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Individualizando o tratamento:papel da anatomia patolgica nas
atuais decises da oncologia
Sesso Oncopatolgica do Hospital
Aliana
Gustavo Godoy
Salvador, 25 de maro de 2010
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Diagnstico
Origem de carcinoma no identificada clinicamente em
3%. Pavlidis et al, 2003; McCredie et al, 1991 ; Muir & Weiland, 1995 ; Parkin et al,
1997 ; Briasoulis & Pavlidis, 1997 ; Hainsworth & Greco, 1993
Apenas a minoria dos pacientes tero doenas com
potencial de cura ou para as quais exista benefcio
substancial de sobrevida.
O uso apropriado da patologia diagnstica especializadae exames radiogrficos selecionados identificaro esses
pacientes.
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Estratificao de risco: mama
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Mama: quimioterapia adjuvante
Metanlise EBCTCG (Early Breast Cancer Trialists'
Collaborative Group): Lancet 1998
14.000 mulheres Quando comparado a CMF, esquema baseado em antraciclina
reduz em 11% o risco anual de recidiva e 16% de mortalidade
(absoluto de 3% em 5 anos e 4% em 10 anos).
Maior benefcio antraciclina: hiperexpresso de HER2/neu
(associada recidiva e morte).
Thor et al, 1998; Paik et al, 1998;
Pritchard et al, 2006; Gennari et al, 2008.
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Mama: hormonioterapia adjuvante
IfER status is used to select adjuvant treatment, thestudy should be performed in a well-established, skilled
laboratory.
Harvey et al, 1999
Metanlise EBCTCG (Early Breast Cancer Trialists'
Collaborative Group): Lancet 2005
80.273 mulheres estgio I ou II
Benefcio de 5 anos de tamoxifeno restrito a ER-positivo ou
desconhecido
Reduo absoluta em 15 anos em recidiva e mortalidade 12% e
9%, respectivamente.
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Mama: biolgico paliativo
25% das pacientes hiperexpressam HER2/neu.
Pegram, Pauletti, Slamon, 1998
Pacientes tratados com quimioterapia e trastuzumabeapresentam sobrevida mais longa (25 vs. 20 meses,P=.05).
Seidman et al, 2002
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Mama: biolgico paliativo
Lapatinibe um inibidor de tirosina quinase deHER2/neu e EGFR (epidermal growth factor receptor)
Combinao capecitabina/lapatinibe (GSK-EGF100151)
324 pacientes que falharam a antraciclinas, taxanes e
trastuzumabe. SLP 8 meses vs. 4 meses (P
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Mama: biolgico adjuvante
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Estratificao de risco: mama
Risk stratification by hormonal receptor (ER, PgR) and
HER2 status in small (1cm) invasive breast cancer: Who
might be a possible candidate for adjuvant treatment? #564
Axillary lymph node involvement was much more common in HER-2
positive group (33% vs 11%, p < 0.0001) and triple negative (TN) group
(24% vs 11%, p = 0.002) than in hormone receptor positive group
HER-2 positivity and triple negativity were identified as independentprognostic factors to predict DFS (p = 0.026) and OS (p = 0.017) in
T1bN0 tumors. Limiting to T1aN0 tumors, statistical significance was
not maintained
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Estratificao de risco: mamaTumor phenotype and characteristics of metastatic brain
involvement in breast cancer patients: Potential clinical
consequences. #1026, #1064, #1069 (Ki67)
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Individualizao do tratamento: mama
Identification of a subpopulation of metastatic breast
cancer (MBC) patients with very high HER2 expression
levels and possible resistance to trastuzumab. #1059
MBC patients with very high levels of HER-2 could represent a sub-
group with de novo resistance to trastuzumab who may benefit from
combined therapy.
The HERmark assay was used to measure H2T in formalin-fixed,
paraffin-embedded (FFPE) primary breast tumor specimens.
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Cncer de mama
O que colhemos da A. Patolgica!
Tu
Axila Biologia ( imunohistoqumica)
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Microsatellite instability (MSI) in stage II and III colon
cancer treated with 5FU-LV or 5FU-LV and irinotecan
(PETACC 3-EORTC 40993-SAKK 60/00 trial). #4001, #4121
Microsatellite instability is a strong prognostic factor for RFS and OS when
considering Stage II, even in pts treated with 5FU (w/o IRI).
Estratificao de risco: clon
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Estratificao de risco: clon
Evaluation of CD133, VEGF, orEGFR as predictive
markers of distant recurrence after preoperative
chemoradiotherapy in rectal cancer. #4050
Elevated CD133 but not VEGF or EGFR on formalin-fixed paraffin-
embedded specimens may be a predictive marker of distant recurrence
and poor survival after preoperative CRT in rectal cancer.
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Estratificao de risco: clon
Immune infiltrates in liver metastases of colorectal cancer
and response to chemotherapy. #E15069
Positively stained tumor infiltrating lymphocytes in the invasive margin of
the liver metastasis allowed to predict response to chemotherapy.
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Individualizao de tratamento: clon
Crystal Study (+ #4068):
1,198 patients to FOLFIRI with or without cetuximab. Cetuximab was associated with an improved PFS (P=.048).
Improved OS confined to wild types of KRAS.
Van Cutsem et al, 2009
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Estratificao de risco: pulmo
A novel histopathological evaluation method for predicting
the outcome of non-small cell lung cancer treated by
neoadjuvant therapy. #e11574
Smaller area of residual tumor (400 mm2) and absence of pleural invasion
predict a better outcome of NSCLC in patients who receive neoadjuvant
therapy.
