Carcinoma mammario triple nega0ve Nuove acquisizioni biologiche. Giuseppe Curigliano MD PhD UNIMI & IEO
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1 Carcinoma mammario triple nega0ve Nuove acquisizioni biologiche Giuseppe Curigliano MD PhD UNIMI & IEO
2 Outline San Antonio Breast Cancer Symposium, December 5-9, 2017 The year of DNA Repair targe?ng Olaparib approved in BRCA mutated breast cancer Predic?ng response to therapy Non- invasive tes?ng
3 Transla0onal highlights San Antonio Breast Cancer Symposium, December 5-9, 2017 Heterogeneity of TNBCs ü Pathologic heterogeneity ü Genomic heterogeneity ü Transcriptomic heterogeneity ü Poten?al biomarkers
4 Molecular subtyping San Antonio Breast Cancer Symposium, December 5-9, 2017 Lehmann 2011: 7 subtypes ü Basal- like 1 and 2 ü Luminal androgen receptor ü Mesenchymal ü Mesenchymal stem- like ü Immunomodulatory ü Unstable
5 Molecular subtyping San Antonio Breast Cancer Symposium, December 5-9, 2017 Four subtypes LAR Mesenchymal BL immune suppressed BL immune activated Four subtypes LAR Mesenchymal Basal-like 1 Basal-like 2 Immunomodulatory BL, basal-like; LAR, luminal androgen receptor Burstein MD, et al. Clin Cancer Res. 2015;21(7): Lehmann BD, et al. BDPLoS One. 2016;11(6):e
6 San Antonio Breast Cancer Symposium, December 5-9, 2017 Genomics scars to guide therapy This presenta?on is the intellectual property of the author/presenter. Contact them at for permission to reprint and/or distribute.
7 San Antonio Breast Cancer Symposium, December 5-9, 2017 DNA Repair S 2017 This presentation is the intellectual property of the presenter. Contact them at ed.liu@jax.org for permission to reprint and/or distribute.
8 San Antonio Breast Cancer Symposium, December 5-9, 2017 DNA Repair SABCS This presentation is the intellectual property of the presenter. Contact them at for permission to reprint and/or distribute.
9 San Antonio Breast Cancer Symposium, December 5-9, 2017 BRCAness SABCS This presentation is the intellectual property of the presenter. Contact them at for permission to reprint and/or distribute.
10 AstraZeneca oral ATR inhibitor AZD6738 combinations Combination therapy preclinical activity +Olaparib (PARPi) breast primary explant xenograft ATM$ proficient$ +Carboplatin breast primary explant xenograft ATM$ proficient$
11 How will we identify in clinic who will best respond to these approaches? Homologous Recombina0on Deficiency (HRD) detect iden0fies BRCA1/BRCA2- deficient tumors with 98.7% sensi0vity (AUC = 0.98). Integra?ng all of the classes of muta?onal signatures thus reveals a larger propor?on of individuals with breast cancer harboring BRCA1/BRCA2 deficiency (up to 22%) than hitherto appreciated (~1 5%) who could have selec?ve therapeu?c sensi?vity to PARP inhibi?on Nature Medicine, March 2017
12 HRDetect identifies additional BRCA1/BRCA2 defective tumours
13 Developing transcrip?onal biomarkers of DNA Damage Response BRCA1,MRE11A,NBS1,TDG and XPA transcript levels associated with PARP inhibitor resistance CHEK2 and MK2 transcript levels associated with sensi?vity The PARPi7 signature associated with basal- like subtype in clinical datasets Now explored in I- SPY2 Carbo/Veliparib as a part of mul?component biomarker Wolf et al SABCS 2017 S2-06
14 So where have these biomarkers of DNA Damage response (DDR) and Genomic Instability been used in trials? What have we learnt?
15 Do HRD Scar Scores predict response to a platinum in neo-adjuvant therapy? Telli et al Clin Cancer Res; 22(15);
16 GBG GeparSixto randomised design and showed High HRD group show no ability to select platinum just more response to either regimen
17 BRCA methyla?on may be Soh BRCAness gbrca muta?on is Hard BRCAness Frequent loss of Methylation or selection of Non-Meth clone Tumour has lost methylation and HR repair defect Primary Tumour DNA Damaging Adjuvant Chemo Residual Micromet Macromet at relapse Platinum Advanced Disease Chemo Non Response Response BRCA1 Meth BRCA1 Non-Meth gbrca tumour usually retains its BRCA mutation gbrcamut tumour Retains its mutation and HR defect gbrca1 Mutated
18 Biomarkers based on measuring a tumour s life history of genome scarring as a diagnostic tattoo have limitations? Early BC Advanced BC
19 Hard BRCAness Breast cancer populations mix those with Hard and Soft BRCAness so we need biomarkers that differentiate S0ll a DNA repair Defec0ve Hells Angel Or Now a DNA Repair Competent Priest SoY BRCAness Combine looking for muta?onal Scar or Taioo in primary to ask Have you ever been DDR deficient? Func?onal assay pre treatment then asks Are you s?ll DDR deficient
20 What s next? Combina?on strategies targe?ng of ATR, Wee1 and PARP and combina?ons with pla?nums in the clinic Genome Scars are a poten?al biomarker to report if a tumour has ever been HR deficient with high Nega?ve Predic?ve Value for BRCAness Soh BRCAness can be reversed or be compensated and so Posi?ve Predic?ve Value for specific DDR therapy is poor without func?onal assays of current BRCAness status These pretreatment func?onal assays are in development as response predictors
21 Tandem duplicator phenotype Robust genomic metrics able to iden?fy cancers characterized by frequent and distributed tandem duplica?ons 2017
22 San Antonio Breast Cancer Symposium, December 5-9, 2017 Individual tumors can show combinations of modal peaks TDP group 1 [TCGA ] TDP group 2 [TCGA-B5-A0K3-01] TDP group 3 [TCGA-EP-A2KA-01] 10Kb 230Kb 1.7Mb TD span size DENSITY TDP group 1/2mix [TCGA-A2-A0D2-01] Kb 230KB TDP group 1/3mix [PD4107a] Kb 1.7Mb TD SPAN SIZE [log 10 (Kb)] TDP group 2/3mix [TCGA ] Mb 230Kb This presentation is the intellectual property of the presenter. Contact them at ed.liu@jax.org for permission to reprint and/or distribute.
