BACKGROUND:Large randomized studies show equivalent survival after breast-conserving surgery (BCS) + adjuvant radiotherapy (RT) and mastectomy. In contrast, more recent observational studies suggest BCS + RT to be superior, but it is questionable whether patients in these treatment arms are comparable. Here, overall survival (OS) and breast cancer-specific survival (BCSS) after BCS + RT and mastectomy are compared within a randomized trial comparing intravenous and inhalation anaesthesia during breast cancer surgery. METHODS:The patient cohort was recruited from the randomized CAN-study. Patients with tumours >30 mm, patients with tumours <10 mm, and patients who underwent BCS without RT were excluded. OS and BCSS were estimated using multivariable Cox regression analyses and three different propensity score models. RESULTS:The final study cohort included 830 women, of whom 601 underwent BCS + RT (median age 64 years) and 229 underwent mastectomy (median age 68 years). Women who underwent mastectomy had more co-morbidities and more unfavourable tumour characteristics. Mastectomy was associated with significantly less favourable OS in unadjusted, adjusted, and two of the three propensity score analyses. BCSS was inferior in the mastectomy group in the unadjusted analysis, with an HR of 2.27 (95% c.i. 1.20 to 4.30). In the adjusted and three propensity score analyses, BCSS was equal in the treatment groups, with an adjusted HR of 1.02 (95% c.i. 0.43 to 2.42). CONCLUSION:In this study, which was designed to approximate a randomized trial as closely as possible, no significant difference in BCSS was observed between BCS + RT and mastectomy. Differences in OS likely reflect occult selection bias of patients with higher co-morbidity burden to mastectomy.

