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  • Schneeweiss, A  (18)
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  • 1
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    Abstract P1-14-01: Adding capecitabine and trastuzumab to neoadjuvant breast cancer chemotherapy - first survival analysis of the GBG/AGO intergroup-study GeparQuattro.
    American Association for Cancer Research (AACR) ; 2012
    In:  Cancer Research Vol. 72, No. 24_Supplement ( 2012-12-15), p. P1-14-01-P1-14-01
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 72, No. 24_Supplement ( 2012-12-15), p. P1-14-01-P1-14-01
    Abstract: Background: Previous results of the GeparQuattro study demonstrated that adding capecitabine either simultaneously or sequentially to EC-Docetaxel (D) neoadjuvant chemotherapy could not increase pathological complete response rates (pCR) (von Minckwitz G, JCO 2010). However, patients with HER2-positive disease treated simultaneously with trastuzumab showed a significant higher pCR rate than patients with HER2-negative disease treated with chemotherapy alone (Untch M, JCO 2010). We here report survival after a median follow up of 58 months including 279 relapses and 191 deaths. Patients and methods: Patients with either large operable (cT3) and locally advanced (cT4) tumors, or hormone-receptor (HR)-negative receptor status, or HR-positive tumors but clinically node-positive disease were recruited to receive 4 cycles of EC (90mg/m2/600mg/m2) and randomized to either 4 cycles of D (100mg/m2) or 4 cycles of DX (75mg/m2/1800mg/m2) or 4 cycles of D (75mg/m2) followed by 4 cycles of X (1800mg/m2) (D→X). Patients with HER-2 positive tumors received 1 year of trastuzumab, the first part concurrent to all chemotherapy cycles. All patients with HR+ tumors received endocrine therapy according to current standard. The intent-to-treat survival analysis included 1421 patients for the chemotherapy question and 1495 patients for the trastuzumab question. Analyses were adjusted by age, stage, size, nodal status, histologic type, grade, hormone-receptor (HR) and HER2-status at baseline (if applicable). Results: No difference in DFS and OS was seen for patients receiving D, DX or D-X overall (hazard ratio 0.978, p = 0.984 and hazard ratio 0.986, p = 0.684, respectively) as well as by phenotype defined according to St. Gallen (all P & gt;0.354). Patients with HER2-positive disease treated additionally with trastuzumab showed significantly better OS (p = 0.015) compared to patients with HER2-negative disease treated with chemotherapy alone. DFS was significantly better for trastuzumab-treated patients with HR-negative tumors (p = 0.046), but not with HR-positive tumors (p = 0.790). OS after first relapse was significantly better in trastuzumab-retreated patients with HER2-positive tumors (p = 0.032) compared to relapsed patients with HER2-negative tumors. Patients with an early response after 4 cycles, with a clinical response at surgery and with a pCR showed a significantly better DFS and OS compared to patients without pCR (p = 0.022, P & lt; 0.0001, P & lt; 0.0001). This benefit was most prominent in patients with triple-negative tumors. Conclusions: Survival analysis of the GeparQuattro study confirmed the results of the primary endpoint analysis on pCR. Capecitabine could not improve outcome when added to anthracycline-taxane-based chemotherapy. As suggested by a recent integrated multi-level meta-analysis (von Minckwitz, BCRT 2011) effect of capecitabine could not be properly assessed in this study as planned docetaxel doses in arms DX and D®X were lower than in arm D. Survival of HER-2 positive patients surmounts that of HER2-negative patients if trastuzumab is used in the neoadjuvant as well as in the metastatic setting. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-14-01.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.SABCS12-P1-14-01
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2012
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  • 2
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    Abstract P1-14-11: nab-paclitaxel at a dose of 125 mg/m2 weekly is more efficacious but less toxic than at 150 mg/m2. Results from the neoadjuvant randomized GeparSepto study (GBG 69)
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Research Vol. 76, No. 4_Supplement ( 2016-02-15), p. P1-14-11-P1-14-11
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 4_Supplement ( 2016-02-15), p. P1-14-11-P1-14-11
