Cáncer de mama HER2+/RE+ vs HER2+/RE : Una misma enfermedad? Dra E. Ciruelos Departamento de Oncología Médica Hospital Universitario 12 de Octubre

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1 Cáncer de mama HER2+/RE+ vs HER2+/RE : Una misma enfermedad? Dra E. Ciruelos Departamento de Oncología Médica Hospital Universitario 12 de Octubre

2 Recurrence of HER2-positive breast cancer (A) Time to distant recurrence (B) Survival Probability Censored Luminal A Luminal B Basal ErbB2+ Probability p< p< Time to distant metastasis (months) Overall survival (months) Sorlie et al. Proc Natl Acad Sci USA 2003;100:

3 Trastuzumab significantly increases median OS in HER2-positive MBC Overall survival (%) RR=0.80 p=0.046 Median OS: 20.3 months Chemo (n=234) Chemo + trastuzumab (n=235) Median OS: 25.1 months Months after enrolment OS was a secondary endpoint in the study Chemo = either doxorubicin or epirubicin + cyclophosphamide or paclitaxel; MBC = metastatic breast cancer; OS = overall survival; RR = relative risk of death Slamon et al. N Engl J Med 2001;344:

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7 Adyuvancia

8 San Antonio Breast Cancer Symposium, December 4-8, 2012 N9831/B 31 Disease Free Survival % Event-Free AC P N Events AC P AC P+H % 69.5% AC P+H 76.8% 64.9% 73.7% 62.2% HRadj=0.60 (95% CI: ) P< % Years from Randomization No. at risk

9 San Antonio Breast Cancer Symposium, December 4-8, 2012 B-31/N9831 Cumulative Incidence of Distant Recurrence as a First Event ER and/or PR Positive ER and PR Negative Cumulative Incidence (%) AC P Δ= 9.6% AC P+H 22.3% 12.7% N Events AC P AC P+H AC P % Δ= 9.6% 11.9% AC P+H N Events AC P AC P+H Years from Randomization

10 San Antonio Breast Cancer Symposium, December 4-8, 2012 B-31/N9831 Overall Survival AC P 93.2% 90.3% 89.8% 84.3% AC P+H 87.0% 84.0% 79.4% 75.2% 8.8% % Survival =2.9% =5.5% =7.6% =8.8% N Events AC P AC P+H HRadj=0.63 (95% CI ) P< No. at risk Years from Randomization

11 San Antonio Breast Cancer Symposium, December 4-8, 2012 % Survival B-31/N9831 Overall Survival ER and/or PR Positive AC P AC P+H AC P N Deaths AC P+H 86% 77.1% P= < P= < ER and PR Negative AC P AC P+H AC P AC P+H N Deaths % 73% HR: 0.61 (95%CI: ) HR: 0.64 (95%CI: ) Years from Randomization No. at risk

12 San Antonio Breast Cancer Symposium, December 4-8, 2012 HERA: DFS ITT for trastuzumab 1 year vs observation across all analyses Median follow-up (% follow-up time after selective crossover) yr MFU (0%) 2006 (4.3%) 2008 (33.8%) 2012 (48.6%) 2 yrs MFU 4 yrs MFU 8 yrs MFU DFS benefit Favours 1 year trastuzumabfavours observation HR (95% CI) No. of DFS events 1 year trastuzumab vs observation 127 vs 220 P< vs 321 P< vs 458 P< vs 570 P<0.0001

13 San Antonio Breast Cancer Symposium, December 4-8, 2012 HERA: DFS ITT for trastuzumab 1 year vs observation according to ER Median follow-up (% follow-up time after selective crossover) yr MFU (0%) yrs MFU (4.2%) yrs MFU (34.9%) yrs MFU (49.9%) ER positive DFS benefit Favours 1 year Favours trastuzumab observation HR (95% CI) No. of DFS events 1 year trastuzumab vs observation 53 vs 82 P= vs 123 P= vs 188 P= vs 253 P= Median follow-up (% follow-up time after selective crossover) yr MFU (0%) yrs MFU (4.5%) yrs MFU (32.5%) yrs MFU (47.1%) ER negative DFS benefit No. of DFS events 1 year trastuzumab vs observation 74 vs 138 P< vs 198 P< vs 270 P= vs 317 P< Favours 1 year Favours trastuzumab observation HR (95% CI)