Purpose: The prognostic role of tumor-infiltrating lymphocytes in luminal breast cancer remains uncertain, partly because density-based metrics do not capture spatial interactions between immune cell subsets. We developed a density-independent spatial metric quantifying macrophage-T cell proximity and assessed its prognostic value. Experimental Design: Using multiplex immunohistochemistry across three breast cancer cohorts (exploratory, n = 17; discovery, n = 687; validation, n = 305), we measured nearest-neighbor distances from T cells to M1-like and M2-like macrophages, benchmarked against a randomly subsampled total macrophage pool. We defined the Macrophage Spatial Polarity Index (MSPI) as the difference between M2-to-T cell and M1-to-T cell affinity scores, where higher values reflect an M2-dominated spatial phenotype. Cox regression was used to assess associations with distant disease-free survival (discovery) and overall survival (validation). Results: M2-like macrophages preferentially localized near T cells, independent of cell density. Higher MSPI was associated with shorter survival in luminal cancers (discovery: HR = 1.45, p < 0.001), with the strongest effect in young women with early-stage disease (HR = 2.16, p < 0.0001). MSPI remained independently prognostic after adjustment for stage, systemic treatment, and diagnosis period (HR = 2.31, 95% CI 1.73-3.09, p < 0.0001) and was non-significant in HER2-positive and triple-negative subtypes. Validation in an independent ER-positive cohort confirmed the finding (HR = 1.30, p = 0.004). Pooled analysis yielded HR = 2.13 (95% CI 1.68-2.70, p = 3.45 x 10-10). Conclusions: MSPI is a robust prognostic biomarker in luminal breast cancer, particularly in young women with early-stage disease, warranting further validation for risk stratification and therapeutic guidance. ### Competing Interest Statement Ioannis Zerdes has received institutional research grants from Gilead Sciences, honoraria paid to his institution from Novartis, personal honoraria from BioMed Central, and part of Springer Nature Group (editorial tasks), all outside of the submitted work. The authors have no conflicts of interest to declare. ### Clinical Trial NCT04168528 ### Funding Statement AM was supported by a grant from the Spanish Carlos III Health Institute (Contratos Miguel Servet 2023: CP23/00133), a postdoctoral grant from the Swedish Cancer Society (CAN 2017/1066), and a postdoctoral grant from the Public Agency of the Government of Catalonia AGAUR (Beatriu de Pinos, 2021). IF was funded through the Erik och Majje Nasstrom donation to Karolinska Institutet. This work was also supported by the regional agreement on medical training and clinical research (ALF) between the Stockholm County Council and Karolinska Institute (HF, IF), the Swedish Breast Cancer Association (BRO/Brostcancerforbundet) (HF, IF), the BRECT Theme Network (HF, IF), the Swedish Cancer Society (AM, HF, IF, FP, PM, NS, JL), the Knut and Alice Wallenberg Foundation (FP), and the Swedish Research Council (NS). The funding sources were not involved in the study design, collection, analyses, or interpretation of data, writing of the report, or decision to submit the article for publication. The Phase IIa segment of the 68Ga-NOTA-Anti-MMR-VHH2 clinical trial ([NCT04168528][1]) was funded by Kom op Tegen Kanker. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: All patient-derived tissue samples and clinical data used in this study were fully de-identified prior to analysis. Each cohort was handled according to local data-protection requirements and the corresponding ethical approvals: - Exploratory cohort: tissue specimens and clinical records were obtained through the Phase IIa segment of the [68Ga]Ga-NOTA-Anti-MMR-VHH2 clinical trial ([NCT04168528][1]). Samples were coded with a study-specific identifier before being transferred to the analysing centre; the investigators performing the spatial and statistical analyses had no access to any direct identifiers (name, personal identification number, address, or date of admission). In the supplementary patient table, exact ages have been replaced with 5-year non-overlapping age bands to further reduce the risk of indirect identification. - Discovery cohort: a Swedish population-based registry cohort of women diagnosed 1992-2005. Clinical and follow-up data were retrieved from the regional cancer registry and medical records under approvals 2009/1174-31/1 and 2010/586-32 (Research Ethics Committee, Karolinska Institute, Stockholm). All variables were pseudonymised by the data custodians before release. Only aggregated demographic, treatment, and outcome variables are reported. - Validation cohort: a population-based breast cancer tissue microarray collection from Uppsala University Hospital and Vasteras Central Hospital (women diagnosed 1985-2004). Samples and clinical data were de-identified by the source biobanks and released under Regional Ethics Committee of Uppsala approvals 99 422, 2005:118, and 2005:118/2. Investigators received only coded data without direct identifiers. No individual-level identifiers (names, personal identification numbers, dates of birth, dates of admission, precise geographical location, or family relationships) were available to the research team or appear in the manuscript or supplementary materials. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT04168528&atom=%2Fmedrxiv%2Fearly%2F2026%2F05%2F24%2F2026.05.17.26352909.atom

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.

Breast cancer management is shifting towards personalized treatment regimens, particularly for early-stage, hormone receptor positive (HR+) invasive breast cancer (IBC) patients following breast conserving surgery (BCS) where locoregional recurrence (LRR) rates are low. A critical unmet need is the development of tools that can both improve prognostic risk assessment and identify which patients are likely to benefit or not benefit from adjuvant radiation therapy (RT). Herein we developed and cross validated a novel multi-omic assay to assess LRR risk and expected RT benefit for early-stage HR+/HER2-negative IBCs. A retrospective multi-institutional cohort of 922 patients (T1-2, N0-1, HR+, HER2-) treated with definitive breast conserving surgery (BCS) with or without adjuvant treatment was used to develop and cross-validate a test to predict IBC LRR after BCS ± RT. Treatment assignment was not randomized. The test integrated NGS and proteomic assay data using two biosignatures to generate results: a Decision Score (DS) to predict 10-year LRR prognosis and a radiation resistance index (RRI) to predict differential RT effect on LRR. Associations between DS and RRI with LRR risk and RT interaction were tested using multivariable Cox models. Increasing continuous DS was associated with increasing LRR risk (HR 3.4 per 5 units; p<.001, n = 922) after adjusting for clinicopathologic risk factors, while RT was associated with reduced LRR risk (HR 0.2; p < .001). Increasing continuous RRI was associated with increasing LRR risk for patients treated with RT (HR = 3.1 per 5 units; RT: RRI pinteraction = 0.002). Biosignature utility was demonstrated for categorical risk groups, which were also associated with differential RT benefit. DS Elevated Risk patients (DS > 5) had higher LRR risk without RT (HR = 4.8; p = .0014) with corresponding 10-year risks of 24

