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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.

The assessment of residual lymphovascular invasion (LVI) in breast cancer patients undergoing neoadjuvant therapy may be a critical factor influencing prognosis and treatment decisions. However, there is a notable discrepancy between the RCB, UICC/AJCC, and ICCR guidelines regarding how LVI should be evaluated and reported in this context. ICCR recommends including LVI in the invasive tumor size for neoadjuvant treated patients with only residual LVI affecting the Residual Cancer Burden (RCB) score. AJCC suggests that LVI should not be evaluated as invasive cancer. However, they do not recommend that such cases are considered as complete response. The RCB method does not address the LVI question at all. This editorial aims to explore the implications of these differing recommendations, highlighting the challenges in clinical practice. Even though there is limited evidence in the literature on this subject, leaving this discrepancy unaddressed leads to high variability in the staging of neoadjuvant-treated breast cancer patients among pathologists. This, in turn, may cause confusion in the clinical decision-making for these patients. The recommendation of the Swedish Breast Pathology Expert Group (KVAST breast) based on current evidence, is to report LVI as a separate prognostic biomarker in neoadjuvant setting and reporting it separately from the RCB treatment response criteria. For breast cancer patients with only LVI as residual disease in the breast without any lymph node metastasis after NACT, the Swedish Breast Pathology Expert Group recommends the following staging: RCB-0, pPR, ypT0, ypN0, L1.

Background: Emerging evidence indicates that estrogen receptor-low (ER-low)/human epidermal growth factor receptor 2 negative (HER2-) breast cancer (BC) may more closely resemble ER-negative (ER-zero, < 1%) rather than ER-positive disease in terms of biological and clinicopathological characteristics. In Sweden, ER-low (ER 1–9%) BC is managed as triple-negative breast cancer (TNBC) and is thus eligible for neoadjuvant chemo-immunotherapy. We aimed to investigate real-world pathological response to neoadjuvant pembrolizumab combined with chemotherapy in ER-low versus ER-zero BC patients within a Swedish population-based multi-center cohort.

Methods: BC patients with indication to receive neoadjuvant pembrolizumab in combination with chemotherapy in Sweden between 2022 and 2024 were included in the study. Clinicopathological data—including pathological complete response (pCR) status, residual cancer burden (RCB) score, stromal tumor-infiltrating lymphocytes (sTILs) levels, and routine tumor characteristics—were retrieved from laboratory information systems. Associations between categorical variables were assessed using chi-squared (χ2) tests and associations between continuous variables and ER status or pCR were analyzed using Mann–Whitney U-test.

Results: The total cohort comprised 441 TNBC cases (ER-zero n = 398; ER-low n = 43). In the ER-zero group, the pCR rate and RCB score 0–1 were 50.5% (95% CI: 45.5% to 55.5%) and 60.8% (95% CI: 55.8% to 65.6%), respectively. In the ER-low group, the corresponding values were 58.1% (95% CI: 42.1% to 73%), and 60.5% (95% CI: 44.4% to 75%), respectively. There were no statistically significant differences in either pCR rate (p = 0.46) or dichotomized RCB score (p = 0.88) between the groups. The ER-low group showed significantly higher sTILs percentage compared to the ER-zero group (median sTILs 25% versus 20%, p = 0.046). However, when sTILs were analyzed as a binary categorical variable using a 30% cut-off, no significant difference was observed (p = 0.33).

Conclusions: We observed no significant difference in pathological response to neoadjuvant chemo-immunotherapy with pembrolizumab between ER-zero and ER-low BCs. These findings support previous evidence suggesting that ER-low tumors behave more similarly to ER-zero than ER-positive.

Background: 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.

Methods: 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.

Results: 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.

Conclusions: Abundance of stromal collagen IV increases risk of dying in breast cancer after DCIS, and collagen IV can promote cell motility in vitro.

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: International guidelines recommend open surgery for atypical ductal hyperplasia (ADH) in the breast due to risk of underestimating malignant disease. Considering the ongoing randomized trials of active surveillance of low-risk ductal carcinoma in situ (DCIS), it seems reasonable to define a low-risk group of women with ADH where a conservative approach is appropriate. The aim here was to evaluate the management and risk for upgrade of lesions diagnosed as ADH in percutaneous breast biopsies in two Swedish hospitals.

