Malattia HER-2 positiva

Transcription

1 Novità sul trattamento del carcinoma mammario Malattia HER-2 positiva Patrizia Vici

2 Neoadjuvant - Adjuvant - Advanced Prognostic/Predictive factors..her-2 heterogeneity..

3 Neoadjuvant Phase II Pre-planned «Trend» advantage from adding pertuzumab

4 Despite identical adjuvant therapy (Trast): Association between pcr and long term outcomes

5 NeoSphere Gianni L et al, SABCS 2012

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7 DFS OS pcr prognostic of good long- term outcomes n.s.

8 DFS n.s. OS: lapatinib better in HR+? DFS OS

9 pcr: strongly prognostic (better OS) for Trastuzumab (pcr vs no pcr), not for Lapat no pcr: OS trend better Lapat

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12 PIK3CA and pcr/dfs/os in HER-2 +

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16 n.s. No advant. dual block p.s. T H L T H p.s. By intrinsic subtype (all arms)

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18 HR-/wt : better pcr Double-block-mutated: low pcr

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20 from NeoALTTO 53% 28%

21 Biomarkers Cher-lob PIK3CA mutation exon 9 or 20 (20% of the pts) Overall, no differences in wt or mutated in pcr (33%vs23% p ns) Trast+Lap: pcr wt 48.4% vs mutated 12.5%, p 0.06 PIK3CA mutations seem to identify pts less sensitive to dual-block Trast/Lap Guarneri V Oncologist 2015

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23 NEOPHOEBE (CBKM120F2203) A phase II, randomized, parallel cohort, two stage, open-label study of neoadjuvant trastuzumab (T control) versus T + BKM120 in combination with weekly paclitaxel in HER2- positive, PI3KCA wild-type (WT) and PIK3CA mutant (mt) primary breast cancer

24 TILs in Her-2 + BC

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27 LPBC epithelial stromal No LPBC Geparsixto HER2 +

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30 EFS Predictive for pcr Prognostic for EFS

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32 BEYOND BIOMARKERS.

33 Residual Disease After Neoadjuvant Therapy for HER2-Positive Early BC Questions remain on optimal approach for patients with residual disease following neoadjuvant therapy, and various trials are currently ongoing in this setting Study Phase Treatment Setting KATHERINE [1] III T-DM1 vs trastuzumab Adj tx in pts with HER2+ BC and residual disease after neoadj tx ABCDE (TBCRC 012) [2] II Dietary intervention ± exercise intervention ± bevacizumab and metronomic chemotherapy Adj tx in pts with HER2+ BC and residual disease after neoadj tx SCRI BRE 186 [3] II Eribulin + trastuzumab Adj tx in pts not achieving pcr after neoadj tx NCT [4] I Preoperative radiation and veliparib Pts with residual disease after neoadj tx NCT [5] NCT [6] I HER2 pulsed DC vaccines Pts with ER- residual disease after neoadj tx 1. ClinicalTrials.gov. NCT ClinicalTrials.gov. NCT ClinicalTrials.gov. NCT ClinicalTrials.gov. NCT ClinicalTrials.gov. NCT ClinicalTrials.gov. NCT

34 Key Ongoing Phase III Neoadjuvant Studies in HER2+ Early Breast Cancer Study Planned N Treatment Primary Endpoint Notes B (NCT ) 220 Docetaxel/carboplatin + PF or H % with steady drug conc > 20 µg/ml NCT CT-P6 vs H pcr Lilac (NCT ) 808 Epirubicin/cyclophosphamide/ paclitaxel + ABP 980 or H pcr PF , CT-P6, ABP 980 are H biosimilars NCT Trastuzumab vs placebo DFS Stage I, preop Tx GeparOcto (NCT ) 950 ETC + HP vs PM(Cb) + HP pcr Comparison of 2 dose-dense approaches + dual HER2 targeting NSABP B-52 (NCT ) 212 Docetaxel/carboplatin/HP, surgery, RT ± estrogen deprivation pcr in breast and posttherapy LN Dual HER2 targeting KRISTINE (NCT ) 432 Docetaxel/carboplatin/HP vs T-DM1/pertuzumab ClinicalTrials.gov. Local pcr Adj therapy: H + pertuzumab or T-DM1 + pertuzumab

35 Adjuvant Trastuzumab benefit confirmed

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37 After adjuvant.