    Abstract: Background: We previously reported that nab-paclitaxel (nP) increases the pathological complete response (pCR, ypT0 ypN0) rate when it replaces solvent-based paclitaxel (P) as part of a sequential taxane followed by epirubicin/cyclophosphamide (EC) neoadjuvant chemotherapy for patients with early breast cancer (Untch et al. SABCS 2014). Here, we report efficacy and safety of patients being treated either with 150 mg/m2 nab-paclitaxel (nP150) before an amendment or with 125 mg/m2 nab-paclitaxel (nP125) thereafter in comparison to solvent-formulated paclitaxel at 80 mg/m2 (P80). Methods: In the GeparSepto study (NCT01583426), 1207 patients were randomized to either nP150 or P80 q1w for 12 weeks followed by 4 cycles of conventionally dosed EC (E: 90mg/m2; C: 600 mg/m2) q3w. The primary objective of the study was to compare the pCR rate (pCR, ypT0 ypN0). Patients with untreated, histologically confirmed uni- or bilateral, cT2- cT4d carcinoma, and no clinically relevant cardiovascular and other co-morbidities were included. Patients with HER2+ tumors received trastuzumab (loading dose 8mg/kg; 6 mg/kg) plus pertuzumab (loading dose 840 mg; 420 mg) q3w concomitantly to all chemotherapy cycles. After a safety analysis showed a higher rate of dose reductions and treatment discontinuations with nP150 compared to P80, weekly dose of nP was reduced to 125 mg/m2. Results: nP was given for the majority of cycles at a dose of 150 mg/m2 to 179 patients and at a dose of 125 mg/m2 to 426 patients. Treatment characteristics were fairly balanced between these two sequential cohorts as well as compared to 601 patients receiving P80 except for HER2 status (HER2-positive: nP150 22%, nP125 37% and P80 33%) and Ki67 ( & lt;20%: nP150 60%, nP125 73% and P80 69%). Taxane treatment was discontinued in 16% (nP150), 11% (nP125) and 6% (P80) of patients, respectively. Median dose per cycle (based on relative total dose intensity (RTDI)) was 129 mg/m2 with nP150, 119 mg/m2 with nP125 and 78 mg/m2 with P80, respectively. Peripheral sensory neuropathy (PNP) grade 3/4 (NCI-CTCAE v4.0) was observed in 15% with nP150, 8% with nP125 and 3% with P80, respectively. pCR was 32% with nP150, 41% with nP125 and 29% with P80 in all patients and 46% with nP150, 49% with nP125 and 26% with P80 in 277 patients with triple-negative breast cancer, respectively. Conclusions: Risk-benefit ratio of nP125 was improved over nP150 with better drug adherence and RTDI, lower frequency of PNP but a higher pCR rate. It should therefore be considered as the preferred schedule when nP is used as neoadjuvant treatment for primary breast cancer. The trial was financially supported by Celgene and Roche. Citation Format: von Minckwitz G, Untch M, Jakisch C, Schneeweiss A, Conrad B, Aktas B, Denkert C, Eidtmann H, Weibringhaus H, Kümmel S, Hilfrich J, Warm M, Paepke S, Just M, Hanusch C, Hackmann J, Blohmer J-U, Clemens M, Costa SD, Gerber B, Nekljudova V, Loibl S. nab-paclitaxel at a dose of 125 mg/m2 weekly is more efficacious but less toxic than at 150 mg/m2. Results from the neoadjuvant randomized GeparSepto study (GBG 69). [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 P1-14-11.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS15-P1-14-11
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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  • 3
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    Abstract P5-16-01: A randomised phase III trial comparing two dose-dense, dose-intensified approaches (ETC and PM(Cb)) for neoadjuvant treatment of patients with high-risk early breast cancer (GeparOcto)
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Research Vol. 77, No. 4_Supplement ( 2017-02-15), p. P5-16-01-P5-16-01
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 4_Supplement ( 2017-02-15), p. P5-16-01-P5-16-01
    Abstract: This abstract was withdrawn by the authors.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS16-P5-16-01
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
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    detail.hit.zdb_id: 1432-1
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  • 4
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    Abstract OT3-3-11: A RANDOMIZED PHASE III TRIAL COMPARING NANOPARTICLE-BASED PACLITAXEL WITH SOLVENT-BASED PACLITAXEL AS PART OF NEOADJUVANT CHEMOTHERAPY FOR PATIENTS WITH EARLY BREAST CANCER (GeparSepto) GBG 69
    American Association for Cancer Research (AACR) ; 2012
    In:  Cancer Research Vol. 72, No. 24_Supplement ( 2012-12-15), p. OT3-3-11-OT3-3-11
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 72, No. 24_Supplement ( 2012-12-15), p. OT3-3-11-OT3-3-11
