Systemic Therapy Considerations in Inflammatory Breast …...Systemic Therapy Considerations in...
Transcript of Systemic Therapy Considerations in Inflammatory Breast …...Systemic Therapy Considerations in...
Systemic Therapy Considerations in Inflammatory Breast Cancer
Shani Paluch-Shimon, MBBS, MSc
Director, Breast Oncology Unit & the Talya Centre for young women with breast cancer
Shaare Zedek Medical Centre, Jerusalem, Israel
ESMO Breast Cancer Preceptorship - November 2018
DisclosuresRoche: Speakers bureau, honoraria, consultancy
Astra Zeneca: Speakers bureau, honoraria, consultancyNovartis: 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
Masuda et al, Annals of Oncology, 2013
Prognosis by response to NAST & subtype
Dawood, Annals of Oncology, 2014
Pre-operative treatment
• ↓ local recurrence• ↓distance recurrence
Chemotherapy
Dawood et al, Annals of Oncology, 2010
Anthracyclines & Taxanesbackbone of chemotherapy
HER2+ IBC
Anti-HER2 therapy
• 1st generation study- NOAH – included IBC• 2nd generation studies- Neo-ALTTO – excluded IBC- NeoSphere – included IBC
NOAH (MO16432): Study design
H, Herceptin® (trastuzumab) (8 mg/kg loading dose then 6 mg/kg) AP, doxorubicin (60 mg/m2), paclitaxel (150 mg/m2); P, paclitaxel (175 mg/m2)CMF, cyclophosphamide, methotrexate, and fluorouracil; aA separate treatment group of HER2-negative patients received chemotherapy only; bHormone receptor-positive patients received adjuvant tamoxifen
APq3w x 3 cycles
Pq3w x 4 cycles
CMFq4w x 3 cycles
CMFq4w x 3 cycles
HER2-positive LABC(IHC 3+ or FISH-positive)
HER2-negative LABC(IHC 0/1+)a
APq3w x 3 cycles
Pq3w x 4 cycles
Surgery followed by radiotherapyb
H + APq3w x 3 cycles
H + P q3w x 4 cycles
H q3w x 4 cycles+ CMF q4w x 3 cycles
H continued q3wto week 52
(n=117) (n=118) (n=99)
19 crossed over to H
An international, open-label, Phase III study of neoadjuvant−adjuvant Herceptin® (trastuzumab) in patients with
locally advanced or inflammatory HER2-positive breast cancer
Gianni et al 2010
NOAH: Baseline characteristicsPatients with HER2-positive disease
Herceptin® (trastuzumab) + chemotherapy
(n=117)
Chemotherapy(n=118)
Stage group, %
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
18
NeoSphere: study design and pCR results
Gianni L, et al. Lancet Oncol 2012; 13:25–32
HR, hormone receptor;HR-positive = estrogen and/or progesterone receptor-positive;HR-negative = estrogen and progesterone receptor-negative
S
U
R
G
E
R
YStudy dosing: q3w x 4
Patients withoperable or locally advanced/inflammatoryHER2-positive BC
Chemo-naive & primary tumors >2 cm (N=417)
TD (n=107)trastuzumab (8→6 mg/kg)docetaxel (75→100 mg/m2)
PTD (n=107)pertuzumab (840→420 mg) trastuzumab (8→6 mg/kg) docetaxel (75→100 mg/m2)
PT (n=107)pertuzumab (840→420 mg)trastuzumab (8→6 mg/kg)
PD (n=96)pertuzumab (840→420 mg)docetaxel (75→100 mg/m2)
29.0
45.8
16.824.021.5
39.3
11.2 17.70
10
20
30
40
50
60
TD PTD PT PD
p = 0.0141
p = 0.0198
p = 0.003bpCR
tpCR
pCR,
% ±
95%
CI
20.0 26.0
5.9
17.4
36.8
63.2
27.3 30.00
1020304050607080
TD PTD PT PD
bpCR
, % ±
95%
CI HR-positive
HR-negative
Patient baseline characteristics, ITT population
Gianni L, et al. Lancet Oncol 2012; 13:25–32ECOG PS, Eastern Cooperative Oncology Group performance status;ER, estrogen receptor; PR, progesterone receptor
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, %01
94.35.7
89.710.3
86.014.0
83.316.7
HR-positive (ER- and/or PR-positive), % HR-negative (ER- and PR-negative), %
46.753.3
46.753.3
47.751.9
47.952.1
Operable, %Locally advanced, %Inflammatory, %
59.833.66.5
60.729.99.3
60.732.76.5
62.532.35.2
Future directions – genomic profiling?
Ross et alHamm et el, 2016, Molecular Cancer Therapeutics
TP53 (62%)MYC (32%)PIK3CA (28%)HER2 (26%)FGFR1 (17%)BRCA2 (15%)PTEN (15%).
Immunotherapy? Reports of PDL1+ lymphocytic infiltrates in IBC
Targeting pathways? Need to distinguish between driver & passenger mutations? Amplifications?
Future directions – immunogenic profiling?Immunotherapy? Reports of PDL1+ lymphocytic infiltrates in IBC
Hamm et el, 2016, Molecular Cancer Therapeutics
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
• Young Women ≤ 40yro• Triple negative• Treatment resistant• Rapid course of disease• Devastating
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