Importance:Molecular residual disease (MRD) detection has potential to transform the selection of adjuvant therapy. Most evidence is from tumor-informed assays. Tissue-free assays not requiring sequencing of the primary tumor may simplify workflows if they offer accuracy similar to that of tumor-informed assays. Objective:To evaluate tissue-free circulating tumor DNA (ctDNA) analysis in patients with triple negative breast cancer (TNBC) and compare the tissue-free assay with tumor-informed assay results. Design, Setting, and Participants:This was a prognostic and exploratory analysis of patients with TNBC at moderate to high risk of recurrence who were participating in the ctDNA surveillance period of c-TRAK TN, a multicenter phase 2 clinical study. Plasma samples were collected from participants every 3 months for up to 2 years after the completion of adjuvant therapy and analyzed prospectively with digital polymerase chain reaction (dPCR). Data for the analysis were from a database lock on September 28, 2021, with subsequent follow-up through January 18, 2023. Data were analyzed from July 2025 to May 2026. Intervention or Exposure:Tissue-free assay leverages cancer differential methylation patterns to detect ctDNA. Main Outcome and Measures:Recurrence-free survival by tissue-free ctDNA detection status. Comparison between tissue-free ctDNA detection and both dPCR and whole-exome sequencing-powered multivariant tumor-informed assays. Results:The analysis included 1026 plasma samples from 159 patients (mean [SD; range] age, 51.4 [11.4; 25.0-78.0] years; 159 females [100%]). The tissue-free assay detected ctDNA in 54 patients (34.0%), with detection strongly associated with risk of recurrence (HR, 27.2; 95% CI, 13.7-54.2; P < .001). Among patients with ctDNA detected by both the tissue-free assay and dPCR (42 patients [26%]), tissue-free detection occurred at an earlier time point in 14 patients (33.3%); dPCR detection occurred before tissue-free detection in no patients. Median lead time to recurrence was 7.9 (95% CI, 6.1-10.5) months for tissue-free vs 5.8 (95% CI, 3.3-10.0) months for dPCR (HR, 0.57; 95% CI, 0.34-0.95; P = .03). Concordance between tissue-free and multivariant tumor-informed assays was good. Among patients detected by both assays (41 of 133), 12 of 41 (29.3%) had ctDNA detected earlier by multivariant tumor-informed assay with 1 (2.4%) earlier by the tissue-free assay. Median lead times to recurrence were 7.6 (95% CI, 4.6-10.5) months with tissue-free and 7.1 (95% CI, 5.7-10.0) months with multivariant tumor-informed assay (HR, 1.46; 95% CI, 0.87-2.44; P = .15). Conclusion and Relevance:In this prognostic study, tissue-free ctDNA detection during surveillance was strongly prognostic for recurrence in patients with TNBC. Comparable lead times between the tissue-free and multivariant tumor-informed assays support tissue-free MRD detection in a clinical trial setting, permitting ctDNA testing when tissue is not available.

Abstract Purpose: Early identification of response to neoadjuvant chemotherapy (NACT) in triple-negative breast cancer (TNBC) can facilitate timely treatment adjustments. This phase II analytic and clinical validity study (TNPET01) evaluated whether [18F]-fluorodeoxyglucose (FDG) or [18F]-fluorothymidine (FLT) positron emission tomography (PET)/CT can predict response after one NACT cycle Patients and Methods: In part A (analytic validity phase), patients with stage II–III TNBC were randomized to FDG or FLT imaging. Baseline repeat scans assessed test–retest repeatability, followed by a post–cycle 1 scan in week 3. Dynamic imaging preceded static acquisitions at 90-, 120-, and 180-minute (FDG) or 90-minute (FLT), evaluating SUVmax, SUVmean, SUVpeak, and SULpeak. Tracer selection for part B was based on prespecified repeatability and response criteria. Part B (clinical validity phase) examined associations between changes in SUV (ΔSUV) after one cycle and post–cycle 3 MRI, end-of-treatment MRI, and residual cancer burden (RCB) at surgery. Exploratory analyses assessed relationships between PET response, Ki-67, and tumor-infiltrating lymphocytes (TIL). Results: Twenty-two patients were enrolled. Both tracers met repeatability thresholds; FDG was selected for part B owing to superior image quality and availability. Fourteen patients underwent FDG-PET across both parts. Reductions in SUVmax/mean after one cycle significantly correlated with mid-treatment MRI response and final RCB score (P < 0.005). Early post–cycle 1 increases in TILs correlated with greater metabolic reduction and lower RCB, whereas Ki-67 changes were not predictive. Conclusions: FDG-PET after one NACT cycle was associated with histologic response and stronger correlations with RCB than MRI. These findings support PET as an early biomarker for treatment response and warrant validation in larger, immunotherapy-era trials.

