E-Learning Triple Negative Breast Cancer is Still an Unmet...

TRIPLE NEGATIVE BREAST CANCER IS STILL AN UNMET NEED

Valentina Guarneri and Maria Vittoria Dieci

University of Padova

Istituto Oncologico Veneto IRCCS, Padova, Italy

Introduction:

Definition, epidemiology, clinical behaviour

State of the art

Neoadjuvant/Adjuvant

Advanced disease

How to improve on CT

Heterogeneity: exploiting TNBC diversity to identify druggable pathways

OUTLINE

Triple negative breast cancer (TNBC) definition:

– lack of expression of estrogen receptor and progesterone receptor

HER2 not overexpressed/amplified

10-20% of all breast cancers

Most BRCAmut carriers develop TNBC

TNBC includes rare histologies

Metaplastic, medullary, adenoid cystic carcinoma

High cell proliferation, poor cellular differentiation, many recurrent copy number

imbalances, and mutations in the TP53

TNBC: INTRODUCTION

Triple negative breast cancer is the most lethal form of breast cancer

TNBC is heterogeneous and harbours several molecular alterations

The prevalence of TNBC is higher in women of Afro–American ethnicity

TNBC is more frequently diagnosed in younger women

Higher risk of earlier relapse

High risk for visceral involvement (CNS included)

Median survival from the time of developing metastases rarely >1 year

Endocrine therapy and anti-HER2 treatments are not effective; high

chemosensitivity

TNBC: INTRODUCTION

HAZARD RATES OF PROGRESSION

AND DEATH: TNBC VS. OTHERS

Liedtke C, et al., J Clin Oncol 2008;26;1275–81. Reprinted with permission. © 2008 American Society of Clinical Oncology. All rights reserved.

3,726 EBC patients diagnosed between 1986-1992

10-yr survival Median OS (from first distant mets)

Luminal A 70% 2.2

Luminal B 54.4% 1.6

Luminal/HER2 46.1% 1.3

HER2 enriched 48.1% 0.7

Basal Like 52.6% 0.5

TN non basal 62.6% 0.9

METASTATIC BEHAVIOUR

OF BC SUBTYPES

Kennecke H, et al., J Clin Oncol 2010;28:3271–7. Reprinted with permission. © 2010 American Society of Clinical Oncology. All rights reserved.

n Brain Liver Lung BoneDistant

Nodal

Pleural/

peritonealOther

Luminal A 458 7.6 28.6 23.8 66.6 15.9 28.2 13.5

Luminal B 378 10.8 32.4 30.4 71.4 23.3 35.2 19.3

Luminal/HER2 117 15.4 4.4 36.8 65 22.2 34.2 13.7

HER2 enriched 136 28.7 45.6 47.1 59.6 25 31.6 16.9

Basal Like 159 25.2 21.4 42.8 39 39.6 29.6 23.9

TN non basal 109 22 32.1 35.8 43.1 35.8 28.4 25.7

p <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 0.32 0.006

VISCERAL INVOLVEMENT

ACCORDING TO BC SUBTYPE

Kennecke H, et al., J Clin Oncol 2010;28:3271–7

TN

HR+/HER2- HER2+

Reprinted from Cortazar P, et al., Lancet 2014;384164–72. Copyright 2014, with permission from Elsevier.

CHEMOSENSITIVITY OF TNBC:

pCR AND LONG-TERM OUTCOME

Introduction:


State of the art

Neoadjuvant/Adjuvant setting

Advanced disease



OUTLINE

Triple-negative tumours benefit from

adjuvant chemotherapy, with possible

exclusion of low-risk “special

histological subtypes” such as

secretory juvenile, apocrine or adenoid

cystic carcinomas [I,A].

Chemotherapy usually consists of four

to eight cycles of anthracycline- and/or

taxane-based regimen. Sequential use

of anthracyclines and taxanes, instead

of concomitant, is recommended [I, B]

Senkus E, et al., Ann Oncol 2015;Suppl 5:v8–30 by permission of Oxford University Press and ESMO.

