Perspectivas de desarrollo de la inmunoterapia en cáncer de mama hereditario. Luis de la Cruz Merino Oncología Médica HUVMacarena (Sevilla)

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2 Perspectivas de desarrollo de la inmunoterapia en cáncer de mama hereditario Luis de la Cruz Merino Oncología Médica HUVMacarena (Sevilla)

3 Outline Immunology and breast cancer Clinical trials with modern immunotherapy in BC Rationale to build up modern immunotherapy in hereditary BC Concluding remarks and future perspectives

4 Outline Immunology and breast cancer Clinical trials with modern immunotherapy in BC Rationale to build up modern immunotherapy in hereditary BC Concluding remarks and future perspectives

5 Study Trial Therapy N Measure Result Denkert et al., JCO 2010 (8) West et al., Breast Cancer Res 2011 (94) Ono et al., Breast Cancer Res Treat 2012 (11) Yamaguchi et al., Hum Pathol 2012 (95) Ignatiadis et al, JCO 2012 (36) Oda et al., Breast Cancer Res Treat 2012 (28) Schmidt et al., Clin Cancer Res 2012 (96) Seo et al., Br J Cancer 2013 (14) Issa-Nummer et al., Plos One 2013 (9) Dieci et al., Ann Oncol 2014 (27) Lee et al., J Breast Cancer 2013 (97) GeparDuo, GeparTrio EORTC10994/ BIG01 Retrospective EC-Doc (GeparDuo) TAC+/-vinorel/capec 1058 TIL Stromal TILs and LPBC with pcr in ER and HER2 FEC vs TET 113 ER- Public gene expression data TILs correlate with pcr Anthracyclin-, cyclophosp- or taxane-based 474, 92 TNBC TIL TILs correlate with pcr in TNBC Retrospective Anthracyclin-taxane-based 68 TIL TILs correlate with pcr Retrospective, 8 cohorts Anthracyclin-taxane-based 996 Public data for STAT1 and immune response gene expression STAT1 and immune response gene modules associate with pcr in all subtypes Retrospective Paclitaxel-FEC 180 CD8, FOXP3, IL17F CD8, FOXP3 correlated with pcr 7 cohorts Anthracyclin-taxane-based 845 IGKC gene expression IGKC predicted to NACT Retrospective Anthracyclin-taxane-based 153 CD8, CD4, FOXP3 CD8, CD4, FOXP3 correlated with pcr GeparQuinto EC-Doc 313 HER2- TIL Stromal TILs and LPBC correlated with pcr Retrospective Anthracyclin-taxane-based 304 TIL Stromal TIL correlated with pcr Retrospective Anthracyclin-taxane-based 175 TIL, CD8, CD4, FOXP3 TILs, CD8, CD4, FOXP3 correlated with pcr Denkert et al., JCO 2015 (38) GeparSixto Carboplatin and anthracyclintaxane-based Salgado et al., JAMA Oncol 2015 (99) NeoALTTO Trastuzumab, lapatinib, or the combination followed by paclitaxel 580 HER2 and TNBC TIL, CXCL9, CCL5, CD8A, CD80, CXCL13, IGKC, CD21, IDO1, PD-1, PD-L1, CTLA4, FOXP3 TILs and immunological factors correlated with pcr 455 HER2+ TIL TILs positive prognostic marker for both pcr and EFS Asano et al., Br J Surg 2016 (100) Retrospective FEC100 + paclitaxel 177 CD8+/FOXP3+ TIL ratio (CFR) CFR correlates with pcr Tab. 1 Main clinical studies analyzing pcr-predictive role of TILs upon neoadjuvant chemotherapy in breast cancer

