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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
    detail.hit.zdb_id: 2662336-5
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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: Breast Cancer Research, Springer Science and Business Media LLC, Vol. 19, No. 1 ( 2017-12)
    Type of Medium: Online Resource
    ISSN: 1465-542X
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2017
    detail.hit.zdb_id: 2041618-0
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  • 5
    In: Oncotarget, Impact Journals, LLC, Vol. 10, No. 20 ( 2019-03-08), p. 1975-1992
    Type of Medium: Online Resource
    ISSN: 1949-2553
    URL: Issue
    Language: English
    Publisher: Impact Journals, LLC
    Publication Date: 2019
    detail.hit.zdb_id: 2560162-3
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  • 6
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 4_Supplement ( 2020-02-15), p. P4-06-13-P4-06-13
    Abstract: Introduction: Triple negative breast cancer (TNBC) is, in general, associated with unfavorable prognosis. However, TNBC it is a heterogenous disease. Thus, we analyzed the prognosis (RFI, OS) of TNBC in association to the molecular subtypes (according to Lehmann et al. 2011) and the prognostic markers uPA (urokinase-type plasminogen activator) and its inhibitor (uPA/PAI-1) within a prospective cohort of breast cancer patients. Material & Methods: The PiA-study was designed as a multicenter cohort of early BC patients (n=1270, 2009 – 2011), treated according to national guidelines from six centers in Germany (Prognostic assessment in routine Application, NCT 01592825). All 153 patients with TNBC (12%) received chemotherapy (neoadjuvant, n=99, or adjuvant, n=54). Tumor characteristics were based on local pathology. IN 81 TNBC patients, fresh frozen tissue was obtained for central uPA/PAI-1 testing by ELISA (FEMTELLE BioMedica Diagnostic) was available. RNA of formalin fixed and paraffin embedded (FFPE) TNBC tumor material (n=125) was analyzed using the GeneChip® U133 Plus 2.0 (Affymetrix). The online Vanderbilt predictor tool was used to determine molecular subtypes (http://cbc.mc.vanderbilt.edu/tnbc). Results: In the total cohort, 89.5% (CI 87.7-91.3) were free of RFI events after 5 years, the TNBC patients showed the poorest outcome with 72.8% (CI 65.5-80.1). In TNBC patients with a low uPA/PAI-1 status significantly more were free of RFI events than in patients with high uPA/PAI-1 status: 93% (CI 79.4-106.4) and 70.5% (CI 58.7-82.3), respectively. By the type 6-Vanderbilt tool, molecular subtypes were assigned as follows: BL1 18%, BL2 12%, IM 22%, M 12% MSL 6%, LAR: 14%, and UNS 16%. Using the type 4 tool we found for BL1 30%, BL2 18%, M 15%, LAR 18%, and UNS 19%. In all survival analysis, the patients with LAR subtype (n=23) had the lowest survival probability, with BL2 subtype N=22) the best: for 5 year RFI 58.7% (CI 29.4-71.8) versus 81.6% (CI 65.3-97.9). In those 54 TNBC patients who were treated with neoadjuvant chemotherapy, 46% of the patients had a pathologically confirmed complete response (ypT0/is ypN0). Counclusion: TNBC is a heterogeneous disease. Patients with TNBC and low uPA/PAI-1 expression have a very low rate of disease recurrence. Particular attention has to be drawn to patients with the LAR subtype, since it seems to have the worst prognosis and may require androgen receptor directed treatment. Outcome results of different endpointsn=125BL1 (n=38)BL2 (n=22)M (n=18)LAR (n=23)UNS (n=24)OS (95% CI)80.3% (67.2-93.4)95.2% (86.2-104.2)71.8% (50.8-92.8)65.2% (44.4-84.4)78.4% (61.5-95.3)RFS (95% CI)78.1% (64.6-91.6)81.6% (65.3-97.9)66.7% (44.9-88.5)50.6% (29.4-71.8)78.6% (62-95.2)RFI (95% CI)78.1% (64.6-91.6)81.6% (65.3-97.9)66.7% (44.9-88.5)58.7% (37.3-80.1)91.3% (79.7-102.9)BCSS (95% CI)80.3% (67.2-93.4)95.2% (86.2-104.2)71.8% (50.8-92.8)82.4% (66.7-98.1)90.9% (78.9-102.9) Citation Format: Martina Vetter, Carolin Hartung, Tilmann Lantzsch, Volker Hanf, Christoph Uleer, Susanne Peschel, Jutta John, Joerg Buchmann, Edith Weigert, Karl-Friedrich Buerrig, Eva-Johanna Kantelhardt, Christoph Thomssen. Prospective analysis of molecular subtypes in triple negative breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-06-13.
