Hormone receptor–positive/Human epidermal growth factor receptor 2–negative (HR+/HER2–) early breast cancer accounts for the majority of breast cancer cases. Although chemotherapy can reduce recurrence risk, its use in HR+/HER2– high-risk disease remains complex in clinical practice. We aimed to examine regional variation in chemotherapy use in Sweden and its association with prognosis. In this population-based cohort study, we included 61,935 women diagnosed with HR+/HER2– early breast cancer between 2007 and 2023, identified through the Swedish National Quality Register for Breast Cancer. Multivariable logistic regression was applied to identify factors that were associated with chemotherapy use across the Swedish healthcare regions. Overall survival was analysed using Kaplan–Meier estimates and regression standardisation based on Cox models, adjusting for clinicopathological and socioeconomic factors. Chemotherapy was administered to 28·0

The aim was to determine the frequency of altered receptor expression between primary breast cancer and liver metastases, and to examine the impact of receptor expression on survival. The conversion frequency of estrogen- (ER), progesterone- (PgR) and human epidermal growth factor receptor 2 (HER2) was investigated. The prognostic value of the receptor status in the primary tumor versus the metastases was estimated. Data on a population-based regional cohort of 7292 breast cancer patients from 2009 to 2018 were collected from the National Breast Cancer Register. Biomarker expression and intrinsic subtype was studied among those who developed liver metastases with available histopathological records. The study included 311 patients with liver metastases. Conversion of ER, PgR and HER2 occurred in 16%, 47% and 12% of patients, respectively. The subtype converted in 26%. HER2 amplification in the primary tumor or metastases was associated with improved survival. Positive ER and PgR in breast cancer and positive ER in liver metastases were beneficial for survival. A combined primary tumor and metastasis receptor evaluation had the highest prognostic value. Receptor conversion from primary tumor to liver metastases is common. HER2 amplification and positive ER or PgR are associated with improved survival. Accordingly, luminal HER2 positive tumors have improved survival compared to other intrinsic subtypes. To personalize treatment for each patient, a liver biopsy is warranted at diagnosis of breast cancer liver metastases.

Abstract Introduction The effectiveness of current follow-up recommendations after breast cancer remain uncertain. Early detection of local recurrence improves survival, but surveillance strategies are largely uniform despite significant differences in recurrence risk. Interval recurrences detected between scheduled visits are more likely in younger patients and those with non-luminal subtypes. In addition, mammography has lower sensitivity in breast cancer survivors compared to healthy women. Supplemental imaging methods, such as magnetic resonance imaging (MRI) or contrast-enhanced mammography (CEM), may improve detection in high-risk groups. This study aims to evaluate whether more sensitive imaging methods enable earlier detection of second breast cancers after breast-conserving surgery (BCS) in patients with high recurrence risk. Methods A multicenter, open-label, R-RCT including patients from the National Quality Register for Breast Cancer. Women aged <50 years, or women of any age with HER2-positive or triple-negative breast cancer who have undergone BCS, will be randomized to standard follow-up with annual mammography for five years or the same regimen with the addition of MRI or CEM at years 2 and 4. The primary endpoint is the number of interval-detected ipsilateral and contralateral second breast cancers within five years. Secondary endpoints include recurrence stage, survival, recall and biopsy rates, false-positive findings, and health-related quality of life. Based on power calculations (4 versus 2%), 2300 patients (1:1) are required to achieve 80% power. Results Recruitment will begin in 2026, with first interim results expected in 2029. Discussion There is an unmet need for individualized breast cancer surveillance guidelines. This study aims to help address this evidence gap.

BACKGROUND:Breast cancer (Bc) is the leading cause of cancer-related death in women. In many patients, BC liver metastases (BCLM) are associated with short survival. The aims of this study were to investigate the risk of and time to BCLM in each BC surrogate subtype, and to determine the incidence of BCLM in a population-based setting. METHODS:The Swedish national breast cancer registry identified patients with Bc in a regional cohort from 2009 to 2018. The cohort was followed until January 2023. Cox regression analysis was used to determine the risk of BCLM for each subtype. Kaplan-Meier estimates determined the probability of BCLM for each subtype over time. RESULTS:In all, 7292 patients with Bc were included in the study. Distant metastases developed in 755 patients (10.4%); of these, 345 (45.7%) developed BCLM. The BCLM incidence rate was 8 per 1000 person-years. Only 13 patients had oligometastases isolated to the liver. Triple-negative, non-luminal human epidermal growth factor receptor 2 (HER2)-positive and luminal B cancers had the highest risk of BCLM. T category, nodal status, and Nottingham histological grade III were also strongly associated with BCLM. The median time from Bc diagnosis to BCLM was 36 months. Patients with HER2-positive BC subtypes developed BCLM early, at a median of only 9 months. CONCLUSION:Bc subtype is correlated to the risk and timing of BCLM development. BCLM are common in advanced Bc, but isolated oligometastases are rare.

