cancer de mama 3n

Dr. Adrián Agustín Nervo

Cancer de Mama Triple NegativoHeterogeneidad TumoralRol de Platinos e Inhibidores PARP

Cancer de Mama Triple Negativo

5

Triple Negativo

PertuzumabTDM1

HerceptinLapatinibPertuzumabTDM1

TamoxifenoIAFulvestrantInhibidores mTorInhibidores cDK

No target disponible

90% DE LOS BRCA 1 MUTADOS

80-90% SON SIMIL – BASALES

10-15% DE LOS TN SON BRCA1 MUTADOS

Triple Negativo

Triple Negativo

Característica Clínicas del 3N

• No asociación consistente con status nodal o estadio y evolución

• Patron de Recaída– Alto riesgo– ILE corto– Sitio diferente de los

luminales:– SNC 30-45%

0.35

0.30

0.25

0.15

0.10

0.05

0

HR 0.20

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

n Bone, %

Soft Tissue, % Viscera, %

TNBC 79 13 13 74

ER+ 123 39 7 54

HER2+ 78 7 12 81

Respuesta a la QT Neoadyuvante

• TNBC often responsive to conventional NAC with good outcome similar to other subtypes

• < pCR = poorer outcome1.0

0.9

0.8

0.7

0.6

0.5

0.41

Yrs After Surgery2 3 4 5 6 7

Prob

abili

ty o

f Bei

ng A

live

pCR/non-TNBCpCR/TNBCRD/non-TNBCRD/TNBC

98%94%

88%

68%

P = .24

P = .0001

SABCS 2014

TNBC

http://www.google.com.ar/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRw&url=http://www.istockphoto.com/vector/movie-projector-doodle-background-32982896&ei=NrUpVafvE4bFggT2wYAI&bvm=bv.90491159,d.cWc&psig=AFQjCNEOzdfoEUXtX244K0w1nXVPlZADNw&ust=1428883034042727

21 publically available gene expression data sets587 TNBC

San Antonio Breast Cancer Symposium, December 9-13, 2014

3N

Basal-like 1 and 2

Mesenchymal-like

Luminal-AR

Immunomodulatory

Vanderbilt: subtipos de 3N- TNBCtype

Lehman et al JCI 2012

Mesenchymal Stem-like


Subtipos Moleculares de Cáncer de Mama

3N

Posible origen de los subtipos 3N

Lim et al Nat Med 2009

Luminal AR

Mesenchymal stem-like

Basal-like+- mesencyhmal features


Dos subtipos mayores de 3N

Masuda et al CCR 2013

Subtypes split by intrinsic subtype by PAM50


Basal-like 1 and 2

Mesenchymal-like

Luminal-AR

Immunomodulatory

Vanderbilt: subtipos de 3N




Basal-like

Luminal

Significancia Clínica de los subtipos 3N

Basal-like TNBCLuminal AR

~80% TNBC10-15% TNBC


High expression hormonal driven pathways

Express androgen receptor

Sensitive in vitro to Bicalutamide

Líneas celulares Luminal AR

San Antonio Breast Cancer Symposium, December 9-13, 2014 Lehman et al JCI 2012

Phase II Trial of Bicalutamide in Patients with Androgen Receptor–Positive, Estrogen Receptor Negative Metastatic Breast Cancer

(TBCRC 011)

ER/PR negative (<=10% b IHC) but AR positive (>10% IHC)

Bicalutamide 150mg qd

Screened 424 patients 12% AR positive – 28 treated on study

0% Response rate

19% (5/26) stable disease >6 months

Benefit possible in strongly AR positive

Trials with Abiraterone and Enzalutamide ongoing

Gucalp et al CCR 2013San Antonio Breast Cancer Symposium, December 9-13, 2014

Masuda et al CCR 2013

Significancia Clinica de la expresión genética de los subtipos

35% LAR intermediate grade

Chemotherapy response – possibly lower pCR in LAR although including RCB-1 no clear difference