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:The prognostic relevance of multifocal and multicentric breast cancer remains unclear and current staging systems do not consider focality. The aim of this study was to explore whether women with multifocal breast cancer have less favourable tumour characteristics and worse survival compared with women with unifocal breast cancer. METHODS:Patient and tumour characteristics were obtained from Breast Cancer Database Sweden 3.0, which includes data for all Swedish women diagnosed with invasive breast cancer between 2008 and 2019 and who underwent surgery. Overall and breast cancer-specific survival rates were calculated using the Kaplan-Meier method and multivariable analysis was used to identify independent predictors of survival using the Cox proportional hazard model. RESULTS:A total of 71 419 women were included in the study: 59 445 (83.2%) had unifocal breast cancer, 7286 (10.2%) had multifocal breast cancer with two invasive foci, and 4688 (6.6%) had multifocal breast cancer with three or more invasive foci. Multifocal breast cancer was associated with higher clinical T and N categories compared with unifocal breast cancer. The median follow-up time was 5.96 (interquartile range 3.078.80) years. The breast cancer-specific 10-year survival rates were 86.1% for women with multifocal breast cancer with three or more foci, 86.5% for women with multifocal breast cancer with two foci, and 88.4% for women with unifocal breast cancer. In a multivariable analysis adjusted for patient and tumour characteristics, the HR for breast cancer-specific death was 1.17 (95% c.i. 1.03 to 1.32) for women with multifocal breast cancer with three or more foci compared with women with unifocal breast cancer. There was no statistically significant difference in overall survival between the three groups. CONCLUSION:The present study suggests that focality provides prognostic information that is additional to that provided by traditional tumour characteristics.

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.

The incidence of trocar site hernia (TSH) after bariatric surgery is unclear. This study aims to describe the cumulative incidence of ventral hernia surgery after laparoscopic bariatric surgery in total and by laparoscopic method (LRYGB; Roux-en-Y Gastric Bypass and LSG; Sleeve Gastrectomy). This was a register based observational study on patients subjected to laparoscopic bariatric surgery (LRYGB or LSG) in Sweden 2009–2019. The Scandinavian Obesity Surgery Registry (SOReg) was linked to the Swedish National Patient Register (NPR) to obtain instances of ventral hernia surgery. Nearby codes were used as proxies for TSH surgery, since a specific procedure code for TSH surgery is lacking. In 64 124 patients, mean follow-up was 67 ± 36 months, LRYGB (n = 52 020) 74 ± 34 months and LSG (n = 12 104) 34 ± 22 months. Mean time between bariatric- and ventral hernia surgery was 36 ± 28 months (range 0–129). The five-year cumulative incidence of surgery for ventral hernia was 2.9

Current treatment for ductal carcinoma in situ (DCIS) of the breast is generic, due to lack of risk stratification tools. We investigate the correlation between expression of collagen IV in the breast and risk of dying of breast cancer. We also explore the effect of collagen IV in vitro. Tissue microarrays from a cohort of women treated for DCIS who later died from breast cancer (n = 43) or were still alive (n = 119), were analysed for collagen IV by immunohistochemistry. Oestrogen receptor positive (ER+), triple negative and human epidermal growth factor receptor 2 amplified (HER2+) cell lines were cultured with and without collagen IV. High expression of stromal collagen IV correlated with increased odds of dying of breast cancer (OR 2.50; 95% CI 1.16–5.39). This association remained when adjusting for tumour size, margin status, comedo necrosis and progesterone receptor negativity (PR−) (OR 4.27; 95% CI 1.64–11.1). Triple negative breast cancer cell lines migrated quicker on collagen IV-coated than on uncoated surfaces. By contrast, collagen IV coating did not affect ER+ and HER2+ cell lines. Abundance of stromal collagen IV increases risk of dying in breast cancer after DCIS, and collagen IV can promote cell motility in vitro.

