presentación de powerpoint...7 cohorts anthracyclin-taxane-based 845 igkc gene expression igkc...

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