Significancia Clínica de los subtipos 3N

Basal-like TNBCLuminal AR Mesenchymal Stem-like

~80% TNBC10-15% TNBC5-10% TNBC


Ca Mama 3N-Mesenchymal stem-like

• Superposición con claudin-low y cáncer de mama metaplásico

• Enriquecido por expresión stem cell-like

• Menor tasa de proliferación que los basal-like

• Frecuente infiltrado inmune

• Niveles intermedios de mutación PIK3CA


Basal-like 1 and 2

Mesenchymal-like

Luminal AR

Immunomodulatory

Vanderbilt: subtipos de 3N




Tumour infiltrating lymphocyctes in breast cancer

Adams et al JCO 2014

3N Predminio Linfocitario

Stromal

Intra-tumoural



Loi et al JCO 2013

ALL ER pos

TNBCHE

R23N Predominio Linfocitario

Analysis of BIG 02-98 AC-CMF +- docetaxel

pre-trastuzumabSan Antonio Breast Cancer Symposium, December 9-13, 2014

Adams et al JCO 2014

Intra-tumoural TILs

Stromal TILs


3N Predominio Linfocitario


Significancia clínica de los subtipos 3N

Basal-like TNBCLuminal AR Mesenchymal Stem-like

~80% TNBC10-15% TNBC5-10% TNBC

Lymphocyte predominant Lymphocyte depleted


Basal-like 1 DNA repair activated

Mesenchymal-like

Luminal AR

Immunomodulatory

Vanderbilt: subtypos de 3N



Basal-like 2 Growth factor receptor


Y saliendo de las tinieblas, vamos a algo más terrenal….o no

Targeting the positives in TNBC Platinums, PARPS and novel approaches to

high risk disease

Andrew TuttDirector

Breakthrough Breast Cancer Research CentreLondon

BRCA1 BRCA2 Mutation associated

Alexandrov et al Nature 2013

Stable genome- low instability

Unstable genome- high instability

TNBCs have highly variable Chromosome structural instability

Triple Negativo: Inestabilidad Genómicaalta heterogeneidad tumoral

pocas mutaciones pasibles de targets

BRCA1 está mutado en ≈15% de pacientes 3N

BRCA1/2 y mecanismos de reparación del ADN

Single strand breaks• Nucleotide excision repair

• Base excision repair• PARP1

Replication lesions• Base excision repair

– PARP1

DNA adducts/base damage • Alkyltransferases

• Nucleotide excision repair

• Base excision repair– PARP1

DNA DAMAGE

Cell death

Environmental factors(UV, radiation, chemicals)

Normal physiology(DNA replication, ROS)

MAJOR DNA REPAIRPATHWAYS

Chemotherapy(alkylating agents, antimetabolites)Radiotherapy

Helleday T, et al. Nat Rev Cancer. 2008;8:193-204. O’Shaughnessy J, et al. ASCO 2009. Abstract 3. Reproduced with permission.

Double strand breaks Nonhomologous end-joining Homologous recombination

– BRCA1/BRCA2

Fanconi anemia pathway Endonuclease-mediated repair

PlatinoUna Larga historia en Cáncer de Mama……

1988 JCO

Platino e Inhibidores de la PARP

BRCA-1BRCA-2

1. Platinum chemotherapyInflicts DNA damage via adducts and DNA crosslinking

2. PARP1upregulationsBase-excision repair of DNA damage

3. Inhibition of PARP1Disables DNA base-excision repair

Cell Survival Cell Death

PARP inhibitor

Pt

Pt

Pt

Pt

Pt

PARP1

PARP1

PARP1

Activo en TNBC BRCA 1 BRCA1 sensibles a agentes

que producen cross-link en el DNA

Platino en 3N metastásicos

TNT Trial-Abst S3-01

RECIST ORR

TTPPFS

ORR 2nd lineToxicity

OS

376 patients

First Line Advanced TNBC or BRCA1/BRCA2 Breast Cancer

Central ER / PR / HER2 Basal PhenotypesGermline BRCA1/2

genotype53BP loss

HR Genome ScarSomatic BRCA1/2

BRCA1 methylationWhole Exome NGS

RNA Seq

Recurrent Disease BXGenome Scars

Reversion MutationsWhole Exome NGS

RNA Seq

Correlative BiologyProgram

TNT - Trial

TNT-Trial Abst S3-01

Platino en 3N metastásico

• Pocos Trials TN específicos ->mayormente subsets• Generalmenteplatinosevaluadosencombinación• Variasdefiniciones de“triple-negativo”• BRCA1/2 mutacionesraramentecaracterizadas

Se nececitanmásestudiosrandomizadoscomparandoplatinos a QT standard of care en 1 y 2línea de tratamientoenenfermedadmetastásica. TNT??

San Antonio Breast Cancer Symposium December 9-13, 2014

BRCA1 Mutation

Carriers with Tumors >2cm

Clinical and Pathological Response

Platino en Neoadyuvancia en BRCA1 Mutatados

.

CISPLATIN 75mg/m2

q 3wks IV x 12 wks

•N = 25•median age: 46 •28% with clinically positive lymph nodes•22 pts completed 4 cycles of Cisplatin

Pathological Response 72%

Gronwald et al ASCO 2009

Platino en Neoadyuvancia

Alta pCR con antraciclinas y taxanos en BRCA1/2 mutados

• BRCA1 mutation pCR 46% vs 22% non-carriers

• Is the effect specific to platinum vs standard of care?

