye.   10;06secs ABSTRACT: 14th European Breast Cancer Conference Abstract no: 4 Abstract no: 1LBA, “Adjuvant chemotherapy with or without atezolizumab for stage II and III triple-negative breast cancer: final analysis of the ALEXANDRA/IMpassion030 phase 3 trial” EBCC 2024, Wednesday 20 March, Young Investigator Innovation Award and oral abstract session, 11:00-12:55 hrs CET,. https://cm.eortc.org/cmPortal/Searchable/ebcc14/config/Normal/#!sessiondetails/0000107210_0 https://www.ejcancer.com/article/S0959-8049(24)00177-1/fulltext MORE: PRESS RELEASE Embargoed: 00.01 hrs CET, Wednesday 20 March 2024 Addition of atezolizumab to chemotherapy after surgery does not improve survival for triple negative breast cancer — Final analysis of the ALEXANDRA/IMpassion030 phase 3 trial — Milan, Italy: Patients with triple-negative breast cancer do not benefit from the addition of atezolizumab to their post-surgery chemotherapy treatment, according to the results of a large phase 3 clinical trial presented at the 14th European Breast Cancer Conference. Triple negative breast cancer, so-called because the cancer cells are not fuelled by oestrogen, progesterone or the HER2 protein, is harder to treat and more likely to spread to other parts of the body. Previous research has suggested that adding an immunotherapy treatment to chemotherapy before surgery can improve survival for this groups of patients. The new results show that including atezolizumab, a type of immunotherapy, with chemotherapy after surgery does not bring the same benefits. The ALEXANDRA/IMpassion030 study is a phase 3 clinical trial that included 2199 people from 31 different countries with stage two or three triple negative breast cancer. Following surgery to remove their cancer, half of the patients were randomly assigned to be treated with chemotherapy plus atezolizumab, with the other half treated with chemotherapy. The final analysis of the trial was presented by Dr Heather McArthur, an Associate Professor in the Department of Internal Medicine and Clinical Director of the Breast Cancer Program at the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern Medical Center in Dallas, Texas, USA. She said: “We know from a previous trial that including the immunotherapy treatment atezolizumab with chemotherapy prior to surgery is beneficial for patients with triple-negative breast cancer. The ALEXANDRA/IMpassion030 trial is the first study to look at the role of chemotherapy with or without atezolizumab post-surgery for early-stage triple-negative breast cancer.” Patients have now been monitored for an average of 32 months. Researchers found no improvement for patients treated with atezolizumab after surgery compared to those not treated with atezolizumab in terms of survival and remaining free of cancer. Among the patients taking atezolizumab there were 141 (12.8%) who had a recurrence or died. Among patients not taking atezolizumab, there were 125 (11.4%) who had a recurrence or died. This equates to a hazard ratio of 1.11 for patients taking atezolizumab. Researchers also found no benefit when looking at different sub-groups, such as patients whose cancer had spread to the lymph nodes and patients with PD-L1 positive cancer, which is used as a marker of cancers that are more likely to respond to immunotherapy. Dr McArthur said: “This is a large international clinical trial looking at treatment for patients with triple-negative breast cancer. The results of this final analysis are important because they show that including the immunotherapy drug atezolizumab alongside chemotherapy does not help when it’s given to patients following surgery. By extension, this also highlights the importance of treating triple-negative breast cancer with chemotherapy and immunotherapy prior to surgery, as per the current standard of care.” The final analysis also showed that the safety of atezolizumab, in terms of unwanted side effects, was consistent with other trials of the treatment. Among the patients treated with atezolizumab and chemotherapy, 54.3% experienced serious side effects. Among those treated with chemotherapy alone, 44.1% experienced serious side effects. The co-chair of the 14th European Breast Cancer Conference is Dr Fiorita Poulakaki, Head of the Breast surgery Department at Athens Medical Center Hospital, Greece, and Vice President of Europa Donna, the European Breast Cancer Coalition, and was not involved with the research. She commented: “We always hope that testing new treatment approaches will improve patients’ outcomes. However, it’s just as important to know when a new treatment added to one that is already in use one is not beneficial, as in this case, to make sure patients aren’t subjected to a treatment that doesn’t work and may cause more side effects. “The results of this final analysis show that chemotherapy with atezolizumab after surgery does not improve disease-free survival for early-stage triple-negative breast cancer. This research therefore highlights the importance of the current approach of treating triple negative breast cancer with chemotherapy and immunotherapy to shrink the tumour before surgery. This is vital information for surgeons and medical oncologists who treat patients with this aggressive type of cancer.” Abstract no: 1LBA, “Adjuvant chemotherapy with or without atezolizumab for stage II and III triple-negative breast cancer: final analysis of the ALEXANDRA/IMpassion030 phase 3 trial”, Young Investigator Innovation Award and Oral abstracts, Wednesday 20 March, 11.00-12.55, Silver room. https://cm.eortc.org/cmPortal/Searchable/ebcc14/config/Normal/#!sessiondetails/0000107210_0 1LBA LBA Oral – Adjuvant chemotherapy with or without atezolizumab for stage II and III triple-negative breast cancer: final analysis of the ALEXANDRA/ IMpassion030 phase 3 trial McArthur1∙ A. Bailey2 ∙ S. Saji3 ∙ … ∙ M. Piccart18 ∙ M. Ignatiadis5 ∙ R. Gelber19 … Show more Affiliations & NotesArticle Info Background: Early-stage triple negative breast cancer (TNBC) is associated with a high risk of distant relapse. ALEXANDRA/IMpassion030 is a global, prospective, randomized, open-label, phase 3 trial that investigated the efficacy and safety of adjuvant atezolizumab (atezo) plus standard anthracycline/taxane chemo (atezo+chemo) versus standard anthracycline/ taxane chemo (chemo alone) in early-stage TNBC. Material and Methods: In ALEXANDRA/IMpassion030 (NCT03498716) patients with resected stage II-III TNBC, confirmed by central pathology review, were randomized 1:1 to receive adjuvant chemo with or without atezo. Patients were stratified by type of surgery (breast conserving vs mastectomy), axillary nodal status (0 vs 1-3 vs ≥4 nodes), and centrally assessed PD-L1 status (IC0 vs IC1/2/3). Adjuvant chemo consisted of weekly paclitaxel 80 mg/m for 12 weeks followed by dose-dense anthracycline (epirubicin 90 mg/m2 or doxorubicin 60 mg/m2) and cyclophosphamide 600 mg/m2 for 4 doses every 2 weeks given concomitantly with atezo 840 mg every 2 weeks followed by maintenance atezo 1200 mg every 3 weeks until completion of 1 year of atezo or the same chemo regimen alone. The primary endpoint was invasive disease-free survival (iDFS) in the intention-to-treat population (ITT). Recruitment stopped after 2199 of the planned 2300 patients were enrolled (1101 atezo+chemo and 1098 chemo alone) on the recommendation of the independent data monitoring committee (IDMC). At the Interim Analysis (IA) with ∼25 months median follow-up and 239 iDFS events the hazard ratio (HR) for iDFS (primary endpoint) crossed the pre-specified futility boundary. The final analysis with ∼32 months median follow-up and 266 iDFS events is reported here. Results: At the final analysis, the HRs remained stable compared to the IA for iDFS at 1.11 (0.87, 1.42) and for secondary endpoints: iDFS in the PDL1+ subset 1.00 (0.73, 1.35), iDFS in the node-positive subset 1.32 (0.97, 1.8), and overall survival 1.23 (0.87, 1.73) for the 2199 patients in the ITT population. At the final analysis, 2177 (99%) were safety-evaluable, 1567 (71.3%) had PD-L1 positive disease and 1067 (48.5%) had node-positive disease. The incidence of grade≥3 treatment related adverse events remained stable with 54.3% in the atezo+chemo arm vs 44.1% in the chemo alone arm. Conclusions: At the final analysis, the addition of atezo to adjuvant anthracycline- and taxane-based chemo did not improve iDFS in the ITT population of stage II-III TNBC or in any of the subgroups interrogated. Safety data remain consistent with the known profile of atezo in early TNBC. Conflict of interest: Advisory Board: Dr. McArthur has consulted for Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Genentech/Roche, Immunomedics, Merck, OBI Pharma, Pfizer, Puma, Spectrum Pharmaceuticals, Syndax Pharmaceuticals, Peregrine, Calithera, Daiichi-Sankyo, Seattle Genetics, AstraZeneca, Gilead, Crown Bioscience, and TapImmune. Corporate-sponsored Research: Dr. McArthur has research supported by Bristol-Myers Squibb MedIm