12024 Background: Cardiotoxicity is a known side effect of trastuzumab and combination with anthracyclines increases the risk for cardiotoxicity. Adjuvant dose-dense (DD) chemotherapy has demonstrated beneficial breast cancer (BC) outcomes in patients with high risk for relapse, but data on long-term cardiac toxicity when combined with trastuzumab is scarce. We have previously reported on the safety of trastuzumab at six years follow-up, in a subset of patients treated with dose-dense chemotherapy in the Pan-European Tailored Chemotherapy (PANTHER) phase III trial. We hereby present long-term safety data from 10-year follow-up from the same subset. Methods: This is a protocol-predefined cardiac safety study, among Swedish sites included in the PANTHER trial, including patients with HER2-positive (HER2+) and HER2-negative (HER2-) BC matched for age, treatment group and institution. Enrolled patients were up to 65 years old with node-positive or high-risk, node-negative BC were randomized 1:1 to either dose tailored (according to hematologic nadirs) and biweekly DD epirubicin and cyclophosphamide followed by docetaxel or standard 5-fluorouracil, epirubicin, and cyclophosphamide plus docetaxel every 3 weeks. Patients with HER2-positive disease received 1 year of adjuvant trastuzumab. They underwent echocardiography (ECHO) or multigated acquisition scanning and electrocardiography at baseline, at 4, 6 and 10 years of follow-up. Data on cardiac medication NT-proBNP, lipid profile and ECG were also collected. Results: ECHO at 10-years follow-up was available for 94 patients; 48 HER2+ (19 DD, 29 control) and 46 HER2- (21 DD, 25 control). Overall, incidence of cardiotoxicity was low. Mean LVEF was 58 % (range 49-68%) and 60.65% (range 50-76%) in HER2+ and HER2- respectively. Only one patient had LVEF < 50% (DD HER2+) and additional 12 patients had LVEF 50-54%, equally distributed between the treatment groups. In total, 27 patients were treated with cardiac medications at this point; 15 (56%) of which had been treated with trastuzumab and 10 of them (n = 7 HER2+), not reporting cardiac medication at previous timepoints. The majority of the patients did not report any symptoms related to heart disease, per NYHA-classification (41 patients in both groups report NYHA class 0). Overall, no significant changes were seen in the biomarkers. Conclusions: Cardiotoxicity of trastuzumab in DD anthracycline chemotherapy, examined in the context of a randomized trial sub-study, was very low. Our results underline the safety of trastuzumab in this context, providing support to offer the patients best treatment options for improving breast cancer survival. Clinical trial information: NCT00798070 .

Supplementary Table S1. Representativeness of Study Participants

Supplementary Table S2. Distribution of clinical and pathologic characteristics according to baseline tumor infiltrating lymphocytes (median value as cut-off)

Supplementary Figure S3: Probability for pathologic complete response in the four groups of the combined classification according to SUVmax at cycle 2 (median value 2.6 as cut-off) and baseline DTIL (median value 8.7% as cut-off)