Importance:Molecular analyses of biospecimens collected from study participants are essential for identifying biomarkers that can tailor treatments to specific subsets of patients who are most likely to benefit. Sharing of data and biospecimens from clinical trials enables personalized, patient-centric use of cancer therapies and accelerates the development of new treatments. Objective:To describe obstacles to sharing data and biospecimens and to propose strategies to enhance access and collaboration. Evidence Review:This is a Special Communication authored by 53 academic investigators and patient representatives from the breast cancer community with extensive experience in conducting clinical and translational research. The article also evaluates the impact of biomarker research on specifying responsive subpopulations in the 29 registrational clinical trials that have led to approval of a new drug for treatment of breast cancer between 2017 and 2024. Findings:Clinical trial participants are increasingly asked to provide tissue and/or body fluid biospecimens for biomarker research that is typically controlled by the sponsoring pharmaceutical company, but published biomarker studies are rare. Among 29 breast cancer registrational studies reported in the past 8 years, none resulted in biomarker research that restricted a drug's approved indication. Herein, strategies to maximize the value of clinical data and biospecimens contributed by participants are proposed, thereby supporting the shared goals of the pharmaceutical industry and academia to improve patient care. These strategies include (1) establishing coleadership structures involving academia and patients in clinical trial design and conduct, (2) ensuring that informed consent forms state that data and biospecimens will be shared with academia for future research, (3) requiring the sharing of clinical data as a condition for regulatory approval, and (4) enabling access to biospecimens and translational research data for independent studies on biomarkers that may indicate drug efficacy and toxicity. Conclusions and Relevance:Data and biospecimen sharing from registrational trials has been suboptimal. Improving clinical data, biospecimens, and biospecimens' related data sharing requires concrete actions and a multidimensional stakeholder approach to accelerate the impact of clinical cancer research on the quality of patient care.