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39 Small HER2 positive tumors What systemic adjuvant therapy, if any, should be recommended for small, HER2-positive cancers (10% of all early-stage breast cancers)? A total of 4220 patients with small (2 cm) HER2-positive BC treated in randomized trials were included in this analysis O'Sullivan C, et al. JCO

40 Small HER2 positive tumors Pts with HR+ disease and tumors < 2 cm DFS (17.3% vs. 24.3%, p < 0.001) OS (7.8% vs. 11.6%, p < 0.005) Pts with HR- disease and tumors < 2 cm DFS (24% vs. 33.4% p < ) OS (12.4% vs. 21.2% p < )

41 Prognostic/Predictive biomarkers Investigation of the association between tumor PTEN protein expression and Disease Free Survival Tissue microarrays

42 Intermediate-levels ERBB2, High levels ESR1 mrna expression Low trastuzumab benefit

43 Arm A n.s. ArmB/C enriched p.s.(not enriched n.s). «Immune enriched» if >9 of 14 immune genes were expressed Enriched: high RFS trastuz, no CT Not from chemo Predictive in arms B and C (trastuz.), not A (chemo) Not enriched: n.s.

44 All PAM50 intrinsic subtypes benefit from trastuzumab Her2-enriched Other Her2+ subtypes

45 CT+trast CT

46 TILs and FinHER (Loi S Ann Oncol 2014) 209 Her-2 + pts Each 10% increase in TILs significantly associated with decrease recurrence in the trastuzumab arm (p 0.025) High TILs -> high trastuzumab benefit

47 90% 80% But 94 pts and 8 recurrences! 80% 64% TIL prognostic (high TIL -->good RFS (Arm A: CT alone) TIL not prognostic for CT/trast High TIL=lack trast efficacy???

48 Advanced

49 PIK3CA represented the greatest prognostic factor, with longer PFS in patients with wild-type vs mutated PIK3CA tumors in both the control (13.8m vs 8.8m) and pertuzumab (21.8m vs 12.5m) groups

50 T-DM1 and PIK3CA mutation PFS [TITLE] M Piccart ASCO 3013 Presented By Martine J. Piccart-Gebhart, MD, PhD at 2013 ASCO Annual Meeting

51 BEYOND BIOMARKERS

52 1 line

53 Prespecified specific threshold not crossed

54 Not better?

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56 TH3ERESA: OR, PFS, OS advantage T-DM1 expanded access 215 US Her2 positive, pretreated advanced BC pts Median n of cycles 8 (3-23) Median T-DM1 treatment duration: 5 mo (0-29) ORR 25.6% Toxicity and activity comparable with that reported in clinical trials Yardley DA Cancer J 2015

57 Eribuline + Trastuzumab I line MBC trial Phase II Wilks S, Puhalla S, O'Shaughnessy J et al: Phase 2, multicenter, single-arm study of Eribulin Mesylate with Trastuzumab as first-line therapy for locally recurrent or metastatic HER2-positive breast cancer. Clin Breast Cancer 2014,

58 1 line: Trast >>> Lapat 652 pts PFS OS In pts centrally confirmed Her2+ OS p.s.

59 Brain met Pts with treated asymptom CNS met and pts developing CNS met during Emilia PFS t. to symptom PD OS

60 Brain met Lap/cape vs Trast/cape No difference in CNS met incidence : 3% vs 5% PFS OS

61 No prior trast Prior trast 1 line Advanced line

62 Focusing on Her-2 heterogeneity

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65 Her-2 heterogeneity IHC Cancer Genome Atlas + Metabric datasets Subtype is more informative than HER2-status on breast cancer specific DFS Prat et al JNCI 2014

66 Triple positive BC (ER+/PgR+/Her2+) Caratterizzazione biologica: crosstalk Miller T W et al. JCO 2011;29: Reciprocal crosstalk between estrogen receptor (ER) α and growth factor receptor signaling pathways.