Anthracycline vs. no CT Anthra+Tax vs. no Tax

PROGRESS IN ADJUVANT CT

Reprinted from EBCTCG. The Lancet 2012;379(9814):432–44 + Supplement. Copyright 2012, with permission from Elsevier.

British Columbia Cancer Agency stage I-III BC (7,178 patients)

1,132 (15.8%) patients with ER neg and HER2 neg BC

Cohort 1: 1986 - 1992 Cohort 2: 2004 - 2008

PROGRESS IN ADJUVANT CT:

EFFECT FOR TNBC

Cossetti RJD, et al., J Clin Oncol 2015;33:65–73. Reprinted with permission. © 2015 American Society of Clinical Oncology. All rights reserved.

ADJUVANT CHEMOTHERAPY FOR

PATIENTS WITH SMALL TNBC

No chemotherapy Chemotherapy

5yrs DFS

T1a: 96%

T1b: 93%

5yrs DFS

T1a: 100%

T1b: 96%

Vaz-Luis I, et al., J Clin Oncol 2014;32:2142–50. Reprinted with permission. © 2015 American Society of Clinical Oncology. All rights reserved.

Guideline statements LoE Consensus

Sequential monotherapy is the preferred choice for MBC. Combination CT

should be reserved for patients with rapid clinical progression, life-

threatening visceral metastases, or need for rapid symptom and/or disease

control.

IA 96% (25) yes

4% (1) abstain

(26 voters)

In patients pre-treated (in the adjuvant or metastatic setting) with an

anthracycline and a taxane, and who do not need combination

chemotherapy, single-agent capecitabine, vinorelbine, or eribulin are the

preferred choices.

Additional choices include gemcitabine, platinum agents, taxanes, and

liposomal anthracyclines.

The decision should be individualised and take into account different

toxicity profiles, previous exposure, patient references, and country

availability.

IB 77.1% (27) yes

20.0% (7) abstain

(35 voters)

UPDATE ON HER2neg ABC

HER2+ HER2+HER2– HER2–

HR –HR +

MBC

(Poly)chemoRx

Paclitaxel+Beva

BRCA mutated

DNA damaging CT

PARPi

Trastuzumab +

Pertuzumab + taxane

Trastuzumab

+ Chemo

Lapatinib +

capecitabine

TDM-1

Lapatinib +

trastuzumab

AI + trastuzumab

AI + lapatinib

SERMs

SERD

AI

OFS

AI+ everolimus

AI + CDK4/6 inh.

Trastuzumab +

taxane

Chemotherapy

HOW TUMOUR BIOLOGY DRIVES

OUR THERAPEUTIC CHOICES

LINES OF CHEMOTHERAPY AND

DURATION ACCORDING TO BC SUBTYPE

Seah DSE, et al., J Natl Compr Canc Netw 2014;12:71–80

Number of lines of chemotherapy

Pro

port

ion

of p

atie

nts

rece

ivin

g ch

emot

hera

py

1 2 3 4 5 6 7 8 9 10 110

10

20

30

40

50

60

70

80

90

100

HR+

TNBC

HER2+

Number of lines of chemotherapy

Dur

atio

n of

che

mot

hera

py (

mo)

1 2 3 4 50

1

2

3

4

5

6

7

8

9

10

Introduction:


State of the art


Advanced disease



OUTLINE

Chemotherapy is the mainstay of treatment in both early and advanced settings.

Treatment options have mostly remained unchanged over years

Recent attempts to further exploit TN chemosensitivity:

1. NEO/ADJUVANT setting:

Schedule

Maintenance

New cytotoxics/new formulations

2. ADVANCED setting:


3. THE PLATINUM SALTS STORY

4. THE BEVACIZUMAB STORY

SYSTEMIC TREATMENT FOR TNBC:

CURRENT STATUS

All patients TN patients

Sparano J, et al., J Clin Oncol 2015;33:2353–60. Reprinted with permission. © 2015 American Society of Clinical Oncology. All rights reserved.