14 San Antonio Breast Cancer Symposium, December 4-8, 2012 HERA: OS ITT for trastuzumab 1 year vs observation across all analyses Median follow-up (% follow-up time after selective crossover) 2005 (0%) 2006 (4.1%) 2008 (30.9%) 2012 (45.5%) 1 yr MFU 2 yrs MFU 4 yrs MFU 8 yrs MFU OS benefit Favours 1 year trastuzumabfavours observation HR (95% CI) No. of deaths 1 year trastuzumab vs observation 29 vs 37 P= vs 90 P= vs 213 P= vs 350 P=0.0005

15 San Antonio Breast Cancer Symposium, December 4-8, 2012 HERA: OS ITT for trastuzumab 1 year vs observation according to ER Median follow-up (% follow-up time after selective crossover) ER positive OS benefit No. of deaths Median follow-up 1 year trastuzumab(% follow-up time after vs observation selective crossover) ER negative OS benefit No. of deaths 1 year trastuzumab vs observation yr MFU (0%) yrs MFU (4.0%) yrs MFU (32.4%) yrs MFU (47.2%) vs 9 P= vs 29 P= vs 75 P= vs 146 P= yr MFU (0%) yrs MFU (4.1%) yrs MFU (29.2%) yrs MFU (43.6%) vs 28 P= vs 61 P= vs 138 P= vs 204 P= Favours 1 year trastuzumab 1 2 Favours observation HR (95% CI) Favours 1 year Favours trastuzumab observation HR (95% CI)

16 San Antonio Breast Cancer Symposium, December 4-8, 2012 HERA: DFS ITT for trastuzumab 1 year vs 2 years according to ER Hormone receptor positive 92.6% received endocrine therapy Hormone receptor negative 2.8% received endocrine therapy Disease-free survival (%) % 83.1% 89.6% 76.1% 82.9% 77.2% Trastuzumab 2 years Trastuzumab 1 year Pts Events HR (2 vs 1) 95% CI p-value 2 years ( ) 0.67 Disease-free survival (%) % 80.1% 75.4% 83.8% 78.9% 74.7% Trastuzumab 2 years Trastuzumab 1 year Pts Events HR (2 vs 1) 95% CI p-value 2 years ( ) year year Years from randomization Years from randomization No. at risk Trastuzumab 2 years Trastuzumab 1 year No. at risk Trastuzumab 2 years Trastuzumab 1 year

17 ER negative San Antonio Breast Cancer Symposium, December 4-8, 2012 PHARE: DFS ITT for trastuzumab 1 year vs 6 months according to ER ER positive DFS Probability HR = 1.34 : 95%CI: ( ), p=0.037 DFS Probability HR = 1.23 : 95%CI: ( ), p= ER negative T 12m T 6m Months Trastuzumab T 12m T 6m ER positive T 12m T 6m Months Trastuzumab T 12m T 6m Trastuzumab 12 months Trastuzumab 6 months Events N DFS-3 Events N DFS-3 ER negative ER positive

18 Neoadyuvancia

19 Baselga, Lancet 2012, 379: NeoAltto: pcr according to ER

20 Gianni, Lancet Oncol 2012, 13: NeoSphere: pcr according to ER 70 pcr, % 95% CI H, trastuzumab; P, pertuzumab; T, docetaxel ER or PR pos ER and PR neg TH THP HP TP 7

21 Schneeweiss, SABCS 2011 Tryphaena: pcr according to ER Pathologic complete response (%) ER- and PR-negative ER- and/or PR-positive ypt0/is FEC+H+P x3 T+H+P x3 (n = 73) FEC x3 T+H+P x3 (n = 75) TCH+P x6 (n = 77) ER, estrogen receptor; FEC, 5-fluorouracil, epirubicin, cyclophosphamide; H, trastuzumab; P, pertuzumab; PR, progesterone receptor; T, docetaxel; TCH, docetaxel/carboplatin/trastuzumab

