"Strategia Multidisciplinare nel Trattamento del Carcinoma della Mammella HER2+"Chieti, 20 Dicembre 2011
Carcinoma della mammella HER2+: terapia Carcinoma della mammella HER2+: terapia
adiuvante, in particolare pT<1cm pN0adiuvante, in particolare pT<1cm pN0
A. Nuzzo U.O. di Oncologia Medica
ospedale Renzetti di Lanciano (CH)
“… Vogliamo ricordarlo con il suo sorriso sempre ironico, con la sua forza di volontà ferrea che andava oltre le avversità della vita, la sua intelligenza e il grande amore per i suoi figli. Vogliamo ricordarlo per come amava la vita e come la vita per lui era un impegno continuo per l’oncologia e per la nostra Associazione. ….”
L’Associazione Italiana di Oncologia Medica
Citri A, Yarden Y,EGF-ERBBsignalling: towardsthe systems level,Nat Rev Mol CellBiol, 7:505,2006
Her2 nelle neoplasie
• Membro della famiglia dei recettori tirosina chinasi dell’EGFR• Ruolo importante nel promuovere la trasformazione neoplastica e la crescita tumorale• Significativa correlazione positiva tra la prevalenza dell’iperespressione e la progressione della malattia.
Citri A, Yarden Y, Nat Rev Mol Cell Biol, 2006
Farmaci in uso clinico contro Her2
Trial schema of North Central Cancer Treatment Group (NCCTG) N9831 and National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31.
Perez E A et al. JCO 2011;29:3366-3373
©2011 by American Society of Clinical Oncology
pT1 39%1585/4045
Kaplan-Meier estimates of (A) event-free survival and (B) overall survival.
Perez E A et al. JCO 2011;29:3366-3373
©2011 by American Society of Clinical Oncology
Trial schema of North Central Cancer Treatment Group (NCCTG) N9831 and National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31.
Perez E A et al. JCO 2011;29:3366-3373
©2011 by American Society of Clinical Oncology
Kaplan-Meier curves showing (A) disease-free survival (DFS) and (B) overall survival (OS) for the comparison of arm A and arm B and (C) DFS and (D) OS for the comparison of arm B and
arm C. Hazard ratios (HRs; with 95% CIs and P values) for pairwise compari...
Perez E A et al. JCO 2011;29:4491-4497
©2011 by American Society of Clinical Oncology
pT1 40 %1283/3222
BCIRG-006
BCIRG-006
D Slamon et al, NEJM 2011
BCIRG-006
D Slamon et al, NEJM 2011
median follow-up 65 months
BCIRG-006
D Slamon et al, NEJM 2011
BCIRG-006 pT1 ≤ 1 cm pN+
D Slamon et al, NEJM 2011
5y DFS HR
AC-T 72%
AC-T-H 86% 0,36 P=0.03
TCH 86% 0.45 P=0.09
HERA trial
Treatment with trastuzumab for 1 year after adjuvant chemotherapy in patients with
HER2-positive early breast cancer: a 4-year follow-up of a randomised controlled trial.
Gianni L, et al: Herceptin Adjuvant (HERA) Trial Study Team.Lancet Oncol. 2011
HERA trial
• Overall, 885 patients (52%) of the 1698 patients in the observation group crossed over to receive trastuzumab, and began treatment at median 22,8 months (range 4,5-52,7) from randomisation.
• In a non-randomised comparison, patients in the selective-crossover cohort had fewer disease-free survival events than patients remaining in the observation group (adjusted HR 0,68; 95% CI 0,51-0,90; p=0·0077).
L Gianni et al, Lancet Oncol. 2011
L Gianni et al, Lancet Oncol. 2011
HERA trial
intention-to-treat analysis
censored analysis
Adjuvant Trastuzumab Breast Cancer TrialsAdjuvant Trastuzumab Breast Cancer TrialsSevere CHF Syst. dysf.
HERACT
CT Trast 0.6% 3.0%
NSABP B-31AC Ptx
AC Ptx+Trast 3.6% 15.9%
NCCTG N 9831AC Ptx
AC Ptx+Trast 2.5/3.3% 14/17%
BCIRG 006AC Docet
AC Docet + trast
TC + Trast1.9%0.4%
18.1%8.6%
FinHERDocet +/- Trast
Vinblast +/- Trast 0% 3.5%
HER2-blockingantibody trastuzumab in conjuction with chemotherapy is the standard adjuvant therapy in HER2–positivetumors ≥ 1 cm or pN+
• With routine mammographic screening and use of breast magnetic resonance imaging it is more common that women present for consideration of adjuvant systemic therapy for small node-negative tumors
B Fisher, JCO 2002
Fig 1.
