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  • Augustin, D  (16)
  • 1
    In: Geburtshilfe und Frauenheilkunde, Georg Thieme Verlag KG, Vol. 72, No. 07 ( 2012-7)
    Type of Medium: Online Resource
    ISSN: 0016-5751 , 1438-8804
    Language: German
    Publisher: Georg Thieme Verlag KG
    Publication Date: 2012
    detail.hit.zdb_id: 2026496-3
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  • 2
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 4_Supplement ( 2018-02-15), p. P1-06-06-P1-06-06
    Abstract: Background: Elderly breast cancer (BC) patients (pts) have been reported to have worse BC-related outcome than younger pts, even within clinical trials such as TEAM. Shak et al. recently showed in a large SEER data analysis that in the high 21-gene recurrence score (RS) group, older pts ( & gt;70y) receive less chemotherapy (CT) and have a worse BC-specific mortality than younger pts. Here, we therefore aimed to see whether there are age-related outcome disparities according to RS groups in pts receiving state-of-the-art CT in the prospective WSG PlanB trial. Material and Methods: PlanB compared 6 cycles of anthracycline-free TC vs. standard anthracycline-taxane based CT (4xECà4xDoc) in patients with high risk pN0 (T2-4, G2-3, & lt;35 years, or high uPA/PAI-1) or pN+ HER2- early BC. 21-gene assay was performed in all HR+ tumors and omission of chemotherapy (CT) recommended in RS≤11 HR+ pN0-1 BC. Final analysis for the CT randomization for RS 12-25 after 60 months median follow-up revealed similar 5-year DFS and OS outcomes for both CT arms (ASCO 2017). Results: In all pts with luminal cancer and RS results (n=2577), there was an age-related significant difference in RS risk group assignment (p & lt;0.0001): in young pts ( & lt;40y), 9.1% had RS≤11, 52.7% RS 12-25, and 38.2% RS & gt;25; in pts 40-69 years, 18.3% had RS≤11, 61% RS 12-25, and 20.7%% RS & gt;25; in elderly pts ( & gt;70y), 19.5% had RS≤11, 55.3% RS 12-25, and 25.2% RS & gt;25. Among patients receiving chemotherapy, RS & gt;25 vs. RS & lt;25 was associated with significantly poorer DFS separately within the elderly subgroup (HR=3.03, 95%-CI [1.15-7.96]) and in those aged 40-69 years (HR=3.14, 95%-CI [2.18-4.52] ); there were only nine events among patients & lt;40y. In particular, among pts receiving CT with RS & gt;25, there were no significant differences in DFS between any two of these three age groups. Conclusion: A substantial percentage of elderly patients ( & gt; 70y) presents with high-risk luminal disease; these patients are candidates for CT. In PlanB, about 25% of elderly luminal BC patients had high-risk (RS & gt;25) tumors. Nevertheless, after receiving modern adjuvant CT, their DFS was comparable to that of non-elderly pts with high-risk RS tumors. Consequently, older BC pts with high-risk luminal tumors who are fit enough to receive adjuvant CT should be treated according to guidelines in order to overcome age-dependent survival disparities which have been observed in registries for high-RS tumors. Citation Format: Harbeck N, Gluz O, Wuerstlein R, Clemens M, Malter W, Reimer T, Nuding B, Stefek A, Pollmanns A, Augustin D, Uleer C, Lorenz-Salehi F, Shak S, Chao C, Christgen M, Kates R, Kreipe H, Nitz U. No age-related outcome disparities according to 21-gene recurrence score groups in early breast cancer patients treated by adjuvant chemotherapy in the prospective WSG PlanB trial [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-06-06.
