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  • American Association for Cancer Research (AACR)  (5)
  • 1
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 4_Supplement ( 2022-02-15), p. P2-12-08-P2-12-08
    Abstract: Background: Pathologic complete response (pCR) after neoadjuvant chemotherapy (NACT) is associated with beneficial long-term outcome in early breast cancer (EBC). pCR is defined as ypT0/is, ypN0. It is well known that pCR rates depend on tumor subtype. However, the impact of different therapy regimens, dose delays and dose reductions on pCR rates is still unclear. This retrospective study analyzed the therapy dose of patients with pCR and non-pCR after NACT for EBC using referenced and delivered summation dose intensity product (SDIP) and relative dose intensity (RDI) calculations. Methods: SDIP of different therapy regimens were calculated by defining a unit dose intensity (UDI) for each therapy (Hryniuk et al. JCO 1998). The UDI is defined as the dose in mg/m2/week that produces a 30% complete or partial remission rate as a single agent in first-line therapy for metastatic breast cancer. For each regimen, the planned dose intensities (PDI) were divided by the UDI for every single drug. The summation dose intensity (SDI) is the addition of the resulting decimal fractions. Multiplying the SDI by the treatment intervals and number of cycles gives the SDIP. SDIP can be divided into referenced SDIP (rSDIP) and delivered SDIP (dSDIP). RDI is the ratio of dSDIP in comparison to rSDIP. Therapy dose calculations were performed for patients who received NACT for EBC at the National Center for Tumor Diseases (NCT) Heidelberg, Germany, between 01/2015 and 08/2019. Results: 590 patients (median age 51 years) were included, median follow up was 38 months, 225 patients (38.1%) achieved pCR. 65 patients (11.0%) were hormone receptor positive HER2 negative (HR+HER2-), 164 (27.8%) were HR-HER2-, 133 (22.5%) were HR+HER2+, 97 (16.4%) were HR-HER2+. Significant difference between the pCR and non-pCR group was observed for HR-status (p & lt;0.001), HER2-status (p & lt;0.001), tumor grading (p & lt;0.001) and Ki-67 (p & lt;0.001). Age of diagnosis (p=0.611), menopause-status (p=0.769), tumor size (p=0.183) and nodal status (p=0.163) did not significantly vary between patients with pCR versus non-pCR. Patients with pCR had significantly higher rates of anemia II° (p=0.006). No significant difference was seen for anemia ≥III°, neutropenia ≥II°, deviation of liver enzymes ≥II°, nephrotoxicity ≥II°, polyneuropathy ≥II° or the administration of red cell and platelet concentrate as well as the use of Granulocyte-Colony Stimulating Factor (G-CSF). 3 year overall survival (OS), metastasis-free survival (MFS) and recurrence-free survival (RFS) were found to be significantly better in patients with pCR (OS: 98.0% vs. 90.2%, p & lt;0.001; MFS: 94.5% vs. 84.6%, p & lt;0.001; RFS: 97.7% vs. 94.0 %, p=0.029). Patients with pCR had a significantly higher mean rSDIP (69.8 vs. 58.9, p=0.001) and dSDIP (59.5 vs. 49.1, p=0.001). Mean RDI did not significantly vary between pCR and non-pCR (0.853 vs. 0.840, p=0.350). Mean rSDIP and dSDIP significantly vary between the tumor subtypes HR+HER2-, HR-HER2-, HR+HER2+, and HR-HER2+ (rSDIP: 47.4, 54.5, 74.3, 76.7; p & lt;0.001; dSDIP: 39.5, 43.3, 62.0, 67.0; p & lt;0.001). Mean rSDIP and dSDIP did not significantly vary between patients with pCR and non-pCR within the tumor subtypes. Conclusion: Outcomes for NACT are consistent with published data concerning pCR rates. It is notable that the pCR group had significantly higher rSDIP and dSDIP than the non-pCR group whereas RDI and toxicity did not significantly vary between the two groups. rSDIP and dSDIP were mainly depending on the tumor subtype. This data confirms that the tumor subtype has a major impact on pCR rate. Whilst this retrospective analysis must be interpreted with caution, the results show that SDIP is an integral parameter for assessing the efficacy and adequate application of combination therapy and is associated with pCR rate and overall survival. Citation Format: Thomas M Deutsch, Michelle Kobel, Manuel Feisst, Fabian Riedel, Katharina Smetanay, Carlo Fremd, Laura Michel, Michael Golatta, Joerg Heil, Markus Wallwiener, Andreas Schneeweiss. Impact of summation dose intensity product on pathologic response in patients receiving neoadjuvant chemotherapy for early breast cancer [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 P2-12-08.