Fisher B et al. JCO 2002;20:4141-4149
©2002 by American Society of Clinical Oncology
pT1 <1cm pN0
Fisher B, et al. J Clin Oncol 2002
Median follow-up time: 87 months
MethodsComprehensive review of the literature describing outcome and prognostic factors in stage T1a, b N0M0 breast cancer
ResultsEarly studies: 10-yr RFS >90% without adjuvant systemic therapy, but some more recent data suggest < outcomePoor prognostic factors: high grade, lymphovascular invasion (LVI), younger age (<35 years), high ki67 and larger tumors within the T1a-b subgroup, HER2 +
Retrospective review of outcomes for pts with pT1a-b pN0 early breast cancre (no adjuvant chemotherapy)
Araki et al, Breast Cancer 2011
Araki et al, Breast Cancer 2011
Clinical outcomes of pts with HER2-overexpressing pT1a-b pN0 early breast cancer
Outcome by combination of HER-2 and HRs status
N= 2130 T1a,bN0M0 patients , HER2+ n=150Adjuvant chemotherapy ~ 50% of patients with HR-negative disease
median follow-up = 4.6 years
91% 92%
99% 92%
Conclusions: In patients with HR–positive disease and pT1a-b, N0 tumors, HER2 overexpression was associated with a worse DFS
Curigliano et al. J Clin Oncol 2009
pT1a pN0 pT1b pN0
San Gallo 2011 no Trastuzumab
ESMO no Trastuzumab
NCCN no Trastuzumab
Current possible clinical management of pts with HER2-overexpressing pT1a-b pN0 breast cancer
Adjuvant Trastuzumab BC TrialsAdjuvant Trastuzumab BC TrialsSevere CHF Syst. dysf.
HERACT
CT Trast 0.6% 3.0%
NSABP B-31AC Ptx
AC Ptx+Trast 3.6% 15.9%
NCCTG N 9831AC Ptx
AC Ptx+Trast 2.5/3.3% 14/17%
BCIRG 006AC Docet
AC Docet + Trast
TC + Trast1.9%0.4%
18.1%8.6%
FinHERDocet +/- Trast
Vinblast +/- Trast 0% 3.5%
< 40 % pT1
~ 0% pT1a-b pN0
ShortHER: TRATTAMENTO ADIUVANTE CON HERCEPTIN PER 3 MESI VERSO 12 MESI, IN ASSOCIAZIONE CON 2
DIFFERENTI REGIMI DI CHEMIOTERAPIA, NELLE PAZIENTI CON CARCINOMA MAMMARIO HER2 POSITIVE
CRITERI DI INCLUSIONE• Donne con carcinoma mammario operato radicalmente• Tumori HER2 positivi, definiti come score 3+ in
immunoistochimica, o come FISH positivi• Tumori candidati a chemioterapia in rapporto alle seguenti
caratteristiche:– linfonodi positivi– linfonodi negativi ad alto rischio secondo San.Gallo (almeno uno
tra i seguenti: T> 2 cm, G3, invasione vascolare/linfatica, elevata proliferazione (Ki67 > 20%), età < 35 anni, recettori ormonali (RE e PG) negativi (< 10%) ; oppure T> 1cm associato ad uno o più dei parametri soprariportati.
Clinical trial for pts with HER2-overexpressing stage pT1a-b pN0 breast cancer
• Small HER2-positive node-negative are rare (6-10% of incidence)
• The rate of events are relatively low
• A large sample size would be needed to confirm the efficacy of trastuzumab
• Could be accepted a treatment arm without trastuzumab?
Treatment benefit from adjuvant trastuzumab for pts with HER2-overexpressing pT1a-b pN0 breast cancer
Araki et al, Breast Cancer 2011
ClinicalTrial.gov: NCT005422451
• Dana-Faber Cancer Institute phase II trial
• women with pT1a-b-c pN0 HER2-positive (400 recruited)
• 12-week regimen of paclitaxel and trastuzumab
• The risk of recurrence for such small cancers remains ill characterized, and given the expectation of better outcomes with these small tumors, it seems hard to justify the rare but potentially serious risks of adjuvant chemotherapy and trastuzumab, including serious infection, congestive heart failure, acute leukemia.
T1a-b HER2-positive tumors
M. Crump et al., J Clinical Oncology 2003
Risk of Acute Leukemia Following Epirubicin-Based Adjuvant Chemotherapy: :
A Report From the National Cancer Institute of Canada Clinical
Trials Group
BCIRG-006
T1a-b HER2-positive tumors
T1a-b HER2-positive tumors
Trastuzumab Trastuzumab + Lapatinib Trastuzumab + Pertuzumab
Conclusions I
• HER2-positivity is an indipendent predictor of disease recurrence and breast cancer-related mortality
• There is no direct evidence that trastuzumab will decrease the recurrence rate among patients with small, HER2-positive tumors.
• few of the women in any of the reported series had T1a tumors ( 5 mm in size).
Conclusions II
• some circumstantial evidence could justify some form of trastuzumab-based adjuvant therapy in most women with T1b (>0.5 to ≤1 cm), N0, HER2-positive breast cancers
• among women with smaller, node-negative, HER2-positive breast cancers, is worth exploring trastuzumab-based chemotherapy regimens that may have less short-term toxicity and may be better tolerated
Conclusions III
• absolute benefits from adjuvant therapies will be smaller in pT1pN0 than in more advanced stage tumors
• adjuvant treatments with the smallest risk of long-term side-effects should be prioritized– Less than 1 year trastuzumab treatment– Trastuzumab either alone or in combination (without
chemotherapy)
• In the absence of randomized clinical trials, the benefits and risks of adjuvant trastuzumab should be discussed with patients with small, HER2-positive breast cancer
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