Background: Analyses of the 2014 EBCTCG database suggested that, in early-stage breast cancer, obesity was strongly independently associated with breast cancer mortality only in pre/peri-menopausal oestrogen-receptor-positive (ER+) disease (Pan et al ASCO 2014). Based on the far larger 2024 EBCTCG database, however, we can now test that unexpected finding and better characterise any relevance of patient characteristics to the association of body mass index (BMI) with distant recurrence and mortality. Methods: We analysed patient-level data on time to distant recurrence and death from the 206,904 women with early-stage breast cancer (entered during 1978-2017 into 147 randomised trials) in the 2024 EBCTCG database who had BMI at entry (within two years of diagnosis) recorded as 15-50 kg/m2 and with complete information on age, ER status, tumour diameter, nodal status, and randomly allocated treatment. Information on menopausal status, tumour grade, and HER2 status was available for most participants. Cox regression was used to estimate the associations of BMI with rates of distant recurrence and breast cancer mortality, calculating hazard rate ratios (RRs) per 5 kg/m2 increase of BMI or comparing 3 BMI groups (obese: BMI 30-50 [mean 34.7]; overweight: BMI 25 to <30 [mean 27.3]; lean: BMI 15 to <25 [mean 22.2] kg/m2). Results: Of the 206,904 women, 60% were postmenopausal at trial entry and 77% had ER+ disease. Their mean BMI was 27.1 (SD 5.6) kg/m2 and 26.0% (53,872) were obese (BMI ≥30 kg/m2). The prevalence of obesity increased from 19% in the early 1980s to 27% in the early 2010s. The overall adjusted rate ratio (RR) of first distant recurrence (ignoring any local or contralateral recurrences) was 1.06 (95% CI 1.05-1.07, p<0.0001) per 5 kg/m2 increase in BMI. The RR for overweight versus lean women was 1.07 (CI 1.04-1.10, p<0.0001), and that for obese versus lean women was 1.17 (95% CI 1.14-1.20, p<0.0001). This approximately log-linear association between BMI and the rate of distant recurrence was seen irrespective of patient or tumour characteristics, type of adjuvant systemic therapy, year of diagnosis, or time since diagnosis. In the 82,464 pre-menopausal women the RR per 5 kg/m2 increase of BMI was 1.08 (1.07-1.10, p<0.0001), and in the 124,440 post-menopausal women it was 1.05 (1.03-1.06, p<0.0001; heterogeneity between RRs p=0.0004). There was little heterogeneity between the RRs in ER+ and ER-poor disease. In the 159,119 women with ER+ disease the RR per 5 kg/m2 increase of BMI was 1.06 (1.05-1.08, p<0.0001), and in the 47,785 with ER-poor disease it was 1.06 (1.04-1.08, p<0.0001). The associations of BMI with breast cancer mortality mirrored those with distant recurrence. Conclusion: Overweight and obesity are associated with increased distant recurrence and breast cancer mortality in all types of patients with early-stage breast cancer, but the risk associated with a substantial (e.g. 5 kg/m2) difference in BMI is only moderate. Nevertheless, randomised assessment of the effects among overweight or obese women with early breast cancer of weight-loss interventions (perhaps utilising a GLP-1 receptor agonist) could usefully be added, using a factorial design, to some current and future adjuvant treatment trials addressing unrelated questions. Reference: Pan H, Gray R, on behalf of the EBCTCG. Effect of obesity in premenopausal ER+ early breast cancer: EBCTCG data on 80,000 patients in 70 trials. J Clin Oncol 2014; 32:5s Citation Format: Hongchao Pan, Richard Gray, Richard Peto, Jeremy Braybrooke, David Dodwell, Robert Hills, Rosie Bradley, Hellen Gelband, Hui Liu, Paul McGale, Carolyn Taylor, Mike Clarke, Wolfgang Janni, Marianne Ewertz, Pamela J Goodwin, Joseph Sparano, Kathy I Pritchard, Jonas Bergh, Sandra M Swain, for the Early Breast Cancer Trialists™ Collaborative Group (EBCTCG). Overweight, obesity and prognosis in 206,904 women in the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) database [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 GS2-09.

