presentación de powerpoint...7 cohorts anthracyclin-taxane-based 845 igkc gene expression igkc...
TRANSCRIPT
Perspectivas de desarrollo de
la inmunoterapia en cáncer de
mama hereditario
Luis de la Cruz Merino Oncología Médica HUVMacarena (Sevilla)
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
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
Study Trial Therapy N Measure Result
Denkert et al., JCO 2010 (8) GeparDuo,
GeparTrio
EC-Doc (GeparDuo)
TAC+/-vinorel/capec
1058 TIL Stromal TILs and LPBC with pCR in ER and HER2
West et al., Breast Cancer Res
2011 (94) EORTC10994/
BIG01
FEC vs TET 113 ER- Public gene expression data TILs correlate with pCR
Ono et al. , Breast Cancer Res
Treat 2012 (11) Retrospective Anthracyclin-, cyclophosp- or
taxane-based
474,
92 TNBC
TIL TILs correlate with pCR in TNBC
Yamaguchi et al., Hum Pathol
2012 (95) Retrospective Anthracyclin-taxane-based 68 TIL TILs correlate with pCR
Ignatiadis et al, JCO 2012 (36) 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
Oda et al., Breast Cancer Res
Treat 2012 (28) Retrospective Paclitaxel-FEC 180 CD8, FOXP3, IL17F CD8, FOXP3 correlated with pCR
Schmidt et al., Clin Cancer Res
2012 (96) 7 cohorts Anthracyclin-taxane-based 845 IGKC gene expression IGKC predicted to NACT
Seo et al., Br J Cancer 2013
(14) Retrospective Anthracyclin-taxane-based 153 CD8, CD4, FOXP3 CD8, CD4, FOXP3 correlated with pCR
Issa-Nummer et al., Plos One
2013 (9) GeparQuinto EC-Doc 313 HER2- TIL Stromal TILs and LPBC correlated with pCR
Dieci et al., Ann Oncol 2014
(27) Retrospective Anthracyclin-taxane-based 304 TIL Stromal TIL correlated with pCR
Lee et al., J Breast Cancer 2013
(97) 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 anthracyclin-
taxane-based
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
Salgado et al., JAMA Oncol
2015 (99)
NeoALTTO
Trastuzumab, lapatinib, or the
combination followed by paclitaxel
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
Study Trial Therapy N Measure Result
Denkert et al., JCO 2010 (8) GeparDuo,
GeparTrio
EC-Doc (GeparDuo)
TAC+/-vinorel/capec
1058 TIL Stromal TILs and LPBC with pCR in ER and HER2
West et al., Breast Cancer Res
2011 (94) EORTC10994/
BIG01
FEC vs TET 113 ER- Public gene expression data TILs correlate with pCR
Ono et al. , Breast Cancer Res
Treat 2012 (11) Retrospective Anthracyclin-, cyclophosp- or
taxane-based
474,
92 TNBC
TIL TILs correlate with pCR in TNBC
Yamaguchi et al., Hum Pathol
2012 (95) Retrospective Anthracyclin-taxane-based 68 TIL TILs correlate with pCR
Ignatiadis et al, JCO 2012 (36) 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
Oda et al., Breast Cancer Res
Treat 2012 (28) Retrospective Paclitaxel-FEC 180 CD8, FOXP3, IL17F CD8, FOXP3 correlated with pCR
Schmidt et al., Clin Cancer Res
2012 (96) 7 cohorts Anthracyclin-taxane-based 845 IGKC gene expression IGKC predicted to NACT
Seo et al., Br J Cancer 2013
(14) Retrospective Anthracyclin-taxane-based 153 CD8, CD4, FOXP3 CD8, CD4, FOXP3 correlated with pCR
Issa-Nummer et al., Plos One
2013 (9) GeparQuinto EC-Doc 313 HER2- TIL Stromal TILs and LPBC correlated with pCR
Dieci et al., Ann Oncol 2014
(27) Retrospective Anthracyclin-taxane-based 304 TIL Stromal TIL correlated with pCR
Lee et al., J Breast Cancer 2013
(97) 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 anthracyclin-
taxane-based
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
Salgado et al., JAMA Oncol
2015 (99)
NeoALTTO
Trastuzumab, lapatinib, or the
combination followed by paclitaxel
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
15+ trials TILs