An interview with: Stefan Paepke MD, Interdisciplinary Breast Centre, Technical University of Munich, Germany, recorded at the 14th European Breast Cancer Conference, Milan, Italy. MILAN, Italy—Women who need surgical implants after their mastectomy for breast cancer could now benefit from mesh-supported prosthetics that bring high rates of satisfaction and psychosocial well-being, with low complication rates. That’s according to findings from German PRO-Pocket-Trial, reported at the 14th European Breast Cancer Conference in Milan. Study patients who had the new “tetanized” mesh-pocket-supported implants positioned by means of a “pre-pectoral” procedure found the technique prevented the unnatural breast mobility after reconstruction sometimes called: “jumping breasts”, while giving a better cosmetic appearance. At the conference, our reporter Peter Goodwin talked with lead author of the study: Stefan Paepke MD, from the Interdisciplinary Breast Centre at the Technical University of Munich, in Germany Stefan Paepke MD PODCAST IN (Sarah MAXWELL): There’s good news for women ….OUT (Peter GOODWIN):  European Breast Cancer Conference.I’m Peter Goodwin  10:48 secs EBCC ABSTRACT: “Mesh-Pocket Supported Prepectoral Direct-to-Implant Breast Reconstruction: Preliminary Results of a Prospective Analysis”  https://www.ejcancer.com/article/S0959-8049(22)01378-8/fulltext Background: Safety and breast aesthetics of direct-to-implant techniques are well recognized. Pre-pectoral techniques add a new dimension supported by the next generation of titanized mesh-pockets. Material and Method: A prospective international, multicentre observational investigation (PRO-Pocket-Trial CLINICALTRIALS.GOV NCT03868514 and DRKS00016673) is performed in 12 clinical centres in Germany and Austria to obtain data regarding patient reported outcome, cosmetic outcome and complications after TiLOOP® Bra Pocket supported prepectoral breast reconstruction up to the 24 months Follow-Up. Results: From 06/2019 until 02/2021, 313 patients with TiLOOP® Bra Pocket supported breast reconstructions were included. Age of the patients was between 23 and 80 years. The mean of the BMI was 24.5 ± 4.5 kg/m2. The most frequent indication for surgery was invasive ductal carcinoma followed by increased breast cancer risk. Unilateral surgery was performed in about 40%. The most frequent incision technique was an inframammary incision followed by inverted T-technique and hockey stick incision. About 70% of the breast implants were of anatomic shape; textured surface was also reported in about 75% of the reconstructions. None of the reported complications was unexpected; currently, 1 dysesthesia, 6 wound healing disturbances, 11 hematomas, 4 capsular fibrosis, 5 infections, 6 necrosis, and 15 seromas are documented. Discussion: Use of TiLOOP® Bra Pocket enables a new standard of prepectoral reconstructive techniques preserving the natural anatomy, thereby avoiding adverse effects associated with submuscular reconstruction, minimizing postoperative pain, risk of bleeding and the lack of animation deformity like “jumping breast phenomenon.” Pocket-supported reconstructive techniques become more valuable in times of changing to implants with smooth surface due to the excellent stabilization of implant position. MORE: Post Market Clinical Follow Up to “Patient Reported Outcome” Using a Titanised Polypropylene Mesh (TiLOOP® Bra Pocket) (PRO-Pocket) Brief Summary: “PRO-Pocket” – International prospective multicentre Post Market Clinical Follow Up to “Patient reported outcome” in primary or secondary breast reconstruction after mastectomy using a titanised polypropylene mesh (TiLOOP® Bra Pocket) This international, multicentre, non-randomised, observational clinical device investigation will be performed to obtain post market information on TiLOOP® Bra Pocket surgical meshes for a period of up to two years. In particular, on patient reported satisfaction (BreastQTM), cosmetic outcome and the rate of complications. The objective of the clinical Investigation is to establish the efficacy and safety of the TiLOOP® Bra Pocket. The Investigation will be performed in ten clinical centres in Germany and Austria. Observational Actual Enrollment : 313 participants Observational Model: Cohort Time Perspective: Prospective Official Title: “PRO-Pocket” – International Prospective Multicenter Post Market Clinical Follow Up to “Patient Reported Outcome” in Primary or Secondary Breast Reconstruction After Mastectomy Using a Titanised Polypropylene Mesh (TiLOOP® Bra Pocket) Actual Study Start Date : July 4, 2019 Actual Primary Completion Date : June 22, 2022 Actual Study Completion Date : November 15, 2023 Primary or secondary breast reconstruction following mastectomy with titanised polypropylene mesh TiLOOP® Bra Pocket Primary Outcome Measures : Quality of Life – Patient reported outcome [ Time Frame: 12 months after study treatment ] The primary endpoint is defined as the change of the four BreastQ domain scores before study treatment compared to twelve months after study treatment. The BreastQ questionnaire yields a domain score in the range from zero to 100. Wheras a score of 100 is the best score. The study hypothesis is that the patient’s QoL after the study intervention treatment is not worse than the QoL prior to the intervention study Ages Eligible for Study: 18 Years and older (Adult, Older Adult) Sexes Eligible for Study: Female Accepts Healthy Volunteers: Yes Sampling Method: Non-Probability Sample Study Population Women with indicated implant based breast reconstruction after mastectomy. Criteria Inclusion Criteria: Age [≥ 18] Indications of breast reconstruction: histologically confirmed breast cancer, precancerous lesions (DCIS, LCIS), mutation carrier with increased breast cancer risk, strong family history (lifetime risk > 15%) The patient is capable to realise the nature, aims and possible consequences of the clinical trial (MPG §20.2.1) Patient information has been provided and all written consents of the patient are available Exclusion Criteria: Metastatic breast cancer Patient with known contraindications against mesh-assisted or plastic-reconstructive breast surgery according to the instruction for use Patient is kept in an institution under judicial or official orders (MPG §20.3) Participate in another operative clinical trial, if it relates to the area of reconstructive breast surgery and/or influences the primary endpoint of the clinical trial Contacts and Locations Go to sections Information from the National Library of Medicine To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor. Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03868514 Locations Austria Universitätsklinik für Frauenheilkunde, Allgemeines Krankenhaus der Stadt Wien Vienna, Austria, 1090 Germany Vivantes Klinikum Am Urban Berlin, Germany, 10967 DRK Kliniken Westend Berlin, Germany, 14050 Universitätsklinikum Bonn Bonn, Germany, 53127 Kliniken Essen Mitte; Evang. Huyssens-Stiftung Essen, Germany, 45136 Agaplesion Markus Krankenhaus Frankfurt, Germany, 60431 Universitätsmedizin Greifswald Greifswald, Germany, 17475 Universitätsklinikum Heidelberg Heidelberg, Germany, 69120 Rotkreuzklinikum München Munich, Germany, 80637 Klinikum rechts der Isar der Technischen Universität München Munich, Germany, 81675 Universitätsklinikum Ulm Ulm, Germany, 89075   GRN Klinik Weinheim Weinheim, Germany treatment . The following four domains are relavant: Satisfaction with breasts, Psychosocial well-being, Physical well-being:chest and Sexual well-being. Secondary Outcome Measures : Quality of Life – Patient reported outcome [ Time Frame: 6 and 24 months after study treatment ] The change of the four BreastQ domain scores before study treatment compared to six months and 24 months after study treamtment. Complication rate [ Time Frame: 6, 12 and 24 months after study treatment ] The number and rate of occurrence of adverse events is reported as a secondary endpoint along with a tabulation of the types of adverse events (6, 12 and 24 months after study treatment). Cosmetic outcome [ Time Frame: 6, 12 and 24 months after study treatment ] The cosmetic outcome is assessed based on photographs 6, 12 and 24 months after study treatment by descriptive statistics (an independent expert, the physician in charge and the patient assess the cosmetic outcome).  

An interview with Sophie Bosma MD PhD, from The Netherlands Cancer Institute, Amsterdam recorded at the 14th European Breast Cancer Conference in Milan. MILAN, Italy—The optimal radiation boost dose to protect young patients with early breast cancer has been investigated with ten years of follow up in the “Young Boost trial” conducted in the Netherlands. The study randomized between giving patients a low radiation dose as a boost to their standard radiotherapy or a high dose. At the 14th European Breast Cancer Conference held in Milan Radiation Oncologist Sophie Bosma MD PhD, from The Netherlands Cancer Institute in Amsterdam reported that a low dose had comparable efficacy with lower toxicity and should now be recommended. In Milan she talked about the findings with Audio Journal of Oncology reporter Peter Goodwin. AUDIO JOURNAL OF ONCOLOG, with: Sophie Bosma MD PhD, Netherlands Cancer Institute IN (Goodwin): “For your young patients ….. OUT: …..for the Audio Journal of Oncology I’m Peter Goodwin 8:46secs SEE: 00180-1/fulltext MORE: News release: Low-dose radiotherapy boost helps prevent local recurrence with better cosmetic outcomes in young breast cancer patients The researchers conclude that the ‘benefit does not justify the increased impact on cosmetic outcomes’. Bosma said: “In both groups local recurrence rates were very low and much better than expected. Although we did find a difference between the two groups in terms of the recurrence rate, this was a small difference which must be weighed against the increase in side effects, such as fibrosis. “Knowing the long-term impact of a treatment on cancer control as well as on unwanted side-effects is crucial in helping individual patients get the best possible treatment.” Michail Ignatiadis MD PhD from the Institut Jules Bordet in Brussels, Belgium, Chair of the 14th European Breast Cancer Conference, who was not involved in the research, said: “Radiotherapy plays an important role in breast cancer treatment, especially in young women where there is a higher risk of the breast cancer returning. This important study provides critical information for the optimal boost radiotherapy dose for achieving local control without compromising the cosmetic outcome.” Abstract no: 4LBA, “Young boost randomized phase III trial of high vs low boost radiation in young breast cancer patients: 10-year results”, https://cm.eortc.org/cmPortal/Searchable/ebcc14/config/Normal#!sessiondetails/0000107220_0 4LBA LBA Mini Oral – Young boost randomized phase III trial of high vs low boost radiation in young breast cancer patients: 10-year results European Journal of Cancer: https://www.ejcancer.com/article/S0959-8049(24)00180-1/fulltext Sophie Bosma et al: 1The Netherlands Cancer Institute, Radiation oncology, Amsterdam – HollandPTC- Delft, The Netherlands; 2Erasmus MC Cancer Institute, Statistics, Rotterdam, The Netherlands; 3The Netherlands Cancer Institute, Radiation oncology, Amsterdam, The Netherlands; 4Institute Curie, Radiation oncology, Paris, France; 5Catharina Hospital, Radiation oncology, Eindhoven, The Netherlands; 6University Medical Center Groningen, Radiation oncology, Groningen, The Netherlands; 7The Netherlands Cancer Institute, Surgical Oncology, Amsterdam, The Netherlands; 8Institute Verbeeten, Radiation oncology, Tilburg, The Netherlands; 9Radboud University Medical Center, Radiation Oncology, Nijmegen, The Netherlands; 10Radiotherapiegroep, Radiation oncology, Arnhem, The Netherlands; 11Amsterdam UMC, Pathology, Amsterdam, The Netherlands; 12Iridium Netwerk, Antwerp, Belgium, University of Antwerp, Faculty of Medicine and Health Sciences, Radiation oncology, Antwerp, Belgium; 13MAASTRO-GROW School for Oncology and Developmental Biology- Maastricht University Medical Centre, Radiation oncology, Maastricht, The Netherlands Background: An extra radiation boost dose to the primary tumour bed in addition to whole-breast irradiation (WBI) reduces local recurrence (LR) risk after lumpectomy. As young age is a risk factor for LR, the young boost trial (NCT00212121) investigated whether an increased boost dose could improve local control in young patients. Here, we present the results of the 10-year primary analysis. Material and Methods: Between 2004 and 2011, patients≤50 yrs with pT1-2, pN0-2a invasive breast cancer after a microscopically complete excision (focally involved margins were allowed) were randomly assigned to receive a boost of 26 Gy (high) or 16 Gy (low) to the tumour bed. Patients were stratified by age, tumour size, lymph node involvement, interstitial/ external boost, and institution. Primary endpoint was local control at 10 years. The revised design (2008) assumed a 3.5% difference in local control at 10 years (from 92 to 95%; power 90%; two-sided significance level α of 5%). All new tumours in the ipsilateral breast were counted as LR. We used competing risk analysis with death as competing risk. Results: In total, 2421 patients were randomized in 32 centres in the Netherlands, France, and Germany. 1211 patients were assigned to a high and 1210 patients to a low boost. Median follow-up was 11.7 years. Baseline characteristics were well-balanced between both two arms. Median age at diagnosis was 45 years (IQR 41-48), the median pathological diameter was 15 mm (IQR 1-80), and 70% was pN0. Tumours were grade 2 or 3 in.82 % and subtype was 67% ER+HER2-, 20% TNBC, and 13% HER2pos. 65% was treated with a sequential boost; 35% with a simultaneously integrated boost. Boost techniques consisted of X-ray beams in 75%, electrons in 20%, 1% interstitial boost and 4% others. Systemic treatment was given to 82% of patients. In total, 109 local recurrences have occurred (61 low boost, 48 high boost). LR was the first event for 42 patients in the low boost and 23 patients in the high boost arm. The 10-year LR-rate for patients treated with a low boost was 4,4% (95% CI 3,4-5,8) versus 2,8% (95% CI 1,9-3,9) in patients treated with a high boost, HR 0.61 (95% 0.39-0.96), p 0.032. Factors significantly associated with LR in multivariable analysis were boost dose, final margin status, subtype, and the use of chemotherapy. The cumulative incidence of marked or moderate fibrosis in the boost area was 27% patients treated with a low boost vs 48% patients treated with a high boost. Conclusions: Local control in young breast cancer patients was excellent. The primary endpoint that a high radiation boost after whole-breast irradiation improves local control by at least 3.5% was not met. The small statistically significant benefit does not justify the increased impact on cosmetic outcomes.