    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: 2018
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    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 3
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 4_Supplement ( 2017-02-15), p. P1-09-05-P1-09-05
    Abstract: Background: Immune and apoptosis biomarkers are potential prognostic/predictive markers in HER2+ EBC. High PD-L1 expression was shown to be predictive for lower pCR after chemotherapy+trastuzumab+/-pertuzumab, particularly in HER2+, ER- disease. Yet, HER2+ EBC co-expressing hormone receptors is a distinct entity. The ADAPT HER2+/HR+ phase II trial (n=376) compared 12 weeks of neoadjuvant T-DM1 + ET vs. trastuzumab (T)+ET and demonstrated pCR rates of about 41% in both (well tolerated) T-DM1 arms. Methods: In order to identify potential early predictors for pCR (i.e. no invasive tumor in breast and lymph nodes), immune markers (PDL1 on infiltrating immune cells (IIC) and on tumor cells (TC); CD8 in invasive margin and in tumor center) and apoptosis markers (bcl-2; mcl-2) were determined by immunohistochemistry (IHC; H-scores) in core biopsy sections obtained at primary diagnosis and at cycle 2. For multivariate logistic regression, each biomarker (separately), clinical factors (Ki-67, cT, cN) and therapy were entered. All analyses were exploratory. Results:Biomarkers were available in up to 326 patients (pts) at baseline and up to 170 pts at 3 weeks (due to low tumor content in 2nd core biopsy). Baseline IIC-PDL1 was associated with pCR in the T-DM1 arm (OR 2.89; 95%CI: 1.11-7.51); IIC-PDL1 at cycle 2 was not associated with pCR. PD-L1 expression in TC was rare (2%); cycle-2 TC-PD-L1 was associated with pCR in all pts and in the pooled TDM-1 arms. High baseline CD8 in tumor center was associated with pCR in the whole cohort (OR 2.4; CI: 1.04 – 5.5) and in the T+ET arm (OR=10.1; CI: 1.12 - 91.6) and at cycle 2 in all pts (OR=9.52; CI: 2.17 – 41), in pooled TDM-1 arms (OR=15.7; CI: 2.49 – 99), and in TDM-1+ET (OR=25.05; CI: 2.12 – 295). Increases in this marker also predicted pCR in all pts, pooled TDM-1, and in TDM-1+ET. Association of cycle-2 CD8 in tumor center with pCR persisted in multivariate models. Lower baseline CD8 in invasive margin was associated with pCR in the T-DM1 arm (OR=0.09; CI: 0.01-0.69), but at cycle 2 in all pts (OR=18.1; CI: 1.60 – 204) and in pooled TDM-1 arms (OR=23.5; CI: 1.1 - 500). This positive impact persisted in multivariate models. Bcl-2 expression at baseline was associated with non-pCR in all pts (OR=0.28, CI: 0.12 - 0.66), in the pooled T-DM1 arms (OR=0.216, CI: 0.08 - 0.61), and particularly in the T-DM1+ET arm (OR=0.14; CI: 0.03 - 0.71). This association persisted in multivariate analysis. At cycle 2, lower bcl-2 had OR=0.16 (CI: 0.03 - 0.96) in the pooled T-DM1 arms. No association with efficacy was seen for mcl-1. Conclusions: The WSG-ADAPT HER2+/HR+ phase II trial is the first international trial to focus on HER2+/HR+ EBC alone and the first to show substantial pCR rates of & gt; 40% after only 12 weeks of T-DM1 -- without standard chemotherapy. Expression of bcl-2 may affect resistance to T-DM1. High immune activity at baseline and/or cycle 2 seems to be associated with pCR. The association of CD8 expression and its changes with therapy efficacy is complex and could depend on ET. Further biomarker analyses are ongoing and will be presented at the meeting. Citation Format: Harbeck N, Nitz UA, Matthias C, Kates R, Braun M, Kümmel S, Schumacher C, Potenberg J, Kraemer S, Kleine-Tebbe A, Augustin D, Aktas B, Forstbauer H, Tio J, Liedtke C, Grischke E-M, de Haas SL, Deurloo R, Schumacher J, Wuerstlein R, Kreipe HH, Gluz O. The role of immune and apoptosis markers for prediction of pCR in the WSG-ADAPT HER2+/HR+ phase II trial evaluating 12-weeks of neoadjuvant TDM1 ± endocrine therapy (ET) versus T + ET in HER2-positive hormone-receptor-positive early breast cancer (EBC) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-09-05.
