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  • American Association for Cancer Research (AACR)  (9)
  • 1
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    Abstract P5-13-36: Germline BRCA 1/2 and other predisposition genes in high-risk early-stage HR+/HER2- breast cancer (BC) patients treated with endocrine therapy (ET) with or without palbociclib: A secondary analysis from the PENELOPE-B study
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 4_Supplement ( 2022-02-15), p. P5-13-36-P5-13-36
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 4_Supplement ( 2022-02-15), p. P5-13-36-P5-13-36
    Abstract: Background: In high-risk hormone-receptor (HR)+/HER2- BC patients germline (g) mutations can be found in approximately 14% in BRCA1/2 and in BRCA1/2 and other BC predisposition genes in 20% (Pohl-Rescigno E, et al. JAMA Oncol 2020). In metastatic BC CDK4/6 inhibitors may have greater activity in patients with a BRCA mutation detected in ctDNA (André F, et al. J Clin Oncol 2020). The PENELOPE-B trial did not to show an improved invasive disease-free survival (iDFS) by adding palbociclib to ET in high-risk HR+/HER2- BC (Loibl S, et al. J Clin Oncol 2021). Methods: Blood samples from 898 of 1250 PENELOPE-B patients were available. 445 patients were sampled following a case-cohort design (220 cases defined as patients with any event during follow-up and 225 randomly selected patients without any event [non-cases]) and analyzed for germline variants in BRCA1/2 and 16 non-BRCA1/2 cancer predisposition genes (ATM, BARD1, BRIP1, CDH1, CHEK2, FANCM, MRE11A, NBN, PALB2, PTEN, RAD50, RAD51C, RAD51D, STK11, TP53, XRCC2) by targeted next generation sequencing (NGS). The primary definition of mutational status was the prevalence of a pathogenic mutation (mt) in one or more analyzed BC predisposition genes. Statistical analyses for time-to-event endpoints (iDFS, distant disease-free survival [DDFS] , and overall survival [OS]) were based on inverse probability weighting: weighted Cox proportional hazard models and Kaplan-Meier estimates were used. Results: 442 of 445 patients (placebo arm: 104 cases and 105 non-cases; palbociclib arm: 114 cases and 119 non-cases) were successfully analyzed for mutational status. A total of 42 (9.5%) patients (placebo arm: 9.1%; palbociclib arm: 9.9%) carried any mutation. 15 (3.4%) patients had a gBRCA1/2 mt (one of whom carried a gATM mt and one a gCHEK2 mt in addition to gBRCA2 mt) and 29 (6.6%) had mutations in one of the other BC predisposition genes (n=8 CHEK2, n=7 PALB2, n=5 ATM, n=2 RAD50, n=1 for BARD1, FANCM, MRE11A, RAD51C, RAD51D, TP53 and n=1 both RAD51D and BRIP1). The mutational status with respect to all genes analyzed showed no significant correlation to clinical baseline variables. With regard to gBRCA1 and gBRCA2 genes only, the mutational status significantly correlated with age but not with other clinical variables: all 15 (100%) gBRCA mt carriers were younger than 50 years compared to 238 (56%) wildtype (wt) patients (p=0.002). The iDFS rate after 3 years was 80.9% in patients with any mutation and 79.5% in patients without. Mutational status (mt vs. wt) based on all genes analyzed was not prognostic (iDFS: hazard ratio 1.015, 95%CI 0.558-1.784; DDFS: 0.970, 95%CI 0.521-1.758; OS: 0.768, 95%CI 0.274-1.615). Neither the mutated patients had a benefit from palbociclib treatment (palbociclib vs placebo; iDFS: hazard ratio 0.766, 95%CI 0.263-3.022; DDFS: 0.897, 95%CI 0.275-3.489; OS: 0.666, 95%CI 0.063-5.671) nor the wt patients (iDFS: hazard ratio 0.918, 95%CI 0.650-1.303; DDFS: 0.966, 95%CI 0.679-1.393; OS: 0.901, 95%CI 0.573-1.433); interaction tests for treatment arm/mutational status for all time-to-event endpoints were not statistically significant. Analysis in the subgroups of patients by gBRCA1/2 showed similar results but had less statistical power. Conclusions: In this case-cohort analysis of 442 patients enrolled in the PENELOPE-B trial, the detection of BC predisposition genes was lower than expected with 