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  • 1
    In: Diagnostics, MDPI AG, Vol. 12, No. 10 ( 2022-10-18), p. 2527-
    Abstract: Tumour-infiltrating lymphocytes (TILs) are considered to have prognostic and predictive value for patients with early breast cancer. We examined 1166 breast cancer patients from a prospective, multicentre cohort (Prognostic Assessment in Routine Application (PiA), n = 1270, NCT 01592825) following recommendations from the International TILs Working Group. TIL quantification was performed using predefined groups and as a continuous variable in 10% increments. The primary objective was the distribution of TILs in different breast cancer types. The second objective was the association with the recurrence-free interval (RFI) and overall survival (OS). Stromal infiltration with more than 60% TILs appeared in 2% of hormone receptor (HR)-positive and HER2-negative tumours, in 9.8% of HER2-positive tumours (any HR) and 19.4% of triple-negative breast cancers (TNBCs). Each 10% increment was associated with an improvement in the prognosis in HER2-positive samples (RFI, hazard ratio 0.773, 95% CI 0.587–1.017; OS, hazard ratio 0.700, 95% CI 0.523–0.937). When defining exploratory cut-offs for TILs, the use of a 30% threshold for the HR-positive and HER2-negative group, a 20% threshold for the HER2 group and a 60% threshold for the TNBC group appeared to be the most suitable. TILs bore prognostic value, especially in HER2-positive breast cancer. For clinical use, additional research on the components of immune infiltration might be reasonable.
    Type of Medium: Online Resource
    ISSN: 2075-4418
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
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  • 2
    In: Breast Care, S. Karger AG, Vol. 16, No. 6 ( 2021), p. 637-647
    Abstract: 〈 b 〉 〈 i 〉 Introduction: 〈 /i 〉 〈 /b 〉 Triple-negative breast cancer (TNBC) is considered the most aggressive type of breast cancer (BC) with limited options for therapy. TNBC is a heterogeneous disease and tumors have been classified into TNBC subtypes using gene expression profiling to distinguish basal-like 1, basal-like 2, immunomodulatory, mesenchymal, mesenchymal stem-like, luminal androgen receptor (LAR), and one nonclassifiable group (called unstable). 〈 b 〉 〈 i 〉 Objectives: 〈 /i 〉 〈 /b 〉 The aim of this study was to verify the clinical relevance of molecular subtyping of TNBCs to improve the individual indication of systemic therapy. 〈 b 〉 〈 i 〉 Patients and Methods: 〈 /i 〉 〈 /b 〉 Molecular subtyping was performed in 124 (82%) of 152 TNBC tumors that were obtained from a prospective, multicenter cohort including 1,270 histopathologically confirmed invasive, nonmetastatic BCs (NCT 01592825). Treatment was guideline-based. TNBC subtypes were correlated with recurrence-free interval (RFI) and overall survival (OS) after 5 years of observation. 〈 b 〉 〈 i 〉 Results: 〈 /i 〉 〈 /b 〉 Using PAM50 analysis, 87% of the tumors were typed as basal with an inferior clinical outcome compared to patients with nonbasal tumors. Using the TNBCtype-6 classifier, we identified 23 (15%) of TNBCs as LAR subtype. After standard adjuvant or neoadjuvant chemotherapy, patients with LAR subtype showed the most events for 5-year RFI (66.7 vs. 80.6%) and the poorest probability of 5-year OS (60.0 vs. 84.4%) compared to patients with non-LAR disease (RFI: adjusted hazard ratio [aHR] = 1.87, 95% confidence interval [CI] 0.69–5.05, 〈 i 〉 p 〈 /i 〉 = 0.211; OS: aHR = 2.74, 95% CI 1.06–7.10, 〈 i 〉 p 〈 /i 〉 = 0.037). 〈 b 〉 〈 i 〉 Conclusion: 〈 /i 〉 〈 /b 〉 Molecular analysis and subtyping of TNBC may be relevant to identify patients with LAR subtype. These cancers seem to be less sensitive to conventional chemotherapy, and new treatment options, including androgen receptor-blocking agents and immune checkpoint inhibitors, have to be explored.