• Requires planned subgroup analyses in randomised trials

Arun B et al -- J Clin Oncol 29:3739-3746

Platino no standard en neo/adyuvanciaSeguimos con nuestro combo

AC x4 – Paclitaxel w

Lig3XRCC1

PolßPNK

PARP

• Rol clave en la reparación del ADN (SSB)• Utiliza la vía de excisión de bases como reparación• Se une directamente al sitio de ADN dañado• Una vez activada, utiliza a NAD como substrato generando múltiples

cadenas de poly(ADP-ribose) • Recluta otras enzimas reparadoras de ADN

Inhibidores PARP

BRCA-1BRCA-21. Platinum chemotherapy

Inflicts DNA damage via adducts and DNA crosslinking

2. PARP1upregulationsBase-excision repair of DNA damage

3. Inhibition of PARP1Disables DNA base-excision repair

Cell Survival Cell Death

PARP inhibitor

Pt

Pt

Pt

Pt

Pt

PARP1

PARP1

PARP1

• Las células con BRCA-1 and BRCA-2 deficiente son marcadamente sensibles a inhibidores PARP

• En presencia de un inhibidor PARP , tienen una marcado déficit en la capacidad de repararse y esto conduce a la apoptosis

Inhibidores PARP en gBRCA m

400 mg td 100 mg td

Estudios en marcha……

R

Potent PARP inhibitor at MTD as

continuous exposure

Physician Choice within SOC options

Capecitabineor

Vinorelbineor

Eribulinor

Gemcitabine

gBRCA1 / BRCA2 Carriers

Advanced anthracycline taxane

resistant breast cancer

Primary endpoint

PFS

Niraparib – BRAVO Trial

BMN 673 – EMBRACA - NCT01945775

OLYMPIAD – Olaparib - NCT02000622

Selective tumor cell killingIncreased

normal tissue toxicity

predicted

Degree of PARP trapping of

inhibitor may be relevant

Combinando QT target con inhibición PARP

BRCA status and HRD Score examined in PrECOG 0105

Every 21 days x 6 cyclesn = 80

Definitive SurgeryAssess

Pathologic Response

Carboplatin AUC 2 D 1, 8

Gemcitabine 1000 mg/m2 D 1, 8

Iniparib 5.6 mg/kg D 1, 4, 8, 11

Newly Diagnosed

Stage I-IIIA (T 1cm by

MRI)

Triple-negative (ER/PR ≤ 5%)

or

BRCA1/2 mutation

Primary Endpoint: Pathologic complete response (pCR) [no invasive disease in breast + axilla]

Secondary Endpoints: Radiographic response by MRI Breast conservation eligibility

SafetyCorrelation of gene expression profiles & gene copy number

with responseTelli et al ASCO 2013

Alta Respuesta Patológica asociada con mutación BRCA1/2

Pathologic Response (n=80)All patients

*******

n = 80

BRCA 1/2 wild-type

n = 61

BRCA 1/2 mutant

n = 19

TN & BRCA 1/2 mutant

n = 16

pCR [RCB 0]; n (%) 29 (36%) 20 (33%) 9* (47%) 9* (56%)

90% CI 27–46 23–44 27-68 33-77

RCB 0/1; n (%) 45 (56%) 31 (51%) 14 (74%) 12 (75%)

90% CI 46-66 40-62 52-89 52-91

* One BRCA1 carrier had bilateral TNBC & achieved pCR in both breasts

Can veliparib sensitized chemotherapy improve on a platinum directed chemotherapy approach?

NCT01506609

Cisplatin with or without rucaparib after preoperative chemotherapy in patients with triple-negative breast cancer (TNBC): Hoosier Cancer

Research Network BRE09-146 Abstract 1019

Sujaata Dwadasi, Yan Tong, Tom Walsh, Michael A. Danso, Cynthia X. Ma, Paula Silverman, Mary-Claire King, Susan M. Perkins, Sunil S. Badve, Kathy Miller

Presented by: Steven Isakoff - Discussant

Randomize

CisplatinX 4 cycle

Cisplatin +Rucaparib30mg IVx3dX 4 cycle

Rucaparib100mg PO q wkX 24 weeks

• Eligibility

– TNBC (or BRCA+)– Residual disease (RCB

2/3, M-P 0-2, node +)– No prior cisplatin (carbo

allowed)

– 128 patients– 65 cisplatin– 63 cis/rucaparib

Median RCB 2.6 v 2.7

1 Year DFSC 83% v C/R 83%

22/128 patients BRCA mutation

DFS C 85% v C/R 100%

Randomise 1:1Double blindN=1320

IDFS

Distant D

FS; O

S

Post neoadjuvant gBRCA TNBC,

Non-PathCR pts

Post adjuvant gBRCA TNBCT2 or N+

Olaparib 300 mg bd 12 month duration

Placebo 12 month duration

Restricted to Germline Mutation carriers

Mejorando la selección de PacientesA Post Neo-adjuvant Umbrella Trial Platform? PHOENIX

New DiagnosisPost-Rx residual disease

Neoadjuvant Rx

Relapse

Vs

No Relapse

Definitive Surgery

Second Adjuvant RxAllocated by

Genomic TriageBalko et al Cancer Discovery 2014

Conclusiones• Cáncer de mama TN tiene subpoblaciones con defectos en la

reparación del ADN: 10-15% BRCA1 mutados

• Defectos en la reparación HR puede generar sensibilidad a platinos o inhibidores PARP

• No data randomizada publicada sobre comparación de platinos vs standard of care en este grupo – TNT?

• Inhibidores PARP promisorios, pero…faltan resultados de estudios fase III

Conclusiones Triple Negativo

Antes de San Antonio 2014

= Después de San Antonio 2014

cancer de mama 3n

Documents