triple negative breast cancer

CANCER DE MAMATRIPLE NEGATIVO

Dr. LUIS MIGUEL ZETINA-TOACHEONCOLOGIA MEDICA

CANCER CONSULTANTS GTONCOMEDICA S.A

Objetivos………………………………..

Clasificacion Genomica Diferentes Tipos de TNBC Importancia de la Clasificacion Caracteristicas Clinicas del TNBC Opciones de Tratamiento Opciones a Futuro

Cancer Growth and Metastases

Tumor

Crece, in

vade y metastasiza

Histologia del cancer de mama

Tipo HistológicoFrecuencia

(%)Supervivencia a

5 años (%)

Carcinoma Ductal Infiltrante 63.6 79

Carcinoma Lobulillar infiltrante 5.9 84

Carcinoma Ductal & Lobular Infiltrante 1.6 85

Carcinoma Medular 2.8 82

Carcinoma Mucinoso 2.1 95

Comedocarcinoma 1.4 87

Enfermedad de Paget 1.0 79

Adenocarcinoma No Esp. 7.5 65

Sin un claro patron

De comportamiento biologico

No establece SVG o SLE

TRATAMIENTO SISTÉMICO DEL CÁNCER DE MAMA METASTÁSICO CON HER2 NORMAL

OPCIONES C

LARAS

DE TRATAMIENTO

. Adapted from Hanahan and Weinberg. Cell. 2000;100:57.

Evadingapoptosis

Self-sufficiency in growth signals

Tissue invasionand metastasis

Limitless replicative potential

Sustainedangiogenesis

Insensitivity to antigrowth

signals

Cancercells

Fundamental Hallmarks of Cancer

ANALISIS GENOMICO DE TUMOR

CLASIFICACIONMOLECULAR

Smalley M. Ashworth A. Nat. Cancer Reviews 2003;3,832-844

Luminal Epithelial CellsLow molecular wt CK 7, 8, 18 and 19Mucin, BCL2, Hormone Receptors

Basal Cells (Myoepithelial cells)High molecular wt CK 5, 6, 14 and 17SMA, Calponina, p63, P-caderin

Perou C, et al. Nature 460:747-752, 2000

Terminal Duct Lobular Unit (TDLU)

Overall and relapse-free survival analysis of the 49 breast cancer patients, uniformly treated in a prospective study, based on different gene expression classification.

Therese Sørlie et al. PNAS 2001;98:10869-10874

©2001 by National Academy of Sciences

ESTABLECE CLARO

PATRON BIO

LOGICO Y TERAPEUTIC

O

Clasificación molecular del Cancer de Mama

6 biomarcadores:

1. RE2. RP3. HER2

4. EGFR5. CK5/66. Ki67

SJ Schnitt et al - 2010

St. Gallen 2011:

1. RE2. RP

3. HER24. Ki67

Why is subtype important?

• Different outcomes• Prognostic significance• Selection of

therapeutic options• Response to treatment

Orígenes del Cancer Mama

Hipótesis I: cada subtipo tiene SU célula de origen

Polyak K - 2007

Orígenes del Cancer De Mama

Hipótesis II: una sola célula de origen para todos los subtipos,y el fenotipo, determinado por eventos genéticos y epigenéticos.

Polyak K - 2007

New Developments in Metastatic Breast Cancer

Metzger-Filho O, et al. J Clin Oncol. 2012;30:1879-1887. Reprinted with permission. © (2012) American Society of Clinical Oncology. All rights reserved.

Heterogeneities in the Nomenclature and Classification of TNBC

EGFR andcytokeratins

Claudin-lowsubtype

Basal-liketumors

TNBCER-negative

PgR-negativeHER2-

negative

BRCA1 mutantand BRCAness Immune system

Different histologicsubtypes

Clasificación molecular del CMTN:Subtipo “basal - like”

Perou CM, 2010

Perou CM, 2010

Clasificación molecular del CMTN:Subtipo “claudin – low”

Aclarando conceptos…

Chacon R - 2010

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 20095. Schneider, B. P. et al. Clin Cancer Res 2008;14:8010-8018

Triple-Negative vs. Basal-Like: DefinitionsER- / 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

“BRCAness”: Characteristics shared between BRCA-associated and sporadic breast cancers.

