NOVI MODALITETI U LIJEČENJU KARCINOMA DOJKE: GDJE SMO SAD?

Prof dr Ermina Iljazović

Medicinski fakultet

Doktorski studij, Dec. 2014; Farmaceutski fakultet

OUTLINE

Pregled terapijskih opcija

Updates u dijagnostici i terapiji

• Napretci u hormonalnoj terapiji

• Chemotherapija i noviteti

• Oncotype Dx

• “Targeted therapy advances”

Follow-up and “what can I do”

AMONG WOMEN

BREAST CANCER

IS THE MOST

COMMONLY

DIAGNOSED FORM

OF MALIGNANT

DISEASE

Howlader N. et all. SEER Cancer Statistic Rewiev: Breast; 2011

PROJECTED NUMBER OF BREAST CANCERS TO 2020

0

500

1000

1500

2000

2500

3000

3500

4000

4500

50001995

2000

2005

2010

2015

2020

new

case

s per

year

0%

1%

2%

3%

4%

1950

1954

1958

1962

1966

1970

1974

1978

1982

1986

1990

1994

1998

2002

2006

2010

2014

year of death

risk o

f death

fro

m c

ancer

befo

re a

ge 7

5 (

%)

STOPA SMRTNOSTI OD KARCINOMA DOJKE 1950-2014

ZAŠTO?

Incidenca je u porastu

•Mamografski skrining

•Faktori okoline

Mortalitet je u padu

Rana detekcija

Bolje terapijske opcije

Terapijski pristupi

TERAPIJSKE OPCIJE KARCINOMA DOJKE

Lokalna terapija

• Lumpektomija + radijacija

• Mastektomija (+/- radiation in more advanced disease)

• Cilj: tretirati primarno sijelo

Sistemska terapija

• Kemoterapija

• Hormonalna terapija

• Ciljana terapija

ŠTA ODREDJUJE TERAPIJSKI SLIJED?

Klinički/patološki stadij i tip tumora

Biološke karakteristike tumora

FAKTORI KOJI UTIČU NA TIP TRETMANA

Dob pacijenta

Histološki podtip & Gradus

Veličina tumora

Status limfnih čvorova

Status hormonskih receptora

Pozitivni ili Negativni

Her-2 neu Expresija

• IHC graded 1+, 2+, 3+

• FISH amplified

PROGNOSTICKI FAKTOR – PREDPOSTAVLJAJU

KLINIČKO PONAŠANJE TUMORA

Prediktivni indikatori – udružen sa

efektivnošću terapije

Prognosticki faktori – udruženi sa dužinom

perioda bez bolesti i ukupnog preživljavanja u

odsustvu adjuvantne terapije

STAGING BREAST CANCER

RANI STADIJI BOLESTI

Hormoni Herceptin Chemo Clinical Trial

Hormon

pozitivniHER-2

pozitivni

Rizik recidiva Pristup

novim

tretmanima

Veličina tumor/ Gradus / Dob / Co-morbiditet

60% 20%

Adjuvantna

Kemoterapija

Terapija koja slijedi primarni tretman;

kemoterapija, zračenje...

PROGRESS IN CHEMOTHERAPY FOR

EARLY STAGE BREAST CANCER

Combination chemotherapy (CMF)

Use of anthracyclines

Addition of taxanes

Superior taxane containing regimens

Addition of trastuzumab

1970s

2000s

BUT: ALL chemotherapy is associated with toxicities and

risks… need better ways to identify which patients will benefit

from treatment

ADJUVANTNA KEMOTHERAPIJA

Stepen benefita varira ovisno od statusa limfnih čvorova i dobi pacijenta.

Stepen benefita varira ovisno od sensitivitetatumora za hormone (ER+ vs. ER-)

SIDE EFFECTS

Kardijala toksičnost

• Anthracyclini povečavaju rizik od kongestivnog srčanog popuštanja

• Taxani povečavaju aritmijeNeuropatije

• TaxanesHypersensitivnost

• Taxanes, zahtijevaju steroideOvarijalna ablacija

• Prematurna menopausa• Infertilnost, Smanjen kvalitet života, aficiranost skeleta

Secondarni maligniteti

SO…HOW CAN WE DO BETTER?

