Triplo Negativo BRCA positivo: quale innovazione

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Triplo Negativo BRCA positivo: quale innovazione

Triplo Negativo BRCA positivo:

quale innovazione

Firenze 20 settembre 2010

Sergio Crispino

Direttore Dipartimento Oncologico USL7 Siena


BRCA1

BP

TNBCs

TNBC Triple Negative Breast Carcinoma

BP Basal Phenotype


TUMORE TRIPLO NEGATIVO

CONCETTI GENERALI

1) TUMORE AGGRESSIVO

2) TUMORE A CATTIVA PROGNOSI

3) CHEMIOSENSIBILE


Characteristics of “Triple Negative” vs. Other Breast Cancers

Characteristic

Other

(N=1421)

number (percent)

“Triple Negative”

(N=180)

Significance

p value *

number (percent)

Mean Age at Diagnosis (yrs) 57.7 53 p < 0.0001

Mean Tumor Size 2.1 cm 3.0 cm p < 0.0001

Tumor Size

T1 (≤ 2 cm) 880 (62.7) 65 (36.5) p < 0.0001

T2 (>2cm to ≤ 5cm) 461 (32.8) 99 (55.6)

T3 (>5cm) 64 (4.6) 14 (7.9)

Missing 16 2

Lymph Node Status

Positive 510 (45.6) 87 (54.4) p = 0.02

Negative 609 (54.4) 70 (44.6)

Missing or Not Tested 302 23

Tumor Grade

I 237 (19.9) 15 (9.8) p < 0.0001

II 616 (51.8) 37 (24.2)

III 336 (28.3) 101 (66.0)

* p values were calculated with the use of the chi‐square test

Dent, R. et al. Clin Cancer Res 2007


Tumor Size by Nodal Status according to “Basal‐Like” Group

Non “Basal‐like” Group

(N=1421)

“Basal‐like” Group

(N=180)

Tumour Size

Lymph Node Positive

Number (percent)

Lymph Node Positive

Number (percent)

5.1 cm 53 (91.4) 12 (92.3)

p


Patterns of Metastatic Spread

• More likely to spread to brain, lung and possibly liver

and less likely to spread to bone and soft tissues

– Tsuda et al. 2000 Am J of Surgical Pathology

– Rodriguez‐Pinilla et al. Clinical Cancer Research 2006

– Fulford et al. Breast Cancer Research and Treatment 2007

– Hicks et al. 2006 Am J of Surgical Pathology

• More likely to present with visceral metastases versus

bone metastases as first site of metastases

– 70% vs 37%, p < 0.001 (Dent et al. SABCS 2007)


Median Time from Distant Relapse to

Death

“Triple Negative”

Breast CA

9 months

Other Breast CA

22 months

0 5 10 15 20 25

Dent R, Trudeau M, Pritchard K, Hana W, Narod S. et al. Clinical Cancer Res 2007


Overall Survival

Other (261 of 1420) “Triple‐negative” (62 of 180)

1.0

0.9

0.8

Probability of survival

0.7

0.6

0.5

0.4

0.3

p


Trattamento

Tumore chemiosensibile:

Quanto


CT senza Platino : RCp = 14

: RCp = 14-34%

Liedtke, MDA 2008 * :

FAC/FEC/AC 24 wks 20%

T/FAC-FEC

FEC 28%

T da solo 12%

Altri 14%

RCp

ACTaxol,

Esserman, 2009

Ixabepilone, Roche H, 2006

34%

Esserman, 2009 34%

Roche H, 2006 19%

--------------------------------------------------------------------------------------------------------------------------------

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• MDA Rouzier 2005: Basal-Like

TFAC RCp 45%

• Carey 2007: : Basal Like (92% TN) AC +/- T Rcp 27%


CT contenente Platino

RCp =22-62% (72% BRCA1)*

RCp

Garber 2007: CDDP 22%

Shroi 2008 : ECF 17%

Torrisi 2008 : ECFT 40%

Leone 2009 : PD +/- AC 34%

Frasci 2009 : PET X 12 wks 62%

--------------------------------------------------------------------------------------------------------------------------------

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* BRCA1 (anche TN) CDDP X 4 (10,25,12 pts) 72%

Narod (poland), Gronwald (Poland-Canada), Byrsky(Poland),

2008-2009:

2009:


Neoadjuvant Chemotherapy in TNBC

Survival by Pathological Response

Liedtke, M. et al. J Clin Oncol; aheadof print on Febr 4, 2008


Tumori Triplo Negativi e BRCA


100 BC

20 TN

4 BRCA1

1 BRCA2 3TNBRCA


MUTATIONS IN BRCA1

Population or subgroup

African-Americans

Americans

Ashkenazi Jewish

Austrians

Belgians

Dutch

Finns

French

French Canadians

Germans

Greeks

Hungarians

Italians

Japanese

Native North Americans

Northern Irish

Norwegians

Pakistanis

Polish

Russians

Scottish

South Africans

Spanish

Swedish

BRCA1 mutation(s)