An interview with: Adri Voogd PhD, Associate Professor of Clinical Epidemiology, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, The Netherlands  MILAN, Italy—Although outcomes following breast conserving surgery (with or without radiotherapy) for ductal carcinoma in situ (DCIS) are excellent, it is still not clear which cases would never have progressed in all events. A 30-year-long population-based epidemiology study reported to the 14th European Breast Cancer conference held in Milan has now brought some granular detailed data showing that breast conserving therapy had become increasingly effective in preventing the emergence of breast cancer over the long term, but that clinical judgement is still needed to balance the benefits against the risks and costs of intervening. The population-based, Netherlands Cancer Registry retrospective cohort study of 25,719 women with DCIS diagnosed from 1989 up to 2021 (all of whom were treated with standard conservative therapy) found there were both successes and limitations with the current standard of care for DCIS. Surprisingly, long-term risk appeared to have been unrelated to tumor grade. Also: despite a continuing improvement in outcomes during this time period, the investigators concluded that specific molecular predictors of outcome still needed to be identified to distinguish intrinsically low-risk tumors (that did not require even conservative therapy) from those that carry a higher risk, and are highly likely to benefit from breast conserving surgery and radiotherapy. After reporting the study findings in Milan, study author Adri Voogd PhD, Associate Professor of Clinical Epidemiology in the Faculty of Health, Medicine and Life Sciences at Maastricht University, Maastricht, The Netherlands, talked with Peter Goodwin. Adri Voogd INTERVIEW IN (GOODWIN): “Breast conserving therpy was  ………” OUT:  “….. for the Audio Journal of Oncology, I’m Peter Goodwin.” 15:53 secs 2024 EBCC, Milan Mini Oral session, Abstract 13: https://event.eortc.org/ebcc14/wp-content/uploads/sites/31/2024/03/EBCC14-Abstract-Book.pdf https://www.nature.com/articles/s41416-024-02785-6 https://www.ejcancer.com/article/S0959-8049(24)00209-0/fulltext Abstract: “Invasive recurrence after breast conserving treatment of ductal carcinoma in situ of the breast in the Netherlands between 1989 and 2021: Time trends and the association with tumour grade” Authors: O’Leary1, L. Duijm2, L. Boersma3, M. van der Sangen4, L. de Munck5, J. Wesseling6, R.J. Schipper7, A. Voogd1. 1Maastricht University, Department of Epidemiology, Maastricht, Netherlands; 2Canisius Wilhelmina Hospital, Department of Radiology, Nijmegen, Netherlands; 3Maastricht University Medical Centre, Department of Radiation Oncology MAASTRO, Maastricht, Netherlands; 4Catharina Hospital, Department of Radiation Oncology, Eindhoven, Netherlands; 5Netherlands Comprehensive Cancer Organization, Department of Research and Development, Utrecht, Netherlands; 6The Netherlands Cancer Institute, Department of Pathology, Amsterdam, Netherlands; 7Catharina Hospital, Department of Surgery, Eindhoven, Netherlands Background: The aim of this study was to provide insight in trends and up-to- date figures of the risk of invasive ipsilateral breast cancer (iIBC) after breast conserving surgery (BCS) of ductal carcinoma in situ (DCIS) with or without adjuvant radiotherapy (RT) and to compare these figures with the risk to develop an invasive breast cancer in the contralateral breast (iCBC). A second aim was to analyze the association between DCIS grade and the risk of iIBC and to compare DCIS grade with the histological grade of the subsequent iIBC. Patients and Methods: In this population-based, retrospective cohort study, the Netherlands Cancer Registry collected information on 25,719 women with DCIS diagnosed in the period 1989–2021 who underwent BCS. Of these 19,034 (74%) received adjuvant radiotherapy. Kaplan-Meier and Cox multivariable regression analyses were performed. Results: 1,135 patients experienced an iIBC. The 10-year cumulative iIBC incidence rates for patients diagnosed in the periods 1989–1998, 1999–2008 and 2009–2021 and undergoing BCS only were 12.6%, 9.0% and 5.0% (P < 0.001), respectively. For those undergoing BCS with RT these figures were 5.7%, 3.7%% and 2.2%, respectively (P < 0.001). The 10-year iCBC rates remained stable: 4.4%, 5.5% and 4.5%, respectively, for the periods 1989– 1998, 1999–2008 and 2009–2021 (P = 0.24). In the multivariable analysis, no statistically significant association was found between the grade of DCIS and the risk of iIBC, neither for the patients undergoing BCS only, nor for those undergoing BCS with RT; the hazard ratio’s for iIBC for DCIS grade 3 versus DCIS grade 1 were 1.11 (95% CI 0.84–1.48, P = 0.47) and 1.04 (95% CI 0.80–1.37, P = 0.75) for the patients who underwent BCS and those undergoing BCS with RT, respectively. Information on grade of DCIS and grade of the subsequent iIBC was available for 721 patients (63.5%). Of the 189 patients with DCIS grade 1, 23 (12%) developed grade 3 iIBC, compared to 62 (24%) of the 256 patients with DCIS grade 2 and 123 (45%) of the 275 patients with DCIS grade 3 (P < 0.001) Conclusions: Since 1989 the risk of iIBC has decreased substantially in patients with DCIS undergoing BCS. Patients currently treated with BCS without RT have a risk of iIBC that is similar to the risk of developing iCBC and patients with adjuvant RT have a risk of iIBC which is 50 percent lower than the risk of iCBC. These low risks of iIBC might have implications for the clinical follow-up of patients with DCIS, such as the frequency of control visits and mammography. Our findings that DCIS grade is not significantly associated with the risk of iIBC stresses the need to intensify research on the tumour biology of DCIS. First, to identify those lesions that have a high risk to become invasive and recur as poorly differentiated invasive breast cancer and second, to identify the ones that are most sensitive to RT. No conflict of interest. European Journal of Cancer 200S1 (2024) 113617  

An interview with Annemiek van Hemert MD PhD, Surgical Oncology Department, Antoni van Leeuwenhoek-Netherlands Cancer Institute (AVL-NKI), Amsterdam Netherlands MILAN, Italy—Four out of five patients with extensive nodal spread of their breast cancer could be spared extensive axillary dissection, if a new method of marking lymph nodes is used. That’s according to the findings of a study from Amsterdam reported at the European Breast Cancer Conference held in Milan. Annemiek van Hemert MD PhD, from the Surgical Oncology Department of the Antoni van Leeuwenhoek-Netherlands Cancer Institute (AVL-NKI) in Amsterdam, The Netherlands, reported her finding from a study using the MARI protocol (“Marking Axillary lymph nodes with Radioactive Iodine seeds”) that predicts cancer outcomes. The protocol was developed at the AVL Hospital in 2014 and is now being used in several Dutch hospitals. After her talk at the Milan conference, van Dr. van Hemert talked with the Audio Journal of Oncology’s chief correspondent Peter Goodwin: Annemiek van Hemert MD PhD (Interview) IN: (GOODWIN) “Annemiek, it’s lovely to have you here in the podcast studio ….OUT:  …..breast cancer conference, I’m Peter Goodwin. 