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  • American Association for Cancer Research (AACR)  (12)
  • 1
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    Abstract 5289: The role of the immune system in lymph node positive ER+ breast cancer
    American Association for Cancer Research (AACR) ; 2015
    In:  Cancer Research Vol. 75, No. 15_Supplement ( 2015-08-01), p. 5289-5289
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 15_Supplement ( 2015-08-01), p. 5289-5289
    Abstract: Estrogen receptor (ER) positive breast cancer (BC) accounts for 70% of BC diagnoses and is associated with a good outcome when treated with conventional therapies, including tamoxifen. However, there remains a sub-population of patients who undergo relapse within 10 years of diagnosis and do not respond well to standard therapies. While lymph node (LN) status is an important indicator of poor prognosis, additional information is needed to more accurately predict patients who will or will not relapse. Previous genomic studies from our lab have shown that immune response is an important feature of LN+ BCs that do not relapse. In addition, other studies have also examined the role of the immune system in ER+ BC, but due to varying study designs, it is unclear how immune response pertains to ER+ BC relapse. The goal of this project is to characterize immune response in ER+ BC by measuring levels of immune markers using immunohistochemistry (IHC) and RNA expression levels and comparing those to tumour characteristics. We have developed a cohort of retrospective ER+ BC patients with tumour samples available through the Hamilton Health Science tumour bank. Patients were selected for eligibility based on ER status, early stage disease, and having long term clinical follow-up. Clinical charts for each patient were reviewed and pathological, treatment, and outcome data were abstracted. Tumour blocks were obtained and sections stained for haematoxylin and eosin were marked for tumour boarders then used to construct Tissue microarrays (TMA) for IHC assays and RNA is to be extracted from each tumour block. 318 patient samples have been obtained that meet eligibility requirements. Among those, 163 are LN- and 110 are LN+, and the remainder have unknown LN status. Primary endpoint for this study is the development of distant metastasis. Roughly 10% of LN- patients developed distant metastasis within 10 years and roughly 20% of LN+ patients developed distant metastasis. In total, 14% of patients came to endpoint during the study period. TMAs were stained for pathological markers, including ER, PR, HER2, and Ki67 as well as immune markers such as CD8 and CD20. RNA expression levels for each of these were also determined and both were compared with clinical outcome. Here we present a retrospective cohort of ER+ BC patients with 10 years of clinical follow-up data that can be used for IHC and RNA analysis. Further, we have examined the association between immune response and prognosis in lymph node positive ER+ BC patients. Citation Format: Jessica G. Cockburn, Amy Gillgrass, Anita Bane. The role of the immune system in lymph node positive ER+ breast cancer. [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 5289. doi:10.1158/1538-7445.AM2015-5289
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2015-5289
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
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  • 2
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    Abstract A022: The use of LN status on developing prognostic gene signatures for ER+ breast cancer
    American Association for Cancer Research (AACR) ; 2013
    In:  Molecular Cancer Research Vol. 11, No. 10_Supplement ( 2013-10-01), p. A022-A022
    Details
    In: Molecular Cancer Research, American Association for Cancer Research (AACR), Vol. 11, No. 10_Supplement ( 2013-10-01), p. A022-A022
    Abstract: Introduction: Estrogen Receptor (ER) positive Breast Cancers account for approximately 70% of all breast cancers and have a better prognosis than ER- breast cancer. These patients are amenable to endocrine treatment, including tamoxifen, which eliminates recurrence in a large group of patients, but approximately 30% will relapse within 15 years of diagnosis. The most important predictor of recurrence in ER+ breast cancer is lymph node (LN) status. Patients with LN metastases (LN+) have increased risk of systemic recurrence, compared to ER+ patients without LN metastases (LN-). However, it is difficult for clinicians to determine appropriate treatment for ER+ LN+ breast cancer, so this group is generally treated aggressively. Several commercially available molecular signatures have been developed to predict outcome of early stage breast cancers, but none have been exclusively designed for ER+ breast cancer patients, inclusive of lymph node status. Methods: Here, three publicly available datasets (Gene Expression Omnibus, NCBI), consisting of gene expression profiles from primary ER+ breast cancer tumours were used to develop prognostic gene signatures. Patients from these cohorts were treated exclusively with tamoxifen for 5 years and were followed for at least 10 years past diagnosis. Gene expression significantly related to high risk of distant metastasis free survival (DMFS) of patients from our training cohort, at 10 years, was examined using the Prediction Analysis of Microarray (PAM, Stanford) and used to comprise our novel molecular signatures. Three independent signatures were developed using cohorts of patients with LN- disease exclusively, LN+ disease exclusively, or combined lymph node status. The performance of these signatures was evaluated using an independent cohort of patients with either LN- or LN+ disease. We also examined biologically relevant pathways, using Gene Set Enrichment Analysis (GSEA, Broad Institute), to examine whether the heterogeneous nature of ER+ breast cancers can be related to phenotype or outcome. Results: Gene expression and DMFS data from LN-, LN+, or combined patient samples were evaluated to identify sets of genes that predict patient outcome. The LN- signature could accurately predict DMFS of LN- patients from independent cohorts, but was unable to assign LN+ patients to low and high risk of DMFS groups. Similarly, the LN+ signature could accurately predict outcome of LN+ patients, but not LN- patients. Conversely, the combined signature was able to predict DMFS of all patients, regardless of LN status. We further evaluated gene set enrichment and found differences in gene sets associated with LN- and LN+ disease and with different outcomes. Conclusions: This research demonstrates the importance of considering the lymph node status of patients with both developing and employing prognostic gene signatures to predict outcome of early stage ER+ breast cancer patients. Also, it appears that the development of a signature using an exclusive population (i.e. LN-) of patients is not optimal to predict outcome in patients with different pathological parameters. In the future, using a combined gene signature may help direct treatment decisions for patients with early stage ER+ breast cancer. Further, understanding the biological heterogeneity of this disease, through GSEA, may lead to discovery of appropriate therapeutic targets for patients. Citation Format: Jessica G. Cockburn, Robin M. Hallett, John A. Hassell, Anita Bane. The use of LN status on developing prognostic gene signatures for ER+ breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr A022.
    Type of Medium: Online Resource
    ISSN: 1541-7786 , 1557-3125
    URL: Article
    DOI: 10.1158/1557-3125.ADVBC-A022
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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  • 3
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    Abstract A124: Characterization of claudin-low breast cancers
    American Association for Cancer Research (AACR) ; 2013
    In:  Molecular Cancer Research Vol. 11, No. 10_Supplement ( 2013-10-01), p. A124-A124
    Details
    In: Molecular Cancer Research, American Association for Cancer Research (AACR), Vol. 11, No. 10_Supplement ( 2013-10-01), p. A124-A124
    Abstract: Molecular profiling of human breast cancers has defined 5 molecular subtypes: luminal A, luminal B, HER2 over-expressing, basal-like and claudin-low. The claudin-low subtype was identified in 2007 and is characterized by low expression of claudin proteins, E-cadherin and markers of luminal differentiation, and is reported to be associated with expression of mesenchymal and cancer stem cell (CSC) markers. The prevalence of this subtype is reported to be between 7-14% and there are an excess of tumors with metaplastic and medullary-like features, an association with poor prognosis and evidence that they may be resistant to conventional chemotherapies. Using information from publicly available gene expression microarray data, we sought to identify immunohistochemical markers of the claudin-low subtype and to further describe the morphological features of claudin-low breast tumors and the overall survival characteristics of patients with these tumors, along with any associations between these tumors and CSC markers. Using the gene expression microarray datasets, we performed hierarchical clustering to assign a molecular subtype to the tumors. Differential gene expression analysis was used to identify genes that were significantly upregulated and downregulated between claudin-low tumors and other tumor subtypes as candidates for immunohistochemical markers for our formalin fixed paraffin embedded (FFPE) tumor cohort. We utilized 943 stage I or stage II, lymph node negative primary invasive breast cancers treated with breast conserving surgery and adjuvant radiation, which had FFPE tumor blocks available for tissue microarray construction. On the basis of IHC expression of ER, PR, HER2, Ki67, EGFR, CK5/6, Claudin proteins and E-cadherin, tumors were classified as luminal A, luminal B, HER2 over-expressing, basal-like or claudin-low. Kaplan-Meier methods were used to estimate overall survival, and Fisher's exact tests were used to compare tumor characteristics and expression of CSC markers (ALDH1, CD44hi/CD24low) between claudin-low and luminal A tumors. Claudin-low tumors comprised 8% of our cohort with an overall survival of 73.6% at a median follow up of 12 years, similar to that of basal-like and HER2 over-expressing subtypes. Compared to luminal A type tumors, the claudin-low tumors were statistically more likely to have circumscribed tumor margins. However, there was no statistically significant association between claudin-low subtype and the expression of CSC markers. The claudin-low subtype represents a minority of invasive breast cancers, however this group is characterized by poor prognosis, and as such the identification of these tumors is useful to determine treatment options in the clinical setting. Citation Format: Kay Dias, Anna Dvorkin-Gheva, Greg Pond, Mark Levine, Timothy Whelan, Anita Bane. Characterization of claudin-low breast cancers. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr A124.