Introduction Neoadjuvant therapy is the standard of care for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC). Studies on first-generation antibody-drug conjugates, such as trastuzumab emtansine (T-DM1), showed equal or slightly lower efficacy than chemotherapy combined with dual HER2 blockade. Trastuzumab deruxtecan (T-DXd) is a next-generation conjugate approved for the treatment of metastatic HER2-positive and HER2-low BC, with greatly improved efficacy compared to T-DM1.Methods and analysis ARIADNE is an academic, international, open-label, randomised, comparative phase IIB trial. A total of 370 patients with non-metastatic HER2-positive BC and an indication for neoadjuvant therapy will be included and randomised 1:1 to receive either (1) docetaxel (or paclitaxel), carboplatin, trastuzumab (H) and pertuzumab (P) for three cycles or (2) T-DXd for three cycles. Further treatment is based on the intrinsic molecular subtype determined by the Prosigna assay: patients with HER2-enriched disease (estimated 60%) continue the same treatment for three more cycles. Patients with oestrogen receptor (ER)-positive and luminal (estimated 30%) disease receive H and P for three cycles, combined with letrozole and ribociclib for two cycles. Patients with ER-negative and luminal, basal-like or normal-like disease (estimated 10%) either continue the same treatment for three more cycles in the case of a radiologic complete response, or, in the case of no complete response, they receive four cycles of dose-dense epirubicin and cyclophosphamide. The primary endpoint of ARIADNE is locally assessed rate of pathologic complete response in the molecularly HER2-enriched population, defined as ypT0/Tis, ypN0, as determined by a pathologist blinded to treatment assignment (intention-to-treat (ITT) analysis). Key secondary endpoints include time-to-event endpoints (event-free, recurrence-free, distant recurrence-free and overall survival), safety, health-related quality of life and translational studies.Ethics and dissemination The study has been approved by the Swedish Medical Products Agency (Läkemedelsverket), the Swedish Ethical Review Authority (Etikprövningsmyndigheten) and the Norwegian Ethics Committee for Clinical Trials on Medicinal Products and Medical Devices, as well as by the review boards at all participating centres. Applications for ethical approval in Belgium, the Netherlands and Italy are ongoing. We intend to publish the results of the study in a scientific journal. The study results will be submitted to the European Union (EU) database within 1 year after the end of the clinical trial (CT).Trial registration number EU CT registration number: 2022-501504-95-00; ClinicalTrials.gov identifier: NCT05900206.

Supplementary Figure S1: Bland-Altman plot depicting correlation between tumor infiltrating lymphocytes assessed manually and using digital image analysis

Supplementary Table S3. Hazard ratios for relapse-free survival estimated using univariate and multivariable proportional hazards regression. SUVmax at cycle 2 (C2) is included as continuous variable in the regression models.

Background Thymidine kinase 1 (TK1) plays a pivotal role in DNA synthesis and cellular proliferation. TK1 has been studied as a prognostic marker and as an early indicator of treatment response in human epidermal growth factor 2 (HER2)-negative early and metastatic breast cancer (BC). However, the prognostic and predictive value of serial TK1 activity in HER2-positive BC remains unknown. Methods In the PREDIX HER2 trial, 197 HER2-positive BC patients were randomized to neoadjuvant trastuzumab, pertuzumab, and docetaxel (DPH) or trastuzumab emtansine (T-DM1), followed by surgery and adjuvant epirubicin and cyclophosphamide. Serum samples were prospectively collected from all participants at multiple timepoints: at baseline, after cycle 1, 2, 4, and 6, at end of adjuvant therapy, annually for a total period of 5 years and/or at the time of recurrence. The associations of sTK1 activity with baseline characteristics, pathologic complete response (pCR), event-free survival (EFS), and disease-free survival (DFS) were evaluated. Results No association was detected between baseline sTK1 levels and all the baseline clinicopathologic characteristics. An increase of TK1 activity from baseline to cycle 2 was seen in all cases. sTK1 level at baseline, after 2 and 4 cycles was not associated with pCR status. After a median follow-up of 58 months, 23 patients had EFS events. There was no significant effect between baseline or cycle 2 sTK1 activity and time to event. A non-significant trend was noted among patents with residual disease (non-pCR) and high sTK1 activity at the end of treatment visit, indicating a potentially worse long-term prognosis. Conclusion sTK1 activity increased following neoadjuvant therapy for HER2-positive BC but was not associated with patient outcomes or treatment benefit. However, the post-surgery prognostic value in patients that have not attained pCR warrants further investigation. Trial registration ClinicalTrials.gov, NCT02568839. Registered on 6 October 2015.

