1-. dr. luis de la cruz-merino - oncologypro · geparquinto ec-doc 313 her2-til stromaltils and...

DISCLOSURES

Roche/MSD-Merck/Celgene: Research Funding

Roche/Celgene/AstraZeneca/Amgen/MSD/Novartis/Sanofi-

Aventis/Pierre Fabré: Advisory Board or Consultant

I am still a clinical oncologist (not immunologist unfortunately…)

OUTLINE

i. TILs as predictive and prognostic factors in BC

ii. TILs working group recommendations

iii. Immune signatures in BC samples

iv. First clinical data with immune checkpointinhibitors in BC

v. Clinical trials ongoing

vi. Final remarks

Study Trial Therapy N Measure Result

Hornychova et al.,Cancer

Invest 2008 (29)Retrospective Anthracyclin-based 73 CD3 CD3, correlated with pCR

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

dataTILs 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

Nabholtz et al., Ann Oncol

2014 (98)TVA phase 2

study

4FEC100+/-Docetax+

panitumumab

47 TNBC CD8, FOXP3 CD8, FOXP3 correlated with pCR


(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


Hornychova et al.,Cancer

Invest 2008 (29)Retrospective Anthracyclin-based 73 CD3 CD3, correlated with pCR


(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

dataTILs 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


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

Nabholtz et al., Ann Oncol

2014 (98)TVA phase 2

study

4FEC100+/-Docetax+

panitumumab

47 TNBC CD8, FOXP3 CD8, FOXP3 correlated with pCR


(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

8 studies NACT (anthras, taxanes)

845 pax multivariate analysis

17 gene modules

Ignatiadis JCO 2012


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


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-

Schalper, Clin Can Res

2014 (104)Retrospective Chemo not specified 636 PDL1, TIL PDL1 associated with better RFS and TILs


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. 2 Main clinical studies analyzing outcome-predictive role of TILs upon adjuvant chemotherapy in breast cancer


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


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


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-

Schalper, Clin Can Res

2014 (104)Retrospective Chemo not specified 636 PDL1, TIL PDL1 associated with better RFS and TILs


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. 2 Main clinical studies analyzing outcome-predictive role of TILs upon adjuvant chemotherapy in breast cancer

TILs prognostic

factor: TNBC/her2

Adams JCO 2014

Mahmoud JCO 2011

Ali Ann Oncol 2014

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)

Pruneri Ann Oncol 2016

TILS EN CÁNCER DE MAMA TRIPLE NEGATIVO


# S1-09 Denkert

� TILs strong predictive marker for pCR in all subtypes, and this pCR is translated intosuvival benefit in her2+ and TNBC

� In luminal BC pts with low TIL-tumors improved prognosis

# S1-07 Karn

� In TNBC, highMHC2/low IL8-VEGF and high B-cell/low IL8-VEGF immune signaturescorrelates with good prognosis (microarray and RNA seq platforms)

� Immune poor TNBC : hight mut load, high clonal heterogeneity, high neoantigen load, poor prognosis

# S1-08 Luen

� Cleopatra study. Significant association between higher TILs& improved OS

� Each 10% increase in stromal TILs associated with 11% reduction in the risk of death3 year OS pertu&stromal TILs>20% was 78%

� Ph 1 trials suggest clinical activity for immune checkpoint inhibitors in BC

� Strong scientific rationale for combos of i-ch-i and chemo. Clinical trials ongoing

SABCS 2016

Galluzzi Cancer Immunol Res AACR 2016

CLINICAL TRIALS ONGOING

OT2-01-17

CLINICAL TRIALS ONGOING

PANGEA-breast

Closing remarks and future perspectives

� TILs as emerging predictive and prognostic factor in BC

� International TILs working group recommendations

� 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

� Search of biomarkers is a must to build up modern

immunotherapy in BC

1-. dr. luis de la cruz-merino - oncologypro · geparquinto ec-doc 313 her2-til stromaltils and...

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