    Type of Medium: Online Resource
    ISSN: 1541-7786 , 1557-3125
    URL: Article
    DOI: 10.1158/1557-3125.ADVBC-A124
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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  • 4
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    Abstract P6-04-02: Ki67 Assessment Protocol: Companion Diagnostic Biomarker for LUMINA Prospective Cohort Study
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 5_Supplement ( 2023-03-01), p. P6-04-02-P6-04-02
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 5_Supplement ( 2023-03-01), p. P6-04-02-P6-04-02
    Abstract: Introduction: Luminal A breast cancer is associated with low proliferation, indolent disease biology and limited benefit from chemotherapy. The LUMINA prospective study recently demonstrated a very low 5 year local recurrence rate (2.3%) in women ≥55 years with grade I-II, T1N0 luminal A breast cancer (defined as ER ≥ 1%, PR & gt;20%, HER2 negative and Ki67 index ≤ 13.25%) treated with breast conservation surgery and endocrine therapy without radiation, supporting the safe omission of radiation in this molecularly defined low risk group. Here, we report the protocol for multicentre Ki67 scoring, the embedded integral companion diagnostic employed in LUMINA. Methodology: Ki67 immunohistochemistry was performed on full-face sections at one of the 3 labs and scored by pathologists using an adaptation of the International Ki67 Working Group (IKWG) method. Prior to the start of the study, quality assurance and quality control programs were set up to standardize staining and scoring protocols. All pathologists completed the IKWG training and calibration exercise using a tissue microarray-based series of 18 breast cancers. Inter-laboratory variability was assessed annually during the study period on a set of 9 breast cancer cases with a range of Ki67 scores that purposely over-represented the 13.25% threshold. Stained slides were scanned and images annotated to demarcate invasive carcinoma. Next, 5 random, non-overlapping, 1 mm virtual cores were generated via software and 100 nuclei assessed per core using a keyboard-based counting aid. Ki67 index was derived as the percentage of all counted tumor nuclei that are positively stained. For cases with high Ki67 heterogeneity, additional virtual cores were generated and scored and a 95% confidence interval (CI) of Ki67 index was estimated. The goal was to confidently assign a case as luminal A (≤13.25%) or B ( & gt; 13.5%). If the 95% CI crossed 13.25% a recount was performed by an additional pathologist. Results: Quality Assurance Programs: Mean Ki67 index across all cases, labs and years was 13% with high concordance across specimens and score ranges. Observed intra-class correlation coefficients (ICC) were ≥ 0.9, showing near perfect agreement in quantitative Ki67 evaluation. About the 13.25% cutpoint, the observed Kappa statistics were ≥ 0.7 indicating excellent agreement for assignment of luminal A vs. B status. A sub-study was conducted to compare the method of randomly selected virtual fields with the IKWG ‘global weighted score’ method for visual assessment of full-face sections. For this purpose, the 9 quality control cases were reassessed by the same pathologist using the updated IKWG method. Results showed an ICC of 0.96 (0.95% CI: 0.91-0.98) indicating that the Ki67 score generated by the methodology employed in LUMINA trial is highly concordant with the IKWG scoring methodology validated for use on full face sections. Ki67 index summary statistics across LUMINA: Of the 724 eligible cases, 69% (n=500) were assigned as luminal A (median Ki67=7.5%; IQR 5.2-9.8%) and 31% (n=224) as luminal B (median Ki67=19%; IQR 17-23%). Median pathologist scoring time was 4 minutes/case; 45% of cases required scoring of & gt; 5 virtual cores. Per protocol, 39% cases where the initial CI crossed 13.25% were rescored by additional pathologist for final luminal A consensus assignment. Conclusions: Ki67 is a practical biomarker for identifying molecularly defined low-risk luminal A cancers. Our structured quality assurance approach for the trial led to excellent reproducibility and concordance among decentralized labs, supporting applicability of a distributed, inexpensive methodology beyond clinical trial settings and in resource restricted environments. Citation Format: Torsten Nielson, Samuel Leung, Nazia Riaz, Zuzana Kos, Anita Bane, Timothy J. Whelan. Ki67 Assessment Protocol: Companion Diagnostic Biomarker for LUMINA Prospective Cohort Study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-04-02.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS22-P6-04-02
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 5
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    Abstract P4-02-16: Prognostic and Predictive Capacity of Tumor Infiltrating Lymphocytes in the MA.20 regional radiotherapy trial