Background: Endocrine therapy alone, with breast surgery offered only at local progression, is still sometimes considered for older women with operable early breast cancer, but the long-term risks of deferring surgery are uncertain. We evaluated long-term outcomes in the three unconfounded randomised trials that compared immediate breast surgery plus tamoxifen versus tamoxifen alone. None of these trials scheduled radiotherapy or chemotherapy. Methods: Individual patient data meta-analyses compared effects on breast cancer outcomes in 3 trials, initiated in the 1980s, among 1082 women (age ≥70, all to receive tamoxifen for at least 5 years) comparing immediate surgery versus surgery only in the event of local progression. Primary outcomes were time to locoregional failure, to distant recurrence, and to breast cancer mortality. Locoregional failure was defined as any locoregional recurrence after surgery or, if no immediate surgery, ≥25% increase in tumour diameter. Age-adjusted intent-to-treat log-rank analyses, stratified by nodal status, were used to estimate first-event-rate ratios (RRs). Results: Median age at randomisation was 76 (IQR 73-80) years, and 63% (666/1082) had clinically estimated tumour diameter >20 mm. Mean follow-up while still alive was 7.3 woman-years. Of 518 women allocated immediate surgery, 45.7% had mastectomy, 47.3% had breast-conserving surgery, and 7.0% had neither. Locoregional failure was greatly reduced by allocation to immediate surgery (RR=0.24, 95% CI 0.19-0.30, p<0.00001). This extreme RR was little affected by age, disease stage, or time period. Although the proportional reduction in the annual rate of locoregional failure was similar during years 0-1, 2-4 and 5-9, the absolute reduction in locoregional failure was mainly before year 5 (Kaplan-Meier 5-year risks 12.1% vs 45.8%). On average over the whole follow-up period the rates of distant recurrence (RR=0.72, 0.57-0.90, p=0.003), breast cancer mortality (RR=0.68, 0.54-0.86, p=0.002), and all-cause mortality (RR=0.83, 0.72-0.97, p=0.016) were also reduced, but these benefits emerged only after years 0-1. The distant recurrence rate ratio was 0.97 (0.67-1.42) during years 0-1 after randomisation, 0.73 (0.49-1.07) during years 2-4 and 0.52 (0.36-0.76) after year 5 (trend: p=0.012). Conclusion: In early breast cancer, immediate breast surgery greatly reduces locoregional progression rates during the first 5 years and approximately halves the annual rates of distant recurrence and of breast cancer death after the first 5 years, despite having had little clinically apparent effect on distant recurrence rates during the first few years. These findings could indirectly inform the planning and interpretation of trials of less extreme de-escalation of surgery or radiotherapy. Citation Format: Robert Hills, CoRosie Bradley, Jeremy Braybrooke, Lucy Davies, David Dodwell, Gurdeep Mannu, Paul McGale, Mike Clarke, Hongchao Pan, Richard Berry, Richard Peto, Carolyn Taylor, Jonas Bergh, Sandra Swain, Stewart Anderson, Allan Hackshaw, Tom Bates, Eleftherios Mamounas, Giorgio Mustacchi, John Robertson, Richard Gray. immediate breast surgery versus deferral of surgery in women aged 70+ years with operable breast cancer: patient-level meta-analysis of the three randomised trials among 1,082 women [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 LB1-01.

PARTNER is a prospective, phase II-III, randomized controlled clinical trial that recruited patients with triple-negative breast cancer1,2, who were germline BRCA1 and BRCA2 wild type3. Here we report the results of the trial. Patients (n = 559) were randomized on a 1:1 basis to receive neoadjuvant carboplatin-paclitaxel with or without 150 mg olaparib twice daily, on days 3 to 14, of each of four cycles (gap schedule olaparib, research arm) followed by three cycles of anthracycline-based chemotherapy before surgery. The primary end point was pathologic complete response (pCR)4, and secondary end points included event-free survival (EFS) and overall survival (OS)5. pCR was achieved in 51% of patients in the research arm and 52% in the control arm (P = 0.753). Estimated EFS at 36 months in the research and control arms was 80% and 79% (log-rank P > 0.9), respectively; OS was 90% and 87.2% (log-rank P = 0.8), respectively. In patients with pCR, estimated EFS at 36 months was 90%, and in those with non-pCR it was 70% (log-rank P < 0.001), and OS was 96% and 83% (log-rank P < 0.001), respectively. Neoadjuvant olaparib did not improve pCR rates, EFS or OS when added to carboplatin-paclitaxel and anthracycline-based chemotherapy in patients with triple-negative breast cancer who were germline BRCA1 and BRCA2 wild type. ClinicalTrials.gov ID: NCT03150576 .