e12566 Background: Adjuvant radiation therapy (RT) has been a standard component of breast conserving therapy (BCT), demonstrating a reduction in local regional recurrence (LRR) and an improvement in breast cancer mortality. In addition, endocrine therapy (ET) has been shown to have both ipsilateral and contralateral risk reduction benefits as well as mortality benefits. Given the benefits of RT and ET are not uniform for all patients, locoregional therapy for early stage- hormone receptor positive (HR+) breast cancer continues to evolve with a focus on individualized risk stratification; genomic and multiomic approaches are increasingly being considered to support informed decision making for patients, allowing clinicians to optimize treatment and identify patients who will have a significant benefit from RT and/or ET and those who will not. Methods: A group of 782 patients (T1/2, N0/1, HR+, HER2-) who underwent breast conservation surgery (BCS) between 1986-2022 were identified from a multi-institutional cohort of which 630 were 50 years or older and node negative. A multi-omic biosignature combining proteomic and genomic biomarkers (AidaBreast, PreludeDx, Laguna Hills, CA) was developed and cross-validated to calculate an individualized Decision Score (DS) on a 10-point scale and corresponding 10-year LRR risk for prognosis. The association between the DS, 10-yr LRR rate, and RT and ET benefit was assessed using multivariable (MVA) Cox proportional hazards. Results: The median age was 66 years old with 74% (465/630) of patients receiving RT and 37% (234/630) receiving ET, and 27% (n=171) receiving both ET and RT. Median follow up was 10 years. 39% (n=246) of patients had a Low Risk Decision Scores (DS≤4) and on MVA had no significant reduction in LRR risk with RT (HR= 0.92; p=.90) or ET (HR= 1.5; p=.65). The corresponding 10-year LRR risks were ≤5% independent of treatment with ET or RT. In contrast, patients with high Decision Scores (DS>4) (61%, n=384) had a significant reduction in LRR risk with RT (HR= 0.5, p=0.03) and had a trend toward reduced LRR rate with ET of (HR=0.5; p=0.16) with corresponding 10-year LRR risks of 20% (95%CI 10%, 28%) vs 12% (95%CI 7%,16%) without vs with RT. On MVA, neither age, grade, nor size were associated with LRR risk (p≥.4) after adjusting for DS. Conclusions: The multi-omic biosignature (AidaBreast, PreludeDX, Laguna Hills, CA) stratifies early-stage HR+ HER2-negative invasive breast cancer patients into those with little to no LRR benefit from RT or ET over 10-years versus those who have a meaningful reduction in LRR risk with adjuvant RT.

BACKGROUND AND OBJECTIVE:Breast cancer liver and lung metastases are common and associated with poor prognosis. Personalized medical treatment of advanced breast cancer, based on established predictive factors, has improved survival during the last decades. In contrast, there is no consensus regarding indications for surgery. The aim of this narrative review is to summarize the current knowledge on the outcome of surgical treatments for breast cancer liver and lung metastases. METHOD:A narrative review of existing evidence for diagnosis and treatment of breast cancer liver and lung metastases. RESULTS:There are no randomized trials to evaluate surgery as an adjunct to medical treatment. In this review, data are reported from case-control studies and meta-analyses on surgery for liver and lung metastases. Selected patients have an improved survival after surgery compared to those who only received medical treatment. The survival benefit is, however, uncertain when adjusting for prognostic factors, and prospective trials are warranted. Anecdotal cases have long-term survival and surgery is safe. CONCLUSION:Surgery for breast cancer liver and lung metastases may be considered in selected cases within prospective studies.

