biomarcadores: ¿nos quitan el microscopio? · (her2) amp brca1/2 germline if: • early onset <...
TRANSCRIPT
Biomarcadores:
¿nos quitan el microscopio?
Federico Rojo
Fundación Jiménez Díaz
Clinical oncology Pathological oncology Molecular oncology Precision
oncology
Today
Evolution from Clinical Oncology
to Precision Oncology
Clinical oncology Pathological oncology Molecular oncology Precision
oncology
Today
Evolution from Clinical Oncology
to Precision Oncology
Cuestión 1.
¿Cuál es el papel del diagnóstico
morfológico (microscopio) en la Era de la
Oncología de Precisión?
Clasificación histológica del cáncer
de mama y su valor pronóstico
Old Nottingham series (1977-89) Recent Nottingham series (1990-2002)
Rakha, EA et al. Breast Can Res 2010
Epstein JI, et al. Eur Urol 2015
Gleason en cáncer de próstata y su
valor pronóstico
Lymphocyte-predominant
breast cancer (LPBC) Stromal TILs Intratumoral TILs
Definitions vary across studies
with stromal TILs of 50–60%
used as a threshold. LPBC can
be used for predefined
subgroup analyses in tumors
with a particularly high immune
infiltrate. However, TILs are a
continuous parameter and the
threshold is arbitrary.
Stromal TILs have been shown
to be predictive for increased
response to neoadjuvant
chemotherapy as well as
improved outcome after
adjuvant chemotherapy. This
parameter is the best one for
characterization of TILs.
Several studies have shown
that intratumoral TILs are more
difficult to evaluate and do not
provide additional predictive/
prognostic information
compared to stromal TILs.
Standardized methodology for pathological
TILs evaluation in breast cancer
Denkert, C et al. J Clin Oncol 2010
pCR 42% vs 3%
iTu-Ly p=0.012 (OR 1.38, 95%CI 1.08 to 1.78)
GeparDuo, n=218
GeparTrio, n=840
Tumor-associated lymphocytes as a
predictor of response on neoadjuvant
anthracyclin/taxane CT
Pages, F et al. NEJM 2005
Pages, F et al. J Clin Oncol 2009
Mlecnik, B et al. J Clin Oncol 2011
Galon, J et al. J Pathol 2014
Mlecnik, B et al. Cell 2016
Immunoscore in the classification of
colorectal cancer 124 studies
Immunoscore in the classification of
colorectal cancer
Fridman, WH et al. Nat Rev Oncol 2015
Cuestión 2.
¿Existen limitaciones al diagnóstico
morfológico?
Interobserver agreement in pathological
assessment: Evaluation of tumor type and
grade in breast cancer
Bueno-de-Mesquita, JM. and van de Vijver, MJ. Ann Oncol 2010
Parkash, V. et al. Am J Clin Pathol 2010
Interobserver agreement in pathological
assessment: Evaluation of lymph nodes
Fragments of lymph node tissue, ranged
between 5 and 16 in pathologists’
evaluation
Fragments of lymph node tissue, ranged
between 1 and 11 in pathologists’
evaluation
Parkash, V. et al. Am J Clin Pathol 2010
Interobserver agreement in pathological
assessment: Evaluation of lymph nodes
Dowsett, M et al. JNCI 2011
Polley, M et al. JNCI 2013
De Nielsen, TO et al. SABCS 2013
Poor reproducibility in Ki67 quantification between observers
NCCN 2016 Guideline Biomarkers in Solid Tumors
Cancer Type
Targetable Alterations
NSCLC EGFR mt BRAF mt ERBB2 mt ALK fusion
ROS1 fusion
RET fusion
MET amp and exon 14 skipping mt
PD-L1 exp
Colorectal KRAS mt exons 2,3,4
NRAS mt exons 2,3,4
BRAF mt MSI (or MMR IHC) if < 70 or older if relative with CRC < 50 or 2 relatives with CRC
Breast ERBB2 (HER2) amp
BRCA1/2 germline if: • early onset < 45 • triple negative breast cancer < 60 • male breast cancer at any age • dx at any age & family hx
ER, PR exp Proliferation
(Genomic