    Abstract: Background: Anthracycline/taxane based regimen are standard of care for neoadjuvant therapy in breast cancer. Recent data from the neo-Tango study suggest that a reverse sequence of taxane followed by the anthracycline can achieve higher pCR rates. Solvent-based taxanes (paclitaxel, docetaxel) cause severe toxicities most likely by the solvents such as cremophor. Nab-paclitaxel is a solvent-free formulation of paclitaxel encapsulated in albumin. It is believed that nab-Paclitaxel compared to solvent based paclitaxel followed by conventional dosed EC might further improve the pCR rate in breast cancer patients receiving neoadjuvant treatment. Previous studies have shown that dual anti-HER blockade is superior to trastuzumab alone resulting in an increase of pCR rate by 20%. Patients and Methods: The GeparSepto trial, a neoadjuvant, randomized phase III study, planned to include 1200 pts, randomized to nab-paclitaxel versus conventional, solvent based paclitaxel given weekly for 12 weeks followed in both arms by 4 cylces conventionally dosed EC. The primary objective is to compare the rate of pCR (ypT0 + ypN0). Further objectives are to compare the pCR rate in predefined subgroups, pCR by other definition, the clinical response rate and the rate of breast conserving surgery after chemotherapy in the two different treatment arms. Women with untreated, histologically confirmed uni- or bilateral, cT2- cT4d carcinoma, and no clinically relevant cardiovascular and other co-morbidities are randomized to receive either paclitaxel (80mg/m2) or nab-paclitaxel (150 mg/ m2) day 1, 8, 15, q d 22 for 4 cycles followed by conventional EC (E (90mg/m2)+C (600 mg/m2)) on day 1 q day 22 for 4 cycles. HER2 positive pts receive trastuzumab (loading dose 8mg/kg followed by 6 mg/kg) and pertuzumab (loading dose 840 mg followed by 420 mg) q3w concomitantly to the chemotherapy. Biomaterial including FFPE form core biopsy, serum, plasma, full blood is collected before randomization, after the 12 cycles for (nab−) paclitaxel therapy and after the 4 cycles of EC before surgery. The HER2, estrogen receptor, progesterone receptor, Ki67 and SPARC status will be centrally tested by immunohistochemistry prior to randomization for stratification. A broad translational program is planned. It has been assumed that solvent based taxane will achieve an overall pCR rate of 33% to be increased using nab-paclitaxel to 41%, corresponding to an odds ratio of 1.41. If 596 patients are enrolled into each arm, a χ2-test will have an 80% power with a 2-sided significance level α=0.05 to show the superiority of nab-paclitaxel. Closed test procedure will be used to test for non-inferiority of nab-paclitaxel first. The trial is registered under NCT01583426. It is financially supported by Roche and Celgene. Results: The centres have been initiated after approval by ethics committee and authorities. First patient in will be this months. It is planned to recruit 18 months in 100 sites in Germany. Conclusion: Geparsepto will investigate the efficacy of neoadjuvant nab-paclitaxel compared to solvent based paclitaxel given weekly and the dual blockade with Trastuzumab and Pertuzumab in HER 2 positive BC. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr OT3-3-11.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.SABCS12-OT3-3-11
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2012
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  • 5
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    Abstract S3-1: Neoadjuvant Chemotherapy in the very young 35 years of age or younger
    American Association for Cancer Research (AACR) ; 2012
    In:  Cancer Research Vol. 72, No. 24_Supplement ( 2012-12-15), p. S3-1-S3-1
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 72, No. 24_Supplement ( 2012-12-15), p. S3-1-S3-1
    Abstract: Background: In young women the course of breast cancer (BC) tends to be more aggressive. In several trials young age at diagnosis was an independent predictive factor for pathological complete response (pCR) after neoadjuvant chemotherapy. Here we investigate especially the rare entity of very young women at age 35 years or younger. Methods: 8949 patients from 8 neoadjuvant German studies with operable or locally advanced, non-metastatic breast cancer and follow-up were included (for details see von Minckwitz G et al, BCRT 2010 and NEJM 2012). A subgroup of 704 patients of age 35 years or younger was analyzed. All patients with endocrine responsive disease received adjuvant endocrine therapy according to institutional standard. We compared pathological complete remission rate (pCR) defined as ypT0, ypN0 and disease free survival rate (DFS) of this very young group with older patients in total and in different histopathological subgroups (as defined previously by von Minckwitz J Clin Oncol 2012). Results: From 8949/6561 had known ER, PR, HER2 and grading. There were less Luminal A and more TNBC in the very young women compared to the one & gt;35 years of age: Luminal A: 131 (21%) vs. 2251 (27%); Luminal B HER2−: 50 (8%) vs. 783 (10%); Luminal B HER2+: 103 (17%) vs. 989 (14%); HER2+/HR−: 72 (11%) vs. 739 (10%); TNBC: 164 (26%) vs. 1415 (19%). The pCR rate was significantly higher in the very young than in the group older than 35 years (23.6% vs. 15.7.