To facilitate equitable access to novel treatments, cancer trial participants should represent as far as possible those that will receive the treatment in practice. We can identify groups who rarely participate in cancer trials by collecting demographic data from participants. In the UK, there is no standardised practice around demographic data capture, leading to inconsistent collection across trials. A lack of systematically collected and published quantitative data from participants in UK cancer trials may limit our ability to identify underrepresented groups. We reviewed availability and completeness of demographic data recorded from 2235 participants in six bladder and six head and neck cancer trials conducted by the Clinical Trials and Statistics Unit at the Institute of Cancer Research (ICR-CTSU) between 2001 and 2023. To assess the representativeness of trial populations, demographic data from trial participants were compared with published data (NHS Digital) from 260,350 people who were treated for these cancers between 2013 and 2022 in England, using chi-squared goodness-of-fit tests and one-sample tests of proportion. A survey was distributed to 12 clinical trials units conducting similar trials to establish which demographic data are routinely collected across the UK. Data on ethnicity, postcode, smoking status, and co-morbidity burden were inconsistently captured across ICR-CTSU trials, with missing data. Amongst the overall trial population, people older than 80 (n = 486/2235, 22

BACKGROUND:In clinical trials, eligibility criteria define a population who may benefit from the intervention without incurring undue safety risks. Despite their value, overly stringent eligibility criteria may pose barriers to inclusive recruitment. They may disproportionately exclude groups of people more likely to be diagnosed at later cancer stages, or have specific co-morbidities which can be associated with socio-demographic or ethnic background. The National Institute for Health and Care Research Innovations in Clinical Trial Design and Delivery for the Under-served (NIHR-INCLUDE) guidance highlighted several groups of people who may be underserved by clinical research. The aim of this review was to assess eligibility criteria in bladder and head and neck oncology trials and consider their potential impact on potentially underserved groups. METHODS:This scoping review included multi-centre, interventional, phase II and III trials in bladder or head and neck cancer, which recruited UK participants between 2013 and 2023. Trials were identified via searches of ClinicalTrials.gov, the International Standard Randomised Controlled Trial Number (ISRCTN) registry, and NIHR Clinical Portfolio Management System (CPMS). Trials' eligibility criteria were categorised and analysed narratively. Trial parameters (recruitment period, funding type, and whether they were of investigational medicinal products (IMPs)) were cross-tabulated with common exclusion criteria using Fisher's exact test. RESULTS:Thirty-eight bladder and 30 head and neck cancer trials met the selection criteria. Twenty-eight out of 68 (41%) had non-commercial sponsors. Fifty-six out of 68 (82%) were of IMPs. Forty-one out of 68 (60%) were industry-funded. Fifty-one out of 68 (75%) were for locally advanced, metastatic, or recurrent disease. Common exclusion criteria relating to pregnancy, performance status, HIV status, and cognitive ability may disproportionately impact some underserved groups suggested by the NIHR-INCLUDE guidance. CONCLUSIONS:This review highlights common exclusion criteria which may disproportionately exclude underserved groups from UK bladder and head and neck oncology trials. To facilitate accessibility to oncology trials, sponsors and triallists should consider how potentially underrepresented groups may be safely included during development of eligibility criteria.

Background: Invasive Lobular Carcinoma (ILC) represents about 15% of all invasive breast cancers (BC). ILC seldom exhibits overexpression of human epidermal growth factor 2 (HER2+), and majority of research focuses on ER+ HER2-negative phenotypes. There is limited data on response of ER+HER2+ ILC to endocrine therapy (ET) and the therapeutic efficacy of combined chemotherapy and anti-HER2 treatments (C+T). This study aims to report the biological responsiveness of ER+HER2+ ILC to perioperative aromatase inhibitors (POAI) and their clinical outcome within POETIC trial, one of the most comprehensive studies of the ER+HER2+ BC. Methods: POETIC trial was a phase III study of post-menopausal patients with ER+ BC, randomized 2:1 to 2-weeks of POAI or control, followed by standard-of-care. This study focused on ER+HER2+ BC (n = 342), 27 of whom had ILC at baseline (B) (17 POAI and 10 control). Ki67 levels were assessed at B and on-treatment (2wk) (low ≤10%; high >10%). Biological response to AI were categorized to LowB -Low2wK (LL); HighB –Low2wk (HL) or HighB–High2wk (HH). Baseline and on-treatment samples were gene expression profiled (NanoString BC360TM) for BC intrinsic subtypes (IS) (Luminal A: LumA, Luminal B: LumB, HER2-enriched: HER2E, Basal) and 46 gene signatures. T-tests were used to compare gene expression profiles (GEP) between ILC and invasive ductal carcinoma (IDC). P-values were adjusted using false discovery rate (FDR). Time to recurrence (TTR) was estimated using Kaplan-Meier method. Results: Among the 27 ILC cases, the clinicopathological characteristics were similar to IDC. At the molecular level, the frequencies of IS in ILC were 22% (n = 6) LumA, 37% (n = 10) LumB and 41% (n =11) HER2E, compared to IDC being 17% (51/301) LumA, 37% (112/301) LumB, 44% (133/301) HER2E, and 2% (5/301) Basal. In terms of early response to POAI in ILC, 33% (5/15) were HH, 53% (8/15) were HL and 14% (2/15) were LL. In comparison in IDC, 53% (100/188) were HH, 36% (68/188) were HL and 9% (17/188) were LL. The 5 HH ILCs were mainly HER2E (1 LumB, 4 HER2E), while most HL were Luminals (1 LumA, 5 LumB, 2 HER2E), and all LL were Luminals, showing the poor anti-proliferative effect conferred by HER2E. There were no distinct GEP associated with ILC compared to IDC in the hierarchical clustering of gene signature scores. IS and immune signatures drove the distinct expression patterns across the population of ILC and IDC. ILC had lower expression of cell adhesion than IDC (T-test FDR < 0.001). The impact of POAI to molecular changes were comparable based on histological tumor types and were driven by their intrinsics subtypes. The 5-year TTR survival probabilities of ILC and IDC were 88% and 89.5% respectively. Fifty-two percent (14/27) of ILC received C+T and all remained recurrence free. Out of the 48% (13/27) ILC that did not receive adjuvant C+T and were only treated with ET, three (23%) had recurrence at 0.7, 2.1 and 4.1 years. Sixty-one percent (183/301) of IDC received C+T, of which 8% (14/183) had a recurrence event. Forty-nine percent (118/301) of IDC did not receive adjuvant C+T, from which 17% (20/118) recurred. Conclusions: This study reported comprehensive study on the molecular features and their clinical behavior of the understudied ER+HER2+ ILC. Our findings suggested there were no distinct molecular profiles between ILC and IDC phenotypes of ER+HER2+ at baseline; their response and molecular changes after POAI were driven by IS as expected. While there was an enrichment of early sensitive tumors to POAI, the combined C+T treatment and ET might represent a good option to preventing recurrence in clinical high risk ILC. However, the small sample size precludes definitive conclusions. Citation Format: Milana Bergamino Sirvén, Xixuan Zhu, Elena López-Knowles, Holly Tovey, Lucy Kilburn, Anthony Skene, Chris Holcombe, Alistair Ring, Ian Smith, John Robertson, Judith Bliss, Eugene F. Schuster, Mitch Dowsett, Maggie Chon U Cheang. Hormone receptor positive (ER+) HER2+ Lobular Breast Carcinoma: Molecular Response to Perioperative Endocrine Therapy and Clinical Outcomes in the POETIC Trial [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P1-11-14.

Background:Optimal surgical margin width in breast conserving surgery (BCS) for ductal carcinoma in situ (DCIS) is not established. The United Kingdom (UK) Association of Breast Surgery (ABS) recommended a 1 mm margin, whereas a minimum of 2 mm has been recommended in the United States of America (USA). This paper uses precise histological margin width data from UK national datasets to understand the impact of surgical margins on time to recurrence (TTR). Methods:Patients were included if aged ≥45-years with a new diagnosis of DCIS alone, between 2003 and 2014, within the English National Health Service (NHS) Breast Screening Programme. Primary treatment included BCS and a minimum histological excision margin width recorded. Exclusion criteria included: prior history of DCIS; prior history of invasive cancer or its diagnosis within 3-months of initial surgical treatment for DCIS. Data was extracted from NHS England National Disease Registration Service (NDRS), ABS and Sloane Project audits. Findings:16,907 patients diagnosed with DCIS having definitive BCS surgery were identified between 2003 and 2014. TTR was found to be significantly shorter for patients with surgical margins <1 mm vs ≥ 1 mm (adjusted hazard ratio (aHR) = 1·32; 95% (confidence interval) CI:1·06-1·63; p = 0·012); <2 mm vs ≥ 2 mm (aHR = 1·19; 95% CI:1·05-1·35; p = 0·0062) and ≥1-<2 mm vs ≥ 2 mm (aHR = 1·18; 95% CI:1·01-1·38; p = 0·032). There was no evidence that increasing the surgical margin width beyond 2 mm significantly improved TTR (aHR = 0·96; 95% CI: 0·86-1·08; p = 0·52 for ≥5 mm vs ≥ 2-<5 mm). The rate of recurrence across 14 years following BCS + radiotherapy was 1·2% per annum, 2129 (13%) patients had a recurrence of which 78% were invasive breast cancers. Interpretation:Patients with DCIS with histological margins of <2 mm, adjusted for other clinical factors, have significantly worse TTR compared to margins ≥2 mm. These findings may inform optimum treatment of patients with DCIS. Funding:An ABS grant covered the cost of data extraction by NHS England and medical writing assistance. The latter was provided by Edge Health, supervised by the co-authors.