Abstract Introduction The effectiveness of current follow-up guidelines after breast cancer (BC) treatment is uncertain. A tailored surveillance according to patient age and tumour characteristics may be more adequate. The aim of this study was to assess the frequency of and the risk factors for detection of ipsilateral locoregional recurrences (LR) and second primary breast cancers (SP) outside of scheduled surveillance in patients with recurrent BC. Method Patients with surgically treated stage I-III BC from Malmö Diet and Cancer Study (MDCS) 1991-2014 (n=1095) and region Västernorrland 2009-2018 (n=1930) were included. Data on the index BC and recurrences were retrieved from medical records. Recurrent events were defined as symptomatic when detected at a patient-initiated visit or breast imaging outside of scheduled annual mammography surveillance. Result Median follow-up time was 6.5 years (Interquartile range: 3.8-10.0). In total, 262 patients had a relapse. The most common first event was distant metastasis (46%) followed by LR (22%) and SP (18%). Fifty-four per cent of LR and 27 % of SP were detected outside of scheduled surveillance. Logistic regression analysis showed that lymph node positive BC (HR 2.12; 95%CI, 1.00-4.60), BC of HER2 positive subtype (HR 5.13; 95%CI, 1.37-25.32) and young age (HR 2.25; 95%CI, 0.98-5.47) were associated with increased probability of having a symptomatically detected recurrence. Discussion Most recurrent events are detected outside of scheduled surveillance. Risk-based tailored surveillance might be more appropriate for subsets of patients.

Abstract &gt;Multifocal breast cancer: tumor biology and prognostic importance Background The incidence of multifocal breast cancer (MBC) varies widely in the literature and recent reports indicate that the incidence of MBC is increasing. Several studies have shown similar tumor biology in the different foci of multifocal tumors, and it has been suggested that multifocal tumors may in fact be intramammary metastases and thus be a sign of a more aggressive cancer type than unifocal tumors. Knowledge regarding outcome and optimal treatment of MBC compared to unifocal breast cancer (UBC) is still limited. The aim of the present study was to explore if multifocal breast cancers have less favorable characteristics and prognosis compared to unifocal breast cancers. Method Patient and tumor characteristics were obtained from Breast Cancer database Sweden (BcBaSe3) including women with invasive breast cancer 2008-2019 who had undergone primary surgery. Women with distant metastases at time of diagnosis, women receiving neoadjuvant systemic therapy, and men were excluded. Overall- and breast cancer specific survival were calculated with Kaplan-Meier and Cox-regression analyses. Results A total of 71607 women met our inclusion criteria, 11961 (16.7%) with MBC and 59512 (83.3%) with UBC. Among women with MBC, 64.1% underwent mastectomy compared to 32.4% of women with UBC and 40.1% with MBC underwent complete axillary lymph node dissection compared to 23.5% of the women with UBC. MBC was associated with higher T-stage (T2 31.9% vs. 25.8% and T3 4.6% vs. 2.6%. p&lt; 0.001) and higher N-stage (N+ 13.7% vs. 8.4%, P&lt; 0.001), compared to UBC. MBC were more often of lobular type (18.8% vs. 12.4%, P&lt; 0.001), of higher grade (grade 3 29.3% vs. 27.3%, p&lt; 0.001), with positive hormone receptor status (88.4% vs. 86.7%, p&lt; 0.001), and Her2 positivity (13.3% vs. 10.9%, p&lt; 0.001). Adjuvant systemic treatment was more frequently administered to women with MBC, adjuvant chemotherapy (45.3% vs. 33.3%, p&lt; 0.001) and endocrine treatment (82.9% vs. 75.3%, p&lt; 0.001). Breast cancer specific 10- year survival was 86.4% and 88.5% for MBC and UBC respectively, hazard ratio for breast cancer death 1.19 (95 % confidence interval, 1.11- 1.28). Overall survival did not differ between the two groups (10-year survival 76.0%, p=0.35) Conclusion MBC appears to have a more aggressive tumor biology than UBC, with the exception of hormone receptor status and MBC is associated with decreased breast cancer specific survival. Further analysis of possible interactions with different treatment methods will be conducted. Citation Format: Emma Söderberg, Malin Sund, Fredrik Wärnberg, Hans Garmo, Anna-Karin Wennstig, Lars Holmberg, Greger Nilsson, Charlotta Wadsten. Multifocal breast cancer: tumor biology and prognostic importance [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 PO5-02-07.