Background and purpose: Adjuvant endocrine treatment (AET) is crucial in early oestrogen receptor (ER)-positive breast cancer (BC), providing reduced recurrence rate and increased overall survival. The aim of this study was to estimate AET adherence rates by age at diagnosis and region in Sweden. Patients and methods: In total, 10,422 women diagnosed with ER-positive BC in 2008–2010 were identified in the Swedish National BC Registry. Information on prescriptions and dispensation of AET was gathered through record linkage to the Swedish Prescription Registry. 1, 3- and 5-year medication possession ratios (MPRs) were calculated. Good adherence was set as MPR ≥ 80%. Results: The 1-, 3- and 5-year AET age-adjusted adherence rates were 94.4, 87.6 and 81.6%, respectively. The 1-, 3- and 5- year adherence rate was significantly highest in the South region (96.2, 90.5 and 86.2%). Regions with an oncologic clinic had higher adherence rate than regions without, 82.8% versus 75.5% at 5-year FU. Women at age 40–64 years (95.6, 89.9 and 84.1%) and 65–74 years at diagnosis (95.7, 89.5 and 84.6%) had significantly higher adherence rate than women ≥ 75 years at diagnosis (89.1, 79.2 and 68.3%). Interpretations: Despite guidelines being national, there were significant differences in adherence between regions in Sweden. As the largest differences were between age groups invited and not invited to mammography screening intervention should focus on women < 40 and ≥ 75 years at diagnosis. Further studies are needed to find strategies to increase overall adherence to AET in early BC.

Objective To analyze differences between screen-detected and non-screen-detected invasive breast cancers by tumour characteristics and age at diagnosis in the nationwide population-based mammography screening program in Sweden. Methods Data were retrieved from the National Quality Register for Breast Cancer for 2008–2017. Logistic regression analysis was used to estimate the likelihood for a tumour to be screen-detected by tumour characteristics and age group at diagnosis. Results In total there were 51,429 invasive breast cancers in the target age group for mammography screening of 40–74 years. Likelihood of screen detection decreased with larger tumour size, lymph node metastases, higher histological grade and distant metastasis. Odds ratios (ORs) for negative oestrogen (ER) and progesterone (PgR) were 0.41 and 0.57; for positive HER2, 0.62; for Ki-67 high versus low, 0.49. Molecular sub-types had OR of 0.56, 0.40 and 0.28, respectively, for luminal B-like, HER2-positive and triple negative versus luminal A-like. Adjusting for tumour size (T), lymph node status (N), age, year and county at diagnosis slightly elevated the ORs. Statistically significant interactions between tumour characteristics and age were found ( p < 0.05) except for ER and PgR. The age group 40–49 deviated most from the other age groups. Conclusions Our study demonstrates that screen-detected invasive breast cancers had more favourable tumour characteristics than non-screen-detected after adjusting for age, year and county of diagnosis, and even after adjusting for T and N. The trend towards favourable tumour characteristics was less pronounced in the 40–49 age group compared to the other age groups, except for ER and PgR.

Background and purpose: We have recently demonstrated that screen-detected invasive breast cancers had more favourable tumour characteristics than non-screen-detected. The objective of the study was to analyse differences in breast cancer treatment between screen-detected and non-screen-detected cases by age at diagnosis, with and without adjustment for tumour (T) and nodal (N) status, within a nationwide, population-based mammography screening programme utilising register data. Material and methods: Data spanning 2008–2017 were collected from the National Quality Register for Breast Cancer. Multivariable logistic regression analysis was used to estimate odds ratios and 95% confidence intervals for treatment disparities between screen-detected and non-screen-detected breast cancer. Results: Among 46,481 women diagnosed with invasive breast cancer aged 40–74 and invited for mammography screening, significant differences in treatment were observed. Screen-detected cases showed higher likelihoods of partial mastectomy compared to mastectomy, endocrine therapy, and radiotherapy, whereas chemotherapy and antibody therapy were less likely compared to non-screen-detected cases. However, when adjusting for surgery type, screen-detected cases showed lower likelihoods of radiotherapy. Age at diagnosis significantly influenced treatment odds ratios, with interactions observed for all treatments except radiotherapy adjusted for surgery. Differences increased with age, except for endocrine therapy. Radiotherapy adjusted for surgery type showed no age-related interaction. Adjusting for T and N did not alter these patterns. Interpretation: In general, screen-detected cases received less aggressive treatment, such as mastectomy, chemotherapy, and antibody therapy, compared to non-screen-detected cases. Disparities increased with age, except for endocrine therapy and radiotherapy adjusted for surgery. Differences persisted after adjusting for T and N, suggesting that these factors cannot solely explain the results.