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 5_Supplement ( 2023-03-01), p. P4-02-16-P4-02-16
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 5_Supplement ( 2023-03-01), p. P4-02-16-P4-02-16
    Abstract: Background: The benefit of regional nodal irradiation (RNI) in patients with low burden metastatic axillary disease was established in MA.20 showing that patients randomized to receive adjuvant whole breast irradiation (WBI) plus RNI experienced a significantly better disease free survival (DFS) and distant disease free survival (DDFS) compared to those who received WBI alone and this advantage was maintained in the hormone receptor negative subgroup. Stromal tumor infiltrating lymphocytes (sTILs) have shown prognostic and predictive value in HER2 positive and triple negative breast cancers. To date, clinical importance of immune infiltrates as prognostic and predictive biomarkers in the context of benefit from RNI has not been shown. Methods: 1064 full-face hematoxylin and eosin (H & E) stained sections and formalin fixed paraffin embedded primary tumor blocks assembled into 16 tissue microarrays (TMAs) in quadruplicates linked with clinical data were accessible from the original 1832 patients in the MA.20 trial for this retrospective-prospective translational study conducted according to the REMARK guidelines. sTILs were assessed on scanned images of H & E sections according to the International Immuno-Oncology Working Group method, and on TMAs by CD8 immunohistochemistry (IHC) using a validated assay. Biomarkers were scored by pathologists blinded to the clinical data and analyzed as continuous and categorical variables using prespecified median cutpoints. The median follow-up was 9.5 years. Cox proportional regression modelling was used after adjusting for clinicopathological factors and treatments. Hazard ratios (HR) with 95% confidence intervals (CI) were reported for the primary endpoint of DFS and secondary endpoint of DDFS. Predictive value was assessed by the interaction test between the treatment arm and the biomarkers in the full cohort and an IHC defined non-luminal A subgroup. Results: 1035 cases were evaluable for sTILs on H & E sections. Of these 52.6% (n=544) cases with ≥10% sTILs displayed a significant correlation with age & lt; 50 years, grade III, tumor size & gt;2cm, hormone receptor negative status, and non-luminal A subgroup (p & lt; 0.05). Of the 857 evaluable cases on TMAs, CD8+sTILs (≥16) were observed in 49.8% (n=427) cases and showed a significant association with grade III, ER negativity and non-luminal A status (p & lt; 0.05). For the full cohort, H & E sTILs assessed as a continuous parameter, were not prognostic for DFS (HR 0.993; 95% CI 0.984-1.003; p=0.18) but provided prognostic information for DDFS (HR 0.988; 95% CI 0.977-0.999; p=0.04) in multivariate analyses. H & E sTILs did not show predictive value as a continuous variable. Similarly, using the prespecified cutpoint (≥10%), H & E sTILs were neither prognostic nor predictive. Increasing level of CD8+sTILs was associated with significantly improved DFS (HR 0.99; 95% CI 0.983-0.998; p=0.02) and DDFS (HR 0.98; 95% CI 0.97-0.99; p=0.002) in multivariate analyses. For the full cohort, CD8+sTILs as a continuous variable, showed a significant improvement in DDFS for patients randomized to WBI and RNI (HR 0.979; 95%CI 0.959-0.999; p(interaction) =0.04) compared to WBI alone and a trend (HR 0.977; 95%CI 0.954-1.001; p(interaction) =0.06) for better outcome was observed for the non-luminal A subgroup. CD8+sTILs at the prespecified cutpoint (≥16) were not prognostic or predictive. Conclusions: Pre-treatment tumoral infiltration with stromal lymphocytes provided positive prognostic information for DFS (CD8+sTILs) and DDFS (H & E sTILs and CD8+sTILs) when examined as a continuous variable but failed to do so at prespecified cutpoints. While CD8+sTILs as a continuous variable predicted benefit from RNI, significant prediction results were not seen for prespecified cutpoint or related biomarker H & E sTIL. These results require further validation. Citation Format: Nazia Riaz, Bingshu Chen, Anita Bane, Dongxia Gao, Elisabeth Stovgaard, Zuzana Kos, Samuel Leung, Elahe Shenasa, Wendy Parulekar, Shelley Chambers, Torsten Nielson, Timothy J. Whelan. Prognostic and Predictive Capacity of Tumor Infiltrating Lymphocytes in the MA.20 regional radiotherapy trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-02-16.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS22-P4-02-16
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 6
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    Abstract P5-02-01: Analytical validation and prognostic potential of an automated digital scoring protocol for Ki67: An International Ki67 Working Group study