Abstract Background: TNBCs in patients (pts) who are germline BRCA wild type (gBRCAwt) may show homologous recombination deficiency and genomic instability, resulting in a BRCA-like phenotype. The PARTNER Trial tested olaparib in combination with neoadjuvant carboplatin and paclitaxel in pts with TNBC (gBRCAwt). Methods: Pts with TNBC diagnosed locally were confirmed centrally with immunohistochemistry for ER, PR, HER2 and EGFR, CK5/6 and AR to define basal-like TNBC, before entry to the PARTNER trial. Pts were gBRCAwt. Tumours were assessed for tumour infiltrating lymphocytes (TILs). Pts were randomised 1:1 to research (R) and control arms (C). Pts received neoadjuvant carboplatin AUC 5, day(d) 1, with paclitaxel 80mg/m2 d1, 8, 15, every (q) 3 weeks (w), x 4 cycles(cy), +/- olaparib 150mg bd, po, d3-14 q 3w. Then all pts had 3cy of anthracycline chemotherapy before surgery. Primary endpoint was pathological complete response (pCR), and secondary endpoints included event-free survival (EFS), and overall survival (OS). A total of 454 patients were needed to attest 90% power with 5% significance assuming pCR rate of 50% in C and 65% in R. Results: From Sept 2016 to Dec 2021, 559 pts with TNBC (gBRCAwt) were randomised at 29 UK centres. Data cut-off was 30/11/23 with median (med) follow-up of 38 months (m). There were 276 R and 264 C pts in the intention-to-treat population. Pt and tumour characteristics were balanced between the arms: med pt age 49 years; 95% ECOG 0; 36% previous oophorectomy or post-menopausal; 95% tumour size ≤50mm; TILS score ≥60% in 22%. In R, 88% received at least 80% of the planned olaparib dose. More than 90% of patients in both R and C received at least 80% of the planned carboplatin (R 96% and C 94%) and paclitaxel (R 100% and C 99%) doses.Of 543 pts, 141 (51.1%) in R and 140 (52.4%) in C had a pCR with a difference of -1.3% (95% CI -9.7% to 7.0%, p-value=0.753). Percentage of pts with pCR increased with increasing TILs; pCR rate was 32% with TILs 0-10%, increasing to 67% with TILs 90-100%. Estimated EFS at 36 months (m) was 80% in R and 79% in C (log-rank p>0.9); estimated OS at 36m was 90% in R and 87.2% in C (log-rank p=0.8). Estimated 36m EFS rate was 90.4% (95% CI, 86.4 to 94.5) in pts with pCR and 70% (95% CI, 64.2 to 76.2) in pts with non-pCR (HR=0.3, 95% CI 0.2 to 0.4; p < 0.001). Estimated 36m OS was 95.7% (95% CI, 93.0 to 98.5) in pts with pCR, and 83% (95% CI, 78 to 88.2) in pts with non-pCR (HR=0.2, 95% CI 0.1 to 0.3; p < 0.001). More events and deaths were observed in non-pCR pts compared to pCR pts regardless of the treatment received. Conclusions: Neo-adjuvant olaparib in the dose and schedule tested, in addition to carboplatin/taxol and anthracycline chemotherapy in basal-like TNBC in gBRCAwt patients, did not improve pCR rates, EFS or OS. Pts who achieved a pCR had significantly better EFS and OS than those with non-pCR. These results are in marked contrast to the significant benefit of olaparib in those with gBRCA mutations reported in parallel. Citation Format: Jean E. Abraham, Karen Pinilla, Louise Grybowicz, Alimu Dayimu, Nikolaos Demiris, Caron Harvey, Lynsey M. Drewett, Rebecca Lucey, Alexander Fulton, Anne N. Roberts, Joanna R. Worley, Anita Chhabra, Wendi Qian, Richard M. Hardy, Stephen Chan, Tamas Hickish, Devashish Tripathi, Ramachandran Venkitaraman, Mojca Persic, Shahzeena Aslam, Daniel Glassman, Sanjay Raj, Annabel Borley, Jeremy P. Braybrooke, Stephanie Sutherland, Emma Staples, Lucy C. Scott, Mark Davies, Cheryl A. Palmer, Margaret Moody, Mark J. Churn, Jacqueline C. Newby, Mukesh B. Mukesh, Amitabha Chakrabarti, Rebecca R. Roylance, Philip C. Schouten, Nicola Levitt, Karen McAdam, Anne C. Armstrong, Ellen R. Copson, Emma McMurtry, Marc Tischkowitz, Elena Provenzano, Helena Earl, PARTNER Trial Group. PARTNER Trial: Neoadjuvant olaparib in triple negative breast cancer (TNBC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT012.