The effectiveness of current follow-up guidelines after breast cancer treatment is uncertain. Tailored surveillance based on patient age and tumor characteristics may be more adequate. This study aimed to analyze the frequency of ipsilateral locoregional recurrences (LR) and second primary breast cancers (SP) detected outside of scheduled surveillance and to analyze risk factors associated with these events. Patients with surgically treated early-stage breast cancer from the Malmö Diet and Cancer Study (MDCS), 1991–2014 (n = 1080), and the Västernorrland region, 2009–2018 (n = 1648), were included. Clinical and pathological information on the primary tumor and recurrences was retrieved from medical records. The mode of recurrence detection was defined as detection within (planned) or outside (symptomatic) of scheduled surveillance. The median follow-up was 6.5 years. Overall, 461 patients experienced a recurrence. The most common initial event was distant metastasis (47

Abstract Introduction International guidelines recommend open surgery for Atypical Ductal Hyperplasia (ADH) in the breast due to risk of underestimating malignant disease. The aim here was to evaluate the management and risk for upgrade of lesions diagnosed as ADH in percutaneous breast biopsies in two Swedish institutions. Methods All women with a screen-detected or symptomatic ADH diagnosed on percutaneous biopsy between 2013-2022 at Sundsvall and Umeå University Hospitals were included. Women with lesions classified as Breast imaging-reporting and data system (BI-RADS) 5 (highly suspicious) or 6 (confirmed malignancy) were excluded. Data were retrieved from medical records and histopathology reports. Odds ratio (OR) and 95 % confidence intervals (CI) for upgrade to malignant diagnosis after surgery was calculated by logistic regression analysis. Results Altogether, 101 women were included, mean age 56.1 years (range 36-93 years). Most women were selected from the national mammography screening program due to microcalcifications. Biopsies were performed with vacuum-assisted biopsy (VAB)(60.4%) or core-needle biopsy (CNB)(39.6%). Forty-eight women (47.5%) underwent surgery. Presence of a first degree relative with breast cancer (p < 0.001), more extensive microcalcifications (p=0.01), biopsies with ADH bordering DCIS (p=0.01) and CNB as opposed to VAB (p=0.02) increased the likelihood of surgical excision. Among the women undergoing surgery, eleven were upgraded to Ductal Carcinoma in Situ and seven to invasive breast cancer (overall upgrade rate 37.5%). In these women, no variable correlating to risk of upgrade in the surgical specimen was identified. After median 74 months of follow-up (range 4-105 months), one out of 53 women managed conservatively (1.9%) developed subsequent ipsilateral DCIS. Conclusion The upgrade rate to carcinoma was 37.5% after surgery while the estimated 5-year risk of ipsilateral upgrade in women managed conservatively was 1.9%. Acknowledging the short median follow-up time, these results indicate that the selection for non-surgical management in a subset of women was appropriate. Summary of histopathological results after surgical excision of ADH Citation Format: Charlotta Wadsten, Gunilla Rask. Management and risk of upgrade of Atypical Ductal Hyperplasia in the breast – a population-based retrospective cohort analysis [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 PO1-23-03.