10:15 secs EBCC ABSTRACT 14 “Omission of axillary lymph node dissection in cN2-3 breast cancer patients with an excellent response on primary systemic treatment is safe: 4-year oncologic outcome of the MARI protocol” https://cm.eortc.org/cmPortal/Searchable/ebcc14/config/Normal/#!sessiondetails/0000107230_0 https://www.ejcancer.com/article/S0959-8049(24)00210-7/fulltext Background: Axillary lymph node staging techniques (e.g., sentinel lymph node biopsy, MARI = Marking Axillary lymph nodes with Radioactive Iodine seeds, and TAD = targeted axillary dissection) after primary systemic therapy (PST) are associated with low false negative rates. This observation has stimulated the use of tailored axillary treatment, including the omission of axillary lymph node dissection (ALND). However, robust data on the oncologic outcomes following tailored axillary treatment after PST are lacking, especially in patients with extensive nodal disease. In this study, we present the axillary recurrence rate, disease free survival and overall survival of node positive breast cancer patients with >3 suspicious axillary lymph nodes treated according to the MARI-protocol. Methods: This prospective registry study was conducted between 2014 and 2021. We enrolled patients with pathologically proven node positive breast cancer and >3 suspicious axillary lymph nodes who were treated according to the MARI protocol. Clinical nodal stage pre-PST was assessed by FDG-PET/CT. After PST, the MARI node was excised. Patients with a pathologic complete response (pCR) of the MARI node received radiation treatment. Patients with residual disease of the MARI node received ALND plus radiotherapy (RT). Primary endpoint was axillary recurrence rate (aRR). Secondary endpoints were invasive disease-free survival (DFS) and overall survival (OS). Survival estimates were calculated using the Kaplan-Meier method. Results: Of 218 patients included, 86 (39%) patients had hormone receptor positive (HR+)/ human epidermal growth factor 2 negative (HER2-) breast cancer; 41 (19%) HR+/HER2+; 36 (17%) HR-/HER2+ and 55 (25%) had triple negative (TN) breast cancer. Median (IQR) age was 50 (42–57) years. FDG-PET/CT identified extra-axillary lymph nodes (periclavicular/ parasternal) in 39% (n = 85) of the patients. 47% of patients (103 of 218) had a pCR of the MARI node and were treated with RT alone, whereas 53% of patients (115 of 218) had residual disease of the MARI node and underwent ALND plus RT. Median (IQR) follow up was 44 (26–62) months. As shown in table 1, aRR was 2.9% (n= 3) in the MARI-pCR group treated with RT alone and 3.5% (n = 4) in MARI-non pCR group treated with ALND and RT. Invasive DFS and OS was worst in MARI-non pCR patients who underwent ALND plus RT. Conclusion: Omission of axillary lymph node dissection after PST in selected node positive breast cancer patients with >3 suspicious lymph nodes using the MARI protocol is associated with an excellent oncologic outcome. MORE: Breast cancer patients can safely avoid extensive removal of lymph nodes if they respond well to primary systemic treatment Milan, Italy: Patients with breast cancer that has started to spread to the lymph nodes in the armpit can safely avoid extensive removal of the lymph nodes if their treatment is tailored to their response to cancer-killing therapies such as chemotherapy before surgery. In a presentation to the 14th European Breast Cancer Conference today (Friday) in Milan, Annemiek Van Hemert, a doctor and PhD student in the Surgical Oncology Department of Antoni van Leeuwenhoek-Netherlands Cancer Institute (AVL-NKI) in Amsterdam (The Netherlands), said: “If we are able to predict the response based on the removal of only one lymph node, it means we can safely avoid extensive removal of the lymph nodes if no living tumour cells are left. This will avoid serious complications, such as painful swelling in the arm, known as lymphoedema. “However, although clinicians use a number of staging techniques to predict the response, until now robust data on cancer outcomes have been lacking, especially in patients whose cancer has spread to more than three lymph nodes.” Dr Van Hemert and colleagues, led by Professor Marie-Jeanne Vrancken Peeters at the AVL-NKI, carried out a study involving 218 patients between 2014 and 2021 to investigate cancer outcomes of the MARI protocol (“Marking Axillary lymph nodes with Radioactive Iodine seeds”). The protocol was developed at the AVL Hospital in 2014 and is now being used in several Dutch hospitals. Today’s presentation gives outcomes after four years for the rate of cancer recurrence in the axillary nodes, patients’ overall survival and disease-free survival. “We focused on patients with more extensive axillary lymph node disease: the patients where we know there were cancer cells in more than three nodes. We used FDG-PET/CT scans to assess the extent of cancer spread to the lymph nodes,” said Dr Van Hemert [1]. “We marked the largest axillary lymph node with a radioactive iodine seed. After this, patients underwent primary systemic treatment: either chemotherapy or targeted therapies that find and attack cancer cells. Then surgery was performed. During the surgery, we only removed the marked lymph node, the MARI node, and examined it for any remaining living tumour cells. “Whenever the MARI node showed there were no residual tumour cells, in other words a pathological complete response (pCR) to the primary systemic treatment, then we did not remove any additional lymph nodes. Patients who had residual disease in the MARI node had further lymph nodes removed: known as an axillary lymph node dissection. All patients received radiation treatment.” The MARI procedure had a false negative rate of 7% which means that it missed living cancer cells in 7% of cases. After an average of 44 months (with a range of 26-62 months), the rate of cancer recurrence in the axillary nodes was 2.9% in the 103 patients who received radiation alone with no further lymph node removal – 47% of the study’s 218 patients. “In addition, survival rates after 44 months in these patients were excellent,” said Dr Van Hemert. “The overall survival rate was 95%, and 89% of patients survived without a recurrence of invasive disease. This means that we can safely omit the extensive removal of axillary lymph nodes in patients who achieve a pCR in the MARI node after primary systemic treatment.” The axillary recurrence rate in the 115 patients (53%) who required further lymph node removal was 3.5%, with an overall survival rate of 90% and a disease-free survival rate of 82%. She said primary systemic treatment had improved greatly in recent years, and up to 70% of patients treated this way achieved a pCR, but surgeons were still removing all the axillary lymph nodes. “The pathologist would say: ‘Nice, you have removed 18 lymph nodes and none of them contained residual tumour cells’. So this raised the question: did we do the right thing for the patient by removing so many nodes with all the ensuing complications? “We hope that other clinicians will think of implementing this de-escalation strategy so that more patients with breast cancer will benefit from what we have shown: surgical removal of axillary nodes can be safely omitted in around 80% of patients treated with primary systemic therapy.” The researchers will be collecting further data on outcomes over a longer period. They have also started the DESCARTES trial [2] to investigate the safety of omitting radiation treatment in a selected group of patients with tumours smaller than two centimetres in diameter, no evidence of the cancer spreading to the lymph nodes and pCR after primary systemic treatment. The co-chair of the 14th European Breast Cancer Conference is Dr Fiorita Poulakaki, Head of the Breast surgery Department at Athens Medical Centre Hospital, Greece, and Vice President Europa Donna, the European Breast Cancer Coalition, and she was not involved with this particular research project. She commented: “When we treat patients for breast cancer, it is important to ensure that treatment itself causes as little harm to the patients as possible. The results from this study suggest a way to help us avoid side effects that affect the quality of life and can sometimes cause considerable long-term distress to patients. Every day we cure patients, making sure they live long lives, but at the same time we should care also about survivorship issues. We look forward to further results from this trial.”    