23 San Antonio Breast Cancer Symposium, December 5-9, 2017 What are the drivers for TDP formation? Small duplica?ons = BRCA loss Large duplica?ons CCNE1 % tumor samples BRCA1 mt/meth *** *** *** non (1091) g1 (115) g1/2mix (30) g1/3mix (11) g2 (67) g3 (10) g2/3mix (16) ALL TUMOR TYPES BRCA1 WT *** *** *** non (57) g1 (56) g1/2mix (11) g1/3mix (8) g2 (12) g3 (NA) g2/3mix (NA) *** *** non (68) g1 (37) g1/2mix (8) g1/3mix (NA) g2 (19) g3 (NA) g2/3mix (10) % tumor samples non (19) g1 (NA) g1/2mix (NA) g1/3mix (NA) g2 (15) g3 (NA) g2/3mix (NA) CCNE1 amp/fbxw7 mt non (1150) g1 (105) ** * *** *** ** g1/2mix non (322) (31) g1/3mix (8) (16) g2 g1/2mix (68) (NA) g3 g1/3mix (9) (NA) g2/3mix (NA) (18) g3 (NA) g2/3mix (NA) non (73) g1 (50) * *** g1/2mix non (625) (14) g1/3mix (12) (13) g2 g1/2mix (12) (NA) g3 g1/3mix (NA) (NA) g2/3mix g2 (14) (NA) g3 (NA) g2/3mix (NA) TNBC OV UCEC ALL TUMOR NON TNBC TNBC OTHER TYPES CCNE1 non amp and FBXW7 WT non (55) g1 (33) g1/2mix (NA) g1/3mix (NA) g2 (15) g3 (NA) g2/3mix (NA) OV non (22) g1 (NA) This presentation is the intellectual property of the presenter. Contact them at ed.liu@jax.org for permission to reprint and/or distribute.
24 San Antonio Breast Cancer Symposium, December 5-9, 2017 What are the drivers for TDP formation? SABCS 2 This presentation is the intellectual property of the presenter. Contact them at ed.liu@jax.org for permission to reprint and/or distribute.
25 San Antonio Breast Cancer Symposium, December 5-9, 2017 What are the drivers for TDP formation? SABCS This presentation is the intellectual property of the presenter. Contact them at for permission to reprint and/or distribute.
26 San Antonio Breast Cancer Symposium, December 5-9, 2017 What are the drivers for TDP formation? 2017 This presentation is the intellectual property of the presenter. Contact them at for permission to reprint and/or distribute.
27 San Antonio Breast Cancer Symposium, December 5-9, 2017 What are the drivers for TDP formation? 2017 This presentation is the intellectual property of the presenter. Contact them at for permission to reprint and/or distribute.
28 San Antonio Breast Cancer Symposium, December 5-9, 2017 Biomarkers SABCS
29 San Antonio Breast Cancer Symposium, December 5-9, 2017 Biomarkers 2017
30 San Antonio Breast Cancer Symposium, December 5-9, 2017 Biomarkers SABCS
31 San Antonio Breast Cancer Symposium, December 5-9, 2017 Biomarkers SABCS 2
32 San Antonio Breast Cancer Symposium, December 5-9, 2017 Biomarkers SABCS
33 San Antonio Breast Cancer Symposium, December 5-9, 2017 Biomarkers SABCS
34 San Antonio Breast Cancer Symposium, December 5-9, 2017 Biomarkers SABCS
35 San Antonio Breast Cancer Symposium, December 5-9, 2017 Progress in predic-ng response in TN Summary gbrca1/2 muta?on is clearest diagnos?c of HR defects that persist and are targetable Scar assays report if a tumor has ever been HR deficient high nega?ve predic?ve value; Soh BRCAness can be reversed HRD scar posi?ve predic?ve value for DDR therapy??; Muta?onal scars need valida?on as predic?ve biomarkers Inhibitors have different effects on PARP1 cataly?c inhibi?on / trapping which affect efficacy; Combina?on strategies targe?ng ATR, Wee1 and PARPi / pla?num making progress in clinic Proof- of- principle that liquid biopsies can iden-fy pa-ents at very high relapse risk Large valida?on studies and clinical u?lity studies needed
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