Lisa A. Carey The Oncologist 2011;16:71-78

©2011 by AlphaMed Press

Lehmann B, et al. JCI, 121:2750, 2011

Prat A, Perou CM, 2009

En resumen….(con respecto a la clasificación)

CÁNCER DE MAMA:

Conjunto de neoplasias distintas que asientan en la mama

CÁNCER DE MAMA TRIPLE NEGATIVO:

Grupo heterogéneo de un subtipo de cáncer de mama

New Developments in Metastatic Breast Cancer

What Is a Triple-Negative Breast Cancer (TNBC)? “Triple negative”: ER negative, PgR negative, HER2

negative

– Depending on thresholds used to define ER and PgR positivity and methods for HER2 testing

TNBC accounts for 10% to 17% of all breast carcinomas

Significantly more aggressive than other molecular subtype tumors

Majority grade 3 tumors

Most frequently high grade invasive ductal carcinomas of no special type

Reis-Filho JS, et al. Histopathology. 2008;52:108-118.

Who gets triple negative breast cancer?

15 % of breast cancer in US Young women African American women BRCA1 positive

Any woman can get any type of breast cancer

Epidemiology

Carey LA et al - 2006Carolina Breast Cancer Study

n = 1.424

New Developments in Metastatic Breast Cancer

Characteristics and Features of TNBC Phenotype Weak relationship between tumor size and nodal status

Rapid rise in risk of recurrence following diagnosis

Peak risk of recurrence at 1-3 yrs

Distant recurrence rarely preceded by local recurrence

Local recurrence not predictive of distant recurrence

Increased mortality rate first 5 yrs

Majority of deaths occurs within first 5 yrs

Rapid progression from distant recurrence to death

Dent R, et al. Clin Cancer Res. 2007;13:4429-4434.

New Developments in Metastatic Breast Cancer

Clinical Characteristic of Metastatic TNBC

No consistent association with nodal status or stage

Relapse pattern

– Higher risk

– Early timing

– Sites differ from luminal:

– CNS 46% of time n Bone, % Soft Tissue, % Viscera, %

TNBC 79 13 13 74

ER+ 123 39 7 54

HER2+ 78 7 12 81

Liedtke C, et al. J Clin Oncol. 2008;26:1275-1281. Lin NU, et al. Cancer. 2008;113:2638-2645.

0.35

0.30

0.25

0.15

0.10

0.05

0

HR 0.20

0 1 2 3 4 5 6 7 8 9 10Yrs After First Surgery

Other (290 of 1421)Triple negative (61 of 180)

Rates of distant recurrences in triple-negative and other breast cancers.

Dent R et al. Clin Cancer Res 2007;13:4429-4434

©2007 by American Association for Cancer Research

Opciones de manejo

QuimioterapiaRadioterapia

Terapia endócrinaTerapia dirigida

Opciones de manejo

Ca de mama RE/P (+) Ca de mama HER2 (3+)

Cirugía Neoadyuvancia

/adyuvancia (antraciclinas – taxanos)

Radioterapia +/- Terapia endócrina

(5 años) Recaída: hormonoterapia

2da y 3era linea

Cirugía Neo Ady (antraciclinas –

taxanos Trastuzuma/Pertuzumab)

Radioterapia +/- Recaída: ( Kadcyla,

capecitabina, lapatinib, gemcitabina,vinorelbine, eribulina, ixabepilona, etc)

Myths about triple negative breast cancer

• There are no effective treatments.• Patients are doomed to relapse.• Women with triple negative cancers are

doomed to die of their disease.• You have to have a mastectomy for triple

negative breast cancer.

Opciones de manejo

Ca de mama Triple (-)

• Cirugía• Neoadyuvancia /adyuvancia

(antraciclinas – taxanos)• Radioterapia +/-• Recaída

( capecitabina, platinos,• gemcitabina, inhib. de PARP• Bevacizumab, PIK3, PDL1.• Terapia endócrina NO• Terapia dirigida NO

