Post on 07-Sep-2019
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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