Background: There is currently no standardised definition for patients at high risk of recurrence of human epidermal growth factor receptor 2 (HER2)-negative early breast cancer (eBC; stages 1-3) after surgery. This modified Delphi panel aimed to establish expert UK consensus on this definition, separately considering hormone receptor (HR)-positive and triple-negative (TN) patients.Methods: Over three consecutive rounds, results were collected from 29, 24 and 22 UK senior breast cancer oncologists and surgeons, respectively. The first round aimed to determine key risk factors in each patient subgroup; subsequent rounds aimed to establish appropriate risk thresholds. Consensus was pre-defined as >= 70% of respondents.Results: Expert consensus was achieved on need to assess age, tumour size, tumour grade, number of positive lymph nodes, inflammatory breast cancer and risk prediction tools in all HER2-negative patients. There was additional agreement on use of tumour profiling tests and biomarkers in HR-positive patients, and pathologic complete response (pCR) status in TN patients. Thresholds for high recurrence risk were subsequently agreed. In HR-positive patients, these included age <35 years, tumour size >5 cm (as independent risk factors); tumour grade 3 (independently and combined with other high-risk factors); number of positive nodes >= 4 (independently) and >= 1 (combined). For TN patients, the following thresholds reached consensus, both independently and in combination with other factors: tumour size >2 cm, tumour grade 3, number of positive nodes >= 1.Conclusions: The results may be a valuable reference point to guide recurrence risk assessment and decision-making after surgery in the HER2-negative eBC population.

508 Background: High TIL counts are associated with a lower risk of breast cancer recurrence, especially in women with ER negative, HER2 negative tumors and, possibly, greater benefit from trastuzumab in women with HER2 positive cancer: the FinHER trial reported a differential effect of trastuzumab based upon TIL status. We performed a meta-analysis of randomized trials of trastuzumab in early breast cancer to attempt to validate this finding. Methods: TILs were quantified in 4097 women in 5 randomized controlled trials (NSABP B-31, FinHER, HERA, Intergroup N9831, PACS-04). All trials contributed to the Early Breast Cancer Trialists' Collaborative Group individual patient data meta-analysis of trastuzumab for women with HER2 positive tumors which found a significant benefit for trastuzumab therapy. TILs were assessed using established International Guidelines, with HERA using digital TIL-scores. The primary outcome was time to first recurrence. Cox regression analyses, adjusted for trial, treatment allocation, and nodal status, were used to quantify the prognostic value of TILs; and standard stratified logrank tests were used to assess the differential effect of trastuzumab therapy. Results: The median percentage TILs was 13% (Interquartile Range 5-30), with fewer than 10% of patients exhibiting TILs >50%. The prognostic value of TILs was confirmed, with patients with higher TILs being at lower risk for recurrence (adjusted hazard ratio per 10% increase in TILs 0.87 (95% CI 0.84-0.90), p<.0001) with similar effects in both treatment groups. Outcomes improved steadily with increasing TILs, and unadjusted 10-year recurrence rates fell from 30% in women with TILs <10% to 15% in those with TILs 70% or greater. Consequently, analyses of the predictive effect of TILs were stratified into 5 groups (0-9, 10-19, 20-39, 40-59, 60+). Overall, there was a highly significant benefit of trastuzumab on recurrence (HR 0.62 (0.54-0.70) p<.0001), but there was no evidence of any interaction between TILs and the proportional reduction in recurrence (p=0.8 for heterogeneity and trend). Conclusions: While higher TILs are associated with lower recurrence rates, there was no indication that the proportional reduction in recurrence with trastuzumab varied by TILs, although the number of patients with high levels was limited. Owing to a lower underlying recurrence rate, absolute benefits from trastuzumab were lower, but still substantial, in women with high TIL tumors. Clinical trial information: NCT00045032 , ISRCTN76560285 , NCT00005970 , NCT00004067 , NCT00054587 . [Table: see text]

503 Background: Suppressing ovarian function of women with breast cancer may improve outcome by preventing estrogenic stimulation of any residual cancer, particularly for pre-menopausal women with estrogen receptor (ER)-positive tumors. We report a collaborative meta-analysis of individual participant data from randomized trials of ovarian ablation or suppression. Methods: Data were sought from randomized trials that compared ovarian ablation or suppression versus not. Primary analyses included only premenopausal women age < 55 with ER-positive or unknown tumors, stratified into those who received no chemotherapy, or remained premenopausal following chemotherapy, and those whose menopausal status following chemotherapy was not ascertained. Standard log-rank methods estimated ER-weighted annual event rate ratios (RR). Results: Individual patient data were provided for 25 of 27 relevant trials, comprising 14,993 (98.7%) of 15,195 women randomized. Overall, fewer breast cancer recurrences were seen with ovarian ablation/suppression than control (RR = 0·82, 95%CI 0·77–0·88; p < 0·0001). Recurrence reductions were significantly (p = 0.0003) larger among women (n = 7,213) known to be premenopausal prior to ovarian suppression (RR = 0·70, 0·63–0·78; p = 0·0003) than among those (n = 7,786) whose menopausal status was uncertain after chemotherapy (RR = 0·91, 0·83–0·99; p = 0·03). For known premenopausal women, 15-year risk of recurrence was improved by 12·1% (28·9% vs 41·0%; p < 0·0001. 15-year breast cancer and all-cause mortality were improved by 8·0% (20·9% vs 28·9%; RR 0·69, 0·60–0·80; p < 0·0001) and 7.2% (26·0% vs 33·1%; RR = 0·73, 0·64–0·82; p < 0·0001), respectively, with no increase in deaths without recurrence (RR = 0·88, 0·67–1·14; p = 0·33). Recurrence reductions were significantly (p = 0·003) larger among premenopausal women aged under 45 (RR = 0·63, 0·55–0·72; p < 0·0001) than among those aged 45-54 (RR = 0·84, 0·70–1.00; p = 0·045), but did not differ significantly by other recorded patient or tumor characteristics. Conclusions: For pre-menopausal women aged under 45, ovarian ablation or suppression substantially reduces the 15-year risk of recurrence and death from breast cancer without increasing mortality from other causes.