Johnston S R Clin Cancer Res 2010;16:1979-1987

©2010 by American Association for Cancer Research

Targeted Therapies

Nu

mb

er o

f sa

mp

les

wit

h a

ber

rati

on

s

PI3K/mTOR DNA Repair Ras/MAPK Cell Cycle GFRs0

10

20

30

40TSC1

PIK3CA

PTEN

PIK3R1

RICTORRAPTORAKT1AKT2

AKT3

BRCA1

BRCA2ATM

RB1

AURKA

CDNK2A

CCNE1

CCND3

CCND2

CCND1

CDK6CDK4

NF1CRAFBRAFKRAS EGFR

MET

IGF1RKITFGFR1

FGFR2

FGFR4

PI3K/mTOR inhibitors

Targeted RTK inhibitors

DNA-repair targeting

agents

Cell cycle/mitotic

spindle inhibitors

RAF/MEK inhibitors

Arteaga C, et al. Vanderbilt

Clinically targetable pathways in TNBC

~90% of all patients had an aberration in at least one of these

pathways

Triple Negative Breast Cancer Treatment

• Chemotherapy

• Parp inhibitors • EGFR inhibitors

• Angiogenesis inhibitors

• Tyrosine Kinase inhibitors

Effectiveness of Chemotherapy

Triple Negative / Basal Disease

Chemosensitivity: Pathologic complete response (complete tumor eradication) to preoperative chemotherapy [9, 10].

Lisa A. Carey The Oncologist 2011;16:71-78

©2011 by AlphaMed Press

Basal-like BC Responds to Conventional Chemotherapy

T-FAC

(N=82)*AC-T

(n=107)*

Luminal A/B 7% 7%

Normal-like 0 NA

HER2+/ER- 45% 36%

Basal-like/triple negative 45% 26%

Rouzier, et al. Clin Cancer Res, 2005 Carey LA, et al. Clin Cancer Res 2007

• Basal-like / triple negative breast cancer responds to primary chemotherapy.

Explanation of higher response but worse outcome?

Pathologic Complete Response:

Responsiveness to conventional chemotherapy.

Lisa A. Carey The Oncologist 2011;16:71-78

©2011 by AlphaMed Press

Opciones de manejo:Platinos

Silver, DP et al - 2010

The Role of Carboplatin in TNBC (Neo)

Trial N StandardChemotherapy

Chemo +Carboplatin P-value

CALGB 40603 443 41% 54% 0.003

I-SPY 2 NA 26% 52% 90% prob. for superiority

GeparSixto(TNBC pts) 315 38% 59% <0.05

Sikov W, et al. SABCS 2013.Rugo H, et al. SABCS 2013.

Von Minckwitz G, et al, The Lancet Oncology 15:747, 2014.

Opciones de manejo:Platinos

Silver, DP et al - 2010

Utilidad enBRCA (+)

Adjuvant therapy for early breast cancer (90% are early at diagnosis).

Lisa A. Carey The Oncologist 2011;16:71-78

©2011 by AlphaMed Press

Rates of breast-specific survival in triple-negative and other breast cancers.

Dent R et al. Clin Cancer Res 2007;13:4429-4434

©2007 by American Association for Cancer Research

Rates of distant recurrences following surgery in triple-negative and other breast cancers.

Dent R et al. Clin Cancer Res 2007;13:4429-4434

©2007 by American Association for Cancer Research

Angiogenesis

Taxol + Avastin in metastatic patients

Benefit in triple negative patients

ECOG 2100: Randomized phase III trial of bevacizumab added to paclitaxel in stage IV breast cancer.

Lisa A. Carey The Oncologist 2011;16:71-78

©2011 by AlphaMed Press

Opciones de manejo:Bevacizumab

Hudis CA, Gianni L - 2011

Beneficio en pacientes Triple Negativo

TNBC PatientsER 1-10% (6%)

Age <60 83%T2-T3 86%LN+ 55%Grade III 86%

CALGB/Alliance 40603pCR in Breast and Axilla

Sikov W, et al. SABCS 2013

Opciones de manejo:Ixabepilona

Pacientes MTTSresistentes o progresadasa antraciclinas y taxanos.

Hudis CA, Gianni L - 2011

Study Schema

CarboplatinAUC5

q3wks x 4

Paclitaxel 80 mg/m2 qwk x 12

CP-CEF

P-CEF

HER2 (-) BCStage II/IIIA18-70 years

PS 0/1Good Organ

functionWritten IC

S U

R G

E R

Y

CEF 500/100/500 mg/m2

q3wks x 4

R

CEF 500/100/500 mg/m2

q3wks x 4

Paclitaxel 80 mg/m2 qwk x 12

Enrolled 181 ptsN= 75 for TNBC56% Node positive

pCR rates

CP-CEF P-CEF0

20

40

60

80

100

32%17%

All patients

pC

R r

ate

(%)

CP-CEF P-CEF0

20

40

60

80

100

62%

26%

TNBC patients

pC

R r

ate

(%)

Primary Endpoint

P =0.04

pCR rates by EGFR

expression

EGFR- EGFR+

p=0.010

(%)

0All AllCP CPP P

11.518.2

6.7

45.0

63.6

22.220

40

60

80

p=0.040

p= N.S.

pC

R r

ate

Results

PARP Inhibitors in Development

• Olaparib (Astra Zeneca) PO• Veliparib (ABT888 - Abbvie) PO• BMN-673 (Biomarin) PO• Niraparib (MK-4827) PO• CEP 9722 (Cephalon) PO• GPI 21016 (MGI Pharma) PO• Iniparib (BSI 201 – Sanofi-Aventis) IV• Rucaparib aka AGO 14699 (Pfizer) IV• INO 1001 (Inotek – Genentech/Roche) IV

• Others?

