Positività per HER-2 nei carcinomi subcentimetrici

Transcription

1 Positività per HER-2 nei carcinomi Antonella Ferro U.O. Oncologia Medica Trento Small Tumors Small tumors are becoming increasingly common with the use of mammography > screening Some of these tumors, in spite of small sizes, show poor biological charactheristics affecting prognosis Positive HER-2 Triple negative Poor grading Controversy surrounds the prognosis of these patients with locoregional therapy only and the need for adjuvant systemic therapy.

2 HER2-positivity in small (<1cm) tumors HER2 gene amplification or overexpression is relatively uncommon in small, stage I breast cancers It accounts for fewer than 10% of all occurrences in several studies Nostra casistica Dal 1990 al 2006: 882 casi T1a-b. 62 (7%) HER-2 pos Limiti delle metodiche HER-2 +nel 18.8% dei T 1mic, nel 20.6% dei T 1a, nel 9.7% dei T 1b SABCS 2008; abs 1075

3 Increasing evidence suggests HER2-positivity is a negative prognostic factor in patients with small (<1cm) node-negative tumours Study n Tumour size Endpoint HER2+ vs HER2 % p value Joensuu et al T1a,b 9-year DDFS 67 vs Rakkhit et al T1a,b 5-year RFS 77.1 vs 93.7 < Amar et al T1a,b RFS 92.6 vs Tovey et al T1a,b,c 5-year BCSS 68 vs 96 <0.001 Pagani et al T1a,b RFS 87.1 vs 96.8 NR Norris et al T1a,b,c 10-year RFS 75.6 vs Choi OS DFS 64 Vs vs 73 p<.001 p=.006 S. Swain ASCO 09 BCSS = breast cancer specific survival; DDFS = distant disease-free survival RFS = relapse-free survival; NR = not reported T 1 a e b T1c 852 pt1n0m0 cancer; median followup: 9.5 years. Only 5% received systemic adjuvant therapy Strong erbb2 expression or the presence of >20% Ki-67-positive cells was associated with >20% risk Joensuu et al CCR 2003

4 Poor 10 yr breast cancer specific survival (BCSS) and relapse free survival (RFS) for HER-2 positive T1pN0 tumors Breast cancer-specific survival in T1pN0 cohort (Norris, et al) HER2- /ER+ HER2- /ER- HER2+ /ER+ HER2+ /ER- T1N0 = yr BCSS 10-yr RFS % 89% 85% 70% 78% 77% 75% 61%

5 Outcome of HER2+ T1a,b N0 tumors (without Trastuzumab) ) SABCS 2008 Author Pt # cohorts Median FU Relapses % P value Ananthakrishna n abst 6058 SABCS HER2- HER2+ 48 mo ns Tovey abstr 702 SABCS HER2-58 HER2+ 60 mo HR 6.7 Rakkhit abstr 701 SABCS % HR+ve 23% TN 9% HER2+ve 74 mo HR 2.7 Significant increased recurrence rates among breast cancer patients with HER2-positive, T1a,b N0 M0 tumors. Survival Estimates RFS 5-year 95%CI 10-year 95%CI p-value HER % (69.2%, 84.9%) 61.7% (49.1%, 72%) HR+ HER neg 95.6% (94%, 96.8%) 88.2% (84.4%, 91.1%) TN 90.4% (86.3%, 93.3%) 80.0% (71%, 86.4%) <.0001 DRFS 5-year 95%CI 10-year 95%CI p-value HER % (79.6%, 92.7%) 80.1% (66.8%, 88.5%) HR+ HER neg 97.8% (96.5%, 98.6%) 93.8% (90.7%, 95.9%) TN 95.2% (91.8%, 97.2%) 91.9% (85.9%, 95.4%) <.0001 Rakkhit R et al abst.704 SABCS 2008

6 HER2 positivity alone confers either intermediate- or high-risk status Patients with small (<1cm) node-negative tumours Recurrencefree survival HR+/HER2 TN HER HR: 2.7, 95% CI n Events 5-year RFS a p value HR+/HER2 TN HER < Months from diagnosis The 5-year recurrence rate of HER2-positive patients with tumors that were 1 cm or less was 23% a MDACC recurrence-free survival estimate HR = hormone receptor; TN = triple receptor-negative Rakkhit et al 2008 A tissue microarray (TMA) series was constructed consisting of 4,444 (2026 Node negative) invasive breast cancers diagnosed in British Columbia from 1986 to The TMA series was assessed for estrogen receptor (ER) and HER2. Within the node-negative cohort, 326 patients (16%) had a primary tumor size of 1 cm or less. Furthermore, 268 of these patients (82%) did not receive any adjuvant systemic therapy. Within these two subgroups, only 21 and 16 patients, respectively, had HER2 overexpression. Chia JCO 2008

7 There was a trend toward worse RFS for the HER2-overexpressed patients, but there was no difference in BCSS by HER2 Status T1b Focusing further within the patients with T1b who did not receive any adjuvant systemic therapy (n 225), the HER2- positive patients (n 13) trended to have a worse outcome than HER2-negative pts: 10-year RFS: 68.4% v 81.8% (P.312) Chia JCO 2008