Introduction: Observational studies suggest that breast conserving surgery (BCS) and radiotherapy (RT) offers superior survival compared to mastectomy. The aim was to compare patient and tumour characteristics in women with invasive breast cancer ≤30 mm treated with either BCS or mastectomy, and to explore the underlying reason for choosing mastectomy. Methods: Women registered with breast cancer ≤30 mm and ≤4 positive axillary lymph nodes in the Swedish National Breast Cancer Register 2013–2016 were included. Logistic regression analyses were performed to assess the association of tumour and patient characteristics with receiving a mastectomy vs. BCS. Results: Of 1860 breast cancers in 1825 women, 1346 were treated by BCS and 514 by mastectomy. Adjuvant RT was given to 1309 women (97.1 %) after BCS and 146 (27.6 %) after mastectomy. Variables associated with receiving a mastectomy vs. BCS included clinical detection (Odds Ratio (OR) 4.15 (95 % Confidence Interval (CI) 3.35–5.14)) and clinical stage (T2 vs. T1 (OR 3.68 (95 % CI 2.90–4.68)), N1 vs. N0 (OR 2.02 (95 % CI 1.38–2.96)). Women receiving mastectomy more often had oestrogen receptor negative, HER2 positive tumours of higher histological grade. The most common reported reason for mastectomy was large or multifocal tumours (53.5 %), followed by patient preference (34.5 %). Conclusion: Choice of surgery is strongly associated with key prognostic factors among women undergoing BCS with RT compared to mastectomy. Failure to control for all relevant confounders may bias results in outcome studies in favour of BCS.

BACKGROUND:Studies identifying risk factors for death from breast cancer after ductal carcinoma in situ (DCIS) are rare. In this retrospective nested case-control study, clinicopathological factors in women treated for DCIS and who died from breast cancer were compared with those of patients with DCIS who were free from metastatic disease. METHODS:The study included patients registered with DCIS without invasive carcinoma in Sweden between 1992 and 2012. This cohort was linked to the National Cause of Death Registry. Of 6964 women with DCIS, 96 were registered with breast cancer as cause of death (cases). For each case, up to four controls (318; women with DCIS, alive and without metastatic breast cancer at the time of death of the corresponding case) were selected randomly by incidence density sampling. Whole slides of tumour tissue were evaluated for DCIS grade, comedo necrosis, and intensity of periductal lymphocytic infiltrate. Composition of the immune cell infiltrate, expression of oestrogen receptor, progesterone receptor, human epidermal growth factor receptor 2, and proliferation marker Ki-67 were scored on tissue microarrays. Clinical information was obtained from medical records. Information on date, site, and histological characteristics of local and distant recurrences was obtained from medical records for both cases and controls. RESULTS:Tumour tissue was analysed from 65 cases and 195 controls. Intense periductal lymphocytic infiltrate around DCIS was associated with an increased risk of later dying from breast cancer (OR 2.21. 95% c.i. 1.01 to 4.84). Tumours with more intense lymphocytic infiltrate had a lower T cell/B cell ratio. None of the other biomarkers correlated with increased risk of breast cancer death. CONCLUSION:The immune response to DCIS may influence the risk of dying from breast cancer.

Background Retrospective observational studies suggest a potential role of beta-blockers as a protective strategy against progression and metastasis in invasive breast cancer. In this context, we investigated the impact of beta-blocker exposure on risk for progression to invasive breast cancer after diagnosis of ductal cancer in situ (DCIS).Methods The retrospective study population included 2535 women diagnosed with pure DCIS between 2006 and2012 in three healthcare regions in SwedenExposure to beta-blocker was quantified using a time-varying percentage of days with medication available. The absolute risk was quantified using cumulative incidence functions and cox models were applied to quantify the association between beta-blocker exposure and time from DCIS diagnosis to invasive breast cancer, accounting for delayed effects, competing risks and pre-specified confounders.Results The median follow-up was 8.7 years. One third of the patients in our cohort were exposed to beta-blockers post DCIS diagnosis. During the study period, 48 patients experienced an invasive recurrence, giving a cumulative incidence of invasive breast cancer progression of 1.8% at five years. The cumulative exposure to beta-blocker was associated with a reduced risk in a dose-dependent manner, though the effect was not statistically significant.Conclusion Our observational study is suggestive of a protective effect of beta-blockers against invasive breast cancer after primary DCIS diagnosis. These results provide rationales for experimental and clinical follow-up studies in carefully selected DCIS groups.