6 Study Trial Therapy N Measure Result Denkert et al., JCO 2010 (8) West et al., Breast Cancer Res 2011 (94) Ono et al., Breast Cancer Res Treat 2012 (11) Yamaguchi et al., Hum Pathol 2012 (95) Ignatiadis et al, JCO 2012 (36) Oda et al., Breast Cancer Res Treat 2012 (28) Schmidt et al., Clin Cancer Res 2012 (96) Seo et al., Br J Cancer 2013 (14) GeparDuo, GeparTrio EORTC10994/ BIG01 Retrospective EC-Doc (GeparDuo) TAC+/-vinorel/capec 1058 TIL Stromal TILs and LPBC with pcr in ER and HER2 FEC vs TET 113 ER- Public gene expression data TILs correlate with pcr Anthracyclin-, cyclophosp- or taxane-based 474, 92 TNBC TIL TILs correlate with pcr in TNBC Retrospective Anthracyclin-taxane-based 68 TIL TILs correlate with pcr 15+ trials TILs Retrospective, Anthracyclin-taxane-based 996 Public data for STAT1 and STAT1 and immune response gene modules 8 cohorts immune response gene associate with pcr in all subtypes expression Retrospective Paclitaxel-FEC 180 CD8, FOXP3, IL17F CD8, FOXP3 correlated with pcr predictive factor 7 cohorts Anthracyclin-taxane-based 845 IGKC gene expression IGKC predicted to NACT Retrospective Anthracyclin-taxane-based 153 CD8, CD4, FOXP3 CD8, CD4, FOXP3 correlated with pcr Issa-Nummer et al., Plos One 2013 (9) Dieci et al., Ann Oncol 2014 (27) Lee et al., J Breast Cancer 2013 (97) GeparQuinto EC-Doc 313 HER2- TIL Stromal TILs and LPBC correlated with pcr for pcr Retrospective Anthracyclin-taxane-based 304 TIL Stromal TIL correlated with pcr Retrospective Anthracyclin-taxane-based 175 TIL, CD8, CD4, FOXP3 TILs, CD8, CD4, FOXP3 correlated with pcr Denkert et al., JCO 2015 (38) GeparSixto Carboplatin and anthracyclintaxane-based Salgado et al., JAMA Oncol 2015 (99) NeoALTTO Trastuzumab, lapatinib, or the combination followed by paclitaxel 580 HER2 and TNBC TIL, CXCL9, CCL5, CD8A, CD80, CXCL13, IGKC, CD21, IDO1, PD-1, PD-L1, CTLA4, FOXP3 TILs and immunological factors correlated with pcr 455 HER2+ TIL TILs positive prognostic marker for both pcr and EFS Asano et al., Br J Surg 2016 (100) Retrospective FEC100 + paclitaxel 177 CD8+/FOXP3+ TIL ratio (CFR) CFR correlates with pcr Tab. 1 Main clinical studies analyzing pcr-predictive role of TILs upon neoadjuvant chemotherapy in breast cancer

8 Denkert JCO 2010

9 Issa-Nummer PLOS One 2013

10 Issa-Nummer PLOS One 2013

11 Study Trial Therapy N Measure Result West, Breast Can Res 2011 (94) Retrospective CMF, AC, FEC, CAF 255 CD3 CD3, HR 0.25 (DFS) in anthracycline group Mahmoud, JCO 2011 (15) Retrospective CMF 1334 CD8 CD8, HR 0.58 (BCSS) Liu, Breast Can Res 2012 (17) Retrospective MF, AC, FAC or no chemo 1985 HR CD8 None 216 HER2 None 496 TNBC CD8, HR 0.48 (BCSS) Loi, JCO 2013 (10) BIG A>CMF or AC>CMF 2009 TIL None 256 TNBC Stromal TILs, HR 0.84 (DFS); 0.82 (OS) 297 HER2 None 1078 HR None Adams, JCO 2014 (101) E2197, E1199 AC vs AC>Tx 481 TNBC TIL Stromal TILs, HR 0.86 (DFS); 0.81 (OS) Loi, Ann Oncol 2014 (102) FinHER DX or Vinor>FEC (+Tras in HER2) Ali, Ann Oncol 2014 (103) Dieci et al., Ann Oncol 2015 (6) Lee et al., Am J Clin Pathol 2015 (105) Kotoula et al., Oncotarget 2016 (106) 4 studies, including NEAT 934 TIL None 134 TNBC Stromal TILs, HR 0.79 (DFS); 0.80 (OS) 209 HER2 Stromal TILs, HR 0.77 (DFS) in trastuzumab treated CD8, FOXP3 CD8 in stroma and tumor correlate with 28-21% reduced risk of BCSS, greater in ER- 2 Phase III trials 5-FU, Dox, Epi, INN 1146 TIL TIL have prognostic role in TNBCs and suggested prognostic impact in HER2+ ones Retrospective Chemo+Trastuzumab 447 HER2+ TIL, TLS (Tertiary Lymphoid Structures), MHC 4 prospective trials (HeCOG 10/ ) TILs are independent prognostic factor in HR-/HER2+ BCs anthracyclines - taxane 2618 TILs TILs are prognostic factor in BC Tab Main clinical studies analyzing outcome-predictive role of TILs upon adjuvant chemotherapy in breast cancer