PURPOSE: There is currently no standardised definition for patients at high risk of recurrence of HER2-negative early breast cancer (eBC, stages 1–3) after surgery. Recognising that the assessment of high risk is often multifactorial, the aim of this modified Delphi panel was to establish expert UK consensus on this definition, separately considering HR-positive and triple-negative (TN) patients. METHODS: A total of 45 UK-based clinicians, including breast cancer oncologists and surgeons, were invited to participate. The number of respondents in each of three rounds was 29, 24 and 22 respectively. Statements were developed using the results from a targeted literature review and the guidance of a lead clinician, and comprised free-text, single-choice or numerical formats. The first round aimed to determine which factors are currently used in clinical practice to assess risk of recurrence in the populations of interest. In the subsequent rounds, the objective was to establish thresholds indicative of high risk in a 10-year timeframe for each of the factors retained in Round 1. Between each round, statements were refined, considering the distribution of responses and free-text notes provided by participants. Consensus for single-choice questions was set at a pre-defined threshold of ≥70% of respondents. RESULTS: Consensus was achieved on the need to assess age, tumour size, tumour grade, number of positive nodes, presence of inflammatory breast cancer and one or more risk prediction tools to define high risk of recurrence in all HER2-negative patients. In HR-positive patients, there was agreement on the use of one or more tumour profiling tests and biomarkers to define high risk of recurrence. However, there was no consensus on biomarker use in TN patients, and support for specific biomarkers (such as Ki-67) was conflicting for both sub-populations based on the analysis of free-text notes. Similarly, while there was consensus on the use of pCR status/residual disease to indicate high risk in TN patients, this factor failed to reach consensus for the HR-positive sub-population. Germline BRCA status and menopausal status were not considered to be key factors for risk of recurrence in either biological subtype. In the second and third rounds, thresholds indicative of high recurrence risk were agreed; it should be noted that the free-text responses provided by the participants frequently highlighted that many of the factors should be considered along a continuous scale when assessing the risk of individual patients. In HR-positive patients, these thresholds included: age < 35 years, tumour size >5 cm (each when considered independently from other risk factors); tumour grade 3 (independently or in combination with other factors); number of positive lymph nodes ≥4 when considered independently or ≥1 in combination with other factors. For patients with TN tumours, the following thresholds reached consensus, whether considered independently or in combination with other factors: tumour size >2 cm, tumour grade 3, number of positive lymph nodes ≥1. In several cases, however, no consensus could be reached on the appropriate threshold indicating high risk of recurrence. In the HR-positive sub-population, these included thresholds for age and tumour size, when considered in combination with other factors. In the TN sub-population, this included age, whether independently or in combination with other factors. CONCLUSIONS: The expert consensus reached in this panel highlights that an integrated model is important in assessing recurrence risk in eBC and that definitions of high risk differ according to biological subtype. The results may serve as a valuable reference point for clinicians to use in assessing risk of disease recurrence and in making treatment decisions after surgery in the HER2-negative eBC population. FUNDING: AstraZeneca UK Ltd. Writing support: Costello Medical. Citation Format: Ellen R. Copson, Jean E. Abraham, Jeremy P. Braybrooke, Stuart A. McIntosh, Caroline O. Michie, Carlo Palmieri, Rebecca Roylance, Saiqa Spensley. Expert consensus on the definition of high risk of recurrence in HER2-negative early breast cancer: a modified Delphi panel [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-05-39.