Opciones de manejo:Inhibidores del PARP

PARP 1:Prot. nuclear que va al sitio donde se hallael DNA dañado y cataliza la transferenciade ADP-ribosas del NAD+ para modularla reparación del DNA.

Paciente con BRCA mutado:No tienen mecanismo de reparación del DNApor este medio.

Opciones de manejo:Inhibidores de PARP

DNADNA

dañadoREPARACIÓN

BRCA

Reposiciónde

nucleótidos

EVENTO MUTADO

PARP

Mechanisms of Synthetic Lethality-PARP-1

60Image from: Iglehart JD, Silver DP. Synthetic Lethality-A new direction in cancer-drug development. NEJM 2009; 361 (2) ; 189-191. 2009 Massachusetts Medical Society.

All rights reserved. Permission requested.

Rugo H, et al. SABCS 2013

I-Spy 2 Trial Neoadjuvant Veliparib/Carboplatin followed by wPac/AC

Parp Inhibitors

One trial in metastatic TNBC patients.

Gemcitabine/carboplatin

Improvement in tumor response and survival with Parp inhibitors

Opciones de manejo:Inhibidores de PARP

DNADNA

dañadoREPARACIÓN

BRCA

Reposiciónde

nucleótidos

EVENTO MUTADO

PARP

Inhibidordel

PARP

Paclitaxel + Trastuzumab* +

New Agent A

Paclitaxel + New Agent C

Patient is on Study

Paclitaxel+ Trastuzumab

Paclitaxel + Trastuzumab* +

New Agent B

Paclitaxel

Paclitaxel + New Agent E

AC

ACHER 2 (+)

HER 2(–)

Randomize

Randomize

Surgery

Surgery

Learn and adapt from each patient as

we go along

Paclitaxel + New Agent F

Paclitaxel + Trastuzumab* +

New Agent C

Paclitaxel + New Agent DPaclitaxel +

New Agent GH

Paclitaxel + Trastuzumab* +

New Agent F

MRI

ResidualDisease(Pathology)

Key

64

I-SPY 2 TRIAL:

Learn, Drop, Graduate, and Replace Agents Over Time

Veliparib/Carboplatin GRADUATES in the Triple Negative Signature

SIGNATURE

Estimated pCR Rate(95% probability interval) Probability

Veliparib +Carbo is

Superior to Control

Predictive Probability of Success in

Phase 3Veliparib/

CarboConcurrent

Control

All HER2- 33% (22-43%)

22% (10-35%)

92% 55%

HR+/HER2- 14% (4-27%)

19% (6-35%)

28% 9%

HR-/HER2- 52% (35-69%)

26% (11-40%) 99% 90%

Rugo et. al. SABCS 2013

EGFR inhibitors

Two trials in metastatic breast cancer

Irinotecan/carboplatin + cetuximab

Cetuximab alone or with carboplatin

EGFR Inhibition for TNBC

• TNBC is strongly associated with EGFR expression• EGFR inhibitors combined with platinum • Current data are conflicting

TBCRC 001(n=102)

O’Shaugnessy et al(n=78)

Cetuximab Carboplatin + Cetuximab

Irinotecan + Carboplatin

Irinotecan + Carboplatin + Cetuximab

ORR,% 6 18 49 30

Clinical benefit, % 10 27 NR NR

PFS, mo 2 5.1 4.7

Efficacy data from phase II trials

NR=not reported; PFS=progression-free survival; RR=response rate; TBCRC=Translational Breast Cancer Research Consortium

Carey et al. ASCO 2008; abstr 1009; O’Shaughnessy et al. SABCS 2007; abstr 308.

TNBC recent perspectivesLooking for a target...