12 Study Trial Therapy N Measure Result West, Breast Can Res 2011 (94) Retrospective CMF, AC, FEC, CAF 255 CD3 CD3, HR 0.25 (DFS) in anthracycline group Mahmoud, JCO 2011 (15) Retrospective CMF 1334 CD8 CD8, HR 0.58 (BCSS) Liu, Breast Can Res 2012 Retrospective MF, AC, FAC or no chemo 1985 HR CD8 None (17) TILs prognostic 216 HER2 None 496 TNBC CD8, HR 0.48 (BCSS) Loi, JCO 2013 (10) BIG A>CMF or AC>CMF 2009 TIL None factor: 256 TNBC Stromal TILs, HR 0.84 (DFS); 0.82 (OS) 297 HER2 None 1078 HR None Adams, JCO 2014 (101) E2197, E1199 TNBC/her2 AC vs AC>Tx 481 TIL Stromal TILs, HR 0.86 (DFS); 0.81 (OS) Loi, Ann Oncol 2014 (102) FinHER DX or Vinor>FEC (+Tras in 934 TIL None HER2) 134 Stromal TILs, HR 0.79 (DFS); 0.80 (OS) 209 HER2 Stromal TILs, HR 0.77 (DFS) in trastuzumab treated Ali, Ann Oncol 2014 (103) Dieci et al., Ann Oncol 2015 (6) Lee et al., Am J Clin Pathol 2015 (105) Kotoula et al., Oncotarget 2016 (106) 4 studies, including NEAT CD8, FOXP3 CD8 in stroma and tumor correlate with 28-21% reduced risk of BCSS, greater in ER- 2 Phase III trials 5-FU, Dox, Epi, INN 1146 TIL TIL have prognostic role in TNBCs and suggested prognostic impact in HER2+ ones Retrospective Chemo+Trastuzumab 447 HER2+ TIL, TLS (Tertiary Lymphoid Structures), MHC 4 prospective trials (HeCOG 10/ ) TILs are independent prognostic factor in HR-/HER2+ BCs anthracyclines - taxane 2618 TILs TILs are prognostic factor in BC Tab Main clinical studies analyzing outcome-predictive role of TILs upon adjuvant chemotherapy in breast cancer

13 Salgado Ann Oncol 2015

14 % Stromal TILs Evaluated within the tumor borders Full sections preferred TILs scored as a continuous variable No relevant TIL threshold (by now) Salgado Ann Oncol 2015

15 Salgado Ann Oncol 2015

20 HRD score Sum of: LOH TAI LST Telli Clin Cancer Res 2016

21 HRD score Sum of: LOH TAI LST Telli Clin Cancer Res 2016

22 Telli Clin Cancer Res 2016

23 Telli Clin Cancer Res 2016

25 Outline Immunology and breast cancer Clinical trials with modern immunotherapy in BC Rationale to build up modern immunotherapy in hereditary BC Concluding remarks and future perspectives