TPS1111 Background: The combination of fulvestrant and one of the three approved CDK4/6 inhibitors (i) is the standard of care for patients with ER+/HER2 metastatic breast cancer progressing on first-line endocrine therapy, or relapsing on or within a year of completing adjuvant endocrine therapy. AKT inhibition combined with fulvestrant has recently demonstrated clinically important activity in patients with advanced ER+/HER2- breast cancer progressing on first-line CDK4/6i plus an AI. Monitoring ctDNA dynamics has potential utility as an early response evaluation tool: Lack of suppression of ctDNA at day 15 in patients treated with palbociclib and fulvestrant in the PALOMA-3 trial was predictive for shorter PFS. We designed FAIM to establish whether the addition of the AKT inhibitor, ipatasertib, improves PFS in patients with poor ctDNA suppression during cycle 1 of fulvestrant and CDK4/6i. Methods: FAIM is a phase 2 multi-centre, randomised, open-label superiority trial in patients with ER+/HER2- advanced breast cancer, recruiting at centres in the UK. Patients will undergo ctDNA testing at days 1 and 15 of cycle 1 fulvestrant and CDK4/6 inhibitor. Eligible patients must be aged ≥18, have ER+ (≥1% or Allred score 3/8 or greater) and HER2- advanced breast cancer, measurable disease or assessable bone disease (RECIST 1.1), adequate organ function, fasting glucose ≤150mg/dL and HbA1c ≤7.5% and be eligible for NHS treatment with fulvestrant and CDK4/6i. Patients with diabetes requiring insulin, significant cardiac disease, a history of pneumonitis, or prior exposure to CDK4/6i are excluded. The FoundationOne Liquid CDx assay will be used for ctDNA analysis, a pan-cancer, tumour-agnostic liquid biopsy test that uses error-corrected next-generation sequencing. Patients with poor ctDNA suppression at day 15 will be eligible for the randomised (minimisation) study. Up to 483 patients starting fulvestrant andCDK4/6i will enroll for ctDNA screening to allow 174 patients to enter the randomised study. The primary endpoint of the study is to compare PFS in patients randomised to palbociclib/fulvestrant +/- ipatasertib. Secondary endpoints include safety, overall survival and overall response rate in all randomised patients and PFS in the sub-group of patients with alterations in the PIK3CA/AKT1/PTEN pathway. One hundred patients with ctDNA suppression at day 15, and up to 50 patients with no detectable ctDNA at day 1, will form additional control groups for exploratory outcome comparison to patients with poor ctDNA suppression. Enrolment began in December 2022 and is anticipated to continue for 2 years (NCT04920708). Clinical trial information: NCT04920708 .

Background Anthracycline-taxane chemotherapy for early-stage breast cancer substantially improves survival compared with no chemotherapy. However, concerns about short-term and long-term side-effects of anthracyclines have led to increased use of taxane chemotherapy without anthracycline, which could compromise efficacy. We aimed to better characterise the benefits and risks of including anthracycline, and the comparative benefits of different anthracycline-taxane regimens.Methods We did an individual patient-level meta-analysis of randomised trials comparing taxane regimens with versus without anthracycline, and updated our previous meta-analysis of anthracycline regimens with versus without taxane, as well as analysing 44 trials in six related comparisons. We searched databases, including MEDLINE, Embase, the Cochrane Library, and meeting abstracts to identify trials assessing anthracycline and taxane chemotherapy. Adjuvant or neoadjuvant trials were eligible if they began before Jan 1, 2012. Primary outcomes were breast cancer recurrence and cause-specific mortality. Log-rank analyses yielded first-event rate ratios (RRs) and CIs.Findings 28 trials of taxane regimens with or without anthracycline were identified, of which 23 were deemed eligible, and 15 provided data on 18 103 women. Across all 15 trials that provided individual data, recurrence rates were 14% lower on average (RR 0.86, 95% CI 0.79-0.93; p=0.0004) with taxane regimens including anthracycline than those without. Non-breast cancer deaths were not increased but there was one additional acute myeloid leukaemia case per 700 women treated. The clearest reductions in recurrence were found when anthracycline was added concurrently to docetaxel plus cyclophosphamide versus the same dose of docetaxel plus cyclophosphamide (10-year recurrence risk 12.3% vs 21.0%; risk difference 8.7%, 95% CI 4.5-12.9; RR 0.58, 0.47-0.73; p<0.0001). 