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
Howlader N. et all. SEER Cancer Statistic Rewiev: Breast; 2011 AMONG WOMEN BREAST CANCER IS THE MOST COMMONLY DIAGNOSED FORM OF MALIGNANT DISEASE
1995 2000 2005 2010 2015 2020 new cases per year PROJECTED NUMBER OF BREAST CANCERS TO 2020 5000 4500 4000 3500 3000 2500 2000 1500 1000 500 0
1950 1954 1958 1962 1966 1970 1974 1978 1982 1986 1990 1994 1998 2002 2006 2010 2014 risk of death from cancer before age 75 (%) STOPA SMRTNOSTI OD KARCINOMA DOJKE 1950-2014 4% 3% 2% 1% 0% year of death
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 pozitivni HER-2 pozitivni 60% 20% Rizik recidiva Pristup novim tretmanima Veličina tumor/ Gradus / Dob / Co-morbiditet
Adjuvantna Kemoterapija Terapija koja slijedi primarni tretman; kemoterapija, zračenje...
PROGRESS IN CHEMOTHERAPY FOR EARLY STAGE BREAST CANCER 1970s Combination chemotherapy (CMF) Use of anthracyclines Addition of taxanes Superior taxane containing regimens 2000s Addition of trastuzumab 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 sensitiviteta tumora za hormone (ER+ vs. ER-)
SIDE EFFECTS Kardijala toksičnost Anthracyclini povečavaju rizik od kongestivnog srčanog popuštanja Taxani povečavaju aritmije Neuropatije Taxanes Hypersensitivnost Taxanes, zahtijevaju steroide Ovarijalna 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 Erb-B2 prekomjerna ekspresija Basal-like "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) "Luminalni B -like(her2 pozitivni)" ER pozitivan HER2 prekomjerna ekspresija ili amplifikacija Ki-67 -bilo kakav PR bilo koji "HER2 pozitivan (ne luminalni)" HER2 prekomj.izražen ili amplificiran ER i PR negativni Trostruko negativan (duktalni) ER i PR negativni HER2 negativan Endokrina terapija za sve bolesnice Citotoksična za većinu bolesnica. Citotoksična + anti-her2 + endokrina terapija Nema podataka o ne davanju citotoksične terapije u ovoj skupini bolesnica Citotoksična + anti-her2 terapija Citotoksična terapija Posebni histološki tipovi A. Odgovaraju na endokrinu terapiju Endokrina terapija Citotoksična terapija (adenoidni cistični karcinom se ne moraju liječiti B. Ne odgovaraju na endokrinu terapiju 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 I PR NEG ATIVNI 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 receptorpozitivni 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
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 HER2-normal (HER2-) breast epithelium cell (~20,000 receptors) HER2-positive breast cancer cell (up to 1-2 million receptors) 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-nodenegative 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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