Involving those with a lived experience of the relevant condition in the design of clinical research ensures that studies address real-world needs and priorities, enabling more relevant, ethical, and impactful outcomes. In 2019, the Breast International Group (BIG) established the BIG Patient Partnership to facilitate the meaningful involvement of people affected by breast cancer in the design and conduct of its studies. The members provide a strong international patient voice in academic breast cancer research. The partnership is based on 4 pillars: foundational and ongoing training, meaningful and systematic involvement, patients as a strategic driving force in BIG’s research, and promoting the value of the patients’ voice in research. In this paper, we describe a model to enable performing transnational clinical research for and with patient partners. We hope to inspire organizations and people who are burdened by cancer from different cultural backgrounds to develop an interactive, engaging, and empowering process for researchers and patient partners to work together.

572 Background: Anti-vascular endothelial growth factor (VEGF) tyrosine kinase inhibitors and checkpoint inhibitors (CPI) a standard-of-care treatment for clear cell renal cell carcinoma (ccRCC). We investigated the biology underpinning benefit of anti-VEGFR TKI in the phase II A-PREDICT trial (NCT01693822), evaluating pre- and post-treatment, fresh multiregion tumour biopsies in patients with metastatic ccRCC treated with first-line axitinib. Methods: We analysed 123 tumour samples from 52 patients, 28 with paired pre/post-treatment samples. Post-treatment samples included week-9, nephrectomy, and on-progression timepoints. ‘Responders’ had progression-free survival (PFS) ≥6 months (n=35), ‘non-responders’ with PFS <6 months (n=17). We applied a custom Nanostring panel for gene expression analysis and multiplex immunofluorescence (mIF) for orthogonal validation. Wilcoxin test was used to analyze paired observations. Results: At baseline, angiogenesis scores were similar between responders and non-responders (p=0.22). Post-treatment, the angiogenesis, vascular sprouting, and endothelial cell proliferation signature scores were significantly decreased (p=0.023, 0.0034, & 0.0082, respectively) in all patients, suggesting suppression of angiogenesis and neovascularisation irrespective of clinical outcomes. mIF in 3 patients (with PFS of 3, 5.6, & 100 months) confirms widespread intratumoral vessel depletion. Immune deconvolution analysis shows total levels of T cells and CD8 + T cells were similar pre- and post-treatment, suggesting axitinib did not enhance immune cell trafficking. Rather, axitinib promoted increased levels of exhausted CD8 + T cells post-treatment (p=0.01). M2 tumour-associated macrophages increased post-treatment in responders (p=0.033) but not in non-responders (p=0.44). A minority of patients had durable (>2 years) responses to axitinib (n=7/65, 6 with tissue for analysis). In these patients, we found higher levels of pre-treatment intratumoral cytotoxic immune cells (p=0.041) and NK cells (p=0.015) compared to patients with primary resistant disease. Conclusions: Axitinib suppressed angiogenesis and neovascularisation leading to intratumoral vessel depletion, and therapy response associates with features of an immunosuppressive TME. Baseline endogenous immune priming appears critical for durable response to anti-VEGF therapy. These data are relevant to understanding the clinical efficacy of combined anti-VEGF and CPI regimens. Clinical trial information: NCT01693822 .

