| 1. |
- Björk Gunnarsdottir, Frida, et al.
(författare)
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Co-localization of CD169+ macrophages and cancer cells in lymph node metastases of breast cancer patients is linked to improved prognosis and PDL1 expression
- 2020
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Ingår i: OncoImmunology. - 2162-4011. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Breast cancer is the most common form of cancer in women worldwide. Although the survival among breast cancer patients has improved, there is still a large group of patients with dismal prognosis. One of the most important prognostic factors for poor prognosis is lymph node metastasis. Increasing knowledge concerning the lymph nodes of breast cancer patients indicates that they are affected by the primary tumor. In this study we show that presence of CD169+ subcapsular sinus macrophages in contact with lymph node metastases in breast cancer patients, is related to better prognosis after adjuvant tamoxifen treatment, but only in patients with PDL1+ primary tumors. This is in contrast to the prognostic effect of CD169+ primary tumor-associated macrophages (TAMs). We further show that CD169+ macrophages were spatially associated with expression of PDL1 on nearby cells, both in primary tumors and metastatic lymph node, although PDL1 expression in metastatic lymph node as such did not have further prognostic impact. Our data suggest that CD169+ resident lymph node macrophages have a unique function in targeting immune responses against breast cancer and should be further investigated in detail.
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| 2. |
- De Marchi, Tommaso, et al.
(författare)
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Proteogenomics decodes the evolution of human ipsilateral breast cancer
- 2023
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Ingår i: Communications Biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 6:1
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Tidskriftsartikel (refereegranskat)abstract
- Ipsilateral breast tumor recurrence (IBTR) is a clinically important event, where an isolated in-breast recurrence is a potentially curable event but associated with an increased risk of distant metastasis and breast cancer death. It remains unclear if IBTRs are associated with molecular changes that can be explored as a resource for precision medicine strategies. Here, we employed proteogenomics to analyze a cohort of 27 primary breast cancers and their matched IBTRs to define proteogenomic determinants of molecular tumor evolution. Our analyses revealed a relationship between hormonal receptors status and proliferation levels resulting in the gain of somatic mutations and copy number. This in turn re-programmed the transcriptome and proteome towards a highly replicating and genomically unstable IBTRs, possibly enhanced by APOBEC3B. In order to investigate the origins of IBTRs, a second analysis that included primaries with no recurrence pinpointed proliferation and immune infiltration as predictive of IBTR. In conclusion, our study shows that breast tumors evolve into different IBTRs depending on hormonal status and proliferation and that immune cell infiltration and Ki-67 are significantly elevated in primary tumors that develop IBTR. These results can serve as a starting point to explore markers to predict IBTR formation and stratify patients for adjuvant therapy.
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| 3. |
- Engström, Terese, et al.
(författare)
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Hormone receptor mRNA and protein levels as predictors of premenopausal tamoxifen benefit
- 2024
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Ingår i: Acta Oncologica. - 0284-186X. ; 63, s. 125-136
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Tidskriftsartikel (refereegranskat)abstract
- Background and purpose: Tamoxifen remains an important adjuvant treatment in premenopausal patients with hormone receptor-positive breast cancer. Thus, determination of hormone receptors is important. Here, we compare cytosol-based methods, immunohistochemistry (IHC), and gene expression (GEX) analysis for determining hormone receptor status in premenopausal breast cancer patients from a randomised tamoxifen trial, to evaluate their performance in identifying patients that benefit from tamoxifen. Patients and Methods: Premenopausal patients (n=564) were randomised to 2 years of tamoxifen or no systemic treatment. Estrogen receptor (ER) and progesterone receptor (PR) status by protein expression measured by cytosol-based methods and IHC, and mRNA by GEX analysis were compared in 313 patients with available data from all methods. Kaplan Meier estimates and Cox regression were used to evaluate the treatment-predictive value for recurrence-free interval (RFi) and overall survival (OS). Median follow-up for event-free patients was 26 (RFi) and 33 (OS) years. Results: The mRNA data of ESR1 and PGR distributed bimodally, patterns confirmed in an independent cohort. Kappa-values between all methods were 0.76 and 0.79 for ER and PR, respectively. Tamoxifen improved RFi in patients with ER-positive (ER+) or PR-positive (PR+) tumours (Hazard Ratio [HR] and 95% confidence interval [CI]), cytosol-ER+ 0.53 [0.36–0.79]; IHC-ER+ 0.55 [0.38–0.79]; GEX-ER+ 0.54 [0.37–0.77]; cytosol-PR+ 0.49 [0.34–0.72]; IHC-PR+ 0.58 [0.40–0.85]; GEX-PR+ 0.55 [0.38–0.80]). Results were similar for OS. Interpretation: These methods can all identify patients that benefit from 2 years of tamoxifen with equal performance, indicating that GEX data might be used to guide adjuvant tamoxifen therapy.