%; p & lt; 0.0001). However, this difference was confined to the TNBC subgroup (45% vs. 31%; OR 1.85; 95%CI [1.33–2.56]; p & lt; 0.001). Only in the triple negative cohort age had independent predictive factors for achieving a. pCR. Compared to patients & gt;35 years, in the very young only hormone receptor status and grading had independent predictive information for pCR but not T-stage and nodal-stage. No difference in DFS according to age was seen when the patients had a pCR. Non-pCR patients had a significantly worse DFS when they were very young (DFS HR: 1.35; p = 0.001). Adjusting for T-stage, nodal-stage, age and pCR; within the TNBC pCR but not age had independent prognostic information for DFS (pCR: HR: 0.18 [95%CI 0.13–0.16]; p & lt; 0.0001; age HR: 1.06 [95%CI 0.74–1.51]; p = 0.77); within the Luminal A group age but not pCR had independent prognostic information for DFS (age: HR 2.5 [95% CI 1.6–3.9] p & lt; 0.001; pCR: HR 0.72 [95%CI 0.37–1.41] p = 0.34). In the Luminal A group the worst DFS was seen in the group & lt;=35years/no-pCR and the best DFS in the & lt;=35 years with pCR (log rank p = 0.27; HR 0.05 wide CI due to small sample size; p = 0.5). Conclusion: Very young women are more likely to achieve a pCR after neoadjuvant chemotherapy. This effect is driven mainly by triple negative BC, which is more common in the very young. Age did not influence DFS in TNBC when a pCR was achieved. It can be hypothesized that the very young pts with Luminal A tumors benefit from a pCR, whereas overall pCR is not a predictor in the Luminal A subgroup. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr S3-1.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.SABCS12-S3-1
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2012
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    detail.hit.zdb_id: 1432-1
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  • 6
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    Abstract PD5-05: Pre-therapeutic PD-L1 expression and dynamics of Ki-67 and gene expression during neoadjuvant immune-checkpoint blockade and chemotherapy to predict response within the GeparNuevo trial
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 4_Supplement ( 2019-02-15), p. PD5-05-PD5-05
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 4_Supplement ( 2019-02-15), p. PD5-05-PD5-05
    Abstract: Background In the GeparNuevo trial, the PD-L1 inhibitor durvalumab increased the rate of pathologic complete response (pCR; ypT0 ypN0) in triple-negative breast cancer if treatment started in a two-week window before neoadjuvant taxane/anthracycline chemotherapy (61 % pCR vs. 41%; p = 0.048; Loibl et al. ASCO 2018). Overall, pCR rates increased only numerically from 53 % to 44 % (p = 0.281). Herein, we aimed to evaluate the predictive value of PD-L1 immunohistochemistry in pre-therapeutic core biopsies. In addition, we identified dynamics in gene expression using repeated biopsies. Patients and Methods 174 patients were randomized to receive durvalumab or placebo with neoadjuvant chemotherapy. In the window part, 117 patients received a single dose of durvalumab (or placebo) before chemotherapy. Core biopsies were taken at three times: pre-treatment (“A”; N=174), after the window part (“B”; N=88) and after 12 weeks of nab-Paclitaxel (“C”; N=33). PD-L1 immunohistochemistry in A-biopsies (Ventana SP263 Assay) was recorded as percentage of cells with membranous staining in tumor cells and lymphocytes (TILs). We defined a tumor as PD-L1 high if ≥ 25 % of either compartment was stained. Ki-67 was stained on all available A, B and C biopsies (MIB-1, Dako, 1:100) and recorded as the percentage of tumor cells with nuclear staining. We profiled all available biopsies with targeted RNASeq using the HTG EdgeSeq platform (Oncology Biomarker panel, 2560 genes). Sequencing (IonTorrent S5) was successful in 162 A-, 79 B- and 31 C-biopsies. Results PD-L1 expression was high in 24 % of A-biopsies and was predictive for pCR in the