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