Existe-t-il un sous groupe à risque qui pourrait bénéficier d une modification de la durée de traitement par trastuzumab? X. Pivot CHRU De Besançon

Existe-t-il un sous groupe à risque qui pourrait bénéficier d une modification de la durée de traitement par trastuzumab? X. Pivot CHRU De Besançon

In 25 results of 4 Adjuvant Herceptin trials have definitively changed the standard of care HERA Observation NSABP B-31 4 x AC 4 x paclitaxel 175 mg/m 2 HER2+ (IHC or FISH) Accepted CT: AC, EC, FAC, FEC, ET, AT, CMF 1 year Herceptin 2 years Herceptin HER2+ (IHC or FISH) 1 year Herceptin NCCTG N9831 4 x AC 12 x paclitaxel 9 mg/m 2 BCIRG 6 AC T 4 x AC 4 x docetaxel 6/6 mg/m 2 1 mg/m 2 HER2+ (IHC or FISH) 1 year Herceptin HER2+ (FISH) n=3222 AC TH TCH 1 year Herceptin 6 x docetaxel and platinum salts 75 mg/m 2 75 mg/m 2 or AUC 6 FISH, fluorescence in situ hybridisation 1 year Herceptin

DFS and OS benefits were demonstrated during longterm follow-up in the four pivotal clinical trials of trastuzumab for 1 year Study HERA 1 4 CT±RT T vs. CT±RT NCCTG N9831/ NSABP B-31 5 7 AC Tax+T T vs. AC Tax BCIRG 6 8 DFS OS Follow-up (years) N HR p value HR p value 1 3387.54 <.1.76.26 2 341.64 <.1.66.115 4 341.76 <.1.85.187 8 3399.76 <.1.76.5 2 3351.48 <.1 4 445.52 <.1.61 <.1 8.4 446.6 <.1.63 <.1 AC Tax + T vs. AC Tax.64 <.1.63 <.1 5.4 3222 Tax+Cb T vs. AC Tax.75.4.77.4 AC, doxorubicin and cyclophosphamide; Cb, carboplatin; CT, chemotherapy; DFS, disease-free survival; HR, hazard ratio; OS, overall survival; RT, radiotherapy; T, trastuzumab; Tax, taxane. 1. Piccart-Gebhart MJ, et al. N Engl J Med 25; 353:1659 1672; 2. Smith I, et al. Lancet 27; 369:29 36; 3. Gianni L, et al. Lancet Oncol 211; 12:236 244; 4. Goldhirsch A, et al. Lancet 213; 382:121 128; 5. Romond EH, et al. N Engl J Med 25; 353:1673 1684; 6. Perez EA, et al. J Clin Oncol 211; 29:3366 3373; 7. Perez EA, J. Clin Oncol 214 32: 3744-3752 ; 8. Slamon D, et al. N Engl J Med 211; 365:1273 1283.

Probability In low risk cases: Paclitaxel + Trastuzumab seemed to be enough Phase II trial 46 patients, T < 3 cm Median follow up 4 years Occurrence of only 2 metastatic events 1,,8,6 DFS,4,2 12 24 36 48 6 72 Months Number at risk 46 39 385 366 193 67 5 La Lettre du Cancérologue Tolaney SM, et al. N Engl J Med. 215;372(2):134-41.

Is anthracycline containing regimen required in adjuvant HER2 + Breast Cancer?: BCIRG 6 AC T 4 x AC 6/6mg/m 2 4 x docetaxel 1mg/m 2 HER2+ FISH n=3,15 N+, highrisk N AC TH TCH 1-year Herceptin 6 x docetaxel and carboplatin 75mg/m 2 AUC 6 Slamon D, et al. N Engl J Med 211; 365:1273 1283. 1-year Herceptin

Disease-free survival (%) BCIRG 6 : DFS AC-T TCH AC-T + trastu DFS 5 years 75 % 81 % 84 % All patients HR (vs TC-H),75 ; p =,4,64 ; p <,1 1 8 6 87 % 93 % 92 % 81 % 88 % 87 % 78 % 86 % 84 % 84 % 81 % 75 % AC-T trastuzumab AC-T TCH 4 2 12 24 36 48 6 72 84 Months AC-T = Doxorubine cyclophosphamide followed by docetaxel +/- trastuzumab La Lettre du Cancérologue TCH = Docetaxel carboplatine trastuzumab Slamon. D et al. N Engl J Med. 211;365(14):1273-83.