complete cohort (OR 2.561; 1.183-5.554; p = 0.017). PD-L1 status of the TILs, but not of the tumor cells, was predictive (OR 1.313; 1.040-1.656; P= 0.022). The effect was not specific for durvalumab treatment. Higher levels of Ki-67 were predictive for pCR in B- biopsies in all patients (OR 1.399; 1.053-1.858; P =0.021) and in the placebo arm, but not in the durvalumab arm. Ki-67 levels in C-biopsies were not predictive; neither was the change in Ki-67 between pre-treatment and later time points (B vs. A or C vs. A). In a differential mRNA expression analysis (A vs. B), we found seven differentially expressed genes after one dose of durvalumab. We observed strong effects on gene expression after taxane treatment (A vs. C), but no significant difference according to treatment. These genes were associated with biological processes involved in therapy response. The pre-treatment levels of 12 of 69 markedly differentially expressed genes were associated with worse response to chemotherapy. Conclusion In A-biopsies, PD-L1 in TILs was predictive for response, and in B-biopsies, Ki-67 was predictive, but neither marker could specifically predict response to durvalumab. We observed limited effects of a single half-dose of durvalumab on global gene expression, but could identify substantial differential expression after taxane treatment. The evaluation of gene expression dynamic offers a promising approach for the identification of resistance-associated markers. The study was financially supported by AstraZeneca and Celgene Citation Format: Sinn BV, Loibl S, Karn T, Untch M, Kunze CA, Weber KE, Treue D, Wagner K, Hanusch CA, Klauschen F, Fasching PA, Huober J, Zahm D-M, Jackisch C, Thomalla J, Blohmer J-U, van Mackelenbergh M, Rhiem K, Felder B, von Minckwitz G, Burchardi N, Schneeweiss A, Denkert C. Pre-therapeutic PD-L1 expression and dynamics of Ki-67 and gene expression during neoadjuvant immune-checkpoint blockade and chemotherapy to predict response within the GeparNuevo trial [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD5-05.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS18-PD5-05
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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  • 7
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    Abstract S1-09: Evaluation of tumor-infiltrating lymphocytes (TILs) as predictive and prognostic biomarker in different subtypes of breast cancer treated with neoadjuvant therapy - A metaanalysis of 3771 patients
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Research Vol. 77, No. 4_Supplement ( 2017-02-15), p. S1-09-S1-09
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 4_Supplement ( 2017-02-15), p. S1-09-S1-09
    Abstract: Background: Tumor-infiltrating lymphocytes (TILs) have been shown to be predictive for response to neoadjuvant therapy, in particular in triple-negative and HER2 positive breast cancer, suggesting that subtypes of breast cancer are immunogenic. The role of TILs in luminal breast cancer as well as the impact on prognosis in the different subtypes is less clear. In this study we evaluated TILs in a total of 3771 breast carcinomas from 6 prospective neoadjuvant clinical trials and evaluated their relevance for pCR, DFS and OS in different molecular subtypes. Methods: A total of 3771 tumors from the clinical studies GeparDuo, GeparTrio, GeparQuattro, GeparQuinto, GeparSixto, GeparSepto were evaluated for stromal TILs by standardized methodology. Data on pCR were available for all tumors, DFS and OS was available for 2560 tumors. Logistic regressions, Cox regressions and Kaplan-Meier analyses were performed. In addition, a combined analysis of pCR, survival and TILs in different subtypes was performed. Results: In the complete cohort of 3771 tumors, increased TILs ( & gt;=60%) were observed in 19% of tumors, these tumors with & gt;=60% TILs had a pCR rate of 44% (p & lt;0.0005). Increased stromal TILs ( & gt;=60%) were observed in 30% of TNBC (n=906), in 19% of HER2+ tumors (n=1379) and in 13% of HR+/HER2- tumors (n=1366). In all three subtypes, increased TILs were significantly associated with increased pCR rates (p & lt;0.0005). In univariate logistic regression analysis of stromal TILs as a continuous variable, a 10% increase in TILs increased the probability to achieve a pCR by 16% in TNBC (OR 1.16), 13% in HER2+ (OR 1.13) and 33% in HR+/HER2- (OR 1.31,p & lt;0.0005 for all three groups). Similar results were observed in multivariate logistic regression (p & lt;0.0005 for all three groups). In univariate Cox regression, increased TILs were associated with improved DFS survival