    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: 2022
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  • 2
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 9_Supplement ( 2015-05-01), p. P3-06-45-P3-06-45
    Abstract: Background Clinical decisions in the primary and advanced situation of breast cancer are based on immunohistochemical staining (IHC) and semiquantitative assessment of ER, PgR, HER2 and Ki67. However, IHC carries an up to 20% risk of erroneous results. Moreover, metaanalysis revealed variable discordance rates between primary and metastatic sites (P/M) which may have implications for patient management (Aurilio, Eu J Cancer 2013). Herein, we undertook a pilot study aiming to investigate whether the reported discordance between primary lesion and paired distant metastatic sites is due to technical limitations of the IHC technique and could be improved by mRNA analysis using the MammaTyper® in vitro diagnostic assay. Materials and Methods One 10μm-thick sections from clinical routine FFPE tissues of 28 tumor samples were reexamined by RNA quantitation of ESR1, PGR, HER2 and KI67 using the RNXtract® kit for RNA extraction and MammaTyper® kit for objective assessment of receptor status. RNA levels were normalized using a synthetic in-vitro transcript for normalization according to the 40-DDCT method. Receptor status was reported based on predefined cut-offs according to the instruction for use. mRNA and IHC results were compared between paired primary and metastatic sites. Results Concordance per tumor sample between the two methods was 100% for HER2, 81.9% for ESR1 and 81.5% for PR. Among discrepant samples (N=8), 6 were primary and among these, half (N=3) were due to negative ER by IHC. With the exception of HER2, where no differences were observed for either method, the P/M concordance was superior by MammaTyper® kit (ESR1: 92.85 vs. 76.82, PR: 71.43 vs. 69.23). Importantly, several discordant cases by IHC were ER negative in the primary site, while being ER positive in the metastatic lesion, while being consistently ESR1 positive in both sites, when determined by the more sensitive PCR method. The subtype discordant cases were situated in the lung (2), the liver (1) and the bone marrow (1). Conclusion Our data indicate that receptor status shifts less frequently when determined by PCR methods compared to IHC. While some shifts between primary site and metastases may arise from true progression-related biologic alterations (Prat et al Nat Med 2009), others seem to be related to technical limitations of semiquantitative and subjective IHC, with several cases being conspicuous for ESR1. This finding is of great clinical significance and is consistent with previous reports implicating technical confounders of IHC for large part of the observed P/M deviations (Pusztai, The Oncologist 2010). The implied superiority of RT-qPCR by MammaTyper® vs. routine IHC in detecting true P/M tumor receptor status reversals and the possible clinical impact is clearly worth pursuing in larger datasets. Citation Format: Markus Wallwiener, Andreas Hartkopf, Thomas Deutsch, Lakis Sotiris, Florin-Andrei Taran, Andreas Trumpp, Ralph Wirtz, Andreas Schneeweiss. Concordance/discordance rates of HER2, ER, PR, and Ki67 in matched pair samples of primary (PBC) and metastatic breast cancer (MBC) tissues when comparing IHC with MammaTyper® RT-PCR kit [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-06-45.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
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  • 3
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 15_Supplement ( 2015-08-01), p. 3973-3973
    Abstract: Introduction: Circulating free (cf) microRNAs hold great promises in early detection and prognosis of human diseases such as cancer. However due to the very low amount of cf miRNA in plasma and serum, highly informative miRNAs are lost. Thus, there is an urgent need for highly efficient, sensitive, cost efficient technologies to measure low abundant miRNA in a quantitative manner. Previously, we have successfully measured and validated miRNA profiles of early onset breast cancer cases, healthy controls and breast cancer patients who had developed breast cancer metastasis during follow-up by applying TaqMan Low density arrays. We established and validated miRNA signatures for the early detection of early stage breast cancer, and prognosis and early detection of breast cancer metastasis. However more sensitive microarray platforms with highly dynamic ranges could even improve identified diagnostic signatures especially in respect of early detection of diseases and relapse. Here, we compared the sensitivity of the previously applied array platform TaqMan Low density array (TLDA) with Toray innovative 3D-Gene microarray technology by measuring plasma cf miRNA profiles of 40 individuals (10 healthy controls, 10 early stage breast cancer, 20 metastatic breast cancer patients). Experimental Procedures: Plasma samples were processed within 2 h after blood collection. EDTA blood was centrifuged for 15 min at 1200 g and the supernatant centrifuged again at 12.000 g for 10 min in order