29 Galluzzi Cancer Immunol Res AACR 2016

31 Outline Immunology and breast cancer Clinical trials with modern immunotherapy in BC Rationale to build up modern immunotherapy in hereditary BC Concluding remarks and future perspectives

32 Luen S et al, The Breast 2016

33 Breast and ovarian cancer has far few mutations compared with melanoma and NSCLC Brown et al, Genome Research 2014

34 Association and prognostic significance of BRCA1/2-mutation status with neoantigen load, number of TIL and expression of PD-1/PD-L1 in high grade serous ovarian cancer HR deficient tumors, either BRCA1/2-mut or non- BRCA1/2-mut, demonstrated significantly higher neoantigen loads than HR proficient tumors Lower neoantigen load is associated with inferior overall survival Kyle C. Strickland et al. Oncotarget 2016

serous ovarian cancer BRCA1/2-mutated HGSOCs harbor increased PD-1 and PD-L1

35 Association and prognostic significance of BRCA1/2-mutation status with neoantigen load, number of TIL and expression of PD- 1/PD-L1 in high grade serous ovarian cancer BRCA1/2-mutated HGSOCs harbor increased PD-1 and PD-L1 expression compared to HR proficient HGSOCs Kyle C. Strickland et al. Oncotarget 2016

36 Association and prognostic significance of BRCA1/2-mutation status with neoantigen load, number of TIL and expression of PD-1/PD-L1 in high grade serous ovarian cancer 20 m 56 m 229 m Prognostic significance of BRCA1/2- mutation status and number of CD3+ TILs Kyle C. Strickland et al. Oncotarget 2016

37 SNVs and % stromal TILs by PAM50 subtype Luen S et al, The Breast 2016

38 BRCA 1/2 tumors, combination of characteristic substitution mutation signatures and a distinctive profile of deletions Nik-Zainal, Cell 2012

39 Solinas, SABCS 2016

40 Solinas, SABCS 2016

41 Trials to open in BRCAmut BC

42 Le DT N Engl J Med. Jun 2015

43 VACCINE EFFECT: EVERY TUMOR HAS ITS ACHILLES HEEL Sharma Science 2015

44 Damage Associated Mollecular Patterns DAMPs Galluzzi L, Gomes-de Silva LC, Dewittee H, et al. Combinatorial strategies for the induction of immunogenic cell death. Front Immunol. Mar 2015

45 Which would be the (immune) Achilles heel of BRCAmut BC? i. Extremely sensitive to DNA damaging agents- platinum salts (especially high score HRD)- immunogenic cell death ii. Higher mutational load than other non-hereditary BC??- higher sensitivity to immune checkpoint inhibitors iii. Neoantigen load and PARP inhibitors effect over immune microenvironment unknown by now iv. Why not testing combos with CT (platinum salts) + immune-checkpoint inhibitors???...

46 Schumacher Science 2015

47 Biomarkers, biomarkers, biomarkers Yuan J J Immunother Cancer 2016

48 Closing remarks and future perspectives TILs as emerging predictive and prognostic factor in BC Immune gene signatures may complement TILs information First data with anti-pd1/anti-pd-l1 mabs in BC promising especially in TNBC PD-L1+ Immune combos with chemotherapy may have synergistic effects BRCA+ related to HRD: higher sensitivity to platinum Molecular features leading to immunogenicity in hereditary BC to be determined (mutational load, neoantigen load, TILs, PD1/PD-L1 ) Immunotherapy in hereditary BC will probably play a role but most certainly in the context of combos and hopefully with biomarkers

Immunotherapy in breast cancer. Carmen Criscitiello, MD, PhD European Institute of Oncology Milan, Italy

Immunotherapy in breast cancer Carmen Criscitiello, MD, PhD European Institute of Oncology Milan, Italy Outline Rational for immune-based therapy in breast cancer Immunogenic chemotherapy Targeting immune