in TNBC (HR 0.93 per 10% TILs, p=0.01) and HER2+ BC (HR 0.93 per 10% TILs, p=0.02). In luminal (HR+/HER-) tumors there was no effect of TILs observed on DFS (p=0.46). In the luminal group increased TILs were associated with reduced OS (HR 1.10 per 10% increase in TILs, p=0.01), and increased TILs ( & gt;=60%) were associated with worse survival in Kaplan-Meier analysis in luminal tumors (DFS: p=0.04, OS: p & lt;0.0005). A detailed analysis of subgroups of luminal BC as well as the link to pCR will be presented. Conclusion: Our results suggest that tumor-infiltrating lymphocytes are a strong predictive marker for response to neoadjuvant chemotherapy in all molecular subtypes, and this predictive effect is translated into a survival benefit in HER2+ BC and TNBC. In contrast, a survival benefit is not observed in luminal BC, suggesting a different biology of the immunological infiltrate in this subtype. Citation Format: Denkert C, von Minckwitz G, Darb-Esfahani S, Ingold Heppner B, Klauschen F, Furlanetto J, Pfitzner B, Huober J, Schmitt W, Blohmer J-U, Kümmel S, Engels K, Lederer B, Schneeweiss A, Hartmann A, Jakisch C, Untch M, Hanusch C, Weber K, Loibl S. Evaluation of tumor-infiltrating lymphocytes (TILs) as predictive and prognostic biomarker in different subtypes of breast cancer treated with neoadjuvant therapy - A metaanalysis of 3771 patients [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 S1-09.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS16-S1-09
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
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  • 8
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    Abstract PD2-07: mRNA signatures predict response to durvalumab therapy in triple negative breast cancer (TNBC)– Results of the translational biomarker programme of the neoadjuvant double-blind placebo controlled GeparNuevo trial
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 4_Supplement ( 2019-02-15), p. PD2-07-PD2-07
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 4_Supplement ( 2019-02-15), p. PD2-07-PD2-07
    Abstract: Background: The GeparNuevo trial showed a numerical increase in the pCR rate to 53% vs 44%; p=0.281 compared to placebo in TNBC with the addition of the anti-PD-L1 antibody durvalumab to a neoadjuvant anthracycline-taxane containing chemotherapy (Loibl S et al. ASCO 2018). In a predefined subgroup analysis, a significant increase of the pCR rate was observed for patients that received durvalumab for 2 weeks alone prior to the start of chemotherapy in a window phase (61% vs 41%, p interaction=0.048), while the pCR rate was not increased for the subset of patients that did start durvalumab together with chemotherapy. Here we report the main results of the translational programme for GeparNuevo with a focus on mRNA signatures predictive for pCR in pretherapeutic core biopsies. Methods: A total of 162 baseline FFPE core biopsies were evaluable for expression of 2560 genes using the HTG EdgeSeq® system that combines a modified nuclease protection assay with next generation sequencing. Data was processed as recommended by the HTG and median transformed for further analyses. For differential gene expression analyses, the data was scale-normalized (TMM normalization; EdgeR package) and linear models were fit (limma package). Prior to these analyses, genes were filtered based on minimal expression ( & gt; 4) and variability (IQR & gt; 1). As a first step, predefined immune-genes signature (TILs signature) (Denkert et al. JCO 2016) as well as IFN-gamma signatures were evaluated for correlation with pCR in logistic regression models. Subsequently, we performed a differential gene expression analysis according to therapy response for the durvalumab-arm and the placebo arm using the pre-filtered candidate genes. Gene names are not included in this abstract to allow filing of IP, but full gene names will be presented at the SABCS meeting. Results: The predefined TIL- and IFN-gamma signatures were associated with increased pCR rates in the complete cohort (TIL-signature: OR 1.44, 95% CI 1.15-1.82, p=0.002; IFN-Gamma-signature: OR 1.63, 95% CI 1.22-2.24, p=0.002) as well as in the durvalumab arm (p=0.012 and 0.042) and the placebo arm (p=0.050 and 0.011). These signatures were general pCR predictors without specificity for durvalumab response. Additional 44 genes were significantly (p & lt;0.05) correlated with pCR in the durvalumab arm. Of those, 21 genes were upregulated and 23 genes were downregulated in pCR patients. 