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| 4. |
- Forsare, Carina, et al.
(författare)
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The Prognostic Role of Intratumoral Stromal Content in Lobular Breast Cancer
- 2022
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Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 14:4
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Tidskriftsartikel (refereegranskat)abstract
- Previous studies have shown that high intratumoral stromal content is associated with a worse prognosis in breast cancer, especially in the triple-negative subtype. However, contradictory results have been reported for estrogen-receptor-positive (ER+) breast cancer, indicating that the prognostic role of intratumoral stromal content may be subtype-dependent. In this study, we investigated the importance of intratumoral stromal content for breast cancer-specific mortality (BCM) in a well-defined subgroup (n = 182) of ER+/human-epidermal growth-factor-receptor-2 negative (HER2−) invasive lobular breast cancer (ILC). The intratumoral stromal content was assessed on hematoxylin–eosin-stained whole sections and graded into high stroma (>50%) or low stroma (≤50%). A total of 82 (45%) patients had high-stroma tumors, and 100 (55%) had low-stroma tumors. High-stroma tumors were associated with a lower Nottingham histological grade, low Ki67, and a luminal A-like subtype. After a 10-year follow-up, the patients with high-stroma tumors had a lower BCM (HR: 0.43, 95% CI: 0.21–0.89, p = 0.023) in univariable analysis. Essentially the same effect was found in both the multivariable analysis (10-year follow-up) and univariable analysis (25-year follow-up), but these findings were not strictly significant. In ER+/HER2− ILC, high intratumoral stromal content is an easily assessable histological indicator of a good prognosis.
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| 5. |
- Hartkopf, Andreas D., et al.
(författare)
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Disseminated tumour cells from the bone marrow of early breast cancer patients : Results from an international pooled analysis
- 2021
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Ingår i: European Journal of Cancer. - : Elsevier BV. - 0959-8049. ; 154, s. 128-137
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Presence of disseminated tumour cells (DTCs) in the bone marrow (BM) has been described as a surrogate of residual disease in patients with early breast cancer (EBC). PADDY (Pooled Analysis of DTC Detection in Early Breast Cancer) is a large international analysis of pooled data that aimed to assess the prognostic impact of DTCs in patients with EBC. Experimental design: Individual patient data were collected from 11 centres. Patients with EBC and available follow-up data in whom BM sampling was performed at the time of primary diagnosis before receiving any anticancer treatment were eligible. DTCs were identified by antibody staining against epithelial cytokeratins. Multivariate Cox regression was used to compare the survival of DTC-positive versus DTC-negative patients. Results: In total, 10,307 patients were included. Of these, 2814 (27.3%) were DTC-positive. DTC detection was associated with higher tumour grade, larger tumour size, nodal positivity, oestrogen receptor and progesterone receptor negativity, and HER2 positivity (all p < 0.001). Multivariate analyses showed that DTC detection was an independent prognostic marker for overall survival, disease-free survival and distant disease-free survival with hazard ratios (HR) and 95% confidence intervals (CI) of 1.23 (95% CI: 1.06–1.43, p = 0.006), 1.30 (95% CI: 1.12–1.52, p < 0.001) and 1.30 (95% CI: 1.08–1.56, p = 0.006), respectively. There was no association between locoregional relapse-free survival and DTC detection (HR 1.21; 95% CI 0.68–2.16; p = 0.512). Conclusions: DTCs in the BM represent an independent prognostic marker in patients with EBC. The heterogeneous metastasis-initiating potential of DTCs is consistent with the concept of cancer dormancy.
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| 6. |
- Inasu, Maria, et al.
(författare)
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High CYP27A1 expression is a biomarker of favorable prognosis in premenopausal patients with estrogen receptor positive primary breast cancer
- 2021
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Ingår i: npj Breast Cancer. - : Springer Science and Business Media LLC. - 2374-4677. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- 27-hydroxycholesterol (27HC), synthesized from cholesterol by the enzyme CYP27A1, differentially impacts estrogen receptor positive (ER+) breast cancer (BC) cell growth depending on estrogen levels. This study examined the association between CYP27A1 expression and prognosis in a cohort of 193 premenopausal patients with lymph node-negative primary BC with limited exposure to adjuvant systemic cancer treatments. In multivariable analyses among patients with ER+ tumors, high CYP27A1 protein and mRNA expressions were associated with four- and eight-fold reductions in the incidence of distant recurrence-free survival events: HRadj = 0.26, 95% CI = 0.07–0.93 and HRadj = 0.13, 95% CI = 0.03–0.60, respectively. In vitro studies revealed that 27HC treatment potently inhibited ER+ BC cell proliferation under lipid-depleted conditions regardless of estradiol levels, transcriptionally mediated through the downregulation of ER signaling with a concomitant upregulation of cholesterol export. Importantly, if validated, these results may have implications for adjuvant treatment decisions in premenopausal patients, especially when de-escalation of therapy is being considered.