    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: 2017
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 4
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 4_Supplement ( 2016-02-15), p. S5-03-S5-03
    Abstract: Background: In HER2+ early breast cancer (eBC) pCR rates after standard neoadjuvant chemo- + anti-HER2 therapy differ according to hormone-receptor (HR) status. Molecular analysis reveals HER2+/HR+ BC as a distinct entity within HER2+ BC. The ADAPT HER2+/HR+ phase II trial aims to identify early responders to endocrine + anti-HER2 therapy. Methods: The trial completed recruitment in January 2015 (n=376). Patients (pts.) were randomized to 12 weeks of neoadjuvant therapy: A:T-DM1 (3.6 mg/kg q3w) vs. B:T-DM1 with endocrine therapy (ET) (pre-: tamoxifen; postmenopausal: aromatase inhibitor) vs C:trastuzumab q3w+ET. After surgery, standard chemotherapy at investigators' discretion and completion of 1y trastuzumab were recommended. Trial tests pCR (yPN0 and ypT0/is) in after T-DM1 or T-DM1+ET compared to T+ET. Biomarkers are measured at baseline and after 3 weeks. Results: Pre-planned interim analysis (n=130) aimed to identify an early-response biomarker (e.g. Ki-67 drop) and to validate trial assumptions. Median age was 49 years; 55% were pre-menopausal; 40% had cT1 tumors, 51% cT2; 68% had cN0, 27% cN1; 75% had G3. Median baseline Ki67 was 30%. In all arms, more than 95% received all 4 therapy cycles. 16 SAEs were reported in 13 pts (A:7; B:6; C:3); all CTC grade 1 (1), 2 (11) or 3 (4); all pts completely recovered without sequelae. Overall pCR rate was 30.8%: T-DM1: 40.5%, T-DM1+ET: 45.8%, T+ET: 6.7%. The difference between either arm T-DM1 arm vs. T+ET was significant (p & lt;0.001). Exploratory analysis suggests benefit of adding ET to T DM1 in pre- (pCR: 27.3% for T-DM1 single agent vs. 45.5% with ET) but not in postmenopausal pts (pCR: 60% vs. 46.2%). Substantial early therapy response did not permit Ki-67 quantification in the 3-week biopsy in 43.1% due to low cellularity ( & lt;500 tumor cells). PIK3CA mutation analysis (n=114) revealed a mutation rate of 15.8% (n=18). Overall pCR rate was 35.4% (n=96) for wildtype and 17.6% (n=18) for tumors with PIK3CA mutation. Ongoing biomarker analyses include further mutation analysis and intrinsic subtypes in the total trial collective. Conclusions: The WSG-ADAPT HER2+/HR+ phase II trial is internationally the first large prospective randomized phase II trial specifically conducted within this distinct subtype. Interim analysis demonstrated for the first time clinically meaningful pCR rates ( & gt;40%) after short therapy (12 weeks) of T-DM1 ± ET without systemic chemotherapy in HER2+/HR+ eBC. Final efficacy and safety data will be presented at the meeting together with results of the correlative science program. Citation Format: Harbeck N, Gluz O, Christgen M, Braun M, Kuemmel S, Schumacher C, Potenberg J, Kraemer S, Kleine-Tebbe A, Augustin D, Aktas B, Forstbauer H, Tio J, Liedtke C, Kates RE, Wuerstlein R, de Haas SL, Kiermaier A, Kreipe HH, Nitz U. Final analysis of WSG-ADAPT HER2+/HR+ phase II trial: Efficacy, safety, and predictive markers for 12-weeks of neoadjuvant TDM1 with or without endocrine therapy versus trastuzumab+endocrine therapy in HER2-positive hormone-receptor-positive early breast cancer. [abstract] . In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr S5-03.
    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: 2016
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 5
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 72, No. 24_Supplement ( 2012-12-15), p. P2-10-08-P2-10-08
    Abstract: Background: Routine use of multigene RT-PCR based assays as Recurrence Score (RS) vs. single markers (grade, uPA/PAI-1, HR, HER2, Ki-67) is controversially discussed in early BC. Several definitions of luminal A/B subtypes have been proposed by St. Gallen guidelines and individual researchers (grade 1/2 vs. 3, Ki-67 cut-offs 14 or 20%). Recently, integration of PR & gt;20% was proposed as an immunhistochemical luminal A subtype definition (Ki-67 & lt;14%). Here, we present the final WSG-planB trial correlation analysis of risk assessment tools and the first prospective comparison of central and local pathology IHC/FISH assessment, RT-PCR for single markers, impact of central/local grade regarding allocation of patients to luminal A/B subtypes. Methods: planB trial (04/09 to 11/11: n=2,449 randomized for 6xTC vs. 4xEC-4xDOC in locally HER2− BC; n=3197 registered; n=3072 available for central tumor bank). RS was used as selection criterion for chemotherapy (CTx) omission in HR+ BC (if RS & lt;11 in pN0/pN1). Risk assessment by grade, HR, HER2 (IHC/FISH), Ki-67 was evaluated locally and centrally by an independent trial pathologist in all tumors. Clinical risk was estimated using AdjuvantOnline 8.0 (cut-off of 88% of breast cancer specific survival after 10 years without therapy in HR+ disease). Results: RS distribution in 2569 