Enterprise Interest Speaker and consultant for Astrazeneca, MSD, BMS, Roche, Pfizer, Novartis, Sanofi Resarch grants from BMS, Roche, MSD, Novartis

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1 Enterprise Interest Speaker and consultant for Astrazeneca, MSD, BMS, Roche, Pfizer, Novartis, Sanofi Resarch grants from BMS, Roche, MSD, Novartis

2 Centre Jean Perrin Centre de Lutte contre le Cancer d'auvergne Clermont-Ferrand - France - "Biomakers before and after neoadjuvant chemotherapy" Frédérique Penault-Llorca and Nina Robin

3 Neoadjuvant treatment Initial concept Early introduction of a systemic treatment Locally advanced BC Survival benefit? Conservative surgery Meta-analysis NACTvs adjuvant CT No difference in OS/DFS Augmentation of breast conservation rate Evolution of the concept Clinical situation allowing in vivo analysis of tumor response Prognosis of pcr in HER2 and TNBC Dynamic evaluation Treatment adjusment

4 Different Goals Before Prediction of response to NACT After Prognosis Prediction of response to different drugs During Treatment adaption

5 Predictive factors of response to NACT classical biomarkers Classical lobular carcinoma Pathologic complete response NOS Lobular Cocquyt % (15/105) 0% (0/31) Mathieu % (42/419) 0% (0/38) Cristofanilli % (138/770) 3% (4/122) Tubiana % ( 67/742) 1% (1/118) Wenzel % ( 25/124) 3% (1/37) Straver % ( 23/195) 2% (1/42) Lips % (190/601) 11% (8/75) Marchio C, J Natl Cancer Inst Monogr Less or no pcr in ILC but no difference in terms of OS/DFS

6 Predictive factors of response to NACT classical biomarkers Clinical response (p= ) Pathological response (p= ) More pcr in high SBR grades Marchio C, J Natl Cancer Inst Monogr. 2011

7 Predictive factors of response to NACT classical biomarkers More pcr with high proliferation Marchio C, J Natl Cancer Inst Monogr. 2011

8 Predictive factors of response to NACT classical biomarkers

9 Predictive factors of response to NACT classical biomarkers pcr TNBC~HER % pcr HR+/HER2-12%

10 Predictive factors of response to NACT intrinsic molecular subtypes by PAM50 pcr basal like ~HER2e 38-37% pcr lum B 16% > lum A 6%

11 2 different HER2+ groups /HR status Less pcr in HER2+, ER +

12 PAM50: PAMELA (SOLTI, HER2+) pcrb to dual HER2 blockade with lapatinib and trastuzumab in all patients, at the time of surgery, predicted by PAM50 HER2-E subtype Comparison between the PAM50 HER2-E versus non HER2-E cases to achieve pcrb from dual HER2 blockade with lapatinib and trastuzumab at the time of surgery Prosigna Breast Cancer Prognostic Gene Signature Assay for use on the ncounter Dx Analysis System is 510(k) cleared and CE-marked for in vitro diagnostic use in the United States and EU, respectively. See territory-specific Package Insert in for details. EU label provided in this presentation.

13 PAM50: PAMELA (SOLTI, HER2+) Courtesy of Dr. Prat SABCS 2016 Prosigna Breast Cancer Prognostic Gene Signature Assayfor use on the ncounter Dx Analysis System is 510(k) cleared and CE-marked for in vitro diagnostic use in the United States and EU, respectively. See territory-specific Package Insert in for details. EU label provided in this presentation.