10-year breast cancer mortality in this group was reduced by 4.2% (0.4-8.1; p=0.0034). No significant reduction in recurrence risk was found for sequential schedules of taxane plus anthracycline when compared with docetaxel plus cyclophosphamide (RR 0.94, 0.83-1.06; p=0.30). For the analysis of anthracycline regimens with versus without taxane, 35 trials (n=52 976) provided individual patient data. Larger recurrence reductions were seen from adding taxane to anthracycline regimens when the cumulative dose of anthracycline was the same in each group (RR 0.87, 0.82-0.93; p<0.0001; n=11 167) than in trials with two-fold higher cumulative doses of non-taxane (mostly anthracycline) in the control group than in the taxane group (RR 0.96, 0.90-1.03; p=0.27; n=14 620). Direct comparisons between anthracycline and taxane regimens showed that a higher cumulative dose and more dose-intense schedules were more efficacious. The proportional reductions in recurrence for taxane plus anthracycline were similar in oestrogen receptor-positive and oestrogen receptor-negative disease, and did not differ by age, nodal status, or tumour size or grade.Interpretation Anthracycline plus taxane regimens are most efficacious at reducing breast cancer recurrence and death. Regimens with higher cumulative doses of anthracycline plus taxane provide the greatest benefits, challenging the current trend in clinical practice and guidelines towards non-anthracycline chemotherapy, particularly shorter regimens, such as four cycles of docetaxel-cyclophosphamide. By bringing together data from almost all relevant trials, this meta-analysis provides a reliable evidence base to inform individual treatment decisions, clinical guidelines, and the design of future clinical trials.

Background: Paclitaxel is commonly used as first-line chemotherapy for HER2-negative metastatic breast cancer (MBC) patients. However, with response rates of 21.5-53.7% and significant risk of peripheral neuropathy, there is need for better chemotherapy. Patients and methods: This open-label phase II/III trial randomised HER2-negative MBC patients 1:1 to either 6 cycles of three-weekly cabazitaxel (25 mg/m2), or, weekly paclitaxel (80 mg/m2) over 18 weeks. The primary endpoint was progression free survival (PFS). Secondary endpoints included objective response rate (ORR), time to response (TTR), overall survival (OS), safety and tolerability and quality of life (QoL). Results: 158 patients were recruited. Comparing cabazitaxel to paclitaxel, median PFS was 6.7 vs 5.8 months (HR 0.87; 80%CI 0.70-1.08, P = 0.4). There was no difference in median OS (20.6 vs 18.2 months, HR 1.00; 95%CI 0.69-1.45, P = 0.99), ORR (41.8% vs 36.7%) or TTR (HR 1.09; 95%CI 0.68-1.75, P = 0.7). Grade & GE;3 adverse events occurred in 41.8% on cabazitaxel and 46.8% on paclitaxel; the most common being neutropenia (16.5%) and febrile neutropenia (12.7%) cabazitaxel and neutropenia (8.9%) and lung infection (7.6%) paclitaxel. Peripheral neuropathy of any grade occurred in 54.5% paclitaxel vs 16.5% cabazitaxel. Mean EQ-5D-5L single index utility score (+0.05; 95%CI 0.004-0.09, P = 0.03) and visual analogue scale score (+7.7; 95%CI 3.1-12.3, P = 0.001) were higher in cabazitaxel vs paclitaxel. Conclusions: Three-weekly cabazitaxel in HER2-negative MBC does not significantly improve PFS compared to weekly paclitaxel, although it has a lower risk of peripheral neuropathy with better patient reported QoL outcomes. It is well tolerated and requires fewer hospital visits.

PURPOSE Survival in stage I seminoma is almost 100%. Computed tomography (CT) surveillance is an international standard of care, avoiding adjuvant therapy. In this young population, minimizing irradiation is vital. The Trial of Imaging and Surveillance in Seminoma Testis (TRISST) assessed whether magnetic resonance images (MRIs) or a reduced scan schedule could be used without an unacceptable increase in advanced relapses. METHODS A phase III, noninferiority, factorial trial. Eligible participants had undergone orchiectomy for stage I seminoma with no adjuvant therapy planned. Random assignment was to seven CTs (6, 12, 18, 24, 36, 48, and 60 months); seven MRIs (same schedule); three CTs (6, 18, and 36 months); or three MRIs. The primary outcome was 6-year incidence of Royal Marsden Hospital stage ≥ IIC relapse (> 5 cm), aiming to exclude increases ≥ 5.7% (from 5.7% to 11.4%) with MRI ( v CT) or three scans ( v 7); target N = 660, all contributing to both comparisons. Secondary outcomes include relapse ≥ 3 cm, disease-free survival, and overall survival. Intention-to-treat and per-protocol analyses were performed. RESULTS Six hundred sixty-nine patients enrolled (35 UK centers, 2008-2014); mean tumor size was 2.9 cm, and 358 (54%) were low risk (< 4 cm, no rete testis invasion). With a median follow-up of 72 months, 82 (12%) relapsed. Stage ≥ IIC relapse was rare (10 events). Although statistically noninferior, more events occurred with three scans (nine, 2.8%) versus seven scans (one, 0.3%): 2.5% absolute increase, 90% CI (1.0 to 4.1). Only 4/9 could have potentially been detected earlier with seven scans. Noninferiority of MRI versus CT was also shown; fewer events occurred with MRI (two [0.6%] v eight [2.6%]), 1.9% decrease (–3.5 to –0.3). Per-protocol analyses confirmed noninferiority. Five-year survival was 99%, with no tumor-related deaths. CONCLUSION Surveillance is a safe management approach—advanced relapse is rare, salvage treatment successful, and outcomes excellent, regardless of imaging frequency or modality. MRI can be recommended to reduce irradiation; and no adverse impact on long-term outcomes was seen with a reduced schedule.

