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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.

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.

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.

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.

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.

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.

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.

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.

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.

Selenium (Se) may help prevent breast cancer (BC) development. Owing to limited observational evidence, we investigated whether prediagnostic Se status and/or variants in the selenoprotein genes are associated with BC risk in a large European cohort. Se status was assessed by plasma measures of Se and its major circulating proteins, selenoprotein P (SELENOP) and glutathione peroxidase 3 (GPX3), in matched BC case-control pairs (2208 for SELENOP; 1785 for GPX3 and Se) nested within the European Prospective Investigation into Cancer and Nutrition (EPIC). Single nucleotide polymorphisms (SNPs, n = 452) in 55 selenoprotein and Se metabolic pathway genes and an additional 18 variants previously associated with Se concentrations were extracted from existing genotyping data within EPIC for 1564 case-control pairs. Multivariable-adjusted logistic regression models were used to calculate the odds ratios (ORs) and 95 % confidence intervals (CIs) of the association between Se status markers, SNP variants and BC risk. Overall, there was no statistically significant association of Se status with BC risk. However, higher GPX3 activity was associated with lower risk of premenopausal BC (4th versus 1st quartile, OR = 0.54, 95 % CI: 0.30–0.98, P_trend = 0.013). While none of the genetic variant associations (P ≤ 0.05) retained significance after multiple testing correction, rs1004243 in the SELENOM selenoprotein gene and two SNPs in the related antioxidant TXN2 gene (rs4821494 and rs5750261) were associated with respective lower and higher risks of BC at a significance threshold of P ≤ 0.01. Fourteen SNPs in twelve Se pathway genes (P ≤ 0.01) in interaction with Se status were also associated with BC risk. Higher Se status does not appear to be associated with BC risk, although activity of the selenoenzyme GPX3 may be inversely associated with premenopausal BC risk, and SNPs in the Se pathway alone or in combination with suboptimal Se status may influence BC risk.