• Other Chemotherapy?• Androgen Receptor• PI3K pathway alterations• EGFR inhibitors• Anti-angiogenics• Src inhibitors• C-Kit alteration• Clinical Trail• Likely will need combos

Opciones de manejo:Otras “potenciales” opciones

1. Anti – EGFR:cetuximab

2. Inhibidores de Tirosin-kinasa: sunitinib

3. Anti – mTOR:everolimus

4. Antiandrógenos: bicalutamida

Santana-Davila R, Pérez EA - 2010

TNBC: potential therapeutic targets

Mayer I A et al. Clin Cancer Res 2014;20:782-790

©2014 by American Association for Cancer Research

SWOG Proposed Study

R

TNBC Post NAC PT1C or N+

N=400

Placebo x 1 year

MK3475 x 1 yearAnti-PD1 antibody

Primary endpoint:

DFS

A randomized, phase III trial to evaluate the efficacy and safety of MK-3475 as adjuvant therapy for triple receptor-negative breast cancer with >1 cm residual invasive cancer or any positive lymph nodes

(>pN1mic) after neoadjuvant chemotherapy

SAFIR 01 Study

Outcomes

Andre F, et al. Lancet Oncol 2014

Targets addressed:

• PI3KCA mutation

• EGFR amplification

• AKT mutation

• FGFR amplification

• IGF-1R amplificationOverall Benefit Rate:12/407 (3%)Response Rate: 4/407 (1%)

17 Targeted Regimens

Novel Agents in Development for TNBC• Met inhibitor: ARQ197, onartuzumab

(Metmab), foretinib• PI3K and/or inhibitor: BKM 120,

temsirolimus (+ neratinib)• HDAC inhibitors: entinostat, vorinosat• Demethylating agents: azacitidine

(+ entinostat)• PARP inhibitors: ABT-888, E7449,

Biomarin-BMN673, AZD2281, rucaparib• Olaparib+ BKM120; • Angiogenesis inhibitor: cediranib

(+ olaparib), ramicurumab, IMC18F1, foretenib, sorafenib

• Hsp90 inhibitors: ganetespib • Aurora kinase inhibitors: ENMD 2076• Androgen Receptor Blockers:

enzalutamide

• EGF inhibitors: erlotinib (+ metformin), apatanib

• Lucitanib (FGFR+VEGF inhibitor)• Masitinib (C-Kit inhibitor)• MEK inhibitors: GSK1120212• Wnt inhibitor: LGK974• CDK inhibitor: dinaciclib, P276-00• FMS-Kit inhibitor: PLX3397 • Apoptosis inducer: LCL161 (deactivating

inhibitor of apoptosis proteins) • Immunotherapy: MUC1 vaccine,

adoptive cellular therapy (DC-CIK)• Cytotoxics: SN38 -NK012, AEZS-108

(LHRH-dox); • Checkpoint inhibitors (anti PD-1, anti

PDL-1)

TNBC: Conclusions

• TNBC is a recognized distinct subtype of BC– ER, PR, HER2-negative by IHC

• Surrogate of basal-like BC– More aggressive biology (morphology, clinical, molecular)

• TNBC responds to a variety of CT agents although no specific standard regimen or agent can be singled out

• TNBC has no identified specific therapeutic target• Represents an heterogeneous group of tumors probably

with different response patterns to different treatments– Introduction of novel agents (PARPi, others) ?– Biomarkers: RAD-51, Neuropilin ?

En conclusión…

• Presente como cáncer de intervalo• Poca asociación entre tamaño de tumor y estado axilar.

• Metástasis tempranas y agresivas.• Recurrencia pico entre 1º y 3º años del diagnóstico.

• La recurrencia local no predice recaída a distancia.

En conclusión…

• Más prevalente en jóvenes.• Fuerte asociación con obesidad.• Alta prevalencia de mets cerebrales.• La mayoría de las muertes son a 5 años.• Altamente quimiosensible.• Todos los tratamientos en estudios.

Triple Negative Breast Cancer

• Represents a subtype of breast cancer with unique molecular and clinical characteristics .

• Characterized by more aggressive clinicopathologic features including younger age, higher mean tumor size, and higher-grade tumors .

• More likely to occur among premenopausal women of African-American descent .

• Association with BRCA1 mutation status. • More likely to develop a recurrence during the

first 3 years following therapy • More aggressive visceral and soft-tissue relapse

and less common bone recurrence.• High response to systemic chemotherapy.

103

Future Directions

• Increase participation in clinical trials.• Design and implement cancer prevention trials

applicable to at risk populations.• Increase understanding of risk factors and

biology underlying triple-negative breast cancer.• Improving treatment strategies. • Continuous review of current methods.

104

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