14 of the 21 upregulated genes are related to tumorbiologically relevant immune cell functions. A total of 6 of the 44 genes had a positive test for interaction (interaction p & lt;0.05) with the therapy arm (durvalumab + NACT vs. placebo + NACT), suggesting that these genes might specifically predict response to durvalumab. Additional analyses investigating the role of molecular tumor subtypes, additional immune gene signatures and other subgroup analyses will be presented at the meeting. Conclusion: Our results show that specific immune-related gene expression signatures predict response to durvalumab in primary triple negative breast cancer. The trial was financially supported by Astra Zeneca and Celgene Citation Format: Loibl S, Sinn BV, Karn T, Untch M, Treue D, Sinn H-P, Weber KE, Hanusch CA, Fasching PA, Huober J, Zahm D-M, Jackisch C, Thomalla J, Blohmer J-U, Marmé F, Klauschen F, Rhiem K, Felder B, von Minckwitz G, Burchardi N, Schneeweiss A, Denkert C. mRNA signatures predict response to durvalumab therapy in triple negative breast cancer (TNBC)– Results of the translational biomarker programme of the neoadjuvant double-blind placebo controlled GeparNuevo trial [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD2-07.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS18-PD2-07
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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    Abstract P1-09-02: Homologous repair deficiency (HRD) as measure to predict the effect of carboplatin on survival in the neoadjuvant phase II trial GeparSixto in triple-negative early breast cancer
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Research Vol. 77, No. 4_Supplement ( 2017-02-15), p. P1-09-02-P1-09-02
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 4_Supplement ( 2017-02-15), p. P1-09-02-P1-09-02
    Abstract: Introduction Addition of carboplatin to anthracycline/taxane-based neoadjuvant chemotherapy has shown to improve pathological complete response (pCR; ypT0 ypN0) rates in patients with triple-negative breast cancer (TNBC) in two large phase II studies (GeparSixto: von Minckwitz et al, Lancet Oncol 2014, CALGB 40603: Sikov WM, J Clin Oncol 2015). Participants of the GeparSixto study showed an improvement of pCR rate from 36.9 to 53.2% (p=0.005) and DFS by absolute 9% (HR 0.56 95% CI 0.33-0.96] p=0.035) with the addition of carboplatin in the TNBC subgroup. No effect was observed in the HER2-positive subgroup. We here report results on homologous repair deficiency (HRD) status in relation to pCR and DFS in the TNBC subgroup. Patients and Methods In the GeparSixto trial (NCT01426880), patients were treated for 18 weeks with paclitaxel 80mg/m2 q1w and non-pegylated-liposomal doxorubicin (NPLD) 20mg/m2 q1w. Patients with TNBC (N=315) received concurrently bevacizumab 15mg/kg i.v. q2w until surgery. All patients were randomized 1:1 to receive concurrently carboplatin AUC 1.5-2 q1w vs no carboplatin. Carboplatin dose was reduced from AUC 2.0 to 1.5 by an amendment after 330 patients. Primary objective is pCR rate (ypT0 ypN0). Event free survival (EFS), and overall survival (OS) were secondary objectives. HR Deficiency status was assessed on FFPE material from pretherapeutic core biopsies. HR Deficiency was defined as either HRD score high or a BRCA mutation. Results HRD status was measurable in 193 of 315 TNBC patients. 101 patients of them were randomly assigned to receive carboplatin and 92 to no additional carboplatin. After median follow-up of 34.3 months 43 event free survival (EFS) events have been reported. HR deficiency was detected in 136 (70.5%) tumors of which 79 (58.1%) showed high HRD score with intact tBRCA. HR deficiency independently predicted pCR (ypT0is ypN0) (odds ratio (OR) 2.506, CI 1.243-5.051, p=0.009). Adding carboplatin to PM significantly increased the pCR rate from 36.6% to 63.2% in HR deficient tumors with intact tBRCA (p=0.018), only marginally from 61.9% to 72.7% in BRCA mutated tumors (p=0.406), and moderately from 20.0% to 40.7% in HR non-deficient tumors (p=0.086). In general, patients with HRD deficient tumors had a better ESF than non HRD deficient ones (HR 1.805 (0.985-3.309); p=0.0526). Patients with high HRD score had an insignificant trend towards an improved EFS compared to those with low HRD score (HR 1.546 (0.764-3.127) p=0.2223). HRD deficiency did not predict carboplatin effect in patients without BRCA mutation (HR 0.8617). In multivariable analysis, only therapy, clinical nodal status before treatment, and lymphocyte predominant breast cancer were significant prognostic on EFS. Conclusion Within the GeparSixto study HR deficiency (either HRD score high or BRCA mutation) was associated