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 4_Supplement ( 2020-02-15), p. P5-02-01-P5-02-01
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 4_Supplement ( 2020-02-15), p. P5-02-01-P5-02-01
    Abstract: Background: The nuclear proliferation biomarker Ki67 has multiple potential roles in breast cancer, including aiding decisions based on prognosis, but has unacceptable between-laboratory variability. Here we tested an open source and calibrated automated digital image analysis (DIA) platform to: (i) Assess inter-laboratory reproducibility of automated Ki67 measurement among 17 participating labs and compare those with standardized pathologist-based visual scoring. (ii) Investigate the comparability of Ki67 measurement across corresponding core biopsy and whole section cases. (iii) Test prognostic potential of the built Ki67 scoring algorithms on an independent cohort. Methods: Two sets of 60 previously stained slides containing 30 core-cut biopsy and 30 corresponding whole tumor sections from 30 ER+ breast cancer cases were sent to 17 participating labs for automated assessment of average Ki67 expression. The blocks were centrally cut and stained for Ki67 using the Mib-1 antibody. The QuPath (open-source software) DIA platform was used to evaluate tumoral Ki67 expression. Calibration of the DIA method was performed in our previous study (Acs et al, Lab Invest 2019). A detailed guideline for building an automated Ki67 scoring algorithm was sent to the participating labs. Visual scoring of average Ki67 expression was performed by pathologists according to published standardized methods (Leung et al, NPJ Br Cancer 2016; Leung et al, Histopath 2019). Locked down DIA Ki67 scoring algorithms were applied to a validation cohort: 222 breast cancer cases from the Karolinska University Hospital in whole section format. Sufficient reproducibility to declare analytical validity was defined as an Intra Class Correlation (ICC) with lower limit of 95% credible interval (CI) & gt;0.80. Markov Chain Monte Carlo routines for generalized linear mixed models were used to estimate ICCs and calculate corresponding CIs. Results: The same-section ICC was 0.902 (CI: 0.852-0.949) across 17 labs using calibrated DIA platform on core biopsy slides and 0.845 (CI: 0.778-0.912) on whole sections. The different-section ICC across the 17 labs was 0.873 (CI: 0.806-0.932) scoring on core biopsy slides and 0.777 (CI: 0.670-0.874) on whole sections. The pathologist-based visual Ki67 scoring showed ICC of 0.860 for all comparisons, respectively (CI: 0.795-0.927). Similar to what was observed for visual Ki67 scoring, the DIA scores are higher for core biopsy slides compared to paired whole sections (p≤0.001; median difference: 5.31%; IQR: 11.50%). Ki67 scores of all locked down DIA algorithms correlates significantly (p≤0.023) with outcome on the validation cohort (observed hazard ratios range: 2.518-2.922). Conclusions: Automated Ki67 evaluation using a calibrated, open-source DIA platform (QuPath) met the pre-specified criterion of success on core biopsies but not on whole sections in the multi-institutional setting. The systematic discrepancy between core biopsy and corresponding whole sections was likely due to pre-analytical factors (tissue handling, fixation) and intratumor heterogeneity. We found that different algorithms built according to calibrated DIA methods had similar prognostic potential. Assessment of clinical utility is planned. Citation Format: Balazs Acs, Samuel C.Y. Leung, Kelley M. Kidwell, Indu Arun, Renaldas Augulis, Sunil S. Badve, Yalai Bai, Anita L. Bane, John M.S. Bartlett, Jane Bayani, Gilbert Bigras, Annika Blank, Signe Borgquist, Henk Buikema, Martin C. Chang, Robin L. Dietz, Andrew Dodson, Anna Ehinger, Susan Fineberg, Cornelia M. Focke, Dongxia Gao, Allen M. Gown, Carolina Gutierrez, Johan Hartman, Judith C. Hugh, Zuzana Kos, Anne-Vibeke Lænkholm, Arvydas Laurinavicius, Richard M. Levenson, Rustin Mahboubi-Ardakani, Mauro G. Mastropasqua, Takuya Moriya, Sharon Nofech-Mozes, C. Kent Osborne, Liron Pantanowitz, Frédérique M. Penault-Llorca, Tammy Piper, Mary Anne Quintayo, Tilman T. Rau, Stefan Reinhard, Stephanie Robertson, Takashi Sakatani, Roberto Salgado, Melanie Spears, Jane Starczynski, Tomoharu Sugie, Bert van der Vegt, Giuseppe Viale, Shakeel Virk, Lila A. Zabaglo, Daniel F. Hayes, Mitch Dowsett, Torsten O. Nielsen, David L. Rimm, International Ki67 in Breast Cancer Working Group, BIG-NABCG. Analytical validation and prognostic potential of an automated digital scoring protocol for Ki67: An International Ki67 Working Group study [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 P5-02-01.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS19-P5-02-01
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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    Abstract C184: Thyroid hormone receptors: Future targets for breast cancer therapy?.