Supplementary table 1 - Biomarkers of interest

This is an example of DDR-deficient case with high TILs and low gene-expression measurements. These cases were confirmed to have high TIL content (black delineation) and are characterized by both high tumour area- stromal area ratio as well as a high tumour cell- stromal cell ratio. Moreover, all these cases were characterized by high grade features, such as necrosis (blue delineation), high mitotic activity (green arrow), and high levels of atypia (blue arrow), and all had a solid growth pattern, with no formation of glands.

BACKGROUND:Integration of sustainability measures into clinical research would translate into less healthcare related climate impacts. METHODS:We assessed climate change impacts, existing sustainability engagement, and challenges and facilitators to climate change mitigation strategies among Breast International Group (BIG) members. A 30 item web based survey assessing climate impacts, sustainability engagement, challenges to and facilitators of engagement, and sustainability integration in funding applications was developed, and circulated electronically between November 2023 and March 2024. RESULTS:Thirty four members (research groups and data centres) and participating sites across 5 continents, and BIG headquarters responded. Twenty six responses were received from 21 organisations, 20 from 17 participating sites. No responses were obtained from 28 groups. Trial conduct at a third of member groups had been impacted by climate change impacts such as destroyed infrastructure. 78 % of groups agreed that sustainability should feature in future funding applications. Most respondents engaged in sustainability initiatives at a host institute and organisational level. However, 39 % of coordinating centres and 65 % of representative sites had none within clinical trials conducted by their organisation. The majority of respondents foresaw challenges to sustainability engagement including competing time pressure, staff attitudes and resource constraints. Of nine potential facilitators to engagement, funding, an evidence base for sustainable research practice and training were the leading themes. CONCLUSION:In the first global survey of its kind, a third of respondents reported that climate change had impacted trial conduct. Integration of sustainability measures was absent in a significant minority. Funding and dedicated resourcing would facilitate increased engagement in cancer clinical trials.

Background: TNBC is molecularly heterogeneous, showing varied responses to therapeutic agents (Txt). We developed a 140-gene classifier (TNBC-ICR) based on random-forest (RF) to cateogorize TNBC into four biological subgroups. It was trained and tested on 551 TNBC (Zhu ESMO Congress 2023), and had better precision in predicting time to recurrence with anthracycline-based (A) txt compared to TNBC-Baylor subtypes (Burstein Clin Cancer Res, 2015) in TACT2 trial (NCT00301925). Here, we assessed the genomic characteristics and clinical value of TNBC-ICR classifier to predict response for standard of care and emerging Txt. Methods: TNBC-ICR, consisting of 1000 decision trees, assigned each case to immune-enriched (IM), luminal-AR (LAR), mesenchymal-like (MES) or highly proliferative basal-like (BL-Prolif) based on RF probabilities linked to these subgroup