(F)EC Q2 vs. (F)EC Q3: Disease-free survival

N=335 HR-

(F)EC Q2

(F)EC Q3

GIM-2: ADJUVANT DOSE-DENSE

CHEMOTHERAPY FOR N+ BC PTS

Reprinted from Del Mastro L, et al., Lancet 2015;385:1863–72. Copyright 2015 with permission from Elsevier.

CMM MAINTENANCE AFTER

ADJUVANT CHEMOTHERAPY

75% TNBC

Presented By Colleoni M, at 2015 ASCO Annual Meeting. Reproduced courtesy of Marco Colleoni.

CMM MAINTENANCE AFTER

ADJUVANT CHEMOTHERAPY

All patients TN patients

Presented By Colleoni M, at 2015 ASCO Annual Meeting. Reproduced courtesy of Marco Colleoni.

Sur

gery

12 weeks 12 weeks

N=1200

R*

*Centrally confirmed:- Subtypes HER 2/ HR- Ki67- SPARC

Paclitaxel80 mg/ m2

weekly

nab-Paclitaxel

125 mg/ m2

weekly

Epirubicin 90 mg/m2

Cyclophosphamide 600 mg/m2

If HER2 positive:

Trastuzumab 8 mg/kg (loading dose) followed

by 6 mg/kg

Pertuzumab (absolute dose per application) 840

mg (loading dose) followed by 420 mg

If H

ER

2 po

sitiv

e: tr

astu

zum

ab

acc.

to A

GO

Gui

delin

es

Core biopsy

Cor

e bi

opsy

* (a

fter

ant

i-HE

R2

trea

tmen

t / b

efor

e st

udy

entr

y)

Arm A

Arm B

Core biopsy

optional

Core biopsy

optional

R*

Cor

e bi

opsy

* (b

efor

est

udy

entr

y)

N=60(HER2 positive)

6 weeks

FINAL STUDY DESIGN

(AFTER 400 PATIENTS RECRUITED)

*Randomizations carried out simultaneouslyPresented by Untch M. San Antonio Breast Cancer Symposium, December 9-13, 2014. Reproduced courtesy of Michael Untch.

GEPAR7: SUBGROUP ANALYSIS

Reprinted from Untch M, Lancet 2016;17(3):345-56. Copyright 2015, with permission from Elsevier.

SCHEME OF THE PHASE III

RANDOMISED ETNA TRIAL

Presented By Gianni L, at 2016 ASCO Annual Meeting. Reproduced courtesy of Luca Gianni.


Treatment options have mostly remained unchanged over years.



Schedule

Maintenance







CURRENT STATUS

In advanced breast cancer patients already treated with anthracyclines and taxanes

(301 study)

ERIBULIN VS. CAPECITABINE

Kaufman PA, et al., J Clin Oncol 2015;33:594–601

E301: OVERALL SURVIVAL

Kaufman PA, et al., J Clin Oncol 2015;33:594–601. Reprinted with permission. © 2015 American Society of Clinical Oncology. All rights reserved.

Overall 0.879 (0.770, 1.003) 15.9 14.5

HER2 status

Positive 0.965 (0.688, 1.355) 14.3 17.1

Negative 0.838 (0.715, 0.983) 15.9 13.5

ER status

Positive 0.897 (0.737, 1.093) 18.2 16.8

Negative 0.779 (0.635, 0.955) 14.4 10.5

Triple negative

Yes 0.702 (0.545, 0.906) 14.4 9.4

No 0.927 (0.795, 1.081) 17.5 16.6

Subgroup HR (95% CI) Eribulin Capecitabine

Median (months)