    American Association for Cancer Research (AACR) ; 2013
    In:  Molecular Cancer Therapeutics Vol. 12, No. 11_Supplement ( 2013-11-01), p. C184-C184
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 12, No. 11_Supplement ( 2013-11-01), p. C184-C184
    Abstract: Introduction: Thyroid receptors (TR) have been documented in breast cancer tissue. Given their role in cell metabolism and proliferation, they may serve as future therapeutic targets. Prior to targeting TRs for therapy, their prevalence and degree of expression must be elucidated. In this study, the expression and sub-cellular location of three TR isoforms (TRA1, TRA2, TRB1) in breast cancer tissue is documented and correlated to standard pathological and clinical prognostic markers. Methods: 131 archived breast tumors were selected sequentially starting from January 2007, to allow for collection of 5-year overall survival (OS) and disease-free survival (DFS) data. The tumors were assessed retrospectively for TRA1, TRA2 and TRB1 expression by immunohistochemistry, using commercially available antibodies. Nuclear versus cytoplasmic location was noted. The Allred score of each tumor was assessed in triplicate; an average score ≥5 was considered significant in the statistical analysis. TR expression was correlated with pathological markers (ER/PR and Her2/neu positivity, tumor size, grade, nodal involvement, lymphovascular invasion, mitotic count) and clinical factors (age, OS, DFS) using correlation analyses and binary regression models. Results: The age of patients was 65±15 (mean± standard deviation) years. The majority had T1c (31%) or T2 (56%) disease, and 39% had lymph node involvement. 60% of tumors were ER positive and 13% were Her2/neu positive. TRs were expressed to some extent in 130 of 131 assessed breast tumors; TRA1 was highly expressed (Allred score ≥5) in 81% of tumors, while TRA2 and TRB1 were highly expressed in 51% and 29% of tumors, respectively. TRA1 and TRA2 were expressed in the nucleus, while 95% of TRB1 receptors were expressed in the cytoplasm. Cytoplasmic TRB1 expression was associated with a mitotic count & lt;10 [OR 0.4 (95%CI 0.20-0.93), p=0.03], but not with other variables. High TRA2 expression was associated with ER [OR 5.5 (95%CI 2.2-13.7), p & lt;0.01] and PR [OR 5.3 (95%CI 2.4-11.8), p & lt;0.01] positivity, and also 5-year DFS [OR 2.6 (95%CI 1.1-6.1), p=0.03] . Conversely, low TRA expression was associated with Her2/neu positivity [OR 3.2, (95%CI 1.0-9.5), p=0.04], high tumor grade [OR 6.0, (95%CI 2.3-15.2), p & lt;0.01] and a mitotic count & gt;10 [OR 2.8, (95%CI 1.4-5.8), p=0.05]. There was no significant association between TR expression and tumor size, lymph node involvement or OS. Conclusion: Thyroid receptors are widely expressed in breast cancer and they are known to influence cellular proliferation. High TRA2 expression is statistically significant in predicting favorable pathologic markers and even 5-year DFS. As with ER, its favorable prognostic profile should not exclude TRA2 as a therapeutic target; it may have the potential to expand our armamentarium of hormone directed therapies. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C184. Citation Format: Katarzyna J. Jerzak, Anita Bane, Bindi Dhesy-Thind. Thyroid hormone receptors: Future targets for breast cancer therapy?. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C184.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.TARG-13-C184
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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    BRCA1 and BRCA2 Mutation Carriers, Oral Contraceptive Use, and Breast Cancer Before Age 50
    American Association for Cancer Research (AACR) ; 2006
    In:  Cancer Epidemiology, Biomarkers & Prevention Vol. 15, No. 10 ( 2006-10-01), p. 1863-1870
    Details
    In: Cancer Epidemiology, Biomarkers & Prevention, American Association for Cancer Research (AACR), Vol. 15, No. 10 ( 2006-10-01), p. 1863-1870