67 Breast Cancer Subtypes: 21% Her-2 positive 7.1% Triple positive N=114,786 ~21% HER2+ ~79% HER2-3.3% 10.8% Breakdown of the 21% HER2+ 0.5% ER+/PR+/HER2+ ER+/PR-/HER2+ ER-/PR+/HER2+ ER-/PR-/HER2+ Bauer K., Cancer. 2010;10:

68 Her-2+/HR+ Trastuzumab benefit less impressive? Even double-block works less in ER+??? [TITLE] Less pcr

69 Less pcr

70 [TITLE] pcr: less predictive value (EFS) Her2+/ER+ tumors

71 Prognostic impact of pcr on DFS according to breast cancer intrinsic subtype no Luminal A no yes Luminal B HER2 pos Luminal B HER2 neg HER2 positive yes Triple neg yes von Minckwitz G et al J Clin Oncol 2012

72 Timing of recurrence 3,394 Her-2 positive pts (44% treated with neoad/adj trastuz) Recurrence : 45% HR+, 55% HR- Recurrence beyond 5yrs: 66% HR+ vs 34% HR neg HR+ OS by HR status Curves tend to converge (late recurrences?) HR-

73 Metastatic Behavior of Breast Cancer Subtypes Frequency among pts who developed mts(%) Brain Liver Lung Bone Distant Nodes Pleura /peritoneum Luminal A Luminal B Luminal/HER HER2 enriched Basal Like TN non basal Pearson s Chi-square test showed p <0.001 in all cases H Kennecke, JCO 2010

74 Montemurro, Cancer 2012 Quantitative expression of HRs may influence response rate to trastuzumab and chemotherapy Receptor positivity Number CR + PR SD+PD P value* (%) (%) (%) ER 0-29% 140 (66) 95 (68) 45 (32) % 72 (34) 38 (53) 34 (47) PgR 0-49% 195 (92) 126 (65) 69 (35) % 17 (8) 7 (41) 10 (59) Multivariate Odds Ratio of response in tumors expressing ER in 30% of cells 0.422, 95% C.I , p = 0.009

75 Different staging? (more bone and less brain recurrences?) Different f up? (timing and type of follow up, since luminal B Her 2+ may recur after years.)

76 Innovative predictive factors???? n.s. Carcinoma mammario triplo positivo. Una nuova entità?

77 Ongoing studies without chemo in HR+/Her2+ tumors PER ELISA (neoadjuvant) ADAPT (neoadjuvant) HERLAPAC 2 (advanced) PERTAIN (advanced)

78 Ph. II random Triple positive Concurrent endocrine neoadjuvant ONGOING Without chemo, but only 12wks.

79 5yr RFS RFS 5yr OS OS 925 pts Her2 pts Her2+

80 RFS OS OS

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82 Triple positive early breast cancer (Vici et al, under rev) Retrospective analysis: 872 TP early BC from 19 italian oncologic centres Cohort A: chemotherapy (-> endocrine therapy) Cohort B: chemotherapy + trastuzumab (-> endocrine therapy

83 3 and 5 year RFS and BCSS in the two cohorts

84 Multivariate logistic regression model of factors impacting survival outcomes in the study population.

85 RFS (1) and BCSS (2) in the overall study population (N=872) according to cohort (m f up 78mo). Overall: trastuzumab benefit, but.

86 Hazard rate of recurrence for the overall study population (panel A) and in pts with ER and PgR staining >50% of tumour cells (TP50, panel B) and other pts (notp50, panel C).. overall TP50 No TP50 Late recurrence, less trastuz effect More relapses in the first 5 yrs, constant effect of trastuz.

87 Stepp analysis of the effect on ER (Panel A) and PgR (Panel B) expression on the hazard of relapse in the two cohorts ER PgR

88 BluePrint 80-gene assay: two distint TP subtypes Neoadjuvant Breast Symphony Trial Compare multigene classifiers to conventional IHC/FISH to predict pcr to standard CT+Her2-block 80-gene assay re-classified more than 1/5 tumors pcr 54% in BP-Her2 pts vs 40% in the IHC/FISH-Her2+ pts (p 0.02) The group with biggest change was the TP group (48% pts are reassigned in the low-responsive-bp Luminal vs 44% assigned to responsive-bp Her2 +) 137 IHC/FISH TP: BP reclassified -> BP Luminal (66, pcr 11%) BP Her2 (60, pcr 45%) In the TP luminal group pcr,low with trastuzumab, was higher with CT+trastuzumab/pertuzumab Whitworth PW, Breast Cancer Symposium 2015

89 Conclusions Distinct diseases within Her-2 positive subgroup Many predictive/prognostic biomarkers under evaluation but few of them showed concordant results (mostly in neoadjuvant setting) Results from a specific setting may not be applicable to other settings Triple-positivity and high HRs degree expression deserve further evaluation In the future different treatments Grazie!