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"Strategia Multidisciplinare nel Trattamento del Carcinoma della Mammella HER2+"
Chieti, 20 Dicembre 2011
Carcinoma della mammella HER2+: terapia
adiuvante, 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
Her2 nelle neoplasie
Citri A, Yarden Y,
EGF-ERBB
signalling: towards
the systems level,
Nat Rev Mol Cell
Biol, 7:505,2006
• 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.
Farmaci in uso clinico contro Her2
Citri A, Yarden Y, Nat Rev Mol Cell Biol, 2006
Trial schema of North Central Cancer Treatment Group (NCCTG) N9831 and National Surgical
Adjuvant Breast and Bowel Project (NSABP) B-31.
pT1 39%
1585/4045
Perez E A et al. JCO 2011;29:3366-3373
©2011 by American Society of Clinical Oncology
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
BCIRG-006
pT1 40 %
1283/3222
BCIRG-006
D Slamon et al, NEJM 2011
BCIRG-006
median follow-up 65 months
D Slamon et al, NEJM 2011
BCIRG-006
D Slamon et al, NEJM 2011
BCIRG-006 pT1 ≤ 1 cm pN+
5y DFS
HR
AC-T
72%
AC-T-H
86%
0,36 P=0.03
TCH
86%
0.45 P=0.09
D Slamon et al, NEJM 2011
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
HERA trial
intention-to-treat
analysis
censored analysis
L Gianni et al, Lancet Oncol. 2011
Adjuvant Trastuzumab Breast Cancer Trials
Severe CHF
Syst. dysf.
0.6%
3.0%
HERA
CT
CT Trast
NSABP B-31
AC  Ptx
AC  Ptx+Trast
NCCTG N 9831
AC  Ptx
AC  Ptx+Trast
BCIRG 006
AC  Docet
AC  Docet + trast
TC + Trast
FinHER
Docet  +/- Trast
Vinblast  +/- Trast
HER2-blocking
antibody
3.6%
15.9%
trastuzumab
in conjuction with
2.5/3.3%
14/17%
chemotherapy
is the
standard adjuvant
therapy
in 18.1%
1.9%
0.4%
8.6%
HER2–positive
tumors ≥ 1 cm or
pN+
0%
3.5%
• 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
Median follow-up time: 87 months
Fisher B, et al. J Clin Oncol 2002
Methods
Comprehensive review of the literature describing
outcome and prognostic factors in stage T1a, b N0M0
breast cancer
Results
Early studies: 10-yr RFS >90% without adjuvant
systemic therapy, but some more recent data suggest
< outcome
Poor 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
Clinical outcomes of pts with HER2-overexpressing
pT1a-b pN0 early breast cancer
Araki et al, Breast Cancer 2011
Outcome by combination of HER-2 and
HRs status
N= 2130 T1a,bN0M0 patients , HER2+ n=150
Adjuvant 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
Current possible clinical management of pts with
HER2-overexpressing pT1a-b pN0 breast cancer
pT1a pN0
pT1b pN0
San Gallo 2011
no
Trastuzumab
ESMO
no
Trastuzumab
NCCN
no
Trastuzumab
Adjuvant Trastuzumab BC Trials
Severe CHF
Syst. dysf.
0.6%
3.0%
3.6%
15.9%
HERA
CT
CT Trast
NSABP B-31
AC  Ptx
AC  Ptx+Trast
NCCTG N 9831
AC  Ptx
AC  Ptx+Trast
BCIRG 006
AC  Docet
AC  Docet + Trast
TC + Trast
< 40 % pT1
14/17%
~2.5/3.3%
0% pT1a-b
pN0
1.9%
0.4%
18.1%
8.6%
0%
3.5%
FinHER
Docet  +/- Trast
Vinblast  +/- Trast
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
T1a-b HER2-positive tumors
• 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.
Risk of Acute Leukemia Following Epirubicin-Based Adjuvant
Chemotherapy:
A Report From the National Cancer Institute of Canada Clinical Trials Group
M. Crump et al., J Clinical Oncology 2003
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
Grazie
Clodoveo Masciarelli