BCSS probability T1 HER2+ Cohorte néerlandaise de 3512 patientes Survie spécifique T1a T1b T1c Temps (années) Temps (années) Temps (années) Treated - Untreated Van Ramshort MS. et al., SABCS 215, S6-6

Several ongoing trials are investigating the optimal duration of trastuzumab in HER2-positive ebc Trastuzumab for <1 year vs. trastuzumab for 1 year Trastuzumab for 2 years vs. trastuzumab for 1 year 6 months 9 weeks 2 years 1 year (standard of care) PHARE 6 months vs. 1 year 1 SOLD 4 9 weeks vs. 1 year HERA 2 years vs. 1 year 7 HERA 1 year vs. observation 8 1 HORG 6 months vs. 1 year 2 SHORT-HER 9 weeks vs. 1 year 5 NCCTG N9831 11 NSABP B-31 12 PERSEPHONE 6 months vs. 1 year 3 FinHer 9 weeks vs. chemo 6 BCIRG 6 12 Trastuzumab for 1 year remains the standard of care in ebc, as recommended by international guidelines 13 15 1. Pivot X, et al. Lancet Oncol 213; 14:741 748; 2. http://clinicaltrials.gov/ct2/show/nct61562; 3. Earl HM, et al. ASCO 213. Abstract TPS667; 4. http://clinicaltrials.gov/ct2/show/nct593697; 5. http://clinicaltrials.gov/ct2/show/nct629278; 6. Joensuu H, et al. J Clin Oncol 29; 34:5685 5692; 7. Goldhirsch A, et al. Lancet 213; 382:121 128; 8. Piccart-Gebhart MJ, et al. N Engl J Med 25; 353:1659 1672; 9. Smith I, et al. Lancet 27; 369:29 36; 1. Gianni L, et al. Lancet Oncol 211; 12:236 244; 11. Perez EA, et al. J Clin Oncol 211; 29:3366 3373; 12. Slamon D, et al. N Engl J Med 211; 365:1273 1283; 13. NCCN Clinical Practice Guidelines in Oncology; Breast Cancer v3.213; 14. Senkus E, et al. Ann Oncol 213 [Epub ahead of print]; 15. Goldhirsch A, et al. Ann Oncol 213 [Epub ahead of print]. Reported Ongoing

DFS (%) OS (%) HERA: Trastuzumab for 2 years did not show any additional benefit compared to 1 year of treatment DFS 1 OS 2 1 8 6 4 89.1% 86.7% 81.6% 81.% 75.8% 76.% Trastuzumab 2 years Trastuzumab 1 year 1 8 6 4 97.4% 96.5% 92.6% 91.4% 86.4% 87.6% Trastuzumab 2 years Trastuzumab 1 year 2 2 1 2 3 4 5 6 7 8 9 1 2 3 4 5 6 7 8 9 Years from randomisation Years from randomisation Patients Events HR (2 vs. 1 year) 95% CI p value 2 years 1553 367.99 (.84, 1.14).86 1 year 1552 367 Patients Events HR (2 vs. 1 year) 95% CI p value 2 years 1553 196 1.5 (.86, 1.28).63 1 year 1552 186 Goldhirsch A, et al. Lancet 213; 382:121 128 1. Goldhirsch A, et al. Lancet 213; 382:121 128; 2. Goldhirsch A, et al. SABCS 212. Oral presentation S5-2.

DDFS (%) OS (%) FinHer: No statistically significant improvement in DDFS or OS with 9 weeks of trastuzumab vs. chemotherapy alone DDFS OS 1 8 6 9.4% 77.6% 83.3% 73.% 1 8 6 95.7% 9.5% 91.3% 82.3% 4 2 Trastuzumab 9 weeks + chemotherapy Chemotherapy 4 2 Trastuzumab 9 weeks + chemotherapy Chemotherapy 1 2 3 4 5 6 7 Years from randomisation 1 2 3 4 5 6 7 Years from randomisation Patients Events HR (9 weeks vs. none) 95% CI p value 9 weeks 115 22.65 (.38, 1.12).12 Chemo 116 31 Patients Events HR (9 weeks vs. none) 95% CI p value 9 weeks 115 12.55 (.27, 1.11).94 Chemo 116 21 CI, confidence interval; DDFS, distant disease-free survival. Joensuu H, et al. J Clin Oncol 29; 27:5685 5692.

DFS (%) OS (%) PHARE: Non-inferiority of 6 months vs. 1 year of trastuzumab was not demonstrated Primary endpoint: DFS OS 1 8 1 8 6 6 4 Trastuzumab 6 months Trastuzumab 1 year 4 Trastuzumab 6 months Trastuzumab 1 year 2 2 12 24 36 48 6 12 24 36 48 6 Patients Events Months from randomisation HR (6 months vs. 1 year) 95% CI p value 6 months 169 219 1.28* (1.5, 1.56) 1 year 169 175.29 HR (95% CI): 1.28 (1.5, 1.56) (above the pre-specified non-inferiority CI of 1.15) Positive heterogeneity test 6 months Patients Events HR (6 months vs. 1 year) 95% CI p value 169 93 1.46 (1.6, 2.1).3 1 year 169 66 Months from randomisation HR (95% CI): 1.46 (1.6, 2.1) Pivot X, et al. Lancet Oncol 213;14:741 748. Pivot X. Lancet Oncol 214; 1:5:125-126

APHINITY Primary Objectif Invasive Disease-Free Survival (IDFS) Expected results in 217

Trastuzumab Chimio Pop cible Niveau de preuve Standard 1 an A + T N+ I Alternative 1 an TC N+ II Alternative 1 an T N- / < 3cm II Avenir? + Pertuzumab APHINITY Sans bénéfice 2 ans I? 9 semaines Shorter? 6 mois? PHARE / PERSEPHONE