Terapia Neoadiuvante nella malattia HER-2 positiva:
Trasferibilità nella pratica clinica
Vincenzo Adamo
UOC Terapie Integrate in Oncologia
AOU Policlinico ”G.Martino” Messina
Sequence of Treatment
for Primary Breast Cancer
Diagnosis and Staging
Diagnosis and Staging
Surgical Resection
Neoadjuvant systemic
therapy
Adjuvant systemic treatment
Surgical Resection
Adjuvant therapy
The Rational for Neoadjuvant Therapy
in Breast Cancer: Which Patients?
 Traditionally: Neoadjuvant systemic therapy should be
considered for patients inoperable at onset: T4, clinical N2-N3
 New data: supporting preoperative or neoadjuvant systemic
therapy in primary operable breast cancer patients
 NCCN Guidelines 2011:neoadjuvant chemotherapy or
trastuzumab plus chemotherapy should be considered for
HER2+ patients
Goals of Neoadjuvant Theapy
in Breast Cancer
 Make tumours more operable, increase the rate of breast conserving
surgeries
 Improve prognosis of certain disease subtypes (i.e. HER2+)
 Have a better idea of prognosis based on response to neoadjuvant
treatment
 Allow patients to start treatment earlier
 Reduce the extent of surgery required in breast and axylla
 Improve DFS and OS using pathological response rate for selection
of subsequent treatment in individual patients
Parametres to assessed
in clinical practice
 pCR and Treatment Outcomes
 Status lymph node (sentinel node biopsy)
 Instrumental evaluation with MRI and PET
 Toxicity
Definition of pCR
 Different definition of pCR are in use:
- Absence of invasive cancer in the breast
- Absence of invasive cancer in the breast and in the axillary
lymph nodes.
- Absence of invasive and in situ cancer cells in the breast and
in the axillary nodes
 There is high degree of concordance between the different
definition
 With very definition pCR identifies cases with favorable
disease
Marchiò C. & Sapino A. JNCI Monogr 2011;43:86–90
Putative Predictive Factors
of pCR
 Tumor size & Tumor grade
 Histological type
 ER/PgR
 Her2/neu
 Proliferative markers ( Ki-67/MIB-1, PCNA)
 Treatment & MDR-1/pgp
pCR to Neoadjuvant Chemotherapy
is correlated with improved DFS & OS
(NSABP B-27)
Disease free-survival
Overall Survival
There was no significant difference in overall survival (OS) between
the treatment arms (data not shown).
Pathologic CR (pCR) was a significant predictor of OS, regardless of treatment.
Bear HD, et al. J ClinOncol. 2006;24(13):2019-2027.
Outcomes of Neoadjuvant Trials with
unselected tumor characteristics
Mazouni C, et al. J Clin Oncol. 2007
Intrinsic sub-types
have different prognosis and
different response to NACT
MD Anderson Neoadjuvant Trial
DFS at 72 months FU
Budzar A. et al Asco 2009
“ ..if
indicated, the majority of the Panel considered that
the neoadjuvant chemotherapy regimen should include
both a taxane and an anthracycline and(for HER2-positive
disease) an anti-HER2 drug.
Thus, the choice of a regimen for adjuvant or neoadjuvant
chemotherapy might be made using similar criteria..’’
Goldhirsch A, et al. Ann Oncol. 2009;20(8):1319-1329.
Impact of treatment
characteristics on the pCR
Untch M. et al J Nat Cancer Inst Monogr 2011.
Impact of treatment
characteristics on the pCR
Untch M. et al J Nat Cancer Inst Monogr 2011.
Schedules and pCR rate in
HER2-positive disease
V, vinorelbine; X, capecitabine; C, carboplatin ;
FEC, 5-fluorouracil, epirubicin, cyclophosphamide.
Pre and Post-operative Chemotherapy
plus Trastuzumab Improve DSF
… Future Clinical Practice….
Anti-HER2 Treatment:
Mechanisms of action
Three Neoadjuvant Trials Using Targeted
Therapies for HER-2 Positive BC
pCRS in Three Trials with
Target Therapies
Guarneri V. et al. ASCO 2011
Efficacy:
Breast and Axillary pCR Rate
Guarneri V. et al. ASCO 2011
Status lymph node
(sentinel node biopsy)
SLNB in relation
to neoadjuvant therapy
 Which is the aim of SLNB in breast cancer patients?

Which patients are usually receiving neoadjuvant?

