"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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