features. Association with genomic characteristics and prognosis were tested in The Cancer Genome Atlas (n=155, TCGA Nature, 2012), METABRIC (n=269, Curtis Nature, 2012), and SCAN-B (n=571, Saal Genome Med, 2015). Association with pathological complete response (pCR) was tested across 4 neoadjuvant (NAT) clinical studies: 1) a combined cohort of MDACC, ISPY-1, LBJ/IN/GEI and USO (MDACC, n=188, Hatzis JAMA 2011), 2) CALGB 40603 (n=389, NCT00861705), 3) BrighTNess (n=482, NCT02032277) and 4) ISPY-2 (n=364, NCT01042379). These studies, all including Paclitaxel (P), assessed the additional benefits of Bevacizumab (Bev), Carboplatin (Carbo), PARP inhibitor (V) or Pembrolizumab (Pem), followed by A and Cyclophosphamide (C). Gene expression data (GE) was available for all studies, with batch correction applied to reduce platform effects before using the TNBC-ICR classifier. Statisical analyses included multivariable Cox regression models to assess the hazard ratio (HR), chi-squared tests to compare genomic characteristics and pCR rates among the subgroups and logistic regression models to assess the significance and odds ratio (OR) of tumor probabilities to IM, LAR, MES and BL-Prolif related to pCR. Results: Using whole exome sequencing data from TCGA and METATRIC (n = 306), TP53 was the most frequently mutated gene, observed in IM (88%), MES (76%), BL-Prolif (85%) and LAR (68%, p = 0.008), with PIK3CA mutations in LAR (41%) and the others (7%, p < 0.001). The pCR rates for IM, LAR, MES and BL-Prolif were as follows: MDACC (P+AC), 33% (18/54), 10% (3/30), 25% (9/36) and 48% (29/60), p = 0.002; CALGB 40603 (P+Carbo+AC+Bev), 67% (76/103), 56% (30/54), 36% (31/86) and 54% (73/136), p < 0.001; BrighTNess P+Carbo+V arm: 69% (51/74), 29% (8/28), 62% (34/55) and 43% (34/80), p < 0.001; P+Carbo arm: 73% (29/40), 37% (7/19), 62% (13/21) and 48% (20/42), p = 0.03; in P arm: 43% (16/37), 17% (3/18), 27% (8/30) and 34% (13/38), p = 0.21; ISPY-2 P arm: 22% (6/27), 50% (5/10), 12% (3/26) and 14% (3/22), p = 0.06; P+Pem arm: 100% (8/8), 60% (3/5), 40% (2/5) and 55% (6/11), p = 0.098; In P arms, pCR rate was generally low but addition of either Carbo or V increased pCR rates in IM and MES subtypes and addition of Pem over P increased pCR rates for IM and BL. There was no consistent association of TNBC-Baylor subtypes to pCR in these studies. Statistical modelling of TNBC-ICR classifier on txt response showed that probability to IM-subgroup predicted pCR (OR = 3.52, p < 0.001) in NAT and better recurrence-free survival in adjuvant chemotherapy-treated subgroups of SCAN-B (HR = 0.38, p = 0.04) and METABRIC (HR = 0.3, p = 0.04). Conclusion: Tumors with higher IM-features had increased pCR rates after NAT. We validated the reproducibility and clinical validity of TNBC-ICR classifier in predicting differential response to therapies, including taxane and immunotherapy, demonstrating its potential as a practical clinically relevant integrative biology-driven machine learning algorithm. Citation Format: Xixuan Zhu, Orsolya Sipos, Katherine A. Hoadley, Jane Bayani, Lucy Kilburn, John M.S. Bartlett, Judith Bliss, David Cameron, Andrew Tutt, Maggie Chon U Cheang. A 140-gene Machine Learning Classifier Predicts Survival and Response to Chemotherapy and Immunotherapy in 2500 TNBC [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P2-01-23.

