Systemic Therapy Considerations in Inflammatory

Breast CancerShani Paluch-Shimon, MBBS, MSc

Director, Breast Oncology Unit

Shaare Zedek Medical Centre, Jerusalem

Israel

DisclosuresRoche: 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

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 characteristics

Patients 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 (86 mg/kg)docetaxel (75100 mg/m2)

PTD (n=107)pertuzumab (840420 mg) trastuzumab (86 mg/kg) docetaxel (75100 mg/m2)

PT (n=107)pertuzumab (840420 mg)trastuzumab (86 mg/kg)

PD (n=96)pertuzumab (840420 mg)docetaxel (75100 mg/m2)

29.0

45.8

16.8

24.021.5

39.3

11.217.7

0

10

20

30

40

50

60

TD PTD PT PD

p = 0.0141

p = 0.0198

p = 0.003bpCR

tpCR

pC

R, %

±9

5%

CI

20.0 26.0

5.9

17.4

36.8

63.2

27.3 30.0

0

10

20

30

40

50

60

70

80

TD PTD PT PD

bp

CR

, % ±

95

% C

I 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, %

0

1

94.3

5.7

89.7

10.3

86.0

14.0

83.3

16.7

HR-positive (ER- and/or PR-positive), %

HR-negative (ER- and PR-negative), %

46.7

53.3

46.7

53.3

47.7

51.9

47.9

52.1

Operable, %

Locally advanced, %

Inflammatory, %

59.8

33.6

6.5

60.7

29.9

9.3

60.7

32.7

6.5

62.5

32.3

5.2

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