10%. This is probably due to the low rate of gBRCA1/2 carriers (3.4%), which could be influenced by the selection criteria of the trial. Patients with gBRCA1/2 or other BC disposition genes had a comparable outcome to non-carriers in the PENELOPE-B tr ial. Citation Format: Sibylle Loibl, Jan Hauke, Karen Gelmon, Frederik Marmé, Corinna Ernst, Miguel Martin, Michael Untch, Hervé Bonnefoi, Erik Knudsen, Seock-Ah Im, Angela DeMichele, Laura Van’t Veer, Sung-Bae Kim, Harry Bear, Nicole McCarthy, Nicholas Turner, Agnieszka Witkiewicz, Federico Rojo, Peter A Fasching, José A García-Sáenz, Catherine M Kelly, Toralf Reimer, Masakazu Toi, Hope S Rugo, Carsten Denkert, Michael Gnant, Andreas Makris, Yuan Liu, Olga Valota, Bärbel Felder, Karsten Weber, Valentina Nekljudova, Eric Hahnen. Germline BRCA1/2 and other predisposition genes in high-risk early-stage HR+/HER2- breast cancer (BC) patients treated with endocrine therapy (ET) with or without palbociclib: A secondary analysis from the PENELOPE-B study [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 P5-13-36.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS21-P5-13-36
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 2
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    Abstract P6-10-04: Landscape of immune-cell signatures in early high-risk breast cancer (BC) reveals clinically-relevant enrichment of immune subpopulations
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 4_Supplement ( 2020-02-15), p. P6-10-04-P6-10-04
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 4_Supplement ( 2020-02-15), p. P6-10-04-P6-10-04
    Abstract: Background: Immunosurveillance suppression, evasion, or avoidance, has emerged as a key targetable hallmark of cancer, driven by e.g. checkpoint expression, T-cell exhaustion, and immunosuppressive tumor microenvironment (TME). Many of these processes generate defined combinations of immune-cell infiltrates at the tumor site, which can be detected by immunohistochemistry (IHC), CyTOF, or more recently can be inferred from gene-expression deconvolution. While significant work has been done to study gene signatures in the TME, the clinical relevance of such immune-cell gene signature on therapy has not been studied to a great extent. We investigate the hypothesis that the individual patterns of immune-cell signatures determine the clinical behavior of breast cancer (BC), in particular response to neoadjuvant chemotherapy. Methods: We performed a retrospective-prospective analysis of a subset of the GeparSepto study (NCT01583426) in which women with primary invasive BC were randomized to either nab-paclitaxel or solvent-based paclitaxel followed by EC. This study was limited to 279 HER2- patients with sufficient quality sample remaining to perform whole-transcriptome RNAseq (~200 × 106 reads per tumor). Immune activity in the TME was inferred by comparing expression of 23 immune-cell-specific gene signatures derived by Bindea et al. (Immunity, 2013) to those from a background population of 1467 similarly-profiled unselected tumor samples from the NantOmics database. Results: Within this cohort the most predominant high immune-cell signatures were for natural killer (NK) cells (71%), and regulatory T-cells (70%). Stimulatory T-cell signatures were high in approximately half of the population including Th2 (53%), effector-memory (53%), follicular helper (51%), Th1 (41%), and Gamma-delta T-cells (39%). While cytotoxic CD8+ T-cell signature was high in only 19.0% of patients, the signature for the CD56dim cytolytic subset of NK cells was high in 48.0% of patients. The most infrequently detected gene signatures were for innate response cell-types: Mast cells (7.5%), Macrophages (10.8%), immature dendritic cells (11.5%) and neutrophils (11.8%). Of the 23 immune signatures, 17 were significantly differentially activated in TNBC compared to hormone-receptor positive (HR+) patients (p & lt;0.05 respectively): 8/10 signatures more active in TNBC are associated with adaptive immune response (e.g. T-cell and B-cell signatures), whereas 5/7 signatures associated with HR+ are related to innate immune response (e.g. eosinophils and dendritic cells). Select adaptive immune signatures were associated with aggressive tumors: Elevated NK CD56dim, Th1, and activated dendritic cell (aDC), signatures were associated with grade 3 tumors as well as with elevated levels of Ki67 (p & lt;0.0001 respectively). The most predictive TME signature for paclitaxel-based therapy was T follicular helper cells (TFH) with DFS and OS hazard ratio of 0.62 (95% CI: 0.47-0.81; p=0.0004) and 0.55 (95% CI: 0.39-0.77; p=0.0005) respectively, as well as a 1.63 (95% CI: 1.12-2.36; p=0.0107) odds-ratio for achieving pCR. Conclusion: Whole-transcriptome sequencing in breast cancer FFPE core biopsies from clinical cohorts can be used to identify immune-cell signatures. Specifically, adaptive immunity through NK rather than T-cell response appears prevalent in high-risk TNBC. The patterns of these immune signatures, in particular the presence of T follicular helper cells, reflect the clinical behavior of breast cancer and might be used to identify tumors with an increased response rate to neoadjuvant chemotherapy. Citation Format: Christopher Szeto, Carsten Denkert, Peter A Fasching, Stephen Benz, Karsten E Weber, Jan Budczies, Andreas Schneeweiss, Elmar Stickeler, Sabine Schmatloch, Christian Jackisch, Thomas Karn, Hans P Sinn, Mathias Warm, Marion van Mackelenbergh, Shahrooz Rabizadeh, Christian Schem, Ernst Heinmöller, Volkmar Müller, Frederik Marmé, Patrick Soon-Shiong, Valentina Nekljudova, Sibylle Loibl, Michael Untch. Landscape of immune-cell signatures in early high-risk breast cancer (BC) reveals clinically-relevant enrichment of immune subpopulations [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 P6-10-04.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS19-P6-10-04
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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  • 3
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    Mesenchymal Stem Cell–mediated Image-guided Sodium Iodide Symporter ( NIS ) Gene Therapy Improves Survival of Glioblastoma-bearing Mice
    American Association for Cancer Research (AACR) ; 2023
    In:  Clinical Cancer Research Vol. 29, No. 5 ( 2023-03-01), p. 930-942
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 29, No. 5 ( 2023-03-01), p. 930-942
    Abstract: Mesenchymal stem cells (MSC) have emerged as cellular-based vehicles for the delivery of therapeutic genes in cancer therapy based on their inherent tumor-homing capability. As theranostic gene, the sodium iodide symporter (NIS) represents a successful target for noninvasive radionuclide-based imaging and therapy. In this study, we applied genetically engineered MSCs for tumor-targeted NIS gene transfer in experimental glioblastoma (GBM)—a tumor with an extremely poor prognosis. Experimental Design: A syngeneic, immunocompetent GL261 GBM mouse model was established by subcutaneous and orthotopic implantation. Furthermore, a subcutaneous xenograft U87 model was used. Bone marrow–derived MSCs were stably transfected with a NIS-expressing plasmid driven by the constitutively active cytomegalovirus promoter (NIS-MSC). After multiple or single intravenous injection of NIS-MSCs, tumoral iodide uptake was monitored in vivo using 123I-scintigraphy or 124I-PET. Following validation of functional NIS expression, a therapy trial with 131I was performed on the basis of the most optimal application regime as seen by 124I-PET imaging in the orthotopic approach. Results: A robust tumoral NIS-specific radionuclide accumulation was observed after NIS-MSC and radioiodide application by NIS-mediated in vivo imaging. NIS immunofluorescence staining of GBM and non-target tissues showed tumor-selective MSC homing along with NIS expression. Application of therapeutically effective 131I led to significantly delayed tumor growth and prolonged median survival after NIS-MSC treatment as compared with controls. Conclusions: A strong tumor-selective recruitment of systemically applied MSCs into GBM was found using NIS as reporter gene followed by successful therapeutic application of radioiodide demonstrating the potential use of NIS-based MSCs as therapy vehicles as a new GBM therapy approach.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-22-1433
