Antonino Musolino

Breast Unit Interaziendale

Provincia di Parma

La Ricerca Clinica e Traslazionale

Breast Cancer Subtypes

Perou et al. Nature 2000

Sorlie et al. PNAS 2001

Luminal A

Luminal B

Basal-Like

HER2+

ER+ 65-75%

ER- 15%

ER- 15-20%

Carcinoma mammario ER/PR+

(Luminal)

BIG 1-98 and ATAC Trials

20

15

10

5

0

Per

cen

t w

ith

ev

ent

1 2 3 4 5

8.1%

6.2%

13.6%

10.2%

Years

HR 95%CI P value

Let vs. Tam 0.81 .70-.93 0.0002

Letrozole

Tamoxifen

0 1 2 3 4 5 6

P value

0.005HR

0.83A vs T

95% CI

(0.73–0.94)

:

Years

0

5

10

15

20

25

Absolute

difference:1.6% 2.6% 2.5% 3.3%

Tamoxifen

Anastrozole

Slide 12

EBCTCG, NEJM 2017

EBCTCG metanalysis on long-term recurrence risk after 5yrs of ET

N=91 trials from individual ER9+ pts allocated to 5 yrs of ETN= 46000 pts still alive and disease-free after 5 yrs

Cooperation between ER and Cyclic D1 pathways enhances proliferation in luminal breast cancer

Cyclin D1

CDK4-6

ER

p RbInhibitory controlInhibitory control

Cell Cycle:

G1 S

proliferation

Inhibitors:

-Palbociclib

-Abemaciclib

-Ribociclib

-CDKN2A/p16

Hortobagyi GN, Ann Oncol 2018

MONALEESA-2: Progression-free Survival

Carcinoma mammario Triplo-negativo

(Basal-like)

Triple Negative Breast Cancer

• Some commonly

encountered features

• More frequent at youger age

• More frequent in black ethnicity

• Almost always High-Grade

• Often p53 positive

• Highly proliferative

• Often N0

• Poor prognosis

• Some unusual histologies are TN and

carry a better prognosis– Medullary

– Aprocrine

– Low grade adeno-squamous

– Low grade spindle cell

• BRCA1-mutated often display this

phenotype

• BRCA1 dysfunctional tumors often

display this phenotype

ERHER2

PgR

Immunohistochemistry

Hazard Functions for Disease Progression Among Patients with TNBC vs. non-TNBC

Liedtke et al. J Clin Oncol 2008

Triple

Negative

Basal

~75% of TNBC have

Basal gene

expression

1. Pal & Mortimer. Maturitas 2009

2. Gluz et al. Ann Oncol 2009

3. Anders & Carey. Oncology 2008

4. Young et al. BMC Cancer 2009

5. Schneider, B. P. et al. Clin Cancer Res 2008

Triple-Negative vs. Basal-Like: Definitions

ER- / PR- / HER2-

~15% of all breast carcinomas

Poorly differentiated

Express CK 5/6, 17, EGFR (+)

• BRCA1-2 mutated tumors

•~5% of Breast Cancer

• 50% BRCA-1 carriers are basal-like

• Basal but not triple negative

• Definition by gene expression

• Includes most BRCA1 mutated tumors

• 15-40% are ER+, PR+ or HER2+

• Triple negative but not basal

• Definition by IHC

• Includes other histologies(medullar, adenoid cystic)

• 10-30% can also include “claudin-low,” a subtype notable for high expression of stem cell markers

• 90% of TNBC do not have BRCA mutations

BRCA 1-2

Cortesi L., Current Cancer Drug Targets 2018

Primary endpoint: progression-free survival by BICR

Slide 8

Slide 9

Slide 10

Carcinoma mammario HER2+

Carcinoma mammario HER2-positivo

•Targets HER2 protein

•High affinity (Kd = 0.1 nM) and

specificity

•95% human, 5% murine

– Decreases potential

for immunogenicity

– Increases potential for

recruiting immune effector

mechanisms

HER2 epitopes recognized by hypervariable

murine

antibody fragment

Human

IgG-1

Trastuzumab:Humanized Anti-HER2 Antibody

Antibody Dependent Cell Mediated Cytotoxicity (ADCC)

HER2 Targeting With Trastuzumab And the Natural History of HER2-Positive Advanced Breast Cancer

Dawood S., et al. J Clin Oncol. 2009

Disease-free Survival

87%85%

67%

75%

N EventsAC T 1679 261AC TH 1672 134

%

HR=0.48, 2P=3x10-12

AC TH

AC T

Years From Randomization B31/N9831

First-in-human, phase I Study of Margetuximab, an Fc-optimized Chimeric mAb, in pts with HER2+ solid tumors

Burris, et al. ASCO 2015 #523

Trastuzumab continually

suppresses HER2 activity

Flags cells for destruction

by the immune system

• Activates ADCC

Trastuzumab and Pertuzumab Bind to Different Regions on HER2 and Have Synergistic Activity

Pertuzumab inhibits HER2 forming

dimer pairs

Suppresses multiple HER signaling

pathways

Flags cells for destruction

by the immune system

• Activates ADCC

HER2 receptor

TrastuzumabPertuzumab

Subdomain IV of HER2

Dimerization domain of HER2

Trastuzumab IV (8 mg/kg loading dose,

followed by 6 mg/kg) plus

Pertuzumab IV (840 mg loading dose,

followed by 420 mg) plus

Docetaxel IV (75→100 mg/m2),

every 3 weeks for 4 cycles

Eligibility (n 63)

Women with histologically

confirmed HER2-positive breast

cancer with locally advanced,

inflammatory, or early stage

tumor (either greater than 2 cm

in diameter or node positive)

with no evidence of metastatic

disease

Randomized Phase IIb Biomarker Study of Immune-mediated Mechanism of Action of Neoadjuvant Trastuzumab (either iv or sc) in Patients with HER2-

positive Breast Cancer (ImmunHER)

R

Pre-randomization phase:

FEC (5FU 500; epirubicin 75;

CTX 500) x 3 cycles

Trastuzumab SC

(fixed dose of 600 mg) plus

Pertuzumab IV (840 mg loading dose,

followed by 420 mg) plus

Docetaxel IV (75→100 mg/m2),

every 3 weeks for 4 cycles

Primary endpoint:

TIL rate on residual disease after either IV trastuzumab or

SC trastuzumab

Primary Objective:

To evaluate variations of host immune response

parameters to either trastuzumab SC or trastuzumab IV

given in combination with pertuzumab and chemotherapy.st

cancer.

Hallmarks of Cancer

Hanahan et al. Cell 2011

Una singola freccia si rompe facilmente, ma non

dieci frecce tenute assieme – Proverbio

giapponese

Email: breast-unit@ao.pr.it

Segreteria: 0521/702316