predictive factor
for pCR
Denkert JCO 2010
Issa-Nummer PLOS One 2013
Issa-Nummer PLOS One 2013
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 02-98 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)
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
Ali, Ann Oncol 2014 (103) 4 studies, including
NEAT
12439 CD8, FOXP3 CD8 in stroma and tumor correlate with 28-21% reduced risk of
BCSS, greater in ER-
Dieci et al., Ann Oncol
2015 (6) 2 Phase III trials 5-FU, Dox, Epi , INN 1146 TIL TIL have prognostic role in TNBCs and suggested prognostic
impact in HER2+ ones
Lee et al., Am J Clin Pathol
2015 (105) Retrospective
Chemo+Trastuzumab 447 HER2+ TIL, TLS (Tertiary
Lymphoid
Structures), MHC
TILs are independent prognostic factor in HR-/HER2+ BCs
Kotoula et al., Oncotarget
2016 (106) 4 prospective trials
(HeCOG 10/97-00-
05-08)
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
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 02-98 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)
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
Ali, Ann Oncol 2014 (103) 4 studies, including
NEAT
12439 CD8, FOXP3 CD8 in stroma and tumor correlate with 28-21% reduced risk of
BCSS, greater in ER-
Dieci et al., Ann Oncol
2015 (6) 2 Phase III trials 5-FU, Dox, Epi , INN 1146 TIL TIL have prognostic role in TNBCs and suggested prognostic
impact in HER2+ ones
Lee et al., Am J Clin Pathol
2015 (105) Retrospective
Chemo+Trastuzumab 447 HER2+ TIL, TLS (Tertiary
Lymphoid
Structures), MHC
TILs are independent prognostic factor in HR-/HER2+ BCs
Kotoula et al., Oncotarget
2016 (106) 4 prospective trials
(HeCOG 10/97-00-
05-08)
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
TILs prognostic
factor:
TNBC/her2
Salgado Ann Oncol 2015
Salgado Ann Oncol 2015
% 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
HRD score
Sum of:
LOH
TAI
LST
Telli Clin Cancer Res 2016
HRD score
Sum of:
LOH
TAI
LST
Telli Clin Cancer Res 2016
Telli Clin Cancer Res 2016
Telli Clin Cancer Res 2016
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
Galluzzi Cancer Immunol Res AACR 2016
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
Luen S et al, The Breast 2016
Breast and ovarian cancer has far few mutations compared
with melanoma and NSCLC
Brown et al, Genome Research 2014
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
Kyle C. Strickland et al. Oncotarget 2016
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
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
Kyle C. Strickland et al. Oncotarget 2016
BRCA1/2-mutated HGSOCs harbor increased PD-1 and PD-L1 expression compared to HR proficient HGSOCs
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
Kyle C. Strickland et al. Oncotarget 2016
Prognostic significance of
BRCA1/2-mutation status and number of
CD3+ TILs
229 m 56 m 20 m
Luen S et al, The Breast 2016
SNVs and % stromal TILs by PAM50 subtype
Nik-Zainal, Cell 2012
BRCA 1/2 tumors, combination of characteristic substitution mutation signatures
and a distinctive profile of deletions
Solinas, SABCS 2016
Solinas, SABCS 2016
Trials to open in BRCAmut BC
Le DT N Engl J Med. Jun 2015
Sharma Science 2015
VACCINE EFFECT: EVERY TUMOR HAS ITS ACHILLES HEEL…
Galluzzi L, Gomes-de Silva LC, Dewittee H, et al. Combinatorial strategies for the induction of immunogenic cell death. Front Immunol. Mar 2015
Damage Associated
Mollecular Patterns
DAMPs
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???...
Schumacher Science 2015
Yuan J J Immunother Cancer 2016
Biomarkers, biomarkers, biomarkers…
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