8 Conclusions of the authors Only 50% of our HER2 positive EBC patients received trastuzumab therapy in The commonest reason for not receiving trastuzumab was low risk status precluding chemotherapy. BUT No HER2 positive patient should be considered low risk Tovey SM et al abst.702 SABCS 2008 HER2 positivity alone confers either intermediate- or high-risk status (St Gallen) HER2 is recognised in guidelines as an independent risk factor Even in T1N0 disease, HER2-positive status is associated with a significant risk of relapse Time (years) Goldhirsch, et al. Ann Oncol 2007

9 A total of 2,130 patients with pt1a-b, pn0, M0; 150 pts with pt1a-b, pn0, HER2-positive tumors In patients with hormone receptor positive, pt1a-bn0, HER2 overexpression was associated with a dire prognosis (HR, 5.2; 95% CI, 1.0 to 25.9). The lack of prognostic value for HER2 status in women with ER-negative tumors is most likely caused by the high risk of disease recurrence for patients who have triple-negative tumors compared with women who have ER-positive and HER2- negative disease. Patients with HER2-positive tumors have worse outcomes than those with HER2-negative tumors, particularly in the subgroup of endocrine-unresponsive tumors. The potential impact of adjuvant trastuzumab therapy in this patient population remains unknown The chance of systemic recurrence through 10 years of followup for HER2-positive, node-negative, stage I breast cancers probably would be a justification to offer adjuvant trastuzumab therapy, even to patients with tumors1 cm

10 Which adjuvant therapy in HER-2 positive infracentimetric cancer? St Gallen 2009 Consensus Conference Should overexpressed or amplified HER be an indication for Chemotherapy? YES 76 NO 22 Uncertain %

11 St Gallen 2009 Consensus Conference Is there a standard regimen for HER2 positive phenotype? % NCCN guidelines

12 Trastuzumab yes or not?

13 Oltre pazienti arruolate in 4 studi clinici multicentrici in adiuvante HERA (ex-usa) BCIRG 006 (global) IHC / FISH (n=5,090) Observation 1 year 2 years FISH (n=3,222) 1 year 1 year NCCTG N9831 (USA) NSABP B-31 (USA) IHC / FISH (n=3,505) 1 year IHC / FISH (n=2,030) 1 year 1 year Standard CTx Doxorubicin + cyclophosphamide Docetaxel Docetaxel + carboplatin Trastuzumab Paclitaxel IHC, immunohistochemistry FISH, fluorescence in situ hybridisation CTx, chemotherapy Piccart-Gebhart et al 2005 Romond et al 2005; Slamon et al 2006 Do small tumors benefit from trastuzumab? Adjuvant Trial NSABP-B31/ NCCTG-9831 (romond EH et al. NEJM, 2005) HERA trial (Piccart-Gebhart MJ et al. NEJM, 2005) BCIRG 006 (Slamon D et al. SABCS, 2006) Fin Her (Joensuu H et al. Nejm, 2006) Node-negative tumors 5.7% 32% 29% 16% Comments > 2 cm and HR + or > 1 cm and HR - All tumors 1 cm Grade 2 or HR negative or 35 yrs Tumors 2 cm and PgR negative S. Swain ASCO 09

14 Trastuzumab migliora DFS indipendentemente dalla dimensione del tumore HERA N9831 / B cm >2-5 cm >5 cm 0-2 cm >2-5 cm >5 cm BCIRG 006 AC DH <2 cm 2 cm DCarboH <2 cm 2 cm DFS, disease-free survival Favours Trastuzumab Favours no Trastuzumab HR Slamon et al 2006 Perez et al 2007; Smith et al 2007 Trastuzumab migliora DFS benefit indipendentemente da coinvolgimento di N HERA N nodes 4+ nodes Not assessed N9831 / B-31 N nodes 4-9+ nodes >10+ nodes BCIRG 006 AC DH DCarboH N- N+ N- N+ N, node Favours trastuzumab Favours no trastuzumab HR Slamon et al 2006 Perez et al 2007; Smith et al 2007

15 Outcome of HER2+ T1c N0 tumors HERA Trial (510 pts) 3 yrs DFS for HER2+: 91.3% with Trastuzumab, vs 86.7% without trastuzumab Treatment of node-negative infra-centimetric HER2+ invasive breast carcinomas: a joint AERIO/REMAGUS study Retrospective multicentre series From 2000 to 2008 HER2+ EBC Infracentimetric breast tumors (T<1cm) N=96 N=75/96 node negative ASCO 09 - M. J. Rodrigues et al., Abstract No: 517

16 AERIO/REMAGUS study Results N=33/75 (44%) treated with CHT N=31 with addition of trastuzumab After 25 months median follow up No pts on CHT + trastuzumab relapsed 7% pts without trastuzumab relapsed ASCO 09 - M. J. Rodrigues et al., Abstract No: 517

17 Trastuzumab in small breast cancer Trastuzumab should be considered also for small HER2+ breast cancer Uncertainty as to administer T in these cases Alone (HERTAX data) With Chemo (maybe sequential) With hormones (in ER+) (TANDEM and EGF3008 data)

18 St Gallen 2009 Consensus Conference Could trastuzumab be given without chemotherapy, but with endocrine therapy, for HER2 positive, highly endocrine responsive and node-negative tumors? YES 33 NO 51 Uncertain % Conclusions HER2 positivity is a powerful negative prognostic factor for patients with tumors 1 cm or less Systemic treatment (chemo, hormone and anti-her2 directed therapies) should be strongly considered in this population Clinical prospective studies including this group are necessary.