HR+ tumors: 0–11 (18%), 12–25 (60%), & gt;25 (22%) (RS1853%/34%/13%). Luminal A subtype based on Ki-67 cut-off of & lt;14%/ & lt;20%: 50.4%/68.8%. If PR & gt;20% was included in the luminal A/Ki-67 & lt;14% definition: 37.6%. Luminal A/B based on local/central grade: 79%/21%; 67.9%/32.1%. In 354 pN0-1 patients, CTx was omitted based on low RS (88% compliance). In this group, 62% were high-risk by clinical-pathological criteria. Allocation to luminal A/B subtypes based on local/central grade varied substantially: overall concordance was 72%, but 40% of locally luminal B (HR+/G3) were luminal A (HR+/G1/2) by central and 60% of centrally luminal B were luminal A locally. Moderate correlations were found between RS and central grade (Spearman correlation rs=0.317; p & lt; 0.001), local grade (0.321; p & lt; 0.001) and Ki-67 (rs = 0.374; p & lt; 0.001), particularly due to poor correlations in the RS group & lt;26. Correlations between groups were: RS12 and luminal A/B Ki-6714 (rs = 0.26; p & lt; 0.001). Inclusion of PR & gt;20% moderately improved the correlation between luminal subtypes and RS to rs=0.34; p & lt; 0.001. Data on allocation to luminal subtypes by local/central Ki-67 will be presented at the meeting. Conclusions: Our results represent the first prospective correlation of different luminal A/B definitions vs. a guideline mentioned gene signature (RS). High RS usually implies high grade and luminal B classification, the converse is not true. There is substantial heterogeneity in risk assessment by luminal A/B classification and grade in low/intermediate RS groups. Concordance for central/local assessment of grade and luminal A/B status was limited. There is strong need for standardization of molecular subtype's immunhistochemical/clinical definition prior to implementation into daily routine. Clinical significance of these findings will be addressed by further follow up of the WSG-planB trial. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-10-08.
    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: 2012
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 6
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 69, No. 2_Supplement ( 2009-01-15), p. 78-
    Abstract: Abstract #78 Background: Taxane based adjuvant chemotherapy (CHT) is standard of care in node-positive breast cancer. Several pre-planned subgroup analyses detected the maximum benefit from taxanes in patients with 1-3 positive lymph nodes (LN). & #x2028; According to the St. Gallen consensus CHT in endocrine responsive tumors is optional in these patients. Recently the ABCSG reported excellent survival data after endocrine therapy +/- bisphosphonates without CHT in low to intermediate risk breast cancer (Gnant et al., ASCO 2008). The EC-Doc trial compares a modern sequential taxane-based regimen with standard FE100C in patients with 1-3 positive LN. & #x2028; Methods: Patients from 18 to 65 years with primary breast cancer and 1 to 3 positive LN were eligible if they had operable breast cancer with histologically confirmed free margins. M0 status was assessed by conventional staging. 2011 patients were randomized to a phase III trial comparing 4 cycles E90C600 q3w followed by 4 cycles of Docetaxel100 q3w (n=1008) (Arm A) versus 6 cycles of F500E100C500 q3w (n=828) or C600M40F600 d1, 8 q4w (n=175) (Arm B). The primary endpoint is EFS. Secondary endpoints are OS, toxicity and quality of life. & #x2028; Results: Baseline characteristics were well balanced between both study arms. Arm A/B: mean age 51.5/51.5 years, median tumor size 2.0/2.0, HR positive 77.7% / 78.3%, G3 34.1% / 34.4%. Toxicity data from the EC-Doc trial were recently presented (Nitz et al. , ASCO 2008). After a median follow up of 41 months both estimated 5-year EFS (91% vs. 86%, p=0.005) and OS (95% vs. 90%, p=0.004) were significantly better in the EC-Doc arm. & #x2028; For the comparison of EC-Doc vs. FE100C the respective values were: HR 0.58, p=0.004, estimated 5 year EFS 91% / 85% and 5 year estimated OS 95% / 91% (p =0.03). For the hormone receptor positive subpopulation the HR was 0.51 in favour of EC-Doc (p= 0.007). & #x2028; Conclusions: Our study indicates a superiority of sequential taxane-based EC-Doc CHT in terms of EFS and OS over standard FE100C in an intermediate risk group. The addition of modern third generation taxane based CHT to conventional endocrine treatment is associated with excellent EFS and OS in patients with 1-3 positive LN. & #x2028; As shown even for the subgroup of patients with HR positive disease the benefit from third generation taxane based CHT is substantial so that an endocrine only adjuvant strategy may result in undertreatment. With respect to the excellent survival rates prospective randomized trials testing the existing genetic tests are mandatory. & #x2028; Updated survival and efficacy analysis in distinct molecular subtypes (Her-2/neu, triple-negative) will be presented. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 78.