0.2 0.5 1.0 2 5

n=755

n=449

n=284

Favours eribulin Favours capecitabine

E301: PRE-SPECIFIED SUBGROUPS

ANALYSIS

ITT populationKaufmann PA, ASCO 2013 (abstract 1049^)

POOLED ANALYSIS OF EMBRACE

AND 301: OS BY PATIENT SUBGROUPS

Twelves C, et al., Breast Cancer Res Treat 2014;148:553–561. used under CC BY-NC (https://creativecommons.org/licenses/by-nc/2.0/)





Schedule

Maintenance







CURRENT STATUS

DRUG-SPECIFIC CHEMOTHERAPY

FOR TNBC?

0

10

20

30

40

50

60

TAC

Gepar31

EC-D EC-D+Bev

Gepar53

PM PM+carbo

(+ Bev)

Gepar64

P-AC P+carbo-AC

(+/- Bev)

CALGB406035

P+carbo+bev

Ca.Pa.Be6nabP-EC

Gepar78

EC-P

(+/-gem)

NeoTango2

nabP-carbo

ADAPT7

pCR RATES (BREAST/AXILLA)

IN TNBC

1. Huober J, BCRT 2010; 2. Earl HM, Lancet Oncol 2014; 3. von Minckwitz G, NEJM 2012; 4. von Minckwitz G, Lancet Oncol 2014; 5. Sikov WM, J Clin

Oncol 2015; 6. Guarneri V, Ann Surg Oncol 2015; 7. Gluz O, SABCS 2015; 8. Untch M, Lancet Oncol 2016

GEPARSIXTO: DFS IN TNBC

Presented by Von Minckwitz G, at SABCS 2015. Reproduced courtesy of Gunter Von Minckwitz.

CALGB 40603 (ALLIANCE)

EVENT FREE SURVIVAL

Presented by Sikov WM, SABCS 2015. Reproduced courtesy of Willian Sikov.

pCR RATES BY gBRCA STATUS

AND CARBOPLATIN IN TNBC

Presented by Von Minckwitz G, at SABCS 2014. Reproduced courtesy of Gunter Von Minckwitz.

pCR RATES BY TREATMENT AND

ACCORDING TO HR DEFICIENCY

STATUS (ypT0 ypN0)

Presented By Von Minckwitz G, at 2015 ASCO Annual Meeting. Reproduced courtesy of Gunter Von Minckwitz.

TNT PHASE III TRIAL FOR TN

METASTATIC BC

Tutt A, et al., SABCS 2014



METASTATIC BC





Schedule

Maintenance







CURRENT STATUS

HYPOXIA-RELATED FEATURES

AND BASAL-LIKE TUMOURS

VEGF 13-gene VEGF-signature

Exp

ress

ion

Perou CM, The Oncologist 2010; 15(5):39-48. By permission by Alphamed Press ©2010

Antiangiogenic approaches work in TNBC at least as well as other subtype,

possibly more

POOLED ANALYSIS OF FIRST-LINE

BEVACIZUMAB: PFS

Miles DW, et al., Ann Oncol 2013;24:2773–80. By permission of Oxford University Press and ESMO.

POOLED ANALYSIS OF FIRST-LINE

BEVACIZUMAB: OS

Miles DW, et al., Ann Oncol 2013;24:2773–80. By permission of Oxford University Press and ESMO.

NSABP-B402GEPAR51

NEOADJUVANT CHEMOTHERAPY

AND BEVACIZUMAB FOR HER2– NEGATIVE BC

Adapted from 1. von Minckwitz G, et al., N Engl J Med 2012;366(4):299-309; and 2. Miklos GL. N Engl J Med 2012;366(17):1638

Subgroup1 No. of pts

Odds Ratio (95% CI)

Test for interaction

All patients 1925 1.29 (1.02-1.65)

Age 0.26

<40 yr 304 1.71 (0.99-2.95)

≥40 yr 1621 1.20 (0.92-1.58)