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 4
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    ENIGMA CHEK2 gether Project: A Comprehensive Study Identifies Functionally Impaired CHEK2 Germline Missense Variants Associated with Increased Breast Cancer Risk
    American Association for Cancer Research (AACR) ; 2023
    In:  Clinical Cancer Research Vol. 29, No. 16 ( 2023-08-15), p. 3037-3050
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 29, No. 16 ( 2023-08-15), p. 3037-3050
    Abstract: Germline pathogenic variants in CHEK2 confer moderately elevated breast cancer risk (odds ratio, OR ∼ 2.5), qualifying carriers for enhanced breast cancer screening. Besides pathogenic variants, dozens of missense CHEK2 variants of uncertain significance (VUS) have been identified, hampering the clinical utility of germline genetic testing (GGT). Experimental Design: We collected 460 CHEK2 missense VUS identified by the ENIGMA consortium in 15 countries. Their functional characterization was performed using CHEK2-complementation assays quantifying KAP1 phosphorylation and CHK2 autophosphorylation in human RPE1–CHEK2-knockout cells. Concordant results in both functional assays were used to categorize CHEK2 VUS from 12 ENIGMA case–control datasets, including 73,048 female patients with breast cancer and 88,658 ethnicity-matched controls. Results: A total of 430/460 VUS were successfully analyzed, of which 340 (79.1%) were concordant in both functional assays and categorized as functionally impaired (N = 102), functionally intermediate (N = 12), or functionally wild-type (WT)–like (N = 226). We then examined their association with breast cancer risk in the case–control analysis. The OR and 95% CI (confidence intervals) for carriers of functionally impaired, intermediate, and WT-like variants were 2.83 (95% CI, 2.35–3.41), 1.57 (95% CI, 1.41–1.75), and 1.19 (95% CI, 1.08–1.31), respectively. The meta-analysis of population-specific datasets showed similar results. Conclusions: We determined the functional consequences for the majority of CHEK2 missense VUS found in patients with breast cancer (3,660/4,436; 82.5%). Carriers of functionally impaired missense variants accounted for 0.5% of patients with breast cancer and were associated with a moderate risk similar to that of truncating CHEK2 variants. In contrast, 2.2% of all patients with breast cancer carried functionally wild-type/intermediate missense variants with no clinically relevant breast cancer risk in heterozygous carriers.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-23-0212
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 5
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    Conditioning Regimens are Associated with Distinct Patterns of Microbiota Injury in Allogeneic Hematopoietic Cell Transplantation
    American Association for Cancer Research (AACR) ; 2023
    In:  Clinical Cancer Research Vol. 29, No. 1 ( 2023-01-04), p. 165-173
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 29, No. 1 ( 2023-01-04), p. 165-173
    Abstract: The gut microbiota is subject to multiple insults in allogeneic hematopoietic cell transplantation (allo-HCT) recipients. We hypothesized that preparative conditioning regimens contribute to microbiota perturbation in allo-HCT. Experimental Design: This was a retrospective study that evaluated the relationship between conditioning regimens exposure in 1,188 allo-HCT recipients and the gut microbiome. Stool samples collected from 20 days before transplantation up to 30 days after were profiled using 16S rRNA sequencing. Microbiota injury was quantified by changes in α-diversity. Results: We identified distinct patterns of