BACKGROUND:The IMPORT LOW trial evaluated partial-breast radiotherapy with intensity-modulated radiotherapy in women with early-stage breast cancer at below average risk of ipsilateral breast tumour recurrence (IBTR). 5-year results concluded non-inferiority of IBTR for reduced-dose and partial-breast radiotherapy, with similar or lower frequency of adverse effects compared with whole-breast radiotherapy. We report outcomes after 10 years. METHODS:IMPORT LOW was a randomised, open-label, multicentre, non-inferiority, phase 3 trial. Women were eligible if they were aged 50 years or older and had had breast conservation surgery for unifocal invasive ductal adenocarcinoma, pT1-2 (tumour size of ≤3 cm), N0-1 (none to three positive axillary nodes), grades 1-3, with microscopic margins of non-cancerous tissue of 2 mm or more. Patients were ineligible if they had a previous malignancy of any kind (except non-melanomatous skin cancer), had undergone mastectomy, or had received neoadjuvant or concurrent adjuvant chemotherapy. Patients were randomly assigned (1:1:1) by randomly permuted blocks to radiotherapy regimens of 40 Gy in 15 fractions to the whole breast (whole-breast group), 36 Gy in 15 fractions to the whole breast plus 40 Gy in 15 fractions to the partial breast (reduced-dose group), or 40 Gy in 15 fractions to the partial breast (partial-breast group). Participants were stratified by treatment centre, without masking. The primary endpoint was IBTR. 10-year outcomes were analysed in the intention-to-treat population. Clinician-reported late adverse effects were evaluated in all participants with available data analysed according to allocated treatment. The study is registered in the ISRCTN registry (ISRCTN12852634) and is now complete. FINDINGS:2018 patients were recruited between May 3, 2007, and Oct 5, 2010, from 30 radiotherapy centres in the UK and randomly assigned to the whole-breast group (n=675), reduced-dose group (n=674), or partial-breast group (n=669). Two participants subsequently withdrew consent. Median age was 63 years (IQR 58-68). 854 (42%) of 2016 patients had grade 1 tumours, 959 (48%) had grade 2 tumours, and 200 (10%) had grade 3 tumours (three tumours were ungradable); 59 (3%) had node-positive disease. Median follow-up was 120 months (IQR 119-122) for the whole-breast group, 121 months (IQR 120-122) for the reduced-dose group, and 120 months (IQR 119-122) for the partial-breast group. By 10 years, IBTR events were reported for 45 of 2016 participants: 17 of 674 in the whole-breast group, 11 of 673 in the reduced-dose group, and 17 of 669 in the partial-breast group, with cumulative incidence of 2·8% (95% CI 1·8-4·5), 1·9% (1·1-3·5), and 3·0% (1·9-4·8), respectively. The estimated absolute difference in 10-year IBTR incidence was -1·02% (95% CI -1·98 to 0·99) for the reduced-dose group and 0·16% (-1·28 to 2·89) for the partial-breast group compared with the whole-breast group. Similar low levels of moderate or marked adverse effects were recorded for participants in all three groups in 10-year clinical assessments. Breast shrinkage had the highest incidence (30 [9%] of 321 in the whole-breast group, 28 [9%] of 322 in the reduced-dose group, and 22 [7%] of 333 in the partial-breast group). INTERPRETATION:Long-term follow-up provides further evidence that partial-breast and reduced-dose radiotherapy are as safe and effective as whole-breast radiotherapy in patients with low-risk early breast cancer. These results reaffirm the use of partial-breast radiotherapy delivered with intensity-modulated radiotherapy in this population as standard of care. FUNDING:Cancer Research UK.

This manuscript critically examines the challenges associated with the design and conduct of academic global breast cancer trials outside the influence of pharmaceutical companies, leveraging insights from the Breast International Group (BIG). In the past 4 decades significant declines in breast cancer mortality have occurred, partly related to industry-academic clinical and translational partnerships with long term study follow up. However, in the past decade these partnerships have largely uncoupled. The increasing complexity and non-alignment of trials, funding constraints, regulatory complexity, declining academic freedom, lack of transparency, and lack of affordability of new agents have become key barriers to equitably improving cancer outcomes. Industry research expenditure in the United States is now 5 fold greater than publically funded academic research. To address these challenges, we advocate for patient centred systemic reforms, with trials balancing commercial interests with public health imperatives. These reforms should include equitable research funding models, streamlined international clinical trial regulatory processes, and increased collaboration across diverse stakeholders. Practical solutions to enhance global trial accessibility and efficacy include leveraging digital technologies, artificial intelligence, real world data, decentralizing clinical trial infrastructure, and embedding translational research frameworks across countries.