    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: 2009
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  • 7
    In: Geburtshilfe und Frauenheilkunde, Georg Thieme Verlag KG, Vol. 71, No. 08 ( 2011-8)
    Type of Medium: Online Resource
    ISSN: 0016-5751 , 1438-8804
    Language: German
    Publisher: Georg Thieme Verlag KG
    Publication Date: 2011
    detail.hit.zdb_id: 2026496-3
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  • 8
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 24_Supplement ( 2011-12-15), p. S4-3-S4-3
    Abstract: Background: Both the Recurrence Score® (RS) multi-gene assay and invasion factors uPA/PAI-1 are recommended by guidelines (ASCO, AGO) for decision support regarding adjuvant chemotherapy (cht) in patients with early breast cancer (BC). In the EC-DOC trial, we previously suggested central grade 3 and high Ki-67 levels as independent predictive markers for enhanced benefit of taxane-based cht in intermediate risk BC. Here, we present the final WSG-Plan B trial correlation analysis of these risk assessment tools. Methods: Plan B trial (evaluating anthracyline-free adjuvant cht, 6xTC, vs. 4xEC-4xDOC in HER2−negative BC; n=2,448 to be randomized for chemotherapy). RS has been used as the selection criterion for cht vs. endocrine therapy alone in HR+ BC (if RS≤11 in pN0 or pN1) since an amendment in August 2009. uPA/PAI-1 (by ELISA) is obtained as an optional risk factor. Evaluation of central grade and luminal B subtype (using 14% or 20% Ki-67 cut-offs) are performed by the independent trial pathologist in all HR+ tumors. Results: From April 2009 to June 2011, 3037 patients have been recruited and 2290 randomized. The study will be completed by August 2011. Data on RS are available in 2361 patients with HR+ tumors: RS is distributed as follows: 0–11 (18%), 12–25 (61%), & gt;25 (21%). In 257 patients with 0–3 involved LN, cht was omitted based on RS results (12.3% of patients after amendment). By the last interim analysis in February 2011, data on central grade are available in 1509 patients and Ki-67 in 592 patients. An only moderate positive correlation was observed between Ki-67 and RS (Spearman's coefficient rs=0.336; p & lt;0.001) as continuous variables and between RS and central grade (rs=0.498, p & lt;0.001). High RS is predictive of high grade G3 (66% of RS25 high risk and 74% of RS30 high risk are G3), but 30–33% of tumors were assessed as G3 within the low-risk RS11-18 group and 14%-40% of G3 tumors were classified as low-risk RS11-18. When considered as risk categories, there was only a weak concordance between RS and uPA/PAI-1, using either standard RS (18; 30) or PlanB cut-offs (low risk ≤11 RS), with 67% of patients having high uPA/PAI-1 within the low/intermediate-RS subgroups. High-risk RS is predictive of high-risk by uPA/PAI-1, poor grade and luminal B subtype. However, the converse is not true, since clinically relevant proportions (between 33–66%) of patients identified by uPA/PAI-1 or Ki-67 as being at high-risk had low or intermediate RS. Final correlation analyses in all Plan B patients with HR+ tumors (n & gt;2.500) will be presented at the meeting. Discussion: For the first time, risk groups according to RS, Ki-67 and uPA/PAI-1 have been prospectively compared within a phase III trial setting both in N0 and N+ early BC. These data show high-risk status according to RS is predictive of high risk by uPA/PAI-1, high grade by central pathology and luminal B subtype, but not converse. In the low and intermediate risk RS groups, there are still patients considered high-risk according to uPA/PAI-1, Ki-67 or central grade. Further follow-up of the WSG-Plan B trial will clarify the clinical significance of these findings regarding patient outcomes. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr S4-3.
    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: 2011
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    detail.hit.zdb_id: 410466-3
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  • 9
    In: Senologie - Zeitschrift für Mammadiagnostik und -therapie, Georg Thieme Verlag KG, Vol. 8, No. 02 ( 2011-5)
    Type of Medium: Online Resource
    ISSN: 1611-6453 , 1611-647X
    Language: German
    Publisher: Georg Thieme Verlag KG
    Publication Date: 2011
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  • 10
    In: Senologie - Zeitschrift für Mammadiagnostik und -therapie, Georg Thieme Verlag KG, Vol. 8, No. 02 ( 2011-5)
    Type of Medium: Online Resource
    ISSN: 1611-6453 , 1611-647X
    Language: German
    Publisher: Georg Thieme Verlag KG
    Publication Date: 2011
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