Better selection of patients for treatment with

chemotherapy

Treat only those patients who are most likely to recur

AND who will therefore benefit most from the

addition of chemotherapy

Take advantage of genomics

Early Stage Breast Cancer –

Overtreatment & Inadequate Treatment

Clinical features are not sufficiently predictive of relapse after

primary therapy, resulting in…

– Overtreatment, because…

– most patients with early stage disease will not have a future

recurrence

– Inadequate treatment, because either…

• treatment is not given because of favorable clinical features,

or

• relapse occurs despite treatment

Hormonalna terapija kod

postmenopauzalnih žena

Aromatase inhibitori- mehanizmi djelovanja

Smith et al., N Engl J Med 348(24):2431-42 2003

AROMATASE INHIBITORI

Anastrazole (Arimidex), Femara (Letrozole), Aromasin (Exemestane)

Poboljšavaju ishod kod postmenopausalnih žena

Side Effects

• Osteopenia, Osteoporosis, Povečan rizik fractura• Moguć porast holesterola• Arthralgias

ESTROGEN RECEPTOR CORRELATES

INVERSELY WITH:

Histological and nuclear grade

Tumor proliferative index

Lymphocitic infiltration

Tumor necrosis

ER/PR NEGATIVNOST KORELIRA SA

LOŠIJOM PROGNOZOM

ER receptor

positivnost je bolji

prediktor ukupnog

preživljavanja u

odnosu na DFS

Kulka et all., 2002

Triple negative

Rak dojke

St. Gallen 2013.

Podtip Kliničko-patološka definicija Preporuka za liječenje

Luminal A

"Luminalni A-like"

ER i PgR pozitivan

HER2 negativan

Ki-67 nizak (≤ 20%)

Samo endokrina terapija

Citotoksična terapija moguća kod nekih :

a) s visokim rizikom za recidiv temeljem 21 i 70 gena

testom

b) 4 i više pozitivna limfna čvora (neki smatraju samo 1),

c) G3,

d) mlade bolesnice) (<35 godina) pola-pola

Luminal B

"Luminalni B-like (HER2 negativni)"

ER pozitivan

HER2 negativan

I najmanje jedno od:a) Ki-67 visok

b) PR negativan ili nizak (manje od 20% stanica)c) Rizik za recidiv visok a temeljen na multi-gene-expression

assay (ako je dostupan)

Endokrina terapija za sve bolesnice

Citotoksična za većinu bolesnica

.

"Luminalni B -like(HER2 pozitivni)"

ER pozitivan

HER2 prekomjerna ekspresija ili amplifikacijaKi-67 -bilo kakav

PR bilo koji

Citotoksična + anti-HER2 + endokrina terapija

Nema podataka o ne davanju citotoksične terapije u ovoj

skupini bolesnica

Erb-B2 prekomjerna

ekspresija

"HER2 pozitivan (ne luminalni)"

HER2 prekomj.izražen ili amplificiran

ER i PR negativni

Citotoksična + anti-HER2 terapija

Basal-like

“Trostruko negativan (duktalni)”

ER i PR negativni

HER2 negativan

Citotoksična terapija

Posebni histološki

tipovi

A. Odgovaraju na endokrinu terapiju Endokrina terapija

B. Ne odgovaraju na endokrinu terapiju

Citotoksična terapija

(adenoidni cistični karcinom se ne moraju liječiti

adjuvantnom citotoksičnom terapijom, ako su limfni čvorovi

negativni.)

KI67 NIZAK (<20%)

KI67 VISOK (≥ 20% )

Luminal A: ER i/ili PR pozitivan; HER-2 negativan, Ki-67 <14%

Luminal B: (HER-2 negativan): ER i/ili PR pozitivan, HER-2 negativan, Ki-67 visok

Luminal B: (HER-2 pozitivan). ER i /ili PR pozitivan, HER-2 pozitivan, Ki-67 bilo koji

HER-2 pozitivan (non luminal): ER i PR negativan, HER-2 pozitivan

Trostruko negativan: ER, PR i HER-2 negativan

SUROGATNI TIP TUMORA-NOVO

LUMINAL A: ER I PGR POZITIVAN, HER2 NEGATIVAN, KI-67 NIZAK (< 20%)

LUMINAL B: (HER-2 NEGATIVAN): ER POZITIVAN,HER2 NEGATIVAN, I NAJMANJE JEDNO OD: A) KI-67 VISOK , B) PR NEGATIVAN ILI NIZAK (MANJE OD 20% STANICA), C) RIZIK ZA RECIDIV VISOK A TEMELJEN NA MULTI-GENE-EXPRESSION ASSAY (AKO JE DOSTUPAN)

