Perspectivas moleculares en la disección del cáncer de mama esporádico y hereditario
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1 Perspectivas moleculares en la disección del cáncer de mama esporádico y hereditario Aleix Prat, MD PhD Medical Oncology, Hospital Clínic Barcelona, Spain
2 mrna microrna Protein DNA Copy Number DNA Methylation Somatic/Germline Mutations
3 TCGA Breast Tumor Significantly Mutated Gene List by Clinical Receptor Status (n=507) Gene All Tumors (n=507) ER+/HER2- (n=330) Clinical HER2+ (n=75) Triple-negative (n=86) #Cases LRT CT #Cases LRT CT #Cases LRT CT #Cases LRT CT PIK3CA E E-10 TP GATA NA NA MAP3K NA NA 0 NA NA CDH NA NA 1 NA NA MLL NA NA 3 NA NA MAP2K NA NA 1 NA NA PTEN NA NA 1 NA NA RUNX NA NA 0 NA NA USH2A E E NA NA 4 NA NA 9 NA NA RYR E E NA NA 5 NA NA 3 NA NA NCOR E E E E-07 1 NA NA 1 NA NA NF E E E E-02 1 NA NA 2 NA NA TBX E E E E-12 0 NA NA 1 NA NA CTCF E E E E-06 1 NA NA 1 NA NA AKT E E E E-12 1 NA NA 0 NA NA PIK3R E E E E-06 4 NA NA 1 NA NA PTPRD E E-02 8 NA NA 2 NA NA 2 NA NA SF3B E E E E-02 1 NA NA 0 NA NA CBFB E E E E-08 0 NA NA 1 NA NA AFF E E-03 6 NA NA 3 NA NA 4 NA NA TBL1XR E E E E-05 1 NA NA 1 NA NA ZFP36L E E E E-04 0 NA NA 1 NA NA RPGR E E-03 5 NA NA 0 NA NA 3 NA NA CDKN1B E E E E-05 0 NA NA 0 NA NA DCAF4L E E-02 4 NA NA 2 NA NA 1 NA NA GPS E E E E-02 1 NA NA 1 NA NA OR6A E E E E-03 0 NA NA 0 NA NA RB E E-03 3 NA NA 1 NA NA E E-02 PTPN E E-03 3 NA NA E E-02 0 NA NA SEPT E E-02 3 NA NA 0 NA NA 1 NA NA HIST1H2BC E E-02 2 NA NA 1 NA NA 1 NA NA CCND E E E E-03 0 NA NA 0 NA NA GPR E E-02 1 NA NA 1 NA NA 1 NA NA CLEC19A E E E E-02 0 TCGA NA et al., Nature, NA (PMID NA ) NA
4 Prevalence of somatic BRCA1/2 mutations in breast cancer Gene # Mut Freq MutSig P-value BRCA % NS BRCA % NS CHEK % NS PALB % NS Data obtained from TCGA (n=1,105) Accessed 03/03/2016
5 TCGA: Integration of 5 data types Nature 2012 Luminal B HER2-enriched Luminal A Basal-like Intrinsic Subtypes Integration of information across 5 platforms demonstrated the existence of 4 main breast cancer classes. which are highly concordant with the main intrinsic subtypes defined by gene 5 expression-only.
6 Pan Cancer 12 Analysis (3500 tumors) Tumor Type # Samples GBM AML 173 AML Lung Adenocarcinoma Lung Squamous Ovarian Endometrial TCGA et al., CELL, 2014 Head & Neck Breast Kidney Clear Cell Colon Rectum Bladder Bladder 122 Breast 845 Colon 190 Endometrial 370 GBM 168 Head & Neck 303 Kidney Clear Cell 480 Lung Adeno 355 Lung Squamous 259 Ovarian Serous 265 Rectum 72
7 BASAL-LIKE Hoadley et al. Cell 2014
8 Somatic copy-number alterations (SCNAs) across 12 cancer-types Hoadley et al. Cell 2014
9 Subtype distribution within BRCA1 and BRCA2 mutated breast cancer BRCA1 somatic/germline (N=38) BRCA2 somatic/germline (N=25) sal-like minal A udinlow r2-enriched minal B rmal-like Data obtained from: Prat & Perou Mol Oncol 2011; Prat, Cruz et al. BCRT 2014; and TCGA