943ins10, M1775R

185delAG, 188del11, 5382insC

2795delA, C61G, 5382insC, Q1806stop

2804delAA, IVS5+3A>G

Exon 2 deletion, exon 13 deletion, 2804delAA

3745delT, IVS11-2A>G

3600del11, G1710X

C4446T

5382insC

5382insC

300T>G, 5382insC, 185delAG

5083del19

L63X, Q934X

1510insG, 1506A>G

2800delAA

816delGT, 1135insA, 1675delA, 3347delAG

2080insA, 3889delAG, 4184del4, 4284delAG, IVS14-1A>G

1A>G

300T>G, 5382insC, C61G, 4153delA

5382insC, 4153delA

2800delAA

E881X

R71G

Q563X, 3171ins5, 1201del11, 2594delC


CHEMIOTERAPIA NEOADIUVANTE NELLE PAZIENTI

BRCA1/2m

Schemi senza CDDP pCR 7-86% Autore

CMF 1/14 7% Byrski 2010

Regimi con Antracicline ACx4 4/9 44% Chappuis 2002

8/15 53% Delaloge 2002

FECx6 2/12 17% Petit 2007

2/15 13% Hubert 2009

FACx4; ACx4 11/51 22% Byrski 2010

Antracicline + Taxani; A+TXT 2/25 8% Byrski 2010

Schemi con CDDP pCR 70-100% Autore

Cisplatino 75 mg/m2

18/25 72%

10/12 83%

Gronwald 2009 - Byrski

Byrski 2010

2/2 100% Silver-Garber 2010


CORRELAZIONE TRA BRCA E RISPOSTE PATOLOGICHE

% di pCR

range

Mutato 7% 100% NOTE

Nei mutati CDDP

apparentemente meglio

che altri schemi.

Mutato vs non mutato 44% vs 4% Mutati meglio rispetto ai

non mutati. (Chappuis 2002)

BRCA1 vs BRCA2 mutato 13% vs 0%

53% vs 0%

BRCA metilazione

+ vs - 75% vs 27

BRCA1 mutato risponde

meglio.

(Hubert 2009),

(Delaloge 2002)

Risposte migliori nei

metilati. (Silver

(Silver-Garber 2010)

BRCA 1 mRNA levels 20% vs 100%*

Risposte migliori nei livelli

più bassi. (Silver-Garber 2010)

* Risposte maggiori (Miller-Payne

score 3-4-5) 3

BRCA1-like

80% Predice risposta o


*

* with decreased BRCA1 activity (mutation, methylation,

reduced mRNA levels)


TURNING

OFF DNA

REPAIR OF

PARP

INHIBITOR


Parp Inhibitor : genotoxic, DNA

damaging

Goal of targeting PARP

• Prevent tumor cells from reparing DNA

themeselves and developing drug

resistance

• Increase the effect of various CT agents:

-Alkylating agents

-DNA topoisomerase II inhibitors

-DNA topoisomerase I inhibitors and antimetabolites

-As well as RT (RT-CT)


Parp Inhibitor , AZD2281 oral Olaparib

New studies

1) Olaparib+ Paclitaxel in metastatic TN phase I/II :

completed april 2010

2) Olaparib+ CDDP neoadj in TN phase I/II : active not

recruiting

3) Olaparib + Cediranib vs Cediranib, Solid

tumors (Recurrent TN, ovarian): phase I NCI


Breast Cancer: Triplo neg

-Malattia più eterogenea:

• Da Tumore Triplo neg

• A Tumori Triplo neg


Schneider, Clin Canc Res 2008


New Drugs

Chemotherapy:

• Ixabepilone

• Nab-paclitaxel

Biotherapy

• Vaccine

• Anti-VEGF

• EGFR

EGFR-targeted

therapy

• Multi targeted

therapy

• mTOR Inhibitors

• Parp Inhibitors

• others


Different studies

1)ABT-888 + CDDP-Vinorelbina

2)Brostallicin + CDDP

3)Panabinostat and Letrozolo

4)UCN-01 87 (hydroxystaurosporine)+CPT-11

6)NK012

7)Estrogen-Anti androgen


1)Conclusioni terapia TN-BRCA

1) Quando testare BRCA

2) Schemi classici sicuramente attivi

3) Necessità di studi per definire la migliore combinazione

: definire ruolo CDDP (soprattutto in adj)

4) Nuovi chemioterapici : Ixabepilone; nab paclitaxel

interessanti


(2)Conclusioni : Terapia Biologica e

sua integrazione con CT

1) Parp inibitori BSI-201, AZD-2281 molto

promettenti, in studio da soli o con CT

(disponibilità stato BRCA)

2) Anti EGFR : quale sottotipi trattare e quale è il

ruolo dei vari bersagli molecolari: K-rasK

ras-raf raf etc

3) Antiangiogenetici: In quale sottogruppo, quali

associazioni e quando


Aspetti organizzativi Nazionali:

-migliorare i servizi per i pazienti

-migliorare contributo Italiano alla ricerca

Contributo ITT e CIPOMO

1) Facilitare accessibilità e fruibilità per i

pazienti: Progetto “expanded option”

2) Gruppo Tumori eredo familiari: studio

sul rapporto tra TN e BRCA in Italia


Ringraziamenti

• Camilla Casi

• Francesca Rastelli

• Monica Valente

• Sandra Biancanelli

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