14 G Pruneri et al Breast Mar 28. pii: S (17) doi: /j.breast C. Solinas et al. / Cancer Treatment Reviews 57 (2017) 8 15

15 TILs assessment requires standardized approaches Lymphocyte predominant breast cancer can be used as a descriptive term for tumors that contain more lymphocytes than tumor cells. However, the thresholds vary between 50% and 60% stromal lymphocytes. Hendry S, et al Adv Anat Pathol Aug 2. doi: /PAP PMID:

16 TILs as Predictive factors of response of NACT G Pruneri et al Breast Mar 28. pii: S (17) doi: /j.breast

17 TILs as Predictive factors of response of NACT G Pruneri et al Breast Mar 28. pii: S (17) doi: /j.breast

18 Summary Before Prediction of response to NACT Histologic subtype Tumor grade HR status HER2 status SBR grade, proliferation Intrinsic classification High TILs

19 Emerging: prediction of response to platinium salts and.parpi? mychoice HRD Clin Cancer Res 2016; 22 (15), 3764

20 After When we don t have a ypt0/is ypn0 Before

21 BIOMARKERS AFTER (PROGNOSTIC AND PREDICTIVE)

22 Residual tumor burden matters G Von Minckwitz J Clin Oncol 2012; 30:

23 Proliferative residual T = poor prognosis Penault-Llorca, Radosevic-Robin, Nat Review Clin Oncol 2016, 13/ 487

24 SBR Univariate Multivariate p Chevallier N 0,0003 NPI&MNPI SBR post tt 0,0004 BGI & MBGI MNPI 0,04 SBR post tt msbr post tt ER PR N msbr More better differentiated tumors after neoadjuvant chemotherapy: 25.2% vs 14.8%; p = Breast Cancer Res Treat Dec;94(3):255-63

25 Ki67 INDEX (post-nat) Ki67 in post NACT residual T Von Minckwit G et al, Clin Canc Res 2013 (PMID ) GeparTrio : 667 pts with post-nat RT, all BC subtypes HRpost-NAT Ki67 low (0 15 %) : 488 pts intermediate ( %) : 77 pts high (> 35%) : 102 pts HR+ HIGH POST-NAT Ki67 : higher risk of relapse and death (HR+ & HR-)

26 HER2+, prognostic value of pcr in HR-

27 CHANGES IN BIOMARKERS Marchio C, J Natl Cancer Inst Monogr. 2015

28 Penault-Llorca, Radosevic-Robin, Nat Review Clin Oncol 2016, 13/ 487 Switch in HR and HER2 (1) High frequency of switches in ER, PR and HER2 (10 50%)

29 Switch in HR and HER2 (2) Repeated assessment of the expression of these receptors should be considered, at least if the biomarkers are negative, equivocal, or potentially hampered by poor cellularity, and when the tumour appears heterogeneous in the surgical specimen Targeted therapy should be administered if HR or HER2 amplification are detected in at least one specimen, regardless of whether that specimen is the primary tumour or the post-nat residual tissue. Penault-Llorca, Radosevic-Robin, Nat Review Clin Oncol 2016, 13/ 487

30 Loss of HER2 in 40% of RT poor prognosis

31 Switch in Ki67 Ki67 INDEX PRE-NAT : POST-NAT Von Minckwitz G et al, Clin Canc Res 2013 (PMID ) GeparTrio : 757 pts with paired pre-nat + post-nat samples HR+ N=490 HR- N=267 pre-nat Ki67 high post-nat Ki67 low : low relapse rate (HR+)

32 In HR + pts, higher benefit of pcr for Gr 3 add proliferation to RCB = RPCB Cortazar 2014

33 RPCB

34 Intrinsic subtypes before and after NACT 25 % 7% 24% 44% Intrinsic subtypes before NACT (n = 282 patients) Intrinsic subtypes after NACT (n = 224 patients, 58 missing data) Abrial C, unpublished data 18% 13% 4% 12% 53%

35 Prognostic value of the intrinsic subtypes evaluated on the residual tumor Intrinsic subtypes OS Lum B Lum A TN Her2+ HR- => HR- HR- => HR+ p= OS in HR-negative patients with a switch to HR+ (Tacca et al, 2007, The Oncologist) Prognostic value of switch DFS p = Abrial C, unpublished data Switch in the luminal group Lum A Lum A Lum B Lum B Lum B Lum A Lum A Lum B p = 0.05 Abrial C, unpublished data