10 Nat Med Aug;15(8): Epub 2009 Aug 2.
11 Increase in the luminal progenitor cell fraction (CD49f+EpCAM+) in the normal breast of BRCA1 mutation carriers Lim et al. Nat Med 2009
12 232 Human Breast Tumors analyzed for FAC sorted epithelial cell signatures Mammary Stem Cell (MaSC) Luminal Progenitor Mature Luminal more similar
13 Prat & Perou, Nat. Med 2009 Mammary development meets cancer genomics
14 Claudin-low subtype HER2 Basal Luminal Data Highlights % of TNBC. 2. Minority are nontnbcs. 3. Low expression of cell-cell junction proteins 4. Stem cell + EMT (mesenchymal) features 5. Metaplastic / Medullary 6. Lymphocyte infiltrates 7. Distinct cell type of origin or developmental stage of arrest. Immune infiltrate Proliferation Claudin 3 Claudin 4 Claudin 7 E-Cadherin
15 Prat, Cruz et al. BCRT 2014 Intrinsic profile of BRCA1-mutated breast tumors Hierarchical clustering of 509 breast samples of TCGA project using the 1,900 intrinsic gene list
16 Prat, Cruz et al. BCRT 2014 Molecular differences between basal-like BRCA1-mutated tumors (n = 14) and basal-like BRCA1non-mutated tumors (n = 79) Total biomarkers evaluated Type of evaluation Comparison (more expressed or amplified) Significant biomarkers identified (FDR = 0 %) BRCA1 MUT 0 17,786 (unique genes) Expression 0 BRCA1 WT (unique proteins or phosphoproteins by RPPA) BRCA1 MUT 0 Expression 0,6% BRCA1 WT 1 BRCA1 MUT 3 1,222 (mature/star mirna strands) Expression 0,2% BRCA1 WT 0 BRCA1 MUT (unique genes) Methylation 1,1% BRCA1 WT 6 BRCA1 MUT ,613 (unique genes) DNA amplification 1,3% BRCA1 WT 0 Percentage of altered biomarkers (%)
17 Prat, Cruz et al. BCRT 2014 Molecular differences between basal-like BRCA1-mutated tumors (n = 14) and basal-like BRCA1non-mutated tumors (n = 79) BRCA1mut BRCA1WT P-value TP53 100% 76% PIK3CA 0% 10% Num. mutations
18 Estimate of the neoantigen repertoire in human cancer Schumacher and Schreiber, Science 2015
19 TIL-related IMMUNE GENES Hierarchical clustering of immune infiltration, BRCA mutations, and intrinsic subtype LUMINAL BASAL-LIKE LOW IMMUNE EXPRESSION HIGH IMMUNE EXPRESSION N=120 familial breast tumors Massink et al. BMC Cancer 2015
20 How should TNBCs be stratified? BRCA1 mutation Immune-activation
21 Selective resistance to the PARP inhibitor olaparib in a mouse model for BRCA1-deficient metaplastic breast cancer Henneman et al PNAS 2015
22 Next: Looking for Biologically Homogeneous Breast Cancer Histology Ductal Metaplastic Lobular Subtype LumA LumB HER2E Basal-like Claudin-low DNA TP53 BRCA1 BRCA2 ESR1 PI3KCA Protein HER2-neg HER2+ Microenv. Immune-activated Immune-inactivated
23 Take-home messages Breast cancer is an heterogeneous disease in terms of many data-types, all of which converge into 4 main intrinsic molecular subtypes (Luminal A and B, HER2-enriched and Basal-like). BRCA1/2 somatic mutations in primary tumors are rare (<2%). However, their prevalence in pre-treated or metastatic disease is less known. Basal-like and LuminalAB/HER2-enriched should be considered two distinct cancer-types, and each might have a distinct cell-type of origin. Although Basal-like breast cancer share many copy-number changes with high grade serous ovarian cancer (HGSOV), the phenotype of Basal-like breast tumors is more similar to squamous lung cell carcinoma and head/neck tumors than HGSOV. The high incidence of Basal-like disease in a BRCA1-mutated carrier could be explained by the aberrant accumulation of luminal/bipotent progenitors in the normal mammary gland.
24 Take-home messages A subgroup of BRCA1-mutated breast cancer fall into the Claudin-low subtype. These tumors might respond differently than BRCA1-mutated Basal-like disease. Within Basal-like disease, BRCA1 mutated and BRCA1 WT tumors have very minor biological differences. BRCA1 mutated seem to be more TP53mut, less PI3KCA mut and have more mutations across the genome. High immune infiltration/activation is a feature of a subset of Basal-like tumors with and without BRCA mutations. These tumors could be targeted with immune check-point inhibitors. Combination of molecular classifications based on tumor intrinsic subtype, tumor DNA germline/somatic mutations, tumor copy number alterations, and tumor/microenviroment gene/protein expression are the present and the future for predicting treatment benefit to specific drugs.