Methods: All women with a screen-detected or symptomatic breast lesion breast imaging-reporting and data system (BI-RADS) 2–4 and a percutaneous biopsy showing ADH between 2013 and 2022 at Sundsvall Hospital and Umeå University Hospital were included. Information regarding imaging, histopathology, clinical features, and management was retrieved from medical records. Odds ratio (OR) and 95% confidence intervals (CI) for upgrade to malignant diagnosis after surgery were calculated by logistic regression analysis.

Results: Altogether, 101 women were included with a mean age 56.1 (range 36–93) years. Most women were selected from the national mammography screening program due to microcalcifications. Biopsies were performed with vacuum-assisted biopsy (60.4%) or core-needle biopsy (39.6%). Forty-eight women (47.5%) underwent surgery, of which 11 were upgraded to DCIS, and 7 to invasive breast cancer (upgrade rate 37.5%). Among the 53 women managed conservatively (median follow-up 74 months), one woman (1.9%) developed subsequent ipsilateral DCIS. The combined upgrade rate was 18.8%. No clinical variable statistically significantly correlating to risk of upgrade was identified.

Conclusions: The upgrade rate of 37.5% in women undergoing surgery compared to an estimated 5-year risk of ipsilateral malignancy at 1.9% in women managed conservatively indicate that non-surgical management of select women with ADH is feasible. Research should focus on defining reproducible criteria differentiating high-risk from low-risk ADH.

Introduction: Fibrillar collagens accumulate in the breast cancer stroma and appear as poorly defined spiculated masses in mammography imaging. The prognostic value of tissue type I collagen remains elusive in treatment-naïve and chemotherapy-treated breast cancer patients. Here, type I collagen mRNA and protein expression were analysed in 2 large independent breast cancer cohorts. Levels were related to clinicopathological parameters, prognostic biomarkers, and outcome.

Method: COL1A1 mRNA expression was analysed in 2509 patients with breast cancer obtained from the cBioPortal database. Type I collagen protein expression was studied by immunohistochemistry in 1395 women diagnosed with early invasive breast cancer.

Results: Low COL1A1 mRNA and protein levels correlated with poor prognosis features, such as hormone receptor negativity, high histological grade, triple-negative subtype, node positivity, and tumour size. In unadjusted analysis, high stromal type I collagen protein expression was associated with improved overall survival (OS) (HR = 0.78, 95% CI = 0.61-0.99, p = .043) and trended towards improved breast cancer–specific survival (BCSS) (HR = 0.65, 95% CI = 0.42-1.01, P = 0.053), although these findings were lost after adjustment for other clinical variables. In unadjusted analysis, high expression of type I collagen was associated with better OS (HR = 0.70, 95% CI = 0.55-0.90, P = .006) and BCSS (HR = 0.55, 95% CI = 0.34-0.88, P = .014) among patients not receiving chemotherapy. Strikingly, the opposite was observed among patients receiving chemotherapy. There, high expression of type I collagen was instead associated with worse OS (HR = 1.83, 95% CI = 0.65-5.14, P = .25) and BCSS (HR = 1.72, 95% CI = 0.54-5.50, P = .357).

Conclusion: Low stromal type I collagen mRNA and protein expression are associated with unfavourable tumour characteristics in breast cancer. Stromal type I collagen might predict chemotherapy response.

Background: Breast cancer is the most common cancer in women. Cancer cells can persist in a prolonged dormant state for years without any clinical evidence of disease creating an urgent need to better understand the molecular mechanisms leading to relapse. This study aimed to identify extracellular matrix (ECM) components associated with hypoxia-induced breast cancer dormancy. The effects of selected ECM proteins on breast cancer cell proliferation were analyzed, along with their correlation with established prognostic markers in human breast cancer tissue.