22 Nahta, Breast Cancer Res Treat Aug;135(1):39-48

23 N 6377 JCO May 2012 JCO 2012 HER2+/ER+ LUMINAL A LUMINAL B, HER2- HER2+/ER- TRIPLE NEGATIVE

24 Chang J. ASCO 2011 TBCRC 006: Neoadjuvant Lapatinib & Trastuzumab Without Chemotherapy Lapatinib (1000 mg/day) Trastuzumab (4 mg/kg load, 2 mg/kg q-weekly) S u r g e r y Bx Weeks Lap (L) + Tras (T) + Endocrine Rx if ER+

25 Chang J. ASCO 2011 Neoadjuvant Lapatinib & Trastuzumab Without Chemotherapy pcr pcr+npcr pcr (%) % 21% 40% 53% 56% 48% 0 All ER+ ER - All ER+ ER-

26 PAMELA trial: PAM50 HER2-enriched phenotype as a predictor to early response to lapatinib and trastuzumab with o without letrozole in HER2-positive breast cancer Trastuzumab + Lapatinib x 18wks +/- AI HER2+ Confirmation of ER/PR by IHC PAM50 intrinsic subtypes Week 2 biopsy: PAM50, KI67, 450 genes Surgery wk Correlation pcr / PAM50 and IHC Weeks 2, 4 and every 4wks Tumor assessments

27 Enfermedad avanzada

28 Montemurro et al, Cancer 2012, 118:17 26 Quantitative expression of HR may influence response rate to trastuzumab and CT in MBC Multivariate Odds Ratio of response in tumors expressing ER in 30% of cells 0.422, 95% C.I , p = 0.009

29 Finn et al, J Clin Oncol Aug 20;27(24): EGF 30001: PFS according to ER HER2+/RE+ HER2+/RE

30 Blackwell, J Clin Oncol 28: , 2010 EGF104900: Phase III Study Evaluated Dual HER2 Blockade Crossover allowed to lapatinib + trastuzumab if progression after at least 4 weeks on therapy Staging occurred at 4, 8, 12, 16 weeks, and then every 8 weeks Steady state of single-agent lapatinib occurs at approximately 7 days

31 Blackwell, J Clin Oncol 28: , 2010 Updated Overall Survival in ITT 80% 70% 6 Month OS 56% L N =145 L+T N =146 Died, N (%) 113 (78) 105 (72) Median, months Hazard ratio (95% CI) 0.74 (0.57, 0.97) Log-rank P value % 12 Month OS

32 Blackwell, J Clin Oncol 28: , 2010

33 Montemurro et al, Cancer 2012, 118:17 26 Maintenance endocrine therapy added to HER2-targeting Group HR 95% C.I. P ER<30% 1 ER 30% No-HT ER 30% and HT ER 30% and HT ER<30 ER 30% No-HT

34 Nahta, Breast Cancer Res Treat Aug;135(1): Expression of HER2 may influence response to endocrine therapy

35 Johnston, J Clin Oncol 2009, 27: EGF 30008: HER2+ Population Letrozole (N = 108) Letrozole + Lapatinib (N = 111) Progressed or died 89 (82%) 88 (79%) Median PFS, mo Hazard ratio (95% CI) 0.71 (0.53, 0.96) p-value Follow-up: 1.8 y

36 Kaufman, J Clin Oncol 2009, 27: TANDEM: HER2+ (central), ER+ (local) Probability Events Median PFS 4.8 months 2.4 months 95% CI 3.7, , 4.6 p value HR % CI 0.47, 0.84 No. at risk A + H A Months CI, confidence interval PFS = time from randomisation to date of progressive disease or death

37 Massarweh S and Schiff R, Clin Cancer Res 2007;13: Compensatory mechanisms: Inhibition of one pathway may led to the activation of the other

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39 Nahta, Breast Cancer Res Treat Aug;135(1):39-48

40 CONCLUSIONES Identificar el subgrupo HER2+/RE+ que depende de la vía estrogénica es esencial para evitar el sobretratamiento con quimioterapia de pacientes que podrían ser óptimamente tratadas con terapia endocrina y antiher2. Existe evidencia que sugiere que este subgrupo de CM HER2+/ER+ puede ser identificado por el alto nivel de expresión del ER / plataformas moleculares (PAM 50). El crosstalk entre las vías estrogénica y HER2 es bidireccional resistencia a los agentes endocrinos resistencia a los agentes antiher2 Nuevos abordajes terapeúticos: - identificación molecular - doble bloqueo HER2 + terapia endocrina