Tumour stage 0.92

cT1-cT3 1690 1.30 (1.01-1.67)

cT4a-cT4d 235 1.23 (0.49-3.10)

Lymph-node stage 0.63

cN0 767 1.20 (0.84-1.74)

cN1-cN3 1096 1.36 (0.98-1.89)

Disease stage 0.16

Operable 1702 1.23 (0.96-1.59)

Locally advanced 223 2.43 (0.96-6.15)

Histologic type 0.91

Ductal or other 1713 1.31 (1.02-1.68)

Lobular 208 1.23 (0.40-3.79)

Tumour grade 0.15

1 or 2 1085 1.01 (0.66-1.53)

3 829 1.48 (1.09-2.02)

Hormone-receptor status 0.07

Negative 663 1.67 (1.21-2.31)

Positive 1262 0.99 (0.66-1.50)

Subgroup Odds Ratio (95% CI) Day test

All patients 1.29 (0.98, 1.92)

Clinical tumour size 0.76

2-4 cm 1.24 (0.85, 1.83)

>4 cm 1.35 (0.93, 1.96)

Clinical nodal status 0.44

Positive 1.15 (0.77, 1.75)

Negative 1.42 (0.98, 2.05)

Hormone receptor status 0.24

Positive 1.67 (1.07, 2.58)

Negative 1.18 (0.82, 1.72)

Age at entry 0.94

<50 yr 1.29 (0.9, 1.83)

≥50 yr 1.30 (0.89, 1.93)

Tumour grade 0.73

Low 0.78 (<0.25, 3.65)

Intermediate 1.21 (0.67, 2.2)

High 1.4 (1.00, 1.91)

BEVACIZUMAB ADDED TO NEOADJUVANT

CHEMOTHERAPY FOR BREAST CANCER

GEPARQUINTO: NEOADJUVANT

BEVACIZUMAB AND SURVIVAL

von Minckwitz G, et al., Ann Oncol 2014;25:2363-72. By permission of Oxford University Press and ESMO.

BEATRICE PHASE III

ADJUVANT TRIAL

Reprinted from Cameron D, Lancet 2013;14:933–42. Copyright 2013, with permission from Elsevier.

Introduction:


State of the art


Advanced disease



OUTLINE

THE GENOMIC COMPLEXITY

OF TNBC

1. Reprinted by permission from Macmillan Publishers Ltd: Nature Stephens PJ, et al., 2009;462(7276):1005-10. Copyright 2009.

2. Reprinted by permission from Macmillan Publishers Ltd: Nature. Shah SP, et al., 2012;486(7403):395-9. Copyright 2012.

Basal-like 1 and Basal-like 2 Cell proliferation, DNA damage response

Immunomodulatory Immune signalling

Mesenchymal-like and Mesenchymal stem-like EMT, motility and growth-factor pathways

Luminal AR Androgen receptor signaling

TNBCTYPE

Lehmann BD, et al., J Clin Invest 2011;121:2750–67. Reproduced with permission of American Society for Clinical Investigation in the format use in an

ecoursepack via Copyright Clearance Center.

DSB, double-strand break; HR, homologous recombination

SSB, single-strand break

PARP

DNA damage (SSBs)

DNA replication

(accumulation of DNA DSBs)

Normal cell

with functional HR pathwayHR-deficient tumour cell

Cell survival Cell death

HR-mediated

DNA repair

Impaired HR-mediated

DNA repair

Tumour-selective cytotoxicity

PARP inhibition

PARP INHIBITION AND TUMOUR-

SELECTIVE SYNTHETIC LETHALITY

Farmer H, et al., Nature 2005;434:917–921; Bryant HE, et al., Nature 2005;434:913–917; McCabe N, et al., Cancer Res 2006;66:8109–8115