An interview with: Tim Rattay MBChB PhD, Consultant Breast Surgeon, University Hospitals of Leicester, Associate Professor in Breast Surgery, Leicester Cancer Research Centre, University of Leicester, England, UK. A report from the 14th European Breast Cancer Conference, Milan, Italy MILAN, Italy—An artificial intelligence tool can predict the risk of lymphedema in a particular patient after breast cancer radiotherapy, according to research findings from Leicester University in the United Kingdom. The 2024 European Breast Cancer Conference in Milan heard how AI can help cancer doctors to individualize radiotherapy regimens after surgery so as to minimize toxicity. Tim Rattay MBChB PhD, Associate Professor in Breast Surgery at the Leicester Cancer Research Centre, University of Leicester and Consultant Breast Surgeon at the University Hospitals of Leicester in the UK, told the conference about his group’s machine-learning algorithm: PRE-ACT (Prediction of Radiotherapy side Effects using explainable AI for patient Communication and Treatment modification) that predicts post-operative lymphedema. After reporting his research in Milan, he gave Peter Goodwin the details. Tim Rattay MBChB PhD: IN: (GOODWIN) “Artificial intelligence …….OUT:  ….. For the Audio Journal Oncology, I’m Peter Goodwin” 14:05 secs EBCC Abstract no: 23: “Development of an explainable AI prediction model for arm lymphoedema following breast cancer surgery and radiotherapy”, https://cm.eortc.org/cmPortal/Searchable/ebcc14/config/Normal/#!sessiondetails/0000108900_0 MORE: AI tool for breast cancer patients following surgery  An international team of researchers, led by the University of Leicester, has developed an artificial intelligence (AI) tool that can predict which breast cancer patients may be at risk of side effects after surgery and radiotherapy. Dr Tim Rattay, a consultant breast surgeon and Associate Professor at the University’s Leicester Cancer Research Centre, presented the development at the 14th European Breast Cancer Conference (EBCC14) in Milan this week (21 March), explaining that the tool will be tested in a clinical trial towards the end of the year in the UK, France, and Netherlands. Some of the factors that increase the risk of side effects are already known, but the PRE-ACT project (Prediction of Radiotherapy side Effects using explainable AI for patient Communication and Treatment modification) aims to make more accurate predictions for each individual patient, as well as providing easily understandable explanations for doctors and patients. Dr Rattay said: “The explainable AI tool shows the reasoning behind its decision-making so it’s easier not only for doctors to make decisions, but also to provide data-backed explanations to their patients. “Thankfully, long-term survival rates from breast cancer continue to increase, but for some patients, this means having to live with the side effects of their treatment, including skin changes, scarring, lymphoedema, which is a painful swelling of the arm, and even heart damage from radiation treatment. “That’s why we’ve developed an AI tool to inform doctors and patients about the risk of chronic arm swelling after surgery and radiotherapy for breast cancer. We hope this will assist doctors and patients in choosing options for radiation treatment and reduce side effects for all patients.” The team of researchers used information from European datasets (REQUITE, Hypo-G and CANTO) on 6,361 breast cancer patients to train different machine learning algorithms to predict arm swelling up to three years after surgery and radiotherapy. The AI tool correctly predicted lymphoedema in an average of 81.6% of cases and correctly identified patients who would not develop it in an average of 72.9% of cases. The overall predictive accuracy of the model was 73.4%. Dr Rattay said: “Patients identified at higher risk of arm swelling could be offered additional supportive measures, such as wearing an arm compression sleeve during treatment, which has been shown to reduce arm swelling in the long-term. Clinicians may also use this information to discuss options for lymph node irradiation in patients, where its benefit may be fairly borderline. We will test the effect of the prediction model on clinician and patient behaviour and use of the prophylactic arm sleeve in the proposed clinical trial.” The researchers will incorporate the current AI model into software that can provide evaluations and predictions to doctors and patients. This will be tested when the PRE-ACT-clinical trial starts later this year. They are also developing the tool further so that it can predict other side effects, such as skin and heart damage. Dr Guido Bologna, Associate Professor at the University of Applied Sciences and Arts of Western Switzerland in Geneva, and co-investigator on the project added: “The final, best-performing model makes predictions using 32 different patient and treatment features, including whether or not patients had chemotherapy, whether sentinel lymph node biopsy under the armpit was carried out, and the type of radiotherapy given.” As part of the trial, the researchers will collect data on genetic markers and imaging data to improve the accuracy of the AI tools, although these will not be used to make predictions in the PRE-ACT trial. The study is funded by the Horizon Europe programme and it is hoped that approximately 780 patients will take part in the clinical trial by early 2026, with a follow up period of two years.    