    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: 2020
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 7
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 9_Supplement ( 2015-05-01), p. P1-04-06-P1-04-06
    Abstract: Introduction: The AKT / mTOR pathway is activated by phosphorylation of the lipid kinase phosphatidylinositol 3-kinase (PI3K) and regulates proliferation, apoptosis, survival and adhesion of tumor cells. In up to 30% of breast cancers, dysregulation of PI3K is reported, resulting from mutations in the PIK3CA gene that encodes the catalytic subunit (p110a). Hotspots of mutations were described in exon 9 (helical domain, E542K, G & gt; A) and exon 20 (kinase domain, H1047R, A & gt; G). Prevalence and the prognostic impact of the PIK3CA mutations as well as the predictive value with regard to endocrine therapy are controversially discussed. In this study we describe the prevalence of PIK3CA mutations in a consecutive cohort of breast cancer patients and its association to tumor characteristics and known prognostic factors. Material & Methods: Fresh frozen tumor samples were obtained from a consecutive cohort of 700 breast cancer patients (inclusion criteria: pTx pNx M0 Gx HRx HER2x) who were primarily operated in 6 centres between 2009 and 2011. Tumor DNA was extracted and analyzed by conventional and quantitative PCR (exon 9: cosmid 763 and exon 20: cosmid 775). Patient data, tumor characteristics and prognostic factors were obtained from patients charts. ER, PgR and HER2 results were based on local pathology, uPA and PAI-1 values were determined centrally. Results: All isolated DNA (n=700) were analyzable by PCR and showed a mutation rate of 22% in the entire cohort; including two tumors with both mutations. Among the tumors with a positive steroid hormone receptor (HR) status (n=606; 87%), we found a mutation rate of 24% for PIK3CA, whereas only 9 (10%) of 94 HR-negative tumors were mutated. Tumors with a PIK3CA mutation were significantly associated with HR positivity / HER2 negativity (p=0,001). 14% of the cohort was HER2 positive. In 98 cases with a HER2 positive tumor 17 DNAs were mutated (17%) and 139 DNAs of the 602 HER2 negative tumors had a positive PIK3Ca mutation status (23%). Of the mutated tumors, 94 % were HR positive, and 11% HER2 positive. Only three samples were HER2 positive and HR-negative. 6% of the mutated tumors were triple negative. No significant association was found to age, menopausal status, tumor stage, nodal status, grading and uPA/PAI-1 status. Most mutant tumors were histological grade 2 (p=0,001). A quarter of the intermediate risk group according to St. Gallen risk estimation had a somatic PIK3CA mutation. Conclusion: In our cohort, nearly all mutated tumors are hormone receptor positive and a minority of all mutated samples is HER2 positive. This data adds important information to the heterogeneous results of other previously published patient cohorts. It suggests a possible role of PI3K-dysregulation with regard to resistance against endocrine therapy and anti-HER2-treatment. Citation Format: Martina Vetter, Kristin Reinhardt, Silke Wegener, Juergen Dittmer, Tilmann Lantzsch, Christoph Uleer, Susanne Peschel, Jutta John, Volker Hanf, Joerg Buchmann, Karl-Friedrich Bürrig, Edith Weigert, Christoph Thomssen, Eva J Kantelhardt. Prevalence of PIK3CA mutations in tumor tissue of a consecutive cohort of breast cancer patients (n=700) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-04-06.
    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: 2015
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 8
    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
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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