microbiota injury that varied by conditioning regimen. Diversity loss was graded into three levels of conditioning-associated microbiota injury (CMBI) in a multivariable model that included antibiotic exposures. High-intensity regimens, such as total body irradiation (TBI)–thiotepa-cyclophosphamide, were associated with the greatest injury (CMBI III). In contrast, the nonmyeloablative regimen fludarabine–cyclophosphamide with low-dose TBI (Flu/Cy/TBI200) had a low-grade injury (CMBI I). The risk of acute GVHD correlated with CMBI degree. Pretransplant microbial compositions were best preserved with Flu/Cy/TBI200, whereas other regimens were associated with loss of commensal bacteria and expansion of Enterococcus. Conclusions: Our findings support an interaction between conditioning at the regimen level and the extent of microbiota injury.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-22-1254
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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  • 6
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    Abstract P1-10-01: Caveolin gene expression predicts for response and clinical outcomes of patients treated with preoperative paclitaxel-based chemotherapy regimens in early stage breast cancer
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 4_Supplement ( 2020-02-15), p. P1-10-01-P1-10-01
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 4_Supplement ( 2020-02-15), p. P1-10-01-P1-10-01
    Abstract: Background: Biomarkers are needed to prognosticate and predict efficacy of therapy for patients undergoing neoadjuvant chemotherapy for HER2-negative breast cancer (BC). Caveolin genes (CAV1, CAV2) are responsible for formation of caveolae, which are 50-100 nM membrane invaginations implicated in endocytosis and transcytosis of nutrients and substances, including albumin. Overexpression of caveolin family genes has been implicated in driving BC progression, but also in predicting response to nab-paclitaxel. We hypothesized that high CAV1/2 expression would correlate with poor clinical outcomes, but that patients with high CAV1/2 expression would have better outcomes with nab-paclitaxel based chemotherapy. Methods: We correlated tumor CAV1/2 RNA expression from available RNA-Seq data with pathologic complete response (pCR) and clinical outcomes (disease-free survival, DFS, and overall survival, OS) in the GeparSepto (G7) clinical trial, which randomized patients with early stage BC to preoperative paclitaxel versus nab-paclitaxel-based chemotherapy regimens. CAV1/2 log-transformed values were analyzed as a continuous variable and dichotomized about the mean for each gene. Multivariable logistic regression models were generated, and included age, T-stage, N-stage, tumor grade (G3 vs G1-2), Ki67 (continuous), and histology (non-ductal versus ductal). Results: There was RNA-Seq expression data available for 279 out of 810 HER2-negative patients, of whom 26.5% were hormone receptor (HR)-negative (triple negative). CAV1 and CAV2 expression values were directly correlated with each other (Pearson coefficient 0.452). There was no difference in CAV1 expression between HR-negative and HR-positive patients, but there was significant up-regulation of CAV2 expression (mean) in HR-negative patients (p=0.003). With regards to pCR, high CAV1/2 expression was associated with a strong benefit from nab-paclitaxel compared to paclitaxel (OR(CAV1)=4.92 (1.70-14.22) and OR(CAV2)=5.39 (1.76-16.47)) in contrast to low CAV1/2 expression (OR(CAV1)=0.94 (0.38-2.34) and OR(CAV2)=0.95 (0.39-2.29)) in multivariate modeling (tests for interaction p=0.023 and p=0.019). For CAV1 this effect continued beyond pCR with regards to survival: high CAV1 expression was associated with superior survival in the nab-paclitaxel arm (HR(DFS)=0.53 (0.27-1.05), HR(OS)=0.29 (0.11-0.77)) but not low CAV1 expression (HR(DFS)=1.37 (0.62-3.04), HR(OS)=2.47 (0.78-7.80)) in multivariate modeling (test for interaction p=0.077 (DFS) and p=0.005 (OS)). No significant