Is there a role of SLNB in patients undergoing neoadjuvant
therapy?
 Should SLNB be performed before or after neoadjuvant therapy?
 Are there sufficient data supporting either approach ?
St Gallen 2007, Annals of Oncol 18: 1133–1144, 2007
SLN Biopsy Prior to Therapy
Disadvantages
• Two operations
• Potentially delays start of chemotherapy
Advantages
• Higher identification rate
• Lower false negative rate
St Gallen 2007, Annals of Oncol 18: 1133–1144, 2007
The Role of SNLB
Inflammatory breast cancer not indicated
– breast lymphedema, due to occluded lymphatics by metastatic
cells
inadequate lymphatic drainage
mapping agents would also be trapped and not travel to the SLN
false-negative rate very high
Locally Advanced (large tumor size)
- Palpable lymphadenopathy  FNA –No Role for SNLB
- Non palpable or Clinically negative LNs SLNB is acceptable
- Before or after neo-adjuvant chemotherapy ?
St Gallen 2007, Annals of Oncol 18: 1133–1144, 2007
Marchiò C. & Sapino A. JNCI Monogr 2011;43:86–90
St Gallen 2011:
SN and ALND
Downstaging Axilla &
Complete Axillary Response
 Strong
prognostic factor
Axillary pCR: 93%
Residual disease: 60%
Hennessey BT, et al. J Clin Oncol.2005;23(36):9304-9311.
Instrumental evaluation: MRI and PET
and Neoadjuvant Chemo in HER2BC
MRI: Evaluation Neoadjuvant
Chemotherapy
 MRI highest accurracy for monitoring chemotherapy
 Change in (residual) tumor size, signal intensity, and
contrast kinetics
 Underestimation possible!
Mc Guire K.P. et al.Ann Surg Oncol 2011
MRI Staging after NACT : Does
Tumor Biology Affect Accuracy?
MRI response versus pathologic response by tumor subtype.
Discrimination and predictive value (a) overall, (b) luminal A/B, and (c) HER2+/TN
Mc Guire K.P. et al.Ann Surg Oncol 2011
Early metabolic response
using PET in Neoadjuvant BC
Keam B.et al.BMC Cancer 2011
Toxicity and neoadjuvant
Chemotherapy in HER2BC
LVEF during and after therapy
LVEF
HER2-positive trastuzumab
HER2-positive control
80
80
60
60
40
40
20
20
Gianni L. et al Lancet 2010
LVEF change during and after
therapy
LVEF change (% units)
HER2-positive trastuzumab
HER2-positive control
30
30
20
20
10
10
0
0
-10
-10
-20
-20
-30
-30
Gianni L. et al Lancet 2010
Cardiac Toxicity
& Trastuzumab
Gianni L. et al Lancet 2010
Cardiac monitoring guidance:
Trastuzumab
• All patients for Herceptin treatment should undergo baseline
cardiac assessment prior to treatment initiation
• For patients with EBC, cardiac assessment should be
performed every 3 months during treatment and at
6, 12 and 24 months following cessation of treatment
• For patients with MBC, cardiac function should be monitored
during treatment (eg every 3 months)
• Patients who develop asymptomatic cardiac dysfunction may
benefit from more frequent monitoring (eg every 6-8 weeks)
CGCC, Cardiac Guidelines Consensus Committee;
EMEA, European Medicines Evaluation Agency
HER2 BC & Neoadjuvant
St Gallen 2011
Intrinsic sub-types
have different prognosis and
different response to NACT
Comments and questions
Conclusive comments
• NACT should be considered as an option for every woman
as far as the indication for adjuvant treatment has been
confirmed
• Many good quality clinical trials suggest that trastuzumab
should be incorporated in the preoperative treatment of
women with HER2-pos (..NCCN guidelines).
open questions
• the preferred combination chemotherapy with trastuzumab
• the optimal duration of trastuzumab in pts who achieve a
pCR after preoperative chemotherapy.
The end
• Stop here
NOAH Neoadjuvant Trial:
pCR Rates
Gianni L. et al. Lancet 2010
pCR After NACT Plus Trastuzumab Predicts
Favorable Survival in HER2+ BC:
Results From the TECHNO
Untch M. et al, JCO 2011
Neoadjuvant Therapy (NAT):
Potential Advantages

Improved Tumor Downstaging
 Inoperable
Operable
 Mastectomy
BCS
 Provides in vivo assessment of anti-tumor effects
 Provides opportunity to assess surrogate biological endpoints
 Early initiation of systemic therapy
 Inhibition of post-surgical growth spurt
 May expedite new drug development
no
pCR and Treatment Outcome
no
 pCR is a robust measure of therapeutic effects and surrogate a
DFS in responder
 Increase pCR rate should correspond to improved efficacy in
the overall patient population
 Prediction of pCR should predict for benefit and allow for
tailoring treatment to indivudual tumor characteristics
BC after NACT:The M.D. Anderson
Cancer Center Experience
no
Chen AM et al. J Clin Oncol. 2004;22:2303-2312.
Scenario for Neoadjuvant Therapy in
HER2 Positive Breast Cancer
no
Trastuzumab
in NACT – pCR
no
T-FEC
T-FEC + H
26.3 %
66.7 %
pCR ER pos
27 %
61 %
pCR ER neg
25 %
70 %
78.9 %
90.3 %
pCR
pN0
Study closed after first 42 pts due to the strong advantage for H
combination H stopped at the end of NACT (6 months)
Buzdar AU et al, PASCO 2004 ; Clin Cancer Res 2007
Locally Advanced with non palpable
or clinically negative LNs
no
St Gallen 2007, Annals of Oncology 18: 1133–1144, 2007
Sentinel Lymph Node Biopsy in BC
patients Treated With NACT
no
Pecha V. et al. Cancer 2011
Valutare se
utile per finire
o simile
Timing of SLNB
Vedere il lavoro di Sapino e mettere lo
schema interessante
Hunt KK, et al. Ann Surg. 2009;250(4):558-566
PET and Neoadjuvant Chemotherapy
…Open Question in Clinical Practice…?
?