PHASE III TRIALS OF PARP

INHIBITORS IN HER2NEG

BRCA1/2MUT BC PATIENTS

Potent PARP inhibitor at

MTD as continuous

exposure

Physician Choice within

SOC options

Capecitabine

or

Vinorelbine

or

Eribulin

or

Gemcitabine

gBRCA1 / BRCA2 Carriers

Advanced anthracycline

taxane resistant breast

cancer

Primary

endpoint

PFS

Olaparib – OLYMPIAD - NCT02000622

Talazoparib (BMN 673)

– EMBRACA - NCT01945775

Niraparib – EORTC / BIG BRAVO Trial

R

POOLED INDIVIDUAL PATIENT DATA

ANALYSIS OF TILS IN PRIMARY TNBC

TREATED WITH ADJUVANT CT

P interaction A vs A+T=0.29

Overall survival

Loi S, SABCS 2015. Reproduced courtesy of Sherene Loi

p=0.0019 p=0.0017

5yr-MFS: 81.5% vs. 46%

HR 0.24, 95%CI 0.09-0.645yr-OS: 91% vs. 55%

HR 0.19, 95%CI 0.06-0.61

Dieci MV, et al., Ann Oncol. 2014;25:611–8. © The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical

Oncology. All rights reserved.

Recurrent/metastatic

TNBC

ECOG PS 0-1

PD-L1+*

CR

PR or SD

PD

Discontinuation

allowed

Treat for 24 mos or

until PD or toxicity

Discontinue

PEMBROLIZUMAB (ANTI-PD-1) IN

TNBC: KEYNOTE-012 TRIAL

Pembrolizumab

10 mg/kg

q2weeks

*PD-L1 positivity definition: PD-L1 expression on >1% of tumour cells (58% of screened patients)

On treatment

Discontinued treatment

Objective response rate: 18.5%

Stable disease: 25.9%

n=32

PEMBROLIZUMAB IN TNBC:

KEYNOTE-012 TRIAL

Nanda R, et al., SABCS 2014. Reproduced courtesy of Rita Nanda

MPDL3280 in n=21 TNBC (PD-L1 IC scores 2/3 )

MPDL3280A (ATEZOLIZUMAB)

IN TNBC

Emens LA, et al., AACR 2015

IC2/3 patients, na ORR

(95% CI)

24-Week PFS

(95% CI)

21 19% (5-42) 27% (7-47)

CR/Pr (n=4)

SD (n=3)

PD (n=9)

Discontinued

New lesion

0 42 84 126

Time on study (days)

168 210 252 294 336 378 420 462 504 546 588

-100

-80

-60

-40

-20

0

20

40

60

80

100

Cha

nge

in s

um o

f lar

gest

dia

met

ers

from

bas

elin

e (%

)

RESULTS<BR />DORA

Presented by Adams SA, et al., ASCO 2016. Reproduced courtesy of Sylvia Adams

Unique subclass of ER-PgR- human tumours characterised by a hormonally regulated

transcriptional programme and response to androgen

ANDROGEN RECEPTOR IN TNBC

Reprinted by permission from Macmillan Publishers Ltd: Doane AS, et al., Oncogene 2006;25:3994–4008, copyright 2006.

PHASE II STUDY OF

ENZALUTAMIDE IN ADVANCED AR+

TNBC (MDV3100-11)

Traina T, et al., 2015 ASCO Annual Meeting. Reproduced courtesy of Tiffany Traina

CLINICAL BENEFIT ACCORDING TO PREDICT AR

Chemotherapy remains the mainstay of treatment:

Anthracycline+taxanes: first choice in the neo-/adjuvant setting (the schedule

matters!)

BRCA-mut (or BRCAwt with BRCAness features?): chance for tailored-

chemotherapy with platinum salts

Novel targets and approaches:

Dissecting the diversity of TNBC helps identifying druggable pathways

PARP inhibitors hold great promises for BRCA-mut patients

Immunotherapy on the horizon: what about predictive markers?

CONCLUSIONS

THANK YOU!

E-Learning Triple Negative Breast Cancer is Still an Unmet...

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