A. Nuzzo U.O. di Oncologia Medica ospedale Renzetti di Lanciano (CH) "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)

L’Associazione Italiana di Oncologia Medica “… 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 Trial schema of North Central Cancer Treatment Group (NCCTG) N9831 and National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31. Timing of chemotherapy, trastuzumab (H), radiation therapy (RT), and hormonal therapy (HT) in B-31 and N9831. AC, doxorubicin and cyclophosphamide; FISH, fluorescent in situ hybridization; HER2, human epidermal growth factor receptor 2; IHC, immunohistochemistry; LVEF, left ventricular ejection fraction; q3w, every 3 weeks; qw, every week; T, paclitaxel. 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. Kaplan-Meier estimates of (A) event-free survival and (B) overall survival. Disease events include local, regional, or distant recurrence; contralateral breast cancer; second primary cancers; or death as a result of any cause. Overall survival is measured from the time of study enrollment to last contact or death. AC, doxorubicin and cyclophosphamide; H, trastuzumab; T, paclitaxel. Entrambe p< 0.001 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. Trial schema of North Central Cancer Treatment Group (NCCTG) N9831 and National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31. Timing of chemotherapy, trastuzumab (H), radiation therapy (RT), and hormonal therapy (HT) in B-31 and N9831. AC, doxorubicin and cyclophosphamide; FISH, fluorescent in situ hybridization; HER2, human epidermal growth factor receptor 2; IHC, immunohistochemistry; LVEF, left ventricular ejection fraction; q3w, every 3 weeks; qw, every week; T, paclitaxel. 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... 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 comparisons were obtained by using stratified proportional hazards modeling. AC, doxorubicin and cyclophosphamide; H, trastuzumab; T, paclitaxel. 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 No difference between two regimens with trastuzumab for the oprimary and secondary end point 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 Among patients with HER2-positive tumors measuring 1 cm or less in the greatest diameter, the estimated 5-year rates of disease-free survival were 86% in the group receiving AC-T plus trastuzumab and 86% in the group receiving TCH, as compared with 72% in the group receiving AC-T (hazard ratio for AC-T plus trastuzumab, 0.36; P = 0.03; hazard ratio for TCH, 0.45; P = 0.09) D Slamon et al, NEJM 2011

Gianni L, et al: Herceptin Adjuvant (HERA) Trial Study Team. 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 Kaplan-Meier estimates of disease-free and overall survival at 4-year median follow-up for 1-year trastuzumab versus observation Disease-free survival intention-to-treat analysis (A), overall survival intention-to-treat analysis (B), disease-free survival censored analysis (C), and overall survival censored analysis (D). L Gianni et al, Lancet Oncol. 2011

Adjuvant Trastuzumab Breast Cancer Trials Severe CHF Syst. dysf. HERA CT CT Trast 0.6% 3.0% NSABP B-31 AC  Ptx AC  Ptx+Trast 3.6% 15.9% NCCTG N 9831 2.5/3.3% 14/17% BCIRG 006 AC  Docet AC  Docet + trast TC + Trast 1.9% 0.4% 18.1% 8.6% FinHER Docet  +/- Trast Vinblast  +/- Trast 0% 3.5% HER2-blocking antibody trastuzumab in conjuction with chemotherapy is the standard adjuvant therapy in HER2–positive tumors ≥ 1 cm or pN+ Nei trial sul tumore alla mammella con trastuzumab in adiuvante, l’incidenza di scompenso cardiaco severo grave o di disfunzione sistolica è stata maggiore col regime nord americano AC-PH (B-31 e N9831) e col regime contenente l’antraciclina e trastuzumab (AC-TH) del trial BCIRG 006. Viceversa, il braccio con trastuzumab senza antraciclina (TCH) del trial BCIRG 006 e i regimi del trial FinHER sono stati associati a un’incidenza più bassa di cardiotossicità. Nel trial HERA, la maggioranza delle pazienti è stata trattata con antracicline; ad ogni modo, il protocollo era unico nel fatto che prevedeva un lungo intervallo di tempo (89 giorni) tra il completamento della terapia con antracicline e l’inizio del trattamento con trastuzumab. Clinicamente, questo sembrava permettere al cuore di ridurre lo stress ossidativo, con una successiva inibizione del recettore HER2 senza un danno eccessivo al cuore.

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. Fig 1. Cumulative incidence of IBTR after treatment with TAM, XRT and placebo, or XRT and TAM. Pairwise comparisons: TAM v XRT + placebo: P = .008; TAM v XRT + TAM: P < .0001; XRT + placebo v XRT + TAM: P = .01. 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 99% 92% 91% 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 NCCN

Adjuvant Trastuzumab BC Trials Severe CHF Syst. dysf. HERA CT CT Trast 0.6% 3.0% NSABP B-31 AC  Ptx AC  Ptx+Trast 3.6% 15.9% NCCTG N 9831 2.5/3.3% 14/17% BCIRG 006 AC  Docet AC  Docet + Trast TC + Trast 1.9% 0.4% 18.1% 8.6% FinHER Docet  +/- Trast Vinblast  +/- Trast 0% 3.5% < 40 % pT1 ~ 0% pT1a-b pN0 Nei trial sul tumore alla mammella con trastuzumab in adiuvante, l’incidenza di scompenso cardiaco severo grave o di disfunzione sistolica è stata maggiore col regime nord americano AC-PH (B-31 e N9831) e col regime contenente l’antraciclina e trastuzumab (AC-TH) del trial BCIRG 006. Viceversa, il braccio con trastuzumab senza antraciclina (TCH) del trial BCIRG 006 e i regimi del trial FinHER sono stati associati a un’incidenza più bassa di cardiotossicità. Nel trial HERA, la maggioranza delle pazienti è stata trattata con antracicline; ad ogni modo, il protocollo era unico nel fatto che prevedeva un lungo intervallo di tempo (89 giorni) tra il completamento della terapia con antracicline e l’inizio del trattamento con trastuzumab. Clinicamente, questo sembrava permettere al cuore di ridurre lo stress ossidativo, con una successiva inibizione del recettore HER2 senza un danno eccessivo al cuore.

Donne con carcinoma mammario operato radicalmente 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.

Small HER2-positive node-negative are rare (6-10% of incidence) 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

Clodoveo Masciarelli Grazie