    Abstract: Background: Understanding the effect of oral contraceptives on risk of breast cancer in BRCA1 or BRCA2 mutation carriers is important because oral contraceptive use is a common, modifiable practice. Methods: We studied 497 BRCA1 and 307 BRCA2 mutation carriers, of whom 195 and 128, respectively, had been diagnosed with breast cancer. Case-control analyses were conducted using unconditional logistic regression with adjustments for family history and familial relationships and were restricted to subjects with a reference age under 50 years. Results: For BRCA1 mutation carriers, there was no significant association between risk of breast cancer and use of oral contraceptives for at least 1 year [odds ratio (OR), 0.77; 95% confidence interval (95% CI), 0.53-1.12] or duration of oral contraceptive use (Ptrend = 0.62). For BRCA2 mutation carriers, there was no association with use of oral contraceptives for at least 1 year (OR, 1.62; 95% CI, 0.90-2.92); however, there was an association of elevated risk with oral contraceptive use for at least 5 years (OR, 2.06; 95% CI, 1.08-3.94) and with duration of use (ORtrend per year of use, 1.08; P = 0.008). Similar results were obtained when we considered only use of oral contraceptives that first started in 1975 or later. Conclusions: We found no evidence overall that use of oral contraceptives for at least 1 year is associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers before age 50. For BRCA2 mutation carriers, use of oral contraceptives may be associated with an increased risk of breast cancer among women who use them for at least 5 years. Further studies reporting results separately for BRCA1 and BRCA2 mutation carriers are needed to resolve this important issue. (Cancer Epidemiol Biomarkers Prev 2006;15(10):1863–70)
    Type of Medium: Online Resource
    ISSN: 1055-9965 , 1538-7755
    URL: Article
    DOI: 10.1158/1055-9965.EPI-06-0258
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2006
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    Abstract 2648: Prognostic significance of thyroid hormone receptor-alpha-2 (THRα2) expression in triple-negative breast cancer: A TCGA study
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 13_Supplement ( 2018-07-01), p. 2648-2648
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 2648-2648
    Abstract: Background: Thyroid hormones promote breast cancer cell proliferation and expression of their cognate nuclear receptors has shown prognostic potential in small cohort studies. Among two isoforms of thyroid hormone receptor alpha (THRα), the alpha1 splice variant (THRα1) promotes thyroid hormone mediated cell proliferation whereas the alpha2 variant (THRα2) opposes it. Hence, THRα2 expression may be a favorable prognostic biomarker in breast cancer. Methods: A publicly available database of breast tumors archived by The Cancer Genome Atlas (TCGA) was employed for this study. We analyzed RNA expression of THRα1 and THRα2 in 106 triple negative breast cancers (TNBCs) and correlated it with tumor stage (I vs II vs III) and nodal involvement (positive vs negative). Tumor grade was not uniformly reported. Univariate Cox proportional hazards regression models were fitted to determine the prognostic impact of THRα1 and THRα2 expression on overall survival (OS) and multivariate models were adjusted for age, tumor stage and radiation treatment. Results: The median age of women was 54 (range 29-90) and 12.3% died. The majority (62.3%) of patients presented with stage II disease; 16.0% were stage III and 17.9% were stage I at diagnosis. There was no significant correlation between THRα1 or THRα2 expression and tumor stage or nodal involvement. Expression of THRα2 was associated with improved OS in both uni- and multi-variate models (Table). Conclusions: In this study, THRα2 expression was independently prognostic for improved OS in TNBC. We previously demonstrated similar results in 158 TNBCs via immunohistochemistry but differentiation between RNA (as opposed to protein) splice variants is more precise. These results support investigation of THRα2 up-regulation or THRα1 inhibition as therapeutic strategies. Table. Prognostic associations of THRα2 expression in TNBCVariableUnivariate HR (95%CI)p valueMultivariate HR (95%CI)p valueLog (THRα2)0.46 (0.26-0.81) & lt;0.010.28 (0.09-0.84)0.02Log (THRα1)0.54 (0.31-0.94)0.031.38 (0.53-3.62)0.51Age (years)0.98 (0.94-1.02)0.370.92 (0.84-1.01)0.10Stage (I vs II vs III vs IV)6.14 (2.19-17.22) & lt;0.0126.03 (4.05-167.14) & lt;0.01Radiation therapy (yes vs no)0.23 (0.04-1.22)0.080.10 (0.02-0.73)0.02 Citation Format: Katarzyna J. Jerzak, Anna Dvorkin-Gheva, Jessica G. Cockburn, Anita Bane, John A. Hassell. Prognostic significance of thyroid hormone receptor-alpha-2 (THRα2) expression in triple-negative breast cancer: A TCGA study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2648.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2018-2648