25 Acknowledgements VHIO, Spain Patricia Galván Cristina Saura Ana Vivancos Javier Cortés Judith Balmaña Josep Tabernero University of North Carolina, NC, USA Chuck Perou Lisa Carey Katie Hoadley Joel S. Parker Montse Muñoz Barbara Adamo Maria Vidal Patricia Galván Laia Paré Susana Garcia Mercedes Marin The entire Laboratory Team and Breast Cancer Unit and Medical Oncology Department GEICAM, Spain Miguel Martín Eva Carrasco Ana Lluch Emilio Alba Joan Albanell SOLTI, Spain Eva Ciruelos Lorena de la Peña Josep Vazquez El CC y la JD
26
27 San Antonio Breast Cancer Symposium, December 9-13, 2014 in partnership with TNT: A randomized phase III trial of carboplatin compared with docetaxel for patients with metastatic or recurrent locally advanced triple negative or BRCA1/2 breast cancer Andrew Tutt, Paul Ellis, Lucy Kilburn, Cheryl Gillett, Sarah Pinder, Jacinta Abraham, Sophie Barrett, Peter Barrett-Lee, Stephen Chan, Maggie Cheang, Mitch Dowsett, Lisa Fox, Patrycja Gazinska, Anita Grigoriadis, Alexander Gutin, Catherine Harper-Wynne, Matthew Hatton, Sarah Kernaghan, Jerry Lanchbury, James Morden, Julie Owen, Jyoti Parikh, Peter Parker, Nazneen Rahman, Rebecca Roylance, Adam Shaw, Ian Smith, Rose Thompson, Kirsten Timms, Holly Tovey, Andrew Wardley, Gregory Wilson, Mark Harries, Judith Bliss on behalf of the TNT trial management group and investigators CRUK/07/012 Making the discoveries that defeat cancer This presentation is the intellectual property of the author/presenter. Contact them at tnt-icrctsu@icr.ac.uk for permission to reprint and/or distribute
28 San Antonio Breast Cancer Symposium, December 9-13, 2014 Objective response Basal-like (Prosigna PAM50) 28 All patients entered by site as TNBC* Basal-like (n=174) Percentage with OR at cycle 3 or 6 (95% CI) Carboplatin Docetaxel 28/86 (32.6%) 31/88 (35.2%) Absolute difference (C-D) -2.6% (95% CI to 11.5) Exact p = 0.75 Non Basal-like (n=36) Carboplatin Docetaxel *353 patients, of which Prosigna results available for 210 Percentage with OR at cycle 3 or 6 (95% CI) /18 (16.7%) 13/18 (73.7%) Absolute difference (C-D) -55.5% (95% CI to -28.6) Exact p < 0.01 Interaction: randomised treatment & basal-like status (Prosigna PAM50): p = 0.01 This presentation is the intellectual property of the author/presenter. Contact them at tnt-icrctsu@icr.ac.uk for permission to reprint and/or distribute
29 San Antonio Breast Cancer Symposium, December 9-13, 2014 Objective response BRCA 1/2 status 29 Germline BRCA 1/2 Mutation (n=43) Carboplatin Docetaxel No Germline BRCA 1/2 Mutation (n=273) Percentage with OR at cycle 3 or 6 (95% CI) /25 (68.0%) 6/18 (33.3%) Absolute difference (C-D) 34.7% (95% CI 6.3 to 63.1) Exact p = 0.03 Percentage with OR at cycle 3 or 6 (95% CI) Carboplatin Docetaxel 36/128 (28.1%) 53/145 (36.6%) Absolute difference (C-D) -8.5% (95% CI to 2.6) Exact p = 0.16 Interaction: randomised treatment & BRCA 1/2 status: p = 0.01 This presentation is the intellectual property of the author/presenter. Contact them at tnt-icrctsu@icr.ac.uk for permission to reprint and/or distribute
30 San Antonio Breast Cancer Symposium Cancer Therapy and Research Center at UT Health Science Center December 9-13, 2014 CALGB 40603: Schema Randomized phase Phase II II Paclitaxel 80 mg/m 2 wkly x 12 ddac x 4 Stage II-III TNBC 2 X 2 Randomization Research biopsiesfrozen and fixed Paclitaxel 80 mg/m 2 wkly x 12 ddac x 4 Bevacizumab 10 mg/kg q2wks x 9 Paclitaxel 80 mg/m 2 wkly x 12 Carboplatin AUC 6 q3wks x 4 Paclitaxel 80mg/m 2 weekly 2 wkly x 12 Carboplatin AUC 6 q3wks x 4 Bevacizumab 10 mg/kg q2wks x 9 ddac x 4 ddac x 4 Surgery & * XRT* No Adjuvant Systemic Treatment Planned* & Research biopsies if residual tumor *MD discretion This presentation is the intellectual property of the author/presenter. Contact him at wsikov@wihri.org for permission to reprint or distribute.
31 % pcr San Antonio Breast Cancer Symposium Cancer Therapy and Research Center at UT Health Science Center December 9-13, 2014 Bevacizumab: Association of Subtype and pcr pcr Breast Basal-like Others No Bev Bev n No Bev Bev Basal-like /162 (45%) 97/152 (64%) Bevacizumab benefit was significantly greater in Basal-like subtype (interaction p=0.024) pcr Breast: Patient group N OR p-value All patients All subtyped Basal-like Non-Basals Others 46 15/25 (60%) 9/21 (43%) This presentation is the intellectual property of the author/presenter. Contact him at wsikov@wihri.org for permission to reprint or distribute.
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