interactions in hazard ratios for DFS and OS were detected for CAV2. With regard to prognostic effects, CAV2 expression was significantly associated with worse DFS and OS for all patients. In particular, high CAV2 expression was associated with poor prognosis for HR-negative patients in multivariate modeling (OR(DFS)=4.40 (1.44-13.46), OR(OS)=9.38 (1.13-77.75)), but not for HR-positive patients (OR(DFS)=1.60 (0.84-3.05), OR(OS)=2.05 (0.92-4.58)) (test for interaction p=0.125 and p=0.186). Conclusions: Higher CAV2 expression is associated with worse DFS and OS, in particular for HR-negative patients, confirming potential prognostic roles for CAV1/2. No significant differences in DFS and OS based on CAV1/2 expression were noted for patients who received nab-paclitaxel based treatment, but the odds of obtaining pCR were improved for patients with high CAV1/2 expression. Taken together, these findings suggest that CAV1/2 expression may offset the negative prognostic factor associated with higher CAV1/2 expression in patients treated with nab-paclitaxel regimens by enhancing the efficacy of treatment, perhaps through increased nab-paclitaxel endocytosis/transcytosis. Citation Format: Terence Williams, Andreas Schneeweiss, Christian Jackisch, Changxian Shen, Karsten Weber, Peter Fasching, Carsten Denkert, Jenny Furlanetto, Ernst Heinmoller, Sabine Schmatloch, Thomas Karn, Christopher Szeto, Marion van Mackelenbergh, Valentina Nekljudova, Elmar Stickeler, Patrick Soon-Shiong, Christian Schem, Barbara Fleige, Volkmar Muller, Frederik Marme, Michael Untch, Sibylle Loibl. Caveolin gene expression predicts for response and clinical outcomes of patients treated with preoperative paclitaxel-based chemotherapy regimens in early stage 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 P1-10-01.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS19-P1-10-01
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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    Inferred Immune-Cell Activity Is an Independent Predictor of HER2-Negative Breast Cancer Prognosis and Response to Paclitaxel-Based Therapy in the GeparSepto Trial
    American Association for Cancer Research (AACR) ; 2023
    In:  Clinical Cancer Research Vol. 29, No. 13 ( 2023-07-05), p. 2456-2465
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 29, No. 13 ( 2023-07-05), p. 2456-2465
    Abstract: Tumor microenvironment (TME) immune markers have been correlated with both response to neoadjuvant therapy and prognosis in patients with breast cancer. Here, immune-cell activity of breast cancer tumors was inferred by expression-based analysis to determine if it is prognostic and/or predictive of response to neoadjuvant paclitaxel-based therapy in the GeparSepto (G7) trial (NCT01583426). Experimental Design: Pre-study biopsies from 279 patients with HER2-negative breast cancer in the G7 trial underwent RNA-seq-based profiling of 104 immune-cell-specific genes to assess inferred Immune Cell Activity (iICA) of 23 immune-cell types. Hierarchical clustering was used to classify tumors as iICA “hot,” “warm,” or “cold” by comparison of iICA in the G7 cohort relative to that of 1,467 samples from a tumor database established by Nantomics LLC. Correlations between iICA cluster, pathology-assessed tumor-infiltrating lymphocytes (TIL), and hormone receptor (HR) status for pathologic complete response (pCR), disease-free survival (DFS), and overall survival (OS) were determined. Results: iICA cluster correlated with TIL levels. The highest pCR rates were observed in hot cluster tumors, and those with relatively higher TILs. Greater inferred activity of several T-cell types was significantly associated with pCR and survival. DFS and OS were prolonged in patients with hot or warm cluster tumors, the latter particularly for HR negative tumors, even if TILs were relatively low. Conclusions: Overall, TIL level better predicted pCR, but iICA cluster better predicted survival. Differences in associations between TILs, cluster, pCR, and survival were observed for HR-positive tumors versus HR-negative tumors, suggesting expanded study of the implication of these findings is warranted.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-22-2213