with a higher pCR in general and an improved EFS. The effect of carboplatin could not be predicted by HR deficiency in this relatively small study. However, the results will help to understand the role of HR deficiency and the value of the HRD score in TNBC especially in patients without BRCA mutation. Citation Format: von Minckwitz G, Timms K, Untch M, Elkin EP, Hahnen E, Fasching PA, Schneeweiss A, Salat CT, Rezai M, Blohmer J-U, Zahm D-M, Jackisch C, Gerber B, Klare P, Kümmel S, Paepke S, Schmutzler R, Chau S, Reid J, Hartman A-R, Nekljudova V, Weber KE, Loibl S. Homologous repair deficiency (HRD) as measure to predict the effect of carboplatin on survival in the neoadjuvant phase II trial GeparSixto in triple-negative early breast cancer [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 P1-09-02.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS16-P1-09-02
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
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  • 10
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    Abstract P4-06-01: Immunomonitoring of triple negative breast cancer patients undergoing neoadjuvant therapy with durvalumab - Results from the prospectively randomized GeparNuevo trial
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 4_Supplement ( 2019-02-15), p. P4-06-01-P4-06-01
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 4_Supplement ( 2019-02-15), p. P4-06-01-P4-06-01
    Abstract: Background: The GeparNuevo trial is a randomized, double-blind, multi-center phase II trial of neoadjuvant therapy in patients with early-stage triple negative breast cancer (TNBC) investigating the role of durvalumab, an anti-PD-L1 antibody, which blocks PD-L1 binding to PD1 and CD80, in addition to standard anthracycline/taxane based chemotherapy (Loibl S et al. ASCO 2018). Methods: In order to determine possible predictive and / or prognostic biomarkers, blood samples were taken before and during the different treatment phases (3 or 4 time points) and evaluated by multicolor flow cytometry by monitoring the absolute cell counts of T cells, B cells and NK cells as well as the frequency, composition and functionality of different immune cell populations using a panel of 35 distinct antibodies. Results: Overall 174 patients were randomized into the GeparNuevo study. 117 patients participated in the window phase of this study and 49 patients provided evaluable material for flow cytometric analyses for material at the above specified time points. Evaluation of the absolute cell count in the whole blood prior and after therapy highlighted a mixed behavior of the total leukocytes. Overall, there was a statistically significant reduction in the lymphocyte count, particularly during the last phase of the treatment (ECdd +/- durvalumab). Further dissection into the different immune populations highlighted an almost complete loss of B cells, which in some patients was also accompanied by a reduction of NK cells, mainly of the CD16+ subset. The loss of CD4+ and CD8+ T cells was less pronounced resulting overall in an enhancement of their percentages within the total lymphocytes. In addition, the different populations have also been evaluated for the expression of PD-L1 activation and exhaustion markers. A pre-specified analysis clearly demonstrated a specific effect of durvalumab during the window phase with mean decreases of 21.7% and 15.0 % in PDL1+ lymphocytes in the CD4+ and CD8+ subgroups, respectively (P & lt;0.001). Currently, all data generated are statistically analyzed focusing on their clinical significance in relation to the treatment received and the pathological complete remission (pCR) of these patients. Conclusion: Using this approach we hope to identify biomarkers, which will allow a better selection of TNBC patients undergoing specific immunotherapies. Final data will be presented at the meeting. The trial and this translational research project were funded by AstraZeneca and Celgene, Germany. Citation Format: Massa C, Schneeweiss A, Karn T, Hanusch CA, Blohmer J-U, Fasching PA, Jackisch C, van Mackelenbergh M, Marmé F, Müller V, Schem C, Stickeler E, Huober J, Weber KE, Untch M, Denkert C, Loibl S, Mueller A, Biehl K, Seliger B. Immunomonitoring of triple negative breast cancer patients undergoing neoadjuvant therapy with durvalumab - Results from the prospectively randomized GeparNuevo trial [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-06-01.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS18-P4-06-01
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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