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 10
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    Abstract 3787: Thyroid hormone induced proliferation of breast cancer cell lines: A novel approach to hormone therapy
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Research Vol. 76, No. 14_Supplement ( 2016-07-15), p. 3787-3787
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 14_Supplement ( 2016-07-15), p. 3787-3787
    Abstract: Introduction: The thyroid hormone (TH) pathway influences cell growth and it may be a novel target for breast cancer (BC) therapy. However, various TH receptor (THR) isoforms exist and some have opposing functions thus complicating the role of THs in BC. Our previous work suggests that THR alpha1 (THRα1) promotes TH-mediated BC proliferation. Here we offer a mechanism that explains these findings. We first evaluated the role of THs on BC cell line proliferation using escalating doses of tri-iodothyronine (T3) and thyroxine (T4). Next, propylthiouracil (PTU) was used to block T4 conversion to T3 demonstrating that observed proliferation was TH dependent. Finally, the anti-proliferative efficacy of a THRα1 inhibitor, dronedarone, was used to demonstrate the necessity of THRα1 downstream of TH signalling. Dronedarone was selected because it is an FDA approved anti-arrhythmic drug, which may also serve as a novel anti-cancer agent. Methods: The effect of increasing concentrations of T3 and T4 on the proliferation of 3 BC cell lines (MCF 7, MD-MB-231, BT-474) in 10% charcoal-stripped phenol-free serum were evaluated at 24 and 48 hours following standard MTT-assay protocols. Increasing doses of PTU and dronedarone were added to cells with 200uM T3 or T4 to measure proliferation of MCF-7 and MD-MB-231 cells using MTT assays. Results: There was a statistically significant increase in the proliferation of MCF7, MD-MB-231 and BT-474 cells with the addition of T3 and T4 at 24 and 48 hours in a dose dependent manner. Of note, BT-474 cells had a significantly slower proliferation rate and required 9 days of incubation prior to detection of proliferation. The addition of PTU reduced proliferation by 50% in MCF7 and MD-MB-231 cells in the presence of T4 at roughly 5 mM compared to the presence of T3 which had an IC50 of 12mM. This shows that TH signalling is mediated by T4 conversion to T3 in these cell lines. PTU alone reduced cell proliferation by 50% at concentrations above 12 mM, suggesting that PTU may also act through other mechanisms. Cell proliferation was not affected by the presence of dronedarone alone, but the combination of 10μM dronedarone and T3 or T4 significantly reduced proliferation of both MCF7 and MD-MB-231 cells. These results suggest that THRα1 is required for TH mediated cell proliferation. A library of compounds similar in structure to dronedarone is being designed to offer additional candidates for more potent THRα1 inhibition. The properties and structures of these novel compounds will be presented. Conclusion: The proliferation of several BC cell lines increases in response to exogenous T3 and T4 when grown in hormone depleted growth media. These results demonstrate the role of specific events contributing to TH-mediated cell proliferation, including T4 conversion to T3 and the necessity of downstream THRα1. Ultimately, in conjunction with our previous work, we propose that THRα1 inhibition is a novel target for cancer therapy. Citation Format: Katarzyna Joanna Jerzak, Jessica G. Cockburn, John Hassel, Kathleen I. Pritchard, Sukhbinder K. Dhesy-Thind, Bane Anita. Thyroid hormone induced proliferation of breast cancer cell lines: A novel approach to hormone therapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3787.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2016-3787
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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