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
    detail.hit.zdb_id: 1225457-5
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  • 8
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    Caveolin Gene Expression Predicts Clinical Outcomes for Early-Stage HER2-Negative Breast Cancer Treated with Paclitaxel-Based Chemotherapy in the GeparSepto Trial
    American Association for Cancer Research (AACR) ; 2023
    In:  Clinical Cancer Research Vol. 29, No. 17 ( 2023-09-01), p. 3384-3394
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 29, No. 17 ( 2023-09-01), p. 3384-3394
    Abstract: Caveolin-1 and -2 (CAV1/2) dysregulation are implicated in driving cancer progression and may predict response to nab-paclitaxel. We explored the prognostic and predictive potential of CAV1/2 expression for patients with early-stage HER2-negative breast cancer receiving neoadjuvant paclitaxel-based chemotherapy regimens, followed by epirubicin and cyclophosphamide. Experimental Design: We correlated tumor CAV1/2 RNA expression with pathologic complete response (pCR), disease-free survival (DFS), and overall survival (OS) in the GeparSepto trial, which randomized patients to neoadjuvant paclitaxel- versus nab-paclitaxel–based chemotherapy. Results: RNA sequencing data were available for 279 patients, of which 74 (26.5%) were hormone receptor (HR)–negative, thus triple-negative breast cancer (TNBC). Patients treated with nab-paclitaxel with high CAV1/2 had higher probability of obtaining a pCR [CAV1 OR, 4.92; 95% confidence interval (CI), 1.70–14.22; P = 0.003; CAV2 OR, 5.39; 95% CI, 1.76–16.47; P = 0.003] as compared with patients with high CAV1/2 treated with solvent-based paclitaxel (CAV1 OR, 0.33; 95% CI, 0.11–0.95; P = 0.040; CAV2 OR, 0.37; 95% CI, 0.1 2–1.13; P = 0.082). High CAV1 expression was significantly associated with worse DFS and OS in paclitaxel-treated patients (DFS HR, 2.29; 95% CI, 1.08–4.87; P = 0.030; OS HR, 4.97; 95% CI, 1.73–14.31; P = 0.003). High CAV2 was associated with worse DFS and OS in all patients (DFS HR, 2.12; 95% CI, 1.23–3.63; P = 0.006; OS HR, 2.51; 95% CI, 1.22–5.17; P = 0.013), in paclitaxel-treated patients (DFS HR, 2.47; 95% CI, 1.12–5.43; P = 0.025; OS HR, 4.24; 95% CI, 1.48–12.09; P = 0.007) and in patients with TNBC (DFS HR, 4.68; 95% CI, 1.48–14.85; P = 0.009; OS HR, 10.43; 95% CI, 1.22–89.28; P = 0.032). Conclusions: Our findings indicate high CAV1/2 expression is associated with worse DFS and OS in paclitaxel-treated patients. Conversely, in nab-paclitaxel–treated patients, high CAV1/2 expression is associated with increased pCR and no significant detriment to DFS or OS compared with low CAV1/2 expression.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-23-0362
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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    Abstract PD5-08: Tumor immune-cell activity assessed by RNAseq is an independent predictor of therapy response and prognosis after neoadjuvant chemotherapy in HER2 negative breast cancer patients - An analysis of the GeparSepto trial
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 4_Supplement ( 2020-02-15), p. PD5-08-PD5-08
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 4_Supplement ( 2020-02-15), p. PD5-08-PD5-08