Abstract Background: Adjuvant endocrine therapy (AET) reduces recurrence and mortality in women with estrogen receptor (ER) positive early breast cancer (EBC). Adherence to AET has been shown to be lower than expected with risk of worse longtime prognosis. In a nationwide study in Sweden women with breast cancer diagnosis 2008-2010 adherence to AET at 5-year follow-up was estimated at 82,5% which is considered good related to recent published studies (manuscript is under review). Differences between regions and age-groups were shown. Present study investigates the impact on adherence of detection mode, tumor characteristics and additional treatment. Methods: Through the Swedish Cancer Registry (SCR) women with a first primary EBC diagnosed 2008-2010 were identified. From the Swedish National Breast Cancer Registry (NKBC) individual tumor and treatment data were collected. Included in the study was patients with ER positive tumors > 10 mm without distant metastasis at diagnosis. Through the Swedish Prescription Registry dispensed treatment from pharmacies was extracted and medication possession rate (MPR) was calculated as number of dispensed doses divided by treatment duration in days. Good adherence to treatment in a patient was set at MPR ≥80%. Adherence at 3- and 5-year follow-up by detection mode, tumor characteristics and additional treatment was estimated. Results: Out of 21 016 women with a first primary BC 2008-2010 registered in the NKBC 10 176 met the inclusion criteria for the study. Among screen-detected tumors the 3- and 5-year adherence were 90,2 respectively 85,1% and 85,4 respectively 78,4% in the non-screen-detected group. In the screen-detected group the tumors were smaller and more often node negative. There was a significantly increased 5-year adherence in patients with stage III disease compared to those with stage I disease (84,1 vs 81,3 %) but not significant at 3-year (89,2 vs 87,3). Adjuvant chemotherapy significantly increased 3- (91.0% vs 85.8%) and 5-year (85.7% vs 79.3%) adherence among screen-detected and non-screen-detected respectively. Conclusions: Adherence to AET in Sweden was good, although there were differences depending on detection mode, tumor stage and additional adjuvant treatment. Stage and additional medical adjuvant treatment depend on each other and should not be seen as independent factors for adherence for AET. Citation Format: Anne Andersson, Anna Von Wachenfeldt, Lennarth Nyström, Frida Isaksson, Pihla Ruohonen. Impact of detection mode, tumor characteristics and additional treatment on adherence to adjuvant endocrine therapy after breast cancer in Sweden [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-01-14.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. Although dose-dense adjuvant chemotherapy administered once every 2 weeks leads to superior outcomes compared with standard regimens once every 3 weeks, the observed improvement is largely limited to studies using the suboptimal paclitaxel schedule once every 3 weeks as control. PANTHER is an international phase III trial which compared sequential epirubicin/cyclophosphamide and docetaxel administered either once every 2 or once every 3 weeks, with tailored dosing at the dose-dense schedule according to hematologic toxicity. In this end-of-study analysis, the median follow-up was 10.3 years. Compared with standard adjuvant chemotherapy, dose-dense treatment improved breast cancer recurrence-free survival (hazard ratio [HR], 0.80 [95% CI, 0.65 to 0.98]; P = .030), event-free survival (HR, 0.78 [95% CI, 0.65 to 0.94]; P = .009), and distant disease-free survival (HR, 0.79 [95% CI, 0.64 to 0.98]; P = .030) while the improvement in overall survival was not statistically significant (HR, 0.82 [95% CI, 0.65 to 1.04]; P = .109). To our knowledge, this is the first trial that confirms the benefit of a dose-dense regimen over a control regimen containing docetaxel once every 3 weeks.

PURPOSE:The safety of local estrogen therapy in patients on adjuvant endocrine treatment is questioned, but evidence on the issue is scarce. This nested case-control registry-based study aimed to investigate whether estrogen therapy affects breast cancer mortality risk in women on adjuvant endocrine treatment.METHODS:In a cohort of 15,198 women diagnosed with early hormone receptor (HR)-positive breast cancer and adjuvant endocrine treatment, 1262 women died due to breast cancer and were identified as cases. Each case was matched with 10 controls. Exposure to estrogen therapy with concurrent use of aromatase inhibitors (AIs), tamoxifen, or both sequentially, was compared between cases and controls.RESULTS:No statistically significant difference in breast cancer mortality risk was seen in patients with exposure to estrogen therapy concurrent to endocrine treatment, neither in short-term or in long-term estrogen therapy use.CONCLUSIONS:The study strengthens current evidence on local estrogen therapy use in breast cancer survivors, showing no increased risk for breast cancer mortality in patients on adjuvant AIs or tamoxifen.