Telomeric Allelic Imbalance/HRD and Cisplatin benefit Andrea L. Richardson M.D. Ph.D. OncoClinicas do Brazil February 8, 2014 Role of pathology: Before Tissue Diagnosis (Histopathology) Validation in additional trials Malignant Ms. Jones undergoes a biopsy Compare Outcomes Standard Treatment OR Empiric clinical trial pathology n. , pl. , -gies . 1 : the study of the essential nature of diseases and especially of the structural and functional changes produced by them 2 : something abnormal: a : the structural and functional deviations from the normal that constitute disease or characterize a particular disease Role of Pathology: Now Tissue Diagnosis (Histopathology) New biomarkers (Pathology) Genomic analysis of tissue (Molecular Pathology) Ms. Jones undergoes a biopsy Validation EGFR Outcomes Standard Treatment Pathologic assessment of response New targets for therapy Clinical trials BRCA1, TNBC and Cisplatin • BRCA1-deficient cells are particularly susceptible to interstrand cross-linking agents like mitomycin C and cisplatin. • A cell line derived from a BRCA1-associated breast tumor is defective in DNA DSBR and is sensitive to cisplatin; these properties are reversed by adding wt BRCA1. – Scully R et al. Mol Cell 4:1093-1099, 1999. – Tassone P. et al. Br J Cancer 88:1285-1291, 2003 • Sporadic triple negative breast cancers (TNBC) share many characteristics with BRCA1-associated cancers • Hypothesis: A subset of sporadic TNBCs may share defects in a BRCA1-associated pathway and have particular susceptibility to DNA cross-linking agents such as cisplatin. Two pre-operative trials of cisplatin therapy in TNBC Cisplatin-1 (cisplatin monotherapy) Eric Winer Judy Garber Paula Ryan • 28 eligible on trial • 10/28 (36%) had complete or near complete pathologic response in breast and lymph nodes • Trial results published in Silver DP, et.al. J Clin Oncol, 2010. Cisplatin-2 (cisplatin + bevacizumab) • 51 eligible patients • 17/44 (39%) who completed treatment had pCR or near pCR • Ryan PD, et. al. J Clin Oncol 27, 551 (2009) TNBC have high levels of Allelic Imbalance BRCA1- TNBC HER2+ ER+/HER2- (HG) Zhigang Charles Wang Telomeric AI Interstitial AI • Perhaps defects in DNA repair are responsible for high level of AI in some TNBC • Is level of AI in TNBC associated with cisplatin response? AI No AI Deletion of BRCA1 leads to genomic instability and quadriradial chromosomes….and telomeric AI Dan Silver mitosis Quad Silver DP et al. Cell 2007, 128: 991-1002 Telomeric allelic imbalance The NtAI was associated with cisplatin sensitivity in breast cancer cell lines, but not interstitial AI. Yang Li, Ph.D. or Birkbak NJ, et al. Cancer Discovery April 2012; 2(4): 366-375. Greater NtAI is associated with better response to cisplatin in patients Cisplatin trial 1 in TNBC Nicolai Juul Birkback Cisplatin trial 2 in TNBC or Birkbak NJ, et al. Cancer Discovery April 2012; 2(4): 366-375. Zoltan Szallasi NtAI is also higher in ovarian cancers with BRCA1 or BRCA2 mutation or wtBRCA that are sensitive to platinum-taxane therapy Birkbak NJ, et al. Cancer Discovery April 2012; 2(4): 366-375. Other Related Studies • B1, B2, Rad51C • BRCA1 mutant • BRCA2 mutant • low BRCA1 mRNA or methylation • Rad51C methyl • intact BRCA and Rad51C • Number of large-scale state transitions or • Number of long LOH regions, > 15 Mb but less “LSTs”, at least 10 Mb, associated with BRCA1 or 2 deficiency (mutation/methylation) than whole chromosome, (Homologous Recombination Deficiency or “HRD score”) associated with BRCA1 or 2, or Rad51C deficiency (mutation/methylation) in ovarian cancer. Papova T. et al. Cancer Res Aug 2012, 72: 5454 Abkevich V. et al. Brit J Cancer Sept 2012, 1-7. Comparison of NtAI and HRD in cisplatin trials Correlation NtAI HRD Specific chromosomal alterations associated with platinum sensitivity • • Significance plots of SNP copy number differences between cisplatin sensitive vs. resistant cases in Cisplatin-1 and Cisplatin-2 169 regions gained or lost in the comparisons in the two trials: Only chr 15q26 was significant in both trials Nicolai Juul Birkback A 10 Mb region with 59 genes with significant gain in cisplatin sensitive cases mRNA gene expression differences between sensitive and resistant • • • • Cisplatin-1 Cisplatin-2 OV-01 Ovarian cancer Carboplatin monotherapy arm – (Ahmed et. al. Cancer Cell 2007) Leave one out comparisons to look for consistently differentially expressed genes across all three trials BLM protein by IF 15q26 genes mRNA high mRNA low Tumors sensitive to cisplatin have high levels of BLM and FANCI BLM protein by IF mRNA high mRNA low BLM and FANCI only associated with response to platinums, not taxane-containing therapies Ovarian cancer two arm trial TNBC neoadjuvant trials BRCA1 methylation and low expression Cisplatin-1 Silver DP et al. J Clin Oncol 2010 Cisplatin-2 Birkbak NJ et al. Cancer Discovery 2012 3-gene mRNA signature predicts cisplatin sensitivity in BRCA wt TNBC BRCA1 / avg (BLM+FANCI) Summary • Number of chromosomal regions with large telomeric allelic imbalance is associated with better response to cisplatin therapy • Low BRCA1 and high BLM and FANCI expression are associated with better response to platinum therapy and are not associated with response to taxane-containing therapies. Acknowledgements Zhigang Charles Wang Yang Li Dirk Iglehart Zoltan Szallasi Nicolai Juul Birkbak Aron Eklund Daniel Silver Christian Bowman-Colin Eric Winer Judy Garber Paula Ryan Breast Cancer Research Foundation V Foundation NCI Harvard SPORE in Breast Cancer And especially thanks to the many patients who participate!
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