An interview with Yasmin Civil MD PhD, UMC Hospital, Amsterdam, Netherlands. MILAN, Italy—Offering MRI-guided partial breast irradiation before surgery to patients with low-risk breast cancer could become the norm, according to Yasmin Civil MD PhD from the UMC Hospital in Amsterdam, who reported five-year results from the ABLATIVE trial of pre-operative MRI-guided single dose partial breast irradiation to the 14th European Breast Cancer Conference. Partial breast irradiation, given before breast-conserving surgery, achieved durable pathologic complete remissions in low-risk breast cancer, and even held out the prospect of surgery-free treatment for some patients. After giving her talk in Milan, Dr. Civil discussed the details of the ABLATIVE study findings with Peter Goodwin: AUDIO JOURNAL OF ONCOLOGY Podcast: IN:  (PETER GOODWIN) “If you are treating …… …OUT:  …… for the Audio Journal of Oncology, I’m Peter Goodwin. (9:13sec)  ABSTRACT:  https://www.ejcancer.com/article/S0959-8049(24)00203-X/abstract#%20 https://www.audiomedica.com/wp-content/2025/09/250908-Yasmin-Civil-Pre-Operative-Partial-Breast-Irradiation-Marked-Benefit-in-Low-Risk-Breast-Cancer-AJO-PRODUCTION-MASTER-copy.mp3 Yasmin Civil MD PhD “Pre-operative magnetic resonance guided single dose partial breast irradiation: five-year results of the ABLATIVE trial” BACKGROUND: Preoperative partial breast irradiation (PBI) can result in decreased irradiated volumes compared with postoperative PBI and may therefore lead to lesstoxicity and improved cosmetic outcome. In the multicenter ABLATIVE trial (NCT02316561), 15/36 patients achieved pathologic complete response 6–8 months after preoperative single-dose PBI. We now present long-term outcomes of preoperative single-dose PBI and breast conserving surgery (BCS) including late toxicity, tumor recurrence, survival, cosmetic outcome and quality of life in low-risk breast cancer patients. PROTOCOL: The ABLATIVE-2 trial is a multicenter prospective single-arm trial using single-dose ablative PBI in low-risk breast cancer patients. Patients ≥ 50 years with non-lobular invasive breast cancer ≤ 2 cm, grade 1 or 2, estrogen receptor-positive, HER2-negative, and tumor-negative sentinel node procedure are eligible. PBI treatment planning performed using a radiotherapy planning CT and -MRI in treatment position. The treatment delivery on a conventional or MR-guided linear accelerator. The prescribed radiotherapy dose is a single dose of 20 Gy to the tumor, and 15 Gy to the 2 cm of breast tissue surrounding the tumor. Follow-up MRIs, scheduled at baseline, 2 weeks, 3, 6, 9, and 12 months after PBI, are combined with liquid biopsies to identify biomarkers for pCR prediction. BCS performed 12 months after radiotherapy or after 6 months, if MRI does not show a radiologic complete response. The primary endpoint is the pCR rate after PBI. Secondary endpoints are radiologic response, toxicity, quality of life, cosmetic outcome, patient distress, oncological outcomes, and the evaluation of biomarkers in liquid biopsies and tumor tissue.  

An interview with Heather McArthur MD MPH, Clinical Director of Breast Cancer, Komen Distinguished Chair in Clinical Breast Research, University of Texas Southwestern Medical Center, Dallas, USA MILAN, Italy—Patients with early breast cancer testing positive for estrogen receptor (ER+) and negative for human epidermal growth factor receptor 2 (HER2-) had markedly better outcomes when immune checkpoint inhibitor therapy was added to their standard chemo- and endocrine therapies before and after surgery. The KEYNOTE-756 phase 3 clinical trial found that patients benefited from having neo-adjuvant and adjuvant pembrolizumab regardless of their age or menopausal status. The study was reported at the 14th European Breast Cancer Conference by Heather McArthur MD MPH, Clinical Director of the Breast Cancer Program and Komen Distinguished Chair in Clinical Breast Research, University of Texas Southwestern Medical Center in Dallas, USA, co-author of the study, led by Javier Cortés MD, Director of the International Breast Cancer Centre in Barcelona, Spain. After her talk she met up with Audio Journal of Oncology reorter Peter Goodwin. AJO podcast interview with Heather McArthur: IN:  “Hello and welcome to the Audio Journal of Oncology… OUT:  ….For the Audio Journal of Oncology, I’m Peter Goodwin. NOTES: The international KEYNOTE-756 trial (which has been running for eight years) randomized 1278 patients with ER-positive, HER2 negative, invasive ductal carcinoma to receive pembrolizumab or placebo in addition to neoadjuvant chemotherapy followed by adjuvant pembrolizumab or placebo in combination with an endocrine therapy. First author Javier Cortés MD, Director of the International Breast Cancer Centre in Barcelona, Spain, said the pathological complete response rate (PCR) was 24.3% in patients treated with pembrolizumab compared to 15.6% in patients treated with the placebo. Speaking before the EBCC 14 conference, Dr. Fatima Cardoso, Director of the Breast Unit of the Champalimaud Clinical Centre in Lisbon, Portugal (the principal investigator for the trial) said that Keynote 756 showed the addition of pembrolizumab to neoadjuvant chemotherapy significantly increased pathological response at the time of surgery, and that this had been true regardless of PD-L1 levels and oestrogen receptor positivity. However, the study found a bigger benefit with higher PD-L1 levels and in ER-low tumors.   ABSTRACT: 14th European Breast Cancer Conference Abstract no: 4: “Neoadjuvant pembrolizumab or placebo + chemotherapy, followed by adjuvant pembrolizumab or placebo plus endocrine therapy for early-stage high-risk ER+/HER2− breast cancer: Results from the phase 3 KEYNOTE-756 study”  https://www.ejcancer.com/article/S0959-8049(24)00200-4/fulltext    

An interview with: Laura J. van ’t Veer PhD, Professor of Laboratory Medicine, Co-leader of the Breast Oncology Program, Director of Applied Genomics, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco. MILAN, Italy—Around 25 per cent of patients with newly-diagnosed triple negative breast cancer will not benefit from neoadjuvant checkpoint inhibitor immunotherapy with pembrolizumab—even though it improves outcomes among the remaining majority. This finding comes from the I-SPY2 TRIAL and was reported at the 2024 European Breast Cancer Conference, held in Milan, Italy, by Laura van ’t Veer, Leader of the Breast Oncology Program at the University of California in San Francisco. A subset of patients with triple-negative early-stage breast cancers, identified in the study through a gene test as having “response predictive sub-types” had a very low likelihood of response to neoadjuvant pembrolizumab, suggesting that such patients could be spared the potential toxicities of immunotherapy. After her talk in Italy Dr van ’t Veer met up with Audio Journal of Oncology reporter Peter Goodwin to discuss the I-SPY findings. INTERVIEW: Laura J. van ’t Veer PhD “Hello, Peter Goodwin her with the Audio Journal of Oncology………..New drugs for breast cancer are traditionally tested in triple negative ……….. from me, Peter Goodwin, Good-bye” 15:46 secs EBCC 2024 ABSTRACT 2LBA “Immune subtyping in the Response Predictive Subtypes (RPS) identifies a subset of triple negative (TN) early- stage breast cancer patients with a very low likelihood of response to neoadjuvant immunotherapy (IO): results from 5 IO arms of the I-SPY2 TRIAL” https://cm.eortc.org/cmPortal/Searchable/ebcc14/config/Normal/#!sessiondetails/0000107210_0 Abstract title: Immune subtyping in the Response Predictive Subtypes (RPS) identifies a subset of triple negative (TN) early-stage breast cancer patients with a very low likelihood of response to neoadjuvant immunotherapy (IO): results from 5 IO arms of the I-SPY2 TRIAL Authors: D.M. Wolf1,, C. Yau2,, J. Haan3,, D. Wehkamp3,, A. Witteveen3,, A. Glas3,, M. Campbell2,, R. Nanda4,, J. Chien5,, R. Shatsky6,, C. Isaacs7,, A. Barcura3,, L. Mittempergher3,, M. Kuilman3,, D. Yee8,, A. DeMichele9,, J. Perlmutter10,, L. Pusztai11,, L. Esserman2,, L.J. van ‘t Veer PhD12,. 