SABCS 2019, 13 December Adjuvant and Extended-Adjuvant Therapy for Patients with Localized HER2-Positive Breast Cancer Martine J Piccart-Gebhart, MD, PhD Scientific Director Jules Bordet Institute Université Libre de Bruxelles Brussels, Belgium
Disclosures Advisory Committee and Oncolytics Biotech Inc, Radius Health Inc Scientific Boards AstraZeneca Pharmaceuticals LP, Camel-IDS, Crescendo Biologics, Debiopharm Group, G1 Therapeutics, Genentech, HUYA Bioscience International, Immunomedics Inc, Lilly, Consulting Agreements Menarini Group, Merck Sharp & Dohme Corp, Novartis, Odonate Therapeutics, PeriphaGen Inc, Pfizer Inc, Roche Laboratories Inc, Seattle Genetics AstraZeneca Pharmaceuticals LP, Genentech, Lilly, Merck Contracted Research Sharp & Dohme Corp, Novartis, Pfizer Inc, Radius Health Inc, Roche Laboratories Inc, Servier, Synthon
Clinical Case n° 1 HER2 positive BC: neoadjuvant therapy 50 y old premenopausal pt (year 2018) • Past medical Hx: unremarkable • Familial medical Hx: colon cancer (father at age 63) • Physical exam: no hypertension, BMI<25 Positive Node • Pathology: ductal invasive carcinoma 4 cm mass grade 3 ER- PgR- HER2 3+ (FISH+) • Breast MRI: unifocal lesion 37 x 18 mm • Work up: no metastatis • Echocardiography: LVEF >65%
Clinical Case n° 1 S U Paclitaxel EC x 4 R Trastuzumab weekly x12 pCR G Pertuzumab Trastuzumab E R Pertuzumab RT Y DISCUSSION Do you agree Do you agree Do you agree POINTS with the choice with continuation with the choice of dual of dual of an HER2 blockade HER2 blockade A-based CTX ? ? ? ?
A Meta Analysis of the Cardiac Events in HERA, NSABP-B31 and NCCTG-9831 N=7 445 followed for 10y Anthracycline-based CT in 97,5% No trastuzumab trastuzumab Baseline LVEF ≤ 60% • • Hypertension Any Cardiac Risk factors • High BMI (>25) Event Age ≥ 60 years • 11.3% Mild Cardiac 8.7% death 0.2% Severe 2.3% Reversibility = 81% in HERA De Azambuja et al, BC Res & Treatment, 2019, doi 10,1007/s10549-019-05453-z
The missing piece of the puzzle… Trastuzumab alone ? Dual HER2 blockade pCR + chemotherapy Continuation of Dual HER2 blockade ? This academic trial would require a few thousands patients
Because the endpoint that really matters to patients is “invasive disease free survival” and because neoadjuvant trials exploring dual HER2 blockade did not show improved “EFS” it is very risky to assume that Trastuzumab Trastuzumab = Trastuzumab pCR pCR + + Trastuzumab + Pertuzumab Pertuzumab Pertuzumab !!!
The PERSEPHONE trial : Trastuzumab 12 m vs 6 m
Clinical Case n° 2 Metastatic HER2 positive BC treated with Neratinib 37 y old premenopausal pt (year 2013) • Unremarkable past and familial medical Hx/ 2 months after the delivery of a baby boy • Physical exam: no hypertension, BMI<25, LVEF>65% • Pathology: ductal invasive carcinoma grade 2 6 cm mass RO+ RPg+ HER2 3+ FISH+ • PET-CT scan: « de novo » metastatic disease with liver, lung, bone involvement
Clinical Case n° 2 Metastatic HER2+ BC showing an impressive response to Neratinib after 10 lines of systemic therapy ! Sequential treatments : 2013 → 2018 Tamoxifen Docetaxel + SURGERY Trastuzumab Trastuzumab + TDM1 EC P.D. + P.D. P.R. P.D. Zoledronic acid Pertuzumab X 3 cycles X 7 cycles one cerebellar X 3 months X 8 months lesion Mastectomy + axill. Dissection + bilateral oophorectomy Stereotactic RT RCB 3 Lapatinib Lapatinib Trastuzumab Trastuzumab Trastuzumab Trastuzumab P.D. + + P.D. Carboplatin + + + P.D. P.D. P.D. & new Trastuzumab Cape Gemcitabine brain Cape Caelyx outside Eribulin (2 months) lesion (1 month) brain (3 months) (3 months) (2 months) (x 6 cycles) Toxicity 2 nd Stereotactic RT +++ Letrozole + Neratinib P.D. Palliative care Response for 10 months !
Baseline FDG PET HER2 PET FDG PET post 3 T-DM1 cycles
Discussion Point Any « mechanistic » hypothesis that could explain the durable response to endocrine therapy + neratinib in this heavily pre-treated patient ?
Clinical Case n° 3 Metastatic HER2 positive BC with benefit from 2 antibody drug conjugates 27 y old premenopausal pt (year 2006) • De Novo metastatic HER2+ HR+ breast cancer with liver involvement • Past medical HX: unremarkable • Familial medical Hx: unremarkable
Clinical Case n° 3 Metastatic HER2 positive BC with benefit from 2 antibody drug conjugates • Received 4 lines of chemotherapy in a peripheral 27 y old premenopausal pt hospital prior to her first consultation at I. Jules Bordet (year 2006) Aim = control of liver disease Docetaxel Trastuzumab 1. EperibucineX 6# 2006 - 2010 LHRH ag/Tam Paclitaxel Trastuzumab 2010 - 2011 2. + Trastuzumab LHRH ag/letrozole X 5 m Lapatinib Radiofrequency Capecitabine 2011 - 2012 LHRH ag/ 3. lapatinib X 6# Ablation of liver Aromasin lesions Lapatinib End 2012 : liver SX unsuccessful Vinorelbine 4. LHRH ag/ + lapatinib Bilateral oophorectomy Fulvestrant X 6 m
Clinical Case n° 3 Metastatic HER2 positive BC with benefit from 2 antibody drug conjugates 2/2013 1/2014 7/2014 1/2014 Liver T-DM1 x 17 # P.D. Eribuline Trastuzumab Trastuzumab X 6# surgery (11 months) liver alone x 6 months (2 lesions resected) 1/2015 P.D. Abemaciclib Liver stable P.D. liver Abemaciclib SYD 985 liver + + Trastuzumab P.D. brain Stop for + Trastuzumab Trastuzumab X 9 # alone x 4 months toxicity 2 brain (2 months) (2 months) lesions Stereotactic RT P.D. Cisplatin liver X 5# Palliative care Death (1/2017) 5 FU (liver Trastuzumab failure)
Clinical Case n° 3 FDG PET and HER2 PET prior to TDM1 and after 3 cycles FDG PET post Baseline FDG PET HER2 PET 3 T-DM1
Clinical Case n° 3 FDG PET and HER2 PET prior to TDM1 and after 3 cycles FDG PET/CT post 15 cycles of T- HER2 PET/CT at progression DM1: liver progression showing no tracer uptake in the liver metastasis
Discussion Point Could imaging help selecting better patients who will benefit from ADCs ?
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