    Abstract: Background: Tumor immune markers such as tumor infiltrating lymphocytes (TILs) or expression-based profiles have been correlated with both response to neoadjuvant chemotherapy and prognosis in early breast cancer (BC) patients. Some chemotherapies, such as paclitaxel, lead to the development of TILs and in some cases, suppression of regulatory T-cells. Therefore, assessment of the tumor microenvironment (TME) could provide important information for clinical decision-making. The aim of this study was to test if RNAseq-based TME classification of BC tumors is predictive of pathological complete Response (pCR) and prognosis in the neoadjuvant GeparSepto (G7) trial (NCT01583426). Methods: We performed a retrospective-prospective analysis of a subset of 810 subjects of the total of 1207 patients of the G7 trial. In G7 HER2-negative early high-risk BC patients were studied to determine if nab-paclitaxel is superior to solvent-based paclitaxel. In addition to the taxane paclitaxel, both treatment arms received epirubicin plus cyclophosphamide before surgery. For this analysis, a subset of 279 HER2 negative patients with sufficient quality of pretherapeutic core biopsies to perform whole-transcriptome RNAseq (~200x106 reads per tumor) was used. Based on RNAseq data, immune activity classification was provided by ImmunityBio (Culver City, CA) by comparison of expression of 23 immune-cell-specific gene signatures as described by Bindea et al. (Immunity, 2013) to those from a reference population of 1467 similarly-profiled unselected tumor samples from a large tumor database (NantOmics, Culver City, CA). Unsupervised hierarchical clustering of inferred immune activities revealed 3 distinct groups termed “hot”, “warm”, and “cold” clusters. Logistic regression analysis based on age, trial arm, tumor size, nodal status, Ki-67, hormone-receptor (HR) status and immune activity cluster (hot/warm vs. cold) as independent variables was performed to predict pCR (ypT0/ypN0). Cox regression analysis with the same covariates was also performed to predict disease-free survival (DFS) and overall survival (OS). Results: Of the 279 patients, 67 had a pCR (24%). The analyzed subset was similar to the main HER2 negative population (pCR-rate: 22%). Patients with a “hot/warm” or “cold” immune activity assessment had a pCR in 30% and 13% of the cases, respectively. The odds-ratio of the multivariate logistic regression analysis was 2.17 (95% CI: 1.00-4.71, p=0.0512). With regard to DFS and OS, T follicular helper cell B-cell, and T-cell signatures seemed to play a prominent role, and the hazard ratios (also “hot/warm” vs. “cold”) for the multivariate analyses were 0.38 (95% CI: 0.21-0.66; p=0.0007) and 0.34 (95%CI: 0.16-0.72, p= 0.0045), respectively. Within the 23 individual immune-cell-specific gene signatures, CD56dimNatural Killer (NK), type 1 helper T-cells, and CD8+ T-cell signatures seemed to be closely associated with achievement of a pCR. RNAseq-based deconvolution of immune-cell activity was corroborated by IHC-based TIL scoring. Immune-hot/warm patients had more intratumoral lymphocytes compared to cold tumors (mean: 11.6% vs. 4.9%, p & lt;0.0001). Specifically, adaptive immunity gene signatures (i.e. CD8+ T-cell signature, CD56dim NK, and Th1) were moderately correlated with the percentage of TILs (rho correlation coefficients from 0.42 to 0.53). Conclusion: TME profiling by RNAseq may be an independent biomarker useful for predicting response to and prognosis after neoadjuvant chemotherapy including taxanes and anthracyclines in early HER2 negative high-risk BC. These results indicate that the further development of this biomarker could be of direct clinical importance. Citation Format: Peter A Fasching, Carsten Denkert, Stephen Benz, Karsten E Weber, Christopher Szeto, Jan Budczies, Andreas Schneeweiss, Elmar Stickeler, Sabine Schmatloch, Christian Jackisch, Thomas Karn, Hans Peter Sinn, Mathias Warm, Marion van Mackelenbergh, Sharooz Rabizadeh, Christian Schem, Ernst Heinmöller, Volkmar Müller, Frederik Marmé, Patrick Soon-Shiong, Valentina Nekljudova, Michael Untch, Sibylle Loibl. Tumor immune-cell activity assessed by RNAseq is an independent predictor of therapy response and prognosis after neoadjuvant chemotherapy in HER2 negative breast cancer patients - An analysis of the GeparSepto trial [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 PD5-08.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS19-PD5-08
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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