Systemic Therapy Considerations in Inflammatory Breast Cancer Shani Paluch-Shimon, MBBS, MSc Director, Breast Oncology Unit Shaare Zedek Medical Centre, Jerusalem Israel
Disclosures Roche: Speakers bureau, honoraria, consultancy Astra Zeneca: Speakers bureau, honoraria, consultancy Novartis: Speakers bureau, honoraria, consultancy Pfizer: Speakers bureau, honoraria, consultancy
IBC 1-6% of all new BC Clinical diagnosis erythema & dermal edema of 1/3 of the breast Dermal lymphatic invasion neither required not sufficient for the Dx = ct4d Usually HR-negative, often HER2+ - commonly Basal & HER2 subtype Needs a systemic work up Multi-modality care - MUST
Pierga et al, Annals of Oncology 2017
Prognosis Overall and event-free survival. (A) Overall survival (n = 107). (B) Overall survival by stage of disease: stage IIIA (n = 48) versus stage IIIB inflammatory breast cancer (IBC; n = 46), P =.0046; stage IIIA versus stage IIIB non-ibc (NIBC; n = 13), P =.018 Low et al,jco, 2004
Prognosis by subtype Li et al, Oncotarget, 2017
Prognosis by response to NAST & subtype Masuda et al, Annals of Oncology, 2013
Dawood, Annals of Oncology, 2014
Pre-operative treatment local recurrence distance recurrence
Chemotherapy
Anthracyclines & Taxanes backbone of chemotherapy Dawood et al, Annals of Oncology, 2010
HER2+ IBC
Anti-HER2 therapy 1 st generation study - NOAH included IBC 2 nd generation studies - Neo-ALTTO excluded IBC - NeoSphere included IBC
NOAH (MO16432): Study design An international, open-label, Phase III study of neoadjuvant adjuvant Herceptin (trastuzumab) in patients with locally advanced or inflammatory HER2-positive breast cancer HER2-positive LABC (IHC 3+ or FISH-positive) HER2-negative LABC (IHC 0/1+) a (n=117) (n=118) (n=99) H + AP q3w x 3 cycles AP q3w x 3 cycles AP q3w x 3 cycles H + P q3w x 4 cycles P q3w x 4 cycles P q3w x 4 cycles H q3w x 4 cycles + CMF q4w x 3 cycles CMF q4w x 3 cycles CMF q4w x 3 cycles H continued q3w to week 52 Surgery followed by radiotherapy b 19 crossed over to H H, Herceptin (trastuzumab) (8 mg/kg loading dose then 6 mg/kg) AP, doxorubicin (60 mg/m 2 ), paclitaxel (150 mg/m 2 ); P, paclitaxel (175 mg/m 2 ) CMF, cyclophosphamide, methotrexate, and fluorouracil; a A separate treatment group of HER2-negative patients received chemotherapy only; b Hormone receptor-positive patients received adjuvant tamoxifen Gianni et al 2010
NOAH: Baseline characteristics Stage group, % Patients with HER2-positive disease Herceptin (trastuzumab) + chemotherapy (n=117) Chemotherapy (n=118) T4, non-inflammatory 42 43 Inflammatory disease 27 26 N2 or ipsilateral nodes 31 31 Hormone receptor status, % ER- and/or PR-positive 36 36 Both negative 64 64 Age group, % <50 years 43 42 50 years 57 58 Gianni et al 2010
NOAH Trial: Preoperative Chemo +/- Trastuzumab for LABC Gianni L, et al; Lancet 2010
bpcr, % ± 95% CI pcr, % ± 95% CI NeoSphere: study design and pcr results Patients with operable or locally advanced/ inflammatory HER2-positive BC Chemo-naive & primary tumors >2 cm (N=417) TD (n=107) trastuzumab (8 6 mg/kg) docetaxel (75 100 mg/m 2 ) PTD (n=107) pertuzumab (840 420 mg) trastuzumab (8 6 mg/kg) docetaxel (75 100 mg/m 2 ) PT (n=107) pertuzumab (840 420 mg) trastuzumab (8 6 mg/kg) PD (n=96) pertuzumab (840 420 mg) docetaxel (75 100 mg/m 2 ) Study dosing: q3w x 4 S U R G E R Y 60 50 40 30 20 10 0 80 70 60 50 40 30 20 10 0 p = 0.0198 p = 0.0141 p = 0.003 45.8 39.3 29.0 21.5 24.0 16.8 17.7 11.2 TD PTD PT PD HR-positive HR-negative 63.2 5.9 36.8 20.0 26.0 27.3 30.0 17.4 TD PTD PT PD bpcr tpcr HR, hormone receptor; HR-positive = estrogen and/or progesterone receptor-positive; HR-negative = estrogen and progesterone receptor-negative Gianni L, et al. Lancet Oncol 2012; 13:25 32 18
Patient baseline characteristics, ITT population TD (n=107) PTD (n=107) PT (n=107) PD (n=96) Median age, years (range) 50 (32 74) 50 (28 77) 49 (22 80) 49 (27 70) ECOG PS, % 0 94.3 89.7 86.0 83.3 1 5.7 10.3 14.0 16.7 HR-positive (ER- and/or PR-positive), % 46.7 46.7 47.7 47.9 HR-negative (ER- and PR-negative), % 53.3 53.3 51.9 52.1 Operable, % 59.8 60.7 60.7 62.5 Locally advanced, % 33.6 29.9 32.7 32.3 Inflammatory, % 6.5 9.3 6.5 5.2 ECOG PS, Eastern Cooperative Oncology Group performance status; ER, estrogen receptor; PR, progesterone receptor Gianni L, et al. Lancet Oncol 2012; 13:25 32
Future Directions Genomic profile of IBC: - Genomic instability - Immune infiltrate - PDL1 over-expression - DNA MMR (Hamm et al Mol Cancer Therapeutics, 2016) Targeting other pathways? - angiogenesis? Bevacizumab - mtor/akt - JAK/STAT - Cell cyle/myc - EGFR Immunotherapy?
Guidelines
In conclusion Systemic therapy should be guided by subtype and stage: Stage III aim cure: - HER2-negative disease anthracycline-taxane based chemotherapy - HER2+ disease Chemotherapy + dual blockade followed by year of anti- HER2 therapy Stage IV disease aim prolong life and palliate - Tailor treatment to symptoms, subtype Clinical trials!!! This is an orphan disease
Thank you