Purpose/Objective(s) The landscape of breast cancer management is evolving with emphasis on the need for personalized treatment regimens to tailor treatment in early-stage, hormone receptor-positive (HR+) invasive breast cancer (BC) patients. Given that locoregional recurrence (LRR) rates are lower in HR+ BC patients, multiple studies have evaluated the role of adjuvant radiation therapy (RT) and/or endocrine therapy (ET) in these patients. Ongoing studies are exploring the integration of clinical and biological factors to better assess patient-specific recurrence risk profiles to individualize treatment in the adjuvant setting. The present study hypothesizes that the interaction of cellular pathways influencing tumor biology can be used as part of a biosignature to predict recurrence risk and the RT and ET benefit for early-stage HR+ HER2-negative BC. Materials/Methods A subset of 704 HR+ T1/T2N0M0 patients with BC who underwent BCS with or without RT between 1987-2002 were identified from a multi-institutional cohort of women. A biosignature that calculates an individualized risk profile was developed and cross-validated. The association between the biosignature and the 10-year LRR rate was assessed. RT and ET benefit were assessed as a function of the biosignature score, using survival analyses and multivariable Cox proportional hazards adjusted for treatment and clinicopathologic (CP) risk factors age, grade, and tumor size. Results Median follow-up was 126 months and the median age was 63 years old for the cohort with 93% (n=661) having T1 disease. 36% of patients (n=253) received ET, 82% (n=584) received RT, with 29% (n=205) receiving both. On multivariable analysis, higher grade (p=.04), younger age (p=.05), and receipt of RT (p=.007) were associated with LRR. However, in a multivariable analysis that incorporated treatment and CP factors, the biosignature was prognostic (p<.001), while the CP factors were not associated with the LRR rate. The biosignature also predicted the benefit from RT (interaction with RT, p<.001) and incremental ET benefit after RT (interaction with ET, p=.0018) over 10 years. Collectively, the biosignature identified a) a Low-Risk Group with a 1% 10-year LRR rate ± RT (HR∼1, p=0.99, n=146), b) an Elevated-Risk Group with a 17% LRR rate without RT and 10% with RT (HR=0.45, p=.018, n=462) and c) a Residual-Risk Group with a 31% LRR rate without RT and 23% with RT (HR=0.62, p=.4, n=96). Conclusion The novel biosignature was prognostic for LRR after BCS and identified clinically meaningful risk groups, predicting differential RT and incremental ET benefit associated with 10-year LRR. This initial validation indicates that the biosignature may be a useful tool to aid in the assessment of the benefit of adjuvant therapy in early-stage HR+ HER2-negative invasive BC.

Abstract Introduction Locally advanced breast cancer (LABC) refers to large primary breast tumours (T3), tumours of any size with chest wall/skin involvement (T4), and/or extensive lymph node involvement (N2-3). LABC may be a consequence of delayed presentation or aggressive tumour biology. The aim of the study was to explore patient characteristics, treatment, and time trends of LABC in a Swedish population-based cohort. Method The study cohort was retrieved from BCBaSe 3.0 including 94 271 patients with invasive breast cancer diagnosed 2008-2019 after exclusion of those with distant metastasis at diagnosis or within 3 months. Comparisons were made between non-LABC (T0-2N0-1) and LABC subcategorized by T-stage (T≥3) and N-stage (N≥2). Result Of all BC, 6565 (7.0 %) were LABC, with a fairly constant proportion over time. A higher proportion of LABC was seen both among the youngest (<40 y; 11.9 %) and among the oldest (80+ y; 15.7 %), and in those with a low level of education (9.5 %). Lobular BC was overrepresented among LABC (16.0 % vs 11.1 % in non-LABC), as were the Her2-positive (17.3 % vs 10.2 %) and triple-negative subtypes (11.0 % vs 7.3 % in non-LABC). On average, 47.2 % of LABC underwent primary surgery, 44.2 % received neoadjuvant treatment ranging from 26.7 % for T0-2N2 to 83.0 % for inflammatory BC, whereas 8.6 % received no treatment. Of those undergoing neoadjuvant treatment, 71.8 % proceeded to surgery. Discussion LABC encompasses a wide range of tumours, comprising both primarily operable and non-operable tumours, with notable distinctions observed between different subgroups of LABC.