36 AND TILS?

37 TNBC : post-nat TILs Dieci V et al, Annals of Oncology 2014 (PMID ) 278 post-nat TNBC RT analyzed for quantity of Tumor-Infiltrating Lymphocytes (TIL) DFS OS 60% of stromal or intratumoral TIL : better metastasis free and overal survival (5 yrs)

38 TNBC : post-nat TILs Dieci V et al, Annals of Oncology 2014 (PMID ) 278 post-nat TNBC RT analyzed for quantity of Tumor-Infiltrating Lymphocytes (TIL) DFS N-and 2cm DFS N+& or T>2cm TILs have a prognostic value in ptswith a large tumor burden post-nact (RT > 2 cm and/or N+)

39 HER2+ BC : CD8/FOXP3 post treatment Ladoire S et al, J Pathol 2011 (PMID ) HER2+ BC treated by a NACT ; residual tumors - analysis of tumor-infiltrating lymphocyte subpopulations by detecting CD8 or FOXP3 (IHC) «The Dijon grading» of TIL-CD8+ or TIL-FOXP3+ density CD8/FOXP3 ratio a) favourable (CD8high, FOXP3low) b) unfavourable (CD8low, FOXP3high) In residual T post-nact unfavourable TIL CD8/FOXP3 score predicts poor survival

40 And PD-L1? Cancer Immunol Res; 3(4) April 2015 Controversial High PD-L1 before NACT: predictor of response Decrease after NCAT Poor prognosis if high after NACT especially for TNBC More data are expected Int J Cancer Mar 15;140(6):

41 PROGNOSTIC SCORES BASED ON POST NAT PARAMETERS

42 Pre NACT Post NACT

43

44 ER+/HER2- BC: the PEPI score

45 Summary Penault-Llorca, Radosevic-Robin, Nat Review Clin Oncol 2016, 13/ 487

46 DEVELOPMENT OF NEW PREDICTIVE BIOMARKERS

47 Gene expression studies Gonzalez-Angulo AM et al, Clin Cancer Res 2012 (PMID ) 21 pairs, analysis of tumor cells only (no stroma) BASAL TNBC RT : PI3K, small G proteins, energy metabolism pathways Hedgehog signaling, immune pathways NON-BASAL TNBC RT : Notch signaling, energy metabolism Hedgehog signaling, immune pathways No change in EMT genes

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49 Identification of actionable targets Balko J et al, Nature Medicine 2012 (PMID ) DUSP4 LOSS IN BASAL-LIKE(BL) TNBC RT post-nat correlates with RAS-ERK (MEK) activation and lower response to NACT DUSP4 LOSS IS A RECURRENCE RISK FACTOR promotes SC-like phenotypes in BL-BC (PMID )

50 Identification of actionable targets Balko J et al, Cancer Discovery 2014 (PMID ) NGS : ENRICHMENT OF ALTERATIONS DURING NAT 20 paired pre-nat + post-nat samples alterations highly enriched post-nat : COAMPLIFICATION of MYC and MCL1 ATM mutations (R337H, R2443Q) TP53 mutation (T253fs*11) CDH1 splice deletions KDM6A (L214fs*) AR (A401V) DPYD (S175W)

51 TNBC : EGFR/HER3 pathway Tao J, Castel P, Radosevic-Robin N et al, Science Signaling pilot NAT in TNBC clinical trials conducted by CJP NAT : anti-egfr Ab (panitumumab (PTMB)/cetuximab (CTX) + cytotoxics 44 RT (26 PTMB et 18 CTX) HER3 protein abundance (IHC) got increased in 25/42 RT increase in EGFR/HER3 dimers post-nat was demonstrated by FRET-FLIM

52 Post NAT Residual cancers have different prognostic value Post NAT ( drug-resistant ) Residual cancers harbor targetable genomic alterations causally associated with resistance to neoadjuvant therapy Molecular profiling of these residual tumors should identify these alterations. In addition, patient-derived xenografts generated with these residual cancers can be used to test novel combinations with activity against these drug-resistant cancers. Adaptative trials Arteaga1 CL & Engelman JA, Cancer Cell 2014 CONCLUSION

53 Future: adaptative trials

54 THANK YOU!