    Type of Medium: Online Resource
    ISSN: 1661-3791 , 1661-3805
    Language: English
    Publisher: S. Karger AG
    Publication Date: 2021
    detail.hit.zdb_id: 2205941-6
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  • 3
    In: Breast Cancer Research and Treatment, Springer Science and Business Media LLC, Vol. 196, No. 3 ( 2022-12), p. 483-493
    Abstract: Phosphatidylinositide-3-kinase (PI3K) regulates proliferation and apoptosis; somatic PIK3CA -mutations may activate these processes. Aim of this study was to determine the prevalence of PIK3CA -mutations in a cohort of early stage breast cancer patients and the association to the course of disease. Patients and methods From an unselected cohort of 1270 breast cancer patients (PiA, Prognostic Assessment in routine application, NCT 01592825) 1123 tumours were tested for the three PIK3CA hotspot-mutations H1047R, E545K, and E542K by qPCR. Primary objectives were the prevalence of somatic PIK3CA -mutations and their association to tumour characteristics. Secondary objective was the association of PIK3CA -mutations to recurrence-free interval (RFI) and overall survival. Results PIK3CA -mutation rate was 26.7% (300 of 1123). PIK3CA -mutations were significantly more frequent in steroid hormone-receptor (SHR)-positive HER2-negative (31.4%), and G1 and G2 tumours (32.8%). Overall, we did not observe a significant association of PIK3CA-mutations to RFI. In SHR-positive BCs with PIK3CA-mutations, a strong trend for impaired  RFI was observed (adjusted HR 1.64, 95% CI 0.958–2.807), whilst in SHR-negative BCs PIK3CA -mutations were insignificantly associated with improved RFI (adjusted HR 0.49; 95% CI 0.152–1.597). Of note, we observed a significantly detrimental prognostic impact of PIK3CA -mutations on RFI in SHR-positive, HER2-negative BCs if only aromatase inhibitors were administered as adjuvant therapy (adjusted HR 4.44, 95% CI 1.385–13.920), whilst no impact was observed in tamoxifen treated patients. Conclusion This cohort study speficies the overall mutation rate of PIK3CA in early breast cancer. The impact of PIK3CA-mutations on RFI and OS was heterogeneous. Our results suggest that estrogen deprivation failes to be active in case of PIK3CA-mutation.
    Type of Medium: Online Resource
    ISSN: 0167-6806 , 1573-7217
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
    detail.hit.zdb_id: 2004077-5
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  • 4
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 4_Supplement ( 2022-02-15), p. P4-07-15-P4-07-15
    Abstract: Introduction. Tumor cells are influenced by their microenvironment, including immune infiltration. These tumor infiltrating lymphocytes (TILs) are considered to have prognostic and predictive value for patients with early breast cancer. The aim of this study was to evaluate the distribution of TILs and the association with survival in unselected sample of breast cancers. Patients and Methods. From a prospective, multicenter cohort of 1,270 breast cancer patients (PiA, Prognostic Assessment in routine application, NCT 01592825), 1,136 samples were evaluated for TIL infiltration inside the borders of the invasive tumor, following the recommendations of the international TILs working group. TILs were assigned to one of these three TILs groups: low TILs ( & lt;10%) intermediate (10-60%) and high TILs ( & gt;60%) and additionally scored as a continuous parameter per 10% increment. Primary objective was the distribution of TILs in different groups dependent on hormone receptor and HER2 status of the tumor (IHC group). Second objective was the association of TILs with recurrence free interval (RFI) and overall survival (OS) in univariate and multivariate analyses. The median observation time was 62 months (1-123). Results. Dependent on the IHC types a specific distribution of TILs was found: more than 60% TILs were detected in 1.5% (12 of 828) of hormone receptor (HR) positive and HER2 negative tumors, 9.7% (17 of 175) of HER2 positive tumors with any HR status and 18.8% (25 of 133) of triple negative breast cancer (TNBC). Patients with HR positive and HER2 negative tumors showed no impact of TILs with regard to RFI and OS. In the HER2 positive group with more than 60% TILs, no RFI event was detected, and with less than 60% TILs, 15% of the patients had an RFI event. The probability of OS was 94% (TILs & gt;60%) and 81% (TILS ≤60%). For TNBC and the same TIL cut off, 88% had no RFI and OS event, compared to 70% with no event for RFI and 74% for OS. Applying 10% increments of TILs to the entire cohort, the multivariate analysis revealed a hazard ratio of 0.895 (95% CI 0.796-1.007) for RFI and a significant hazard ratio of 0.890 (95% CI 0.794-0.997) for OS. Considering the IHC groups, a 10% increment of TILs in HER2 positive tumors led to an increase of RFI (0.792, 95% CI 0.601-1.043) and OS (0.713, 95% CI 0.533-0.955, p & lt;0.05) and in TNBC an increase of RFI (0.906, 95% CI 0.773-1.063) and OS (0.941, 95% CI. 0.795-1.115). There was no effect of TILs for patients with HR positive tumors. For the HER2 positive group the highest likelihood of a significant effect was determined for a cut-off of 20% (RFI: 2.467, 95% CI 0.903-6.735, p=0.078; OS: 4.565, 95% CI 1.583-13.159, p=0.005), for TNBC the highest likelihood was found at a cut-off of 5% (RFI: 1.440, 95% CI 0.627-3.308, p=0.390; OS: 2.035, 95% CI 0.906-4.571, p=0.085). Conclusion. Using data from our multicenter, consecutive enrolled cohort, TILs were ascertained as an independent even not significant prognostic factor for patients with HER2 positive and TN tumours. A 10% increment of TILs led to a 21% better disease specific survival (RFI) for patients with HER2-positive tumors and a 10% better RFI for patients with TNBC. Hence, for clinical implementation of prognostic assessment, we would suggest to use 20% as the cut-off for HER2 positive tumors and 5% for TN tumors. Citation Format: Kathleen Schüler, Daniel Bethmann, Tilmann Lantzsch, Christoph Uleer, Volker Hanf, Susanne Peschel, Jutta John, Marleen Pöhler, Joerg Buchmann, Karl-Friedrich Buerrig, Edith Weigert, Eva Johanna Kantelhardt, Christoph Thomssen, Martina Vetter. Tumor infiltrating lymphocytes as a prognostic factor [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-07-15.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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