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| 7. |
- Jørgensen, Charlotte Levin Tykjær, et al.
(författare)
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Expression of epithelial-mesenchymal transition-related markers and phenotypes during breast cancer progression
- 2020
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Ingår i: Breast Cancer Research and Treatment. - : Springer Science and Business Media LLC. - 0167-6806 .- 1573-7217. ; 181:2, s. 369-381
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: The study aimed to investigate expression of epithelial-to-mesenchymal transition (EMT)-related proteins and phenotypes during breast cancer progression and to relate this to patient outcome. Methods: Protein expression patterns of E-cadherin, N-cadherin, twist, and vimentin were examined by immunohistochemistry on formalin-fixed paraffin-embedded samples from primary tumors (PTs) (n = 419), synchronous lymph node metastases (LNMs) (n = 131) and recurrences (n = 34) from patients included in an observational prospective primary breast cancer study. Markers were evaluated individually and combined as defined EMT phenotypes (epithelial, mesenchymal, partial EMT, and negative). EMT profiles were compared between matched tumor progression stages, and related to clinicopathological data and distant recurrence-free interval (DRFi). Results: N-cadherin-positivity, vimentin-positivity, mesenchymal and partial EMT phenotypes were associated with more aggressive tumor characteristics such as triple-negative subtype. Single EMT markers and phenotype discordance rates between paired tumor samples were observed in the range of 2–35%. Non-epithelial phenotypes were more frequently identified in recurrences compared to PTs, however, no skewness of expression or phenotype was detected between PTs and matched LNMs or between PTs and matched recurrences (Exact McNemar test). Interestingly, patients with a twist positive PT had shorter DRFi, compared to patients with a twist negative PT (hazard ratio (HR) 2.4, 95% confidence interval (CI) 1.2–5.1, P = 0.02). Essentially, the same effect was seen in multivariable analysis (HR 2.5, 95% CI 0.97–6.6, P = 0.06). Conclusion: The epithelial phenotype was indicated to be lost between PTs and recurrences as a reflection of tumor progression. Twist status of the PT was related to long-term prognosis warranting further investigation in larger cohorts.
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| 8. |
- Lundgren, Christine, et al.
(författare)
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PAM50 subtyping and ROR score add long-term prognostic information in premenopausal breast cancer patients
- 2022
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Ingår i: Npj Breast Cancer. - : Springer Science and Business Media LLC. - 2374-4677. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- PAM50 intrinsic subtyping and risk of recurrence (ROR) score are approved for risk profiling in postmenopausal women. We aimed to examine their long-term prognostic value in terms of breast cancer-free interval (BCFi) and overall survival (OS) (n = 437) in premenopausal women randomised to 2 years of tamoxifen versus no systemic treatment irrespective of hormone-receptor status. Intrinsic subtyping added independent prognostic information in patients with oestrogen receptor-positive/human epidermal growth factor 2-negative tumours for BCFi and OS after maximum follow-up (overall P-value 0.02 and 0.006, respectively) and those with high versus low ROR had worse prognosis (maximum follow-up: hazard ratio (HR)(BCFi): 1.70, P 0.04). The prognostic information by ROR was similar regarding OS and in multivariable analysis. These results support that PAM50 subtyping and ROR score provide long-term prognostic information in premenopausal women. Moreover, tamoxifen reduced the incidence of breast cancer events only in patients with Luminal A(PAM50) tumours (0-10 years: HRBCFi(Luminal A): 0.41, HRBCFi(Luminal B): 1.19, P-interaction = 0.02).
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| 9. |
- Lundgren, Christine, et al.
