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

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

Recurrence of HER2-positive breast cancer (A) Time to distant recurrence (B) Survival Probability 1.0 0.8 0.6 0.4 0.2 Censored Luminal A Luminal B Basal ErbB2+ Probability 1.0 0.8 0.6 0.4 0.2 0.0 p<0.01 0.0 p<0.01 0 24 48 72 96 120 144 168 192 0 24 48 72 96 Time to distant metastasis (months) Overall survival (months) Sorlie et al. Proc Natl Acad Sci USA 2003;100:8418 8423

Trastuzumab significantly increases median OS in HER2-positive MBC Overall survival (%) 100 80 60 40 20 0 RR=0.80 p=0.046 Median OS: 20.3 months Chemo (n=234) Chemo + trastuzumab (n=235) Median OS: 25.1 months 0 5 15 25 35 45 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;344:783 792

Adyuvancia

San Antonio Breast Cancer Symposium, December 4-8, 2012 N9831/B 31 Disease Free Survival % Event-Free AC P N Events AC P 2018 680 AC P+H 2028 473 81.4% 69.5% AC P+H 76.8% 64.9% 73.7% 62.2% HRadj=0.60 (95% CI: 0.53-0.68) P<0.0001 11.5% Years from Randomization No. at risk 2028 1959 1848 1747 1675 1611 1514 1293 910 619 350 2018 1887 1689 1529 1423 1329 1232 1027 705 449 255

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 1105 216 AC P+H 1110 124 AC P 911 175 917 103 21.5% Δ= 9.6% 11.9% AC P+H N Events AC P AC P+H Years from Randomization

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 2018 418 AC P+H 2028 286 HRadj=0.63 (95% CI 0.54-0.73) P<0.0001 No. at risk Years from Randomization 2028 1995 1959 1897 1843 1785 1709 1506 1085 735 439 2018 1962 1883 1806 1730 1640 1534 1336 944 604 353

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 1105 206 1110 137 AC P+H 86% 77.1% P= <0.0001 P= <0.0001 ER and PR Negative AC P AC P+H AC P AC P+H N Deaths 911 212 917 149 81.6% 73% HR: 0.61 (95%CI: 0.49-0.76) HR: 0.64 (95%CI: 0.52-0.79) Years from Randomization No. at risk 1110 1002 263 1105 925 204 917 782 176 911 713 148

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) 2005 1 yr MFU (0%) 2006 (4.3%) 2008 (33.8%) 2012 (48.6%) 2 yrs MFU 4 yrs MFU 8 yrs MFU 0.54 0.64 DFS benefit 0.76 0.76 Favours 1 year trastuzumabfavours observation 0 1 2 HR (95% CI) No. of DFS events 1 year trastuzumab vs observation 127 vs 220 P<0.0001 218 vs 321 P<0.0001 369 vs 458 P<0.0001 471 vs 570 P<0.0001

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) 2005 1 yr MFU (0%) 2006 2 yrs MFU (4.2%) 2008 4 yrs MFU (34.9%) 2012 8 yrs MFU (49.9%) ER positive 0.60 0.68 DFS benefit 0.84 0.81 0 1 2 Favours 1 year Favours trastuzumab observation HR (95% CI) No. of DFS events 1 year trastuzumab vs observation 53 vs 82 P=0.0034 87 vs 123 P=0.0049 162 vs 188 P=0.0941 218 vs 253 P=0.0258 Median follow-up (% follow-up time after selective crossover) 2005 1 yr MFU (0%) 2006 2 yrs MFU (4.5%) 2008 4 yrs MFU (32.5%) 2012 8 yrs MFU (47.1%) ER negative 0.50 0.62 DFS benefit 0.70 0.72 No. of DFS events 1 year trastuzumab vs observation 74 vs 138 P<0.0001 131 vs 198 P<0.0001 207 vs 270 P=0.0001 253 vs 317 P<0.0001 0 1 2 Favours 1 year Favours trastuzumab observation HR (95% CI)

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 0.76 0.66 0.85 0.76 Favours 1 year trastuzumabfavours observation 0 1 2 HR (95% CI) No. of deaths 1 year trastuzumab vs observation 29 vs 37 P=0.26 59 vs 90 P=0.0115 182 vs 213 P=0.1087 278 vs 350 P=0.0005

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 2005 1 yr MFU (0%) 2006 2 yrs MFU (4.0%) 2008 4 yrs MFU (32.4%) 2012 8 yrs MFU (47.2%) 0.69 0.84 1.03 1.67 16 vs 9 P=0.2146 20 vs 29 P=0.2063 75 vs 75 P=0.8616 126 vs 146 P=0.1425 2005 1 yr MFU (0%) 2006 2 yrs MFU (4.1%) 2008 4 yrs MFU (29.2%) 2012 8 yrs MFU (43.6%) 0.47 0.64 0.75 0.70 13 vs 28 P=0.0197 39 vs 61 P=0.0279 107 vs 138 P=0.0265 152 vs 204 P=0.0007 0 Favours 1 year trastuzumab 1 2 Favours observation HR (95% CI) 0 1 2 Favours 1 year Favours trastuzumab observation HR (95% CI)