Abstract Background: In post-menopausal women with hormone receptor (HR) positive early breast cancer, aromatase inhibitors (AIs) are more effective than tamoxifen as endocrine therapy. However, some trial reports indicate greater benefit from AIs in lobular than ductal cancers. Invasive lobular cancer can be identified using conventional microscopy and/or immunohistochemistry for e-Cadherin status. We performed an individual patient data meta-analysis to explore possible differential treatment benefits for AI vs tamoxifen in women with lobular vs ductal hormone receptor positive breast cancer. Methods: Individual patient data were collected from three randomised controlled trials (BIG 01-98, TEAM and ATAC) of AI vs tamoxifen for postmenopausal women with estrogen receptor positive breast cancer, as well as results of central pathology review and e-Cadherin expression. Central pathology and e-Cadherin data were available on 9328 and 7654 women. Local pathology data was available for TEAM, BIG 01-98. Data were analysed using the same methodology as the previous EBCTCG meta-analysis of AI vs tamoxifen: results of different methods of diagnosing ductal vs lobular cancer were cross tabulated, and outcomes analysed using log-rank methods, yielding event rate ratios (RR) and confidence intervals. Interactions were evaluated using standard tests for heterogeneity; the primary outcomes were time to any invasive breast cancer recurrence, and time to distant recurrence. Results: Rates of lobular cancer were higher when assessed by central pathology (BIG 01-98 16%; ATAC 16%; TEAM 12%) than e-Cadherin (15% vs 14% vs 9%). Methods agreed in over 80% of cases classified as ductal using either pathology or e-Cadherin, while the agreement rate for lobular cancers was only about 50%. A similar pattern was seen comparing local pathology with either central pathology or e-Cadherin. Consequently, analyses were stratified by pathology and e-Cadherin both separately and together. Consistent with the previous meta-analysis there was a significant reduction in recurrence for AI compared to tamoxifen (RR 0.73 (0.61-0.87) p=0.0004). Exploration of interaction found no evidence of heterogeneity of treatment effect on recurrence by pathology (ductal HR 0.76 (0.64-0.89); lobular HR 0.76 (0.50-1.15) interaction p>0.99; nor by e-Cadherin status (interaction p=0.9). No significant interactions were seen on other endpoints. Conclusion: Analyses of three large trials of adjuvant AI vs tamoxifen found discordance in identifying patients with lobular carcinoma by local or central pathology or e-Cadherin status, indicating variability in the consistency of diagnosis. The trials included showed a benefit for AI over tamoxifen in line with the previous meta-analysis, but with no evidence of differential efficacy in lobular compared to ductal carcinomas, however measured. These data cannot rule out smaller quantitative interactions or differences in site of recurrence: however, in contrast to earlier reports, this meta-analysis of the totality of the data does not identify ductal/lobular cancer as a predictive marker for differential endocrine treatment benefit. Citation Format: Robert K Hills, Steffi Oesterreich, Otto Metzger, David Dabbs, Hongchao Pan, Jeremy Braybrooke, Richard Gray, Richard Peto, Rosie Bradley, Ewan Straiton, Richard Berry, Daniel Rea, David Cameron, Jack Cuzick, Meredith Regan, Mitch Dowsett, Ivana Sestak, Jonas Bergh, Sandra M Swain, John Bartlett, Early Breast Cancer Trialists' Collaborative Group. Effectiveness of aromatase inhibitors versus tamoxifen in lobular compared to ductal carcinoma: Individual patient data meta-analysis of 9328 women with central histopathology, and 7654 women with e-Cadherin status [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD14-08.