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EGFR expresso em 40% a 80% dos casos
Inibidores da tirosina quinase de EGFR
(geftinibe/erlotinibe) demonstraram atividade
em pacientes previamente tratados.Fukuoka et al, 2003; Perez-Soler et al, 2003; Herbst
et al, 2004;
Giaccone et al, 2004; Herbst et al, 2004; Gatzemeier
et al, 2004;
Shepherd et al, 2005; Thatcher et al, 2005; Bezjak et
al, 2006.
Individualizao de tratamento: pulmo
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Individualizao de tratamento: pulmo
A resposta aos agentes envolvendo EGFR maior em:
Mulheres que nunca fumaram;
Adenocarcinoma e bronquioloalveolar;
Mutao na tirosina quinase de EGFR;
Hiperexpresso da protena de EGFR por IMH (?);
K-RAS tipo selvagem.
Tsao et al, 2005; Hirsch et al, 2006;Clark et al, 2006; Miller et al, 2004;
Paez et al, 2004; Lynch et al, 2004;
Pao et al, 2004; Pao et al, 2005.
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Estratificao de risco: pulmo
Molecular and clinical predictors of outcome for cetuximab in non-
small cell lung cancer (NSCLC): Data from the FLEX study. #8007
Not support the hypothesis that KRAS mutation status is predictive for cetuximab efficacy.
K-Ras mutation (mut), EGFR-related, and exploratory markers as
response predictors of cetuximab in first-line advanced NSCLC:Retrospective analyses of the BMS099 trial. #8021, #8022
There was no significant correlation between patient response to C and any
molecular marker evaluated to date (K-RASmut, EGFRmut, EGFR IHC, EGFR
FISH).
Prognostic and predictive impact ofEGFR and K-ras mutation, and EGFR genecopy number in patients with advanced non-small cell lung cancer (NSCLC)
who received first-line cytotoxic chemotherapy. #8096
EGFR mutations were good predictive marker and K-ras mutations were poor predictive marker
in first line cytotoxic chemotherapy.
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Individualizao de tratamento: pulmo
Biomarker analyses from the phase III placebo-controlled
SATURN study of maintenance erlotinib following first-
line chemotherapy for advanced NSCLC. #8020
Erlotinib significantly improving PFS in the EGFR IHC+ group
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Individualizao de tratamento: pulmo
MSH2 and adjuvant cisplatin-based chemotherapy in non-
small cell lung cancer. #CRA7502
HumanMutS homolog 2 (MSH2) protein and excision repair cross-complementing group 1 (ERCC1 ) are required to repair cisplatin-DNA
lesions.
Chemotherapy compared with observation prolonged survival in the
combined MSH2 negative/ERCC1 negative subgroup.
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Individualizao de tratamento: pulmo
Characteristics and outcomes of non-small cell lung
cancer (NSCLC) patients (pts) carrying epidermal growth
factor receptor (EGFR) mutations who progress after initial
erlotinib (E) response. #8064
Pts with EGFR mutations present a biologically different disease which
continued to be sensitive to other treatments after progressing to E.
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Estratificao de risco: SNC
Influence of expression ofEGFR and PTEN on outcome in patients with
primary glioblastoma treated with standard radiochemotherapy and
cetuximab: Interim analysis from the GERT-Protocol. #2050
Expression of EGFR, and coexpression of EGFR/PTEN is associated with significant increase
in PFS after RCHT with TMZ and CTX.
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Individualizao de tratamento: estmago
Efficacy results from the ToGA trial: A phase III study of
trastuzumab added to standard chemotherapy (CT) in first-
line human epidermal growth factor receptor 2 (HER2)-
positive advanced gastric cancer (GC). #LBA4509
H+CT is superior to CT alone. The OS benefit indicates that H
is a new, effective, and well-tolerated treatment for HER2-
positive GC.
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Estratificao de risco: melanoma
Long-term follow-up of patients with minimal sentinel node
tumor burden (< 0.1 mm) according to Rotterdam criteria:
A study of the EORTC Melanoma Group. #9005
Minimal SN tumor burden (< 0.1 mm) indicates relapse rates identical to SN
negative patients.
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Individualizao de tratamento: melanoma
Ulceration of primary melanoma and responsiveness to
adjuvant interferon therapy: Analysis of the adjuvant trials
EORTC18952 and EORTC18991 in 2,644 patients. #9007
Pts with an Ulcerated primary are far more sensitive to IFN than pts with N-
Ulcecated primaries. This hypothesis will now be tested in the EORTC18081
trial, which compares PEG-IFN-2b versus observation in pts with U1c
primaries > 1mm.
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Individualizao de tratamento: melanoma
Association of baseline and on-study tumor biopsy
markers with clinical activity in patients (pts) with
advanced melanoma treated with ipilimumab. #9008
Biomarkers [FOXP3 and indoleamine 2,3-dioxygenase (IDO)] in the tumor
microenvironment are associated with clinical activity in pts treated with
ipilimumab.
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Estratificao de risco: cabea e pescoo
Prognostic significance of HPV and p16 status in patients
with oropharyngeal cancer treated on a large international
phase III trial. #6003, #6004.
Tumor HPV and p16 status is strongly associated with higherOS/PFS.
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Individualizao de tratamento: endomtrio
Responses to hormones are correlated with the presence
and level of hormone receptors and the degree of tumor
differentiation.
Lentz, 1994
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Concluses e perspectivas
A anatomia patolgica norteia a conduta em oncologia e
pode ser utilizada de trs formas:
Ferramenta Diagnstica
Estratificao de risco Individualizao do tratamento
A biologia molecular est se envolvendo cada vez mais na patologia.
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