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 (%) 100 80 60 40 20 90.3% 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 798 185 1.05 (0.85-1.29) 0.67 Disease-free survival (%) 100 80 60 40 20 87.8% 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 755 182 0.93 (0.76-1.14) 0.51 0 1 year 790 175 0 1 year 762 192 0 1 2 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9 Years from randomization Years from randomization No. at risk Trastuzumab 2 years 798 798 747 710 673 642 597 544 321 97 Trastuzumab 1 year 790 790 736 691 663 634 617 559 337 106 No. at risk Trastuzumab 2 years 755 755 695 651 619 581 556 507 312 97 Trastuzumab 1 year 762 762 677 628 602 580 563 512 312 99

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 1.00 1.00 0.75 0.75 DFS Probability 0.50 0.25 HR = 1.34 : 95%CI: (1.02 1.76), p=0.037 DFS Probability 0.50 0.25 HR = 1.23 : 95%CI: (0.92 1.65), p=0.15 0.00 ER negative T 12m T 6m 0 12 24 36 Months 48 60 Trastuzumab T 12m 716 668 568 410 221 6 T 6m 696 639 544 373 207 8 0.00 ER positive T 12m T 6m 0 12 24 36 Months 48 60 Trastuzumab T 12m 974 945 822 570 323 12 T 6m 994 947 809 566 319 15 Trastuzumab 12 months Trastuzumab 6 months Events N DFS-3 Events N DFS-3 ER negative 92 716 0.888 117 696 0.829 ER positive 83 974 0.920 102 994 0.912

Neoadyuvancia

Baselga, Lancet 2012, 379:633 640 NeoAltto: pcr according to ER

Gianni, Lancet Oncol 2012, 13: 25-32 NeoSphere: pcr according to ER 70 pcr, % 95% CI 60 50 40 30 20 10 0 20.0 H, trastuzumab; P, pertuzumab; T, docetaxel 36.8 26.0 63.2 5.9 ER or PR pos ER and PR neg 29.1 30.0 17.4 TH THP HP TP 7

Schneeweiss, SABCS 2011 Tryphaena: pcr according to ER Pathologic complete response (%) ER- and PR-negative ER- and/or PR-positive 83.8 79.4 65.0 46.2 48.6 50.0 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

Nahta, Breast Cancer Res Treat. 2012 Aug;135(1):39-48

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

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 0 2 8 12 Weeks Lap (L) + Tras (T) + Endocrine Rx if ER+

Chang J. ASCO 2011 Neoadjuvant Lapatinib & Trastuzumab Without Chemotherapy pcr pcr+npcr 70 60 pcr (%) 50 40 30 20 10 28% 21% 40% 53% 56% 48% 0 All ER+ ER - All ER+ ER-

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 21-23 Correlation pcr / PAM50 and IHC Weeks 2, 4 and every 4wks Tumor assessments

Enfermedad avanzada

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. 0.222-0.803, p = 0.009

Finn et al, J Clin Oncol. 2009 Aug 20;27(24):3908-15 EGF 30001: PFS according to ER HER2+/RE+ HER2+/RE

Blackwell, J Clin Oncol 28:1124-1130, 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

Blackwell, J Clin Oncol 28:1124-1130, 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 9.5 14 Hazard ratio (95% CI) 0.74 (0.57, 0.97) Log-rank P value.026 41% 12 Month OS

Blackwell, J Clin Oncol 28:1124-1130, 2010

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 0.747 0.516-1.081 0.122 ER 30% and HT 0.502 0.313-0.807 0.004 ER 30% and HT ER<30 ER 30% No-HT

Nahta, Breast Cancer Res Treat. 2012 Aug;135(1):39-48. Expression of HER2 may influence response to endocrine therapy

Johnston, J Clin Oncol 2009, 27:5538 5546 EGF 30008: HER2+ Population Letrozole (N = 108) Letrozole + Lapatinib (N = 111) Progressed or died 89 (82%) 88 (79%) Median PFS, mo 3.0 8.2 Hazard ratio (95% CI) 0.71 (0.53, 0.96) p-value 0.019 Follow-up: 1.8 y

Kaufman, J Clin Oncol 2009, 27:5529 5537 TANDEM: HER2+ (central), ER+ (local) Probability 1.0 0.8 0.6 0.4 Events 87 99 Median PFS 4.8 months 2.4 months 95% CI 3.7, 7.0 2.0, 4.6 p value 0.0016 0.2 HR 0.63 95% CI 0.47, 0.84 No. at risk A + H A 0.0 0 5 10 15 20 25 30 35 40 45 50 55 60 Months 103 48 31 17 14 13 11 9 4 1 1 0 0 104 36 22 9 5 4 2 1 0 0 0 0 0 CI, confidence interval PFS = time from randomisation to date of progressive disease or death

Massarweh S and Schiff R, Clin Cancer Res 2007;13:1950-1954 Compensatory mechanisms: Inhibition of one pathway may led to the activation of the other

Nahta, Breast Cancer Res Treat. 2012 Aug;135(1):39-48

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