LUMINAL B: (HER-2 POZITIVAN):ER POZITIVAN, HER2 PREKOMJERNA EKSPRESIJA ILI AMPLIFIKACIJA, KI-67 BILO KAKAV, PR BILO KOJI

HER-2 POZITIVAN: HER2PREKOMJERNO IZRAŽEN ILI AMPLIFICIRAN, ER IPR NEGATIVNI

TROSTRUKO NEGATIVNI: ER, PR I HER-2 NEGATIVAN

TAMOXIFEN

Tamoksifen je antagonist estrogenskog receptora u tkivu dojki

koristi se kao standardna endokrina (antiestrogenska) terapija za hormonski receptor-pozitivni rani rak dojke kod pre-menopauzalnih žena, kao alternativainhibitorima aromatoze

SIDE EFFECTS TAMOXIFENA

Česti side effects

Napadi vrućine

Rijetki ali ozbiljni side effects

Thromboembolija

Endometrialni karcinom

Cataracta

HER 2 TERMINOLOGY

Human Epidermal growth factor Receptor-2

Also known as

- neu(rat gene)

- c-erbB-2

HER2 protein = p185

HER2-normal (HER2-) breast

epithelium cell (~20,000 receptors)

HER2-positive breast cancer cell

(up to 1-2 million receptors)

HER-2 POSITIVITY

IN BREAST CANCER

OVEREXPRESSION: marked increase in number of HER2 receptors on the cell surface

AMPLIFICATION: increase in number of HER2/neu gene copies in the nucleus

Courtesy of Jeffrey Ross, Albany Medical College, Albany, NY.

HER2 - NEU +

ER/PR receptor

negative

bcl-2 negative

have lymphoid

infiltration

high mitotic index

Menrad et all., 2001

GENETICALLY ENGINEERED

MONOCLONAL ANTIBODY

Qualified women for treatment

with trastuzumab or

Herceptin

ONCOTYPE DX

The Oncotype DX® test is a diagnostic test that helps identify which

women with early-stage, estrogen-receptor positive and lymph-node-

negative breast cancer are more likely to benefit from adding

chemotherapy to their hormonal treatment. This test also helps assess the

likelihood that an individual woman‟s breast cancer will return.

To help doctors figure out a woman’s risk of early-stage, estrogen-receptor-positive breast

cancer coming back (recurrence), as well as how likely she is to benefit from chemotherapy

after breast cancer surgery.

To help doctors figure out a woman’s risk of DCIS (ductal carcinoma in situ) coming back (recurrence) and/or the risk of a new invasive cancer developing in the

same breast, as well as how likely she is to benefit from radiation therapy after DCIS surgery.

MAMMAPRINT (70) I ONCOTYPEDX (21)

IN BREAST CANCER

The Oncotype DX® test is a diagnostic test that helps identify which

women with:

early-stage,

estrogen-receptor positive and

lymph-node-negative breast cancer

benefit from adding chemotherapy to their hormonal treatment.

This test also helps assess the likelihood that an individual woman‟s

breast cancer will return.

RECURENCE SCORE

Biological or Targeted

Therapy

TARGETED THERAPIES FOR

EARLY STAGE BREAST CANCER

Treatments that „target‟ specific proteins or

receptors expressed by tumor

• Hormonal therapy was the first targeted therapy for

breast cancer

Monoclonal antibodies

• Trastuzumab (Herceptin)

LOCALLY ADVANCED BREAST CANCER

Same Treatment but Different Sequence

Systemic therapy first (CT/HT)

Definitive surgery later

Metastatic disease: Principles of Treatment

• Hormonal therapy for indolent disease

• Single agent chemotherapy for aggressive/symptomatic disease or disease not responding to hormonal therapy

• Polyagent chemotherapy for visceral crisis or disease requiring rapid response

• Iv bisphosphonates for bone secondaries

BREAST CANCER TREATMENT:

PROGRESS AND PROMISE

Chemotherapy• Better treatments

• Progress toward targeting only those who will benefit

Hormonal therapy• AIs improve outcome in postmenopausal women

• Premenopausal women – optimal hormonal treatment still unknown

Targeted therapy• Trastuzumab decreases risk of recurrence and improves survival

• Promising new agents being studied

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