Materials and methods: Screening of extracellular matrix proteins was performed in hypoxia-induced dormant MCF-7 breast cancer cells. Proliferation of MCF-7 cells in vitro was subsequently determined in the presence of recombinant ColVII. Adipose tissue-derived mesenchymal stem cells (AdMSCs) subpopulation overexpressing ColVII were indirectly isolated by ColVII receptor integrin-α6 specific antibodies. AdMSCs- MCF-7 3D spheroid cultures were generated to model solid tumour conditions. In addition, the association between ColVII and various prognostic markers was evaluated in clinical samples of human breast cancer tissue.

Results: Dormant MCF-7 cells showed an elevated expression of ColVII while MCF-7 cells cultured on ColVII exhibited reduced proliferation in vitro. In AdMSCs-MCF-7 3D spheroids, a reduced proliferation of MCF-7 cells was observed in Int-α6+/ ColVIIhigh compared with Int-α6-/ ColVIIlow AdMSCs spheroids. In human tissue, high ColVII expression correlated to several positive prognostic markers. Staining for Cytokeratin-5 revealed that ColVIIhigh-expressing cells were predominantly myoepithelial cells.

Conclusion: ColVII is associated with reduced proliferation of breast cancer cells in vitro. ColVII is strongly expressed in myoepithelial cells and in breast cancer tissue the high ColVII expression correlates with several well-known positive prognostic markers, highlighting its potential as a prognostic marker in breast cancer.

The tumor extracellular matrix (ECM) critically regulates cancer progression and treatment response. Expression of the basement membrane component collagen XVIII (ColXVIII) is induced in solid tumors, but its involvement in tumorigenesis has remained elusive. We show here that ColXVIII was markedly upregulated in human breast cancer (BC) and was closely associated with a poor prognosis in high-grade BCs. We discovered a role for ColXVIII as a modulator of epidermal growth factor receptor tyrosine kinase (ErbB) signaling and show that it forms a complex with ErbB1 and -2 (also known as EGFR and human epidermal growth factor receptor 2 [HER2]) and α6-integrin to promote cancer cell proliferation in a pathway involving its N-terminal portion and the MAPK/ERK1/2 and PI3K/AKT cascades. Studies using Col18a1 mouse models crossed with the mouse mammary tumor virus-polyoma virus middle T antigen (MMTV-PyMT) mammary carcinogenesis model showed that ColXVIII promoted BC growth and metastasis in a tumor cell-autonomous manner. Moreover, the number of mammary cancer stem cells was significantly reduced in the MMTV-PyMT and human cell models upon ColXVIII inhibition. Finally, ablation of ColXVIII substantially improved the efficacy of ErbB-targeting therapies in both preclinical models. In summary, ColXVIII was found to sustain the stemness properties of BC cells and tumor progression and metastasis through ErbB signaling, suggesting that targeting ColXVIII in the tumor milieu may have important therapeutic potential.

Purpose: To investigate if molecular subtype is associated with outcome in stage 1 breast cancer (BC). Methods: Tissue samples from 445 women with node-negative BC ≤ 15 mm, treated in 1986–2004, were classified into surrogate molecular subtypes [Luminal A-like, Luminal B-like (HER2−), HER2-positive, and triple negative breast cancer (TNBC)]. Information on treatment, recurrences, and survival were gathered from medical records. Results: Tumour subtype was not associated with overall survival (OS). Luminal B-like (HER2−) and TNBC were associated with higher incidence of distant metastasis at 20 years (Hazard ratio (HR) 2.26; 95% CI 1.08–4.75 and HR 3.24; 95% CI 1.17–9.00, respectively). Luminal B-like (HER2−) and TNBC patients also had worse breast cancer-specific survival (BCSS), although not statistically significant (HR 1.53; 95% CI 0.70–3.33 and HR 1.89; 95% CI 0.60–5.93, respectively). HER2-positive BC was not associated with poor outcome despite no patient receiving HER2-targeted therapy, with most of these tumours being ER+. Conclusions: Stage 1 TNBC or Luminal B-like (HER2−) tumours behave more aggressively. Women with HER2+/ER+ tumours do not have an increased risk of distant metastasis or death, absent targeted treatment.