to remove any cell debris. Cf RNA was isolated from plasma. Cf miRNA profiles of plasma samples of 40 individuals (10 healthy controls, 10 early stage breast cancer, 20 metastatic breast cancer patients) were investigated A: via TaqMan low density arrays (TLDA) and B: via 3D-Gene microarray technology. Expression profiles between both array types and between cases, early stage breast cancer and metastatic breast cancer patients were compared. In addition selected miRNAs were measured with single TaqMan assays. These results were compared with the array based results. Conclusion: The result will be of importance for all scientists who intend to develop and improve diagnostic miRNA panels. Based on our results recommendations for a microarray platform for the investigation of cf miRNA will be given. Citation Format: Melanie Maierthaler, Eric Mennesson, Katarina Cuk, Dharanija Madhavan, Manuela Zucknick, Isabelle Fixe, Alexandra Foucher, Markus Wallwiener, Andreas Schneeweiss, Nadia Normand, Barbara Burwinkel. Comparison of different highly sensitive miRNA array platforms for the investigation of circulating cell-free microRNAs in blood. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3973. doi:10.1158/1538-7445.AM2015-3973
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    RVK:
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
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  • 4
    In: Molecular Cancer Research, American Association for Cancer Research (AACR), Vol. 18, No. 2 ( 2020-02-01), p. 278-286
    Abstract: Mechanisms of intrinsic resistance of serous ovarian cancers to standard treatment with carboplatin and paclitaxel are poorly understood. Seventeen primary serous ovarian cancers classified as responders or nonresponders to standard treatment were screened with DigiWest protein array analysis for 279 analytes. Histone methyl transferase EZH2, an interaction partner of ataxia telangiectasia mutated (ATM), was found as one of the most significantly represented proteins in responsive tumors. Survival analysis of 616 patients confirmed a better outcome in patients with high EZH2 expression, but a worse outcome in patients with low EZH2 and high-ATM–expressing tumors compared with patients with low EZH2 and low-ATM–expressing tumors. A proximity ligation assay further confirmed an association between ATM and EZH2 in tumors of patients with an increased disease-free survival. Knockdown of EZH2 resulted in treatment-resistant cells, but suppression of both EZH2 and ATM, or ATM alone, had no effect. DigiWest protein analysis of EZH2-knockdown cells revealed a decrease in proteins involved in mitotic processes and checkpoint regulation, suggesting that deregulated ATM may induce treatment resistance. Implications: Ovarian cancer is a malignancy with high mortality rates, with to date, no successful molecular characterization strategies. Our study uncovers in a comprehensive approach the involvement of checkpoint regulation via ATM and EZH2, potentially providing a new therapeutic perspective for further investigations.
    Type of Medium: Online Resource
    ISSN: 1541-7786 , 1557-3125
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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  • 5
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 18, No. 21 ( 2012-11-01), p. 5972-5982
    Abstract: Purpose: The use of circulating tumor cells (CTC) as a prognostic marker in metastatic breast cancer (MBC) has been well established. However, their efficacy and accuracy are still under scrutiny mainly because of methods of their enrichment and identification. We hypothesized that circulating miRNAs can predict the CTC status of patients with MBC, and tested for the same. Furthermore, we aimed at establishing a panel of circulating miRNAs capable of differentiating MBC cases from healthy controls. Experimental Design: Circulating miRNAs from plasma of CTC-positive and CTC-negative patients with MBC, and healthy controls, were profiled by TaqMan Human MicroRNA arrays. Candidates from the initial screen were validated in an extended cohort of 269 individuals (61 CTC-positive, 72 CTC-negative, 60 CTC-low MBC cases, and 76 controls). Results: CTC-positive had significantly higher levels of miR-141, miR-200a, miR-200b, miR-200c, miR-203, miR-210, miR-375, and miR-801 than CTC-negative MBC and controls (P & lt; 0.00001), whereas miR-768-3p was present in lower amounts in MBC cases (P & lt; 0.05). miR-200b was singled out as the best marker for distinguishing CTC-positive from CTC-negative patients (AUC 0.88). We identified combinations of miRNAs for differentiating MBC cases from controls (AUC 0.95 for CTC-positive; AUC 0.78 for CTC-negative). Combinations of miRNAs and miR-200b alone were found to be promising prognostic marker for progression-free and overall survival. Conclusion: This is the first study to document the capacity of circulating miRNAs to indicate CTC status and their potential as prognostic markers in patients with MBC. Clin Cancer Res; 18(21); 5972–82. ©2012 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2012
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