1University California San Francisco, Laboratory Medicine, San Francisco, USA. 2University California San Francisco, Surgery, San Francisco, USA. 3Agendia, Research and Development, Amsterdam, The Netherlands. 4University Chicago, Medicine, Chicago, USA. 5University California San Francisco, Medicine, San Francisco, USA. 6University California San Diego, Medicine, San Diego, USA. 7Georgetown University, Medicine, Washington DC, USA. 8University Minnesota, Masonic Cancer Center, Minneapolis, USA. 9University Pennsylvania, Medicine, Philadelphia, USA. 10Gemini Group, Advocacy, Ann Arbor, USA. 11Yale University, Medicine, New Haven, USA. 12University California San Francisco, Helen Diller Family Comprehensive Cancer Center, San Francisco, USA. Background: Neoadjuvant immunotherapy (IO) has become standard of care for early stage TN breast cancer. However, not all patients respond and IO poses significant risk of permanent, life altering immune related adverse events (iRAEs) including adrenal insufficiency and thyroid dysfunction. Previously we showed immune gene expression signatures dominated by STAT1/chemokine/cytokine/dendritic markers associate with pathologic complete response (pCR) in TN treated with IO and developed a clinically applicable Immune classifier (ImPrint) predicting response to IO for both TN and HR+ that is now being used in I-SPY2.2 as part of the Response Predictive Subtypes. This initial ImPrint classifier performed with high accuracy for TN and HR+ patients combined, though we noticed that this classifier could be further improved by reducing the false-negative rate for TN (ie high negative predictive value). Here we report the performance of a refined version of ImPrint for TN patients (ImPrintTN) from 5 IO arms of the I-SPY2 trial. Methods:  150 TN patients from 5 pooled IO arms (anti-PD1, anti-PDL1/PARPi, anti-PD1/TLR9 dual-IO, and anti-PD1 +/- LAG3 dual-IO, all plus taxane/anthracycline) and 128 patients from the taxane/anthracycline concurrent control arm were included in this analysis. Patients in IO arms with FFPE pre-treatment biopsies were divided into treatment- and response-balanced training and test sets; and an IO-response classifier was developed including additional immune signaling and checkpoint markers using pre-treatment mRNA from the training set (n=55). Patient biopsies were classified ImPrintTN+ (likely sensitive) vs. ImPrintTN- (likely resistant), by Agendia Inc using pre-treatment expression data. Performance of ImPrintTN for predicting pCR to IO in the test set, and overall was characterized using standard methods. Results: Overall, the pCR rate for TN over the 5 pooled IO arms was 54%. 66% of TN patients were ImPrintTN+. pCR rates with IO in the independent test set were 71% in ImPrintTN+ vs. 22% in ImPrintTN- (delta-pCR rate 49%; sensitivity=87%; negative predictive value (NPV)=78%). Similar results were observed in all 5IO arms taken together (test plus training), where pCR rates with IO were 74% in ImPrintTN+ vs. 16% in ImPrintTN- (delta-pCR rate 58%; sensitivity=90%; NPV=84%). In the control arm, pCR rates were 30% in ImPrint+ and 15% in ImPrint-, delta-pCR 15%). Conclusions: The https://www.audiomedica.com/wp-content/2025/08/240320-Laura-van-t-Veer-EBCC-2024-Predictive-Subtypes-AJO-PRODUCTION-MASTER-.mp3 Laura J. van ‘t Veer, PhD for TN predicts response and non-response to a variety of IO regimens tested in I-SPY2. Within the ImPrintTN- subset, pCR rates to IO regimens are very low, and similar to that of non-IO containing regimens. Prospective validation is ongoing in I-SPY2.2. Our current data suggest that ImPrintTN may help inform prioritization of IO vs other treatments for TN patients to best balance likely benefit vs risk of serious irAEs.

Érica A. Oliveira PhD: How to Overcome Drug Resistance: Patient Derived Organoids Study Finds Epigenetic Pathways in Colorectal Cancer Interviews with: Érica A. Oliveira PhD, Senior Scientific Officer, Genomics and Evolutionary Dynamics, Institute of Cancer Research, Sutton, London UK And: Christopher Sng MD, Clinical Research Fellow, Institute of Cancer Research and Royal Marsden Hospital, London LONDON, UK—New insights into understanding and overcoming cancer drug resistance have been announced by researchers from the Institute of Cancer Research and the Royal Marsden Hospital in London. Érica Oliviera PhD, Senior Scientific Officer for Genomics and Evolutionary Dynamics, and Christopher Sng MD, Clinical Research Fellow, both at the Institute of Cancer Research and Royal Marsden Hospital in London, tell the Audio Journal of Oncology’s Peter Goodwin about their research on colorectal cancer using so-called “organoids” which perform like miniature replicas of human organs. The research shows how epigenetic factors control drug resistance by influencing DNA expression. The findings set the scene for combatting resistance by using, agents, protocols and combinations designed to modify these epigenetic pathways. The research is published in Cancer Research Volume 85 Issue 15, 1st August 2025: “Epigenetic Heritability of Cell Plasticity Drives Cancer Drug Resistance through a One-to-Many Genotype-to-Phenotype Paradigm” [Cancer Res (2025) 85 (15): 2921–2938] https://aacrjournals.org/cancerres/article/85/15/2921/763888/Epigenetic-Heritability-of-Cell-Plasticity-Drives https://www.audiomedica.com/wp-content/2025/08/Erica-Oliveira-PRODUCTION-MASTER.mp3 Erica Oliveira PhD ABSTRACT Cancer drug resistance is multifactorial, driven by heritable (epi)genetic changes but also by phenotypic plasticity. In this study, we dissected the drivers of resistance by perturbing organoids derived from patients with colorectal cancer longitudinally with drugs in sequence. Combined longitudinal lineage tracking, single-cell multiomics analysis, evolutionary modeling, and machine learning revealed that different targeted drugs select for distinct subclones, supporting rationally designed drug sequences. The cellular memory of drug resistance was encoded as a heritable epigenetic configuration from which multiple transcriptional programs could run, supporting a one-to-many (epi)genotype-to-phenotype map that explains how clonal expansions and plasticity manifest together. This epigenetic landscape may ensure drug-resistant subclones can exhibit distinct phenotypes in changing environments while still preserving the cellular memory encoding for their selective advantage. Chemotherapy resistance was instead entirely driven by transient phenotypic plasticity rather than stable clonal selection. Inducing further chromosomal instability before drug application changed clonal evolution but not convergent transcriptional programs. Collectively, these data show how genetic and epigenetic alterations are selected to engender a “permissive epigenome” that enables phenotypic plasticity. Significance: Drug resistance is driven by genetic–epigenetic memory that enables cancer cells to adopt multiple phenotypic states depending on environmental conditions, supporting integration of evolutionary principles into biomarker discovery and personalized treatment strategies.