(författare)
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Tamoxifen-predictive value of gene expression signatures in premenopausal breast cancer : data from the randomized SBII:2 trial
- 2023
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Ingår i: Breast Cancer Research. - : BMC. - 1465-5411 .- 1465-542X. ; 25:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Gene expression (GEX) signatures in breast cancer provide prognostic information, but little is known about their predictive value for tamoxifen treatment. We examined the tamoxifen-predictive value and prognostic effects of different GEX signatures in premenopausal women with early breast cancer. Methods: RNA from formalin-fixed paraffin-embedded tumor tissue from premenopausal women randomized between two years of tamoxifen treatment and no systemic treatment was extracted and successfully subjected to GEX profiling (n = 437, NanoString Breast Cancer 360™ panel). The median follow-up periods for a recurrence-free interval (RFi) and overall survival (OS) were 28 and 33 years, respectively. Associations between GEX signatures and tamoxifen effect were assessed in patients with estrogen receptor-positive/human epidermal growth factor receptor 2-negative (ER+ /HER2−) tumors using Kaplan–Meier estimates and Cox regression. The prognostic effects of GEX signatures were studied in the entire cohort. False discovery rate adjustments (q-values) were applied to account for multiple hypothesis testing. Results: In patients with ER+/HER2− tumors, FOXA1 expression below the median was associated with an improved effect of tamoxifen after 10 years with regard to RFi (hazard ratio [HR] FOXA1(high) = 1.04, 95% CI = 0.61–1.76, HR FOXA1(low) = 0.30, 95% CI = 0.14–0.67, q interaction = 0.0013), and a resembling trend was observed for AR (HR AR(high) = 1.15, 95% CI = 0.60–2.20, HR AR(low) = 0.42, 95% CI = 0.24–0.75, q interaction = 0.87). Similar patterns were observed for OS. Tamoxifen was in the same subgroup most beneficial for RFi in patients with low ESR1 expression (HRRFi ESR1(high) = 0.76, 95% CI = 0.43–1.35, HRRFi, ESR1(low) = 0.56, 95% CI = 0.29–1.06, q interaction = 0.37). Irrespective of molecular subtype, higher levels of ESR1, Mast cells, and PGR on a continuous scale were correlated with improved 10 years RFi (HR ESR1 = 0.80, 95% CI = 0.69–0.92, q = 0.005; HRMast cells = 0.74, 95% CI = 0.65–0.85, q < 0.0001; and HR PGR = 0.78, 95% CI = 0.68–0.89, q = 0.002). For BC proliferation and Hypoxia, higher scores associated with worse outcomes (HRBCproliferation = 1.54, 95% CI = 1.33–1.79, q < 0.0001; HRHypoxia = 1.38, 95% CI = 1.20–1.58, q < 0.0001). The results were similar for OS. Conclusions: Expression of FOXA1 is a promising predictive biomarker for tamoxifen effect in ER+/HER2− premenopausal breast cancer. In addition, each of the signatures BC proliferation, Hypoxia, Mast cells, and the GEX of AR, ESR1, and PGR had prognostic value, also after adjusting for established prognostic factors. Trial registration This trial was retrospectively registered in the ISRCTN database the 6th of December 2019, trial ID: https://clinicaltrials.gov/ct2/show/ISRCTN12474687 .
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| 10. |
- Lundgren, Christine, et al.
(författare)
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Tumour-infiltrating lymphocytes as a prognostic and tamoxifen predictive marker in premenopausal breast cancer : data from a randomised trial with long-term follow-up
- 2020
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Ingår i: Breast Cancer Research. - : Springer Science and Business Media LLC. - 1465-5411 .- 1465-542X. ; 22:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Tumour-infiltrating lymphocytes (TILs) are of important prognostic and predictive value in human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC) and triple-negative breast cancer (TNBC), but their clinical relevance in oestrogen receptor-positive/HER2-negative (ER+/HER2−) remains unknown. The primary study aim was to analyse the prognostic effect of TILs on the BC-free interval (BCFi) in premenopausal patients stratified by BC subtypes. The secondary aim was to investigate if TILs are predictive of tamoxifen (TAM) benefit. Methods: Archival tissues from primary breast tumours were collected from patients from the SBII:2pre trial, in which 564 premenopausal women were randomised to 2 years of adjuvant TAM or no systemic treatment, regardless of hormone receptor status. TILs were scored on whole tissue sections from 447 patients with available ER status. Tumours were divided into ER+/HER2−, HER2+ and TNBC subtypes by immunohistochemistry and in situ hybridisation. The prognostic value of TILs was analysed in systemically untreated patients (n = 221); the predictive information was investigated in the ER+ subgroup (n = 321) by cumulative incidence curves and Cox regression analyses. The median follow-up was 28 years. Results: High (≥ 50%) infiltration of TILs was a favourable prognostic factor in terms of BCFi (univariable analysis: hazard ratioBCFi (HRBCFi) 0.40; 95% confidence interval (CI) 0.22–0.71; P = 0.002). Similar effects were observed across all BC subtypes. The effect of adjuvant TAM was stronger in patients with ER+ tumours and TILs < 50% (HRBCFi 0.63; 95% CI 0.47–0.84; P = 0.002) than in patients with high immune infiltration (≥ 50%) (HRBCFi 0.84; 95% CI (0.24–2.86); P = 0.77). However, evidence for differential effects of TAM in categories of TILs, i.e. interaction, was weak. Conclusions: We demonstrate a long-term favourable prognostic value of high infiltration of TILs in a cohort of premenopausal BC patients and the positive prognostic effect was extended to the ER+/HER2− subgroup. A beneficial effect of TAM in ER+ patients was observed in patients with tumours of low TIL infiltration, but evidence for a treatment predictive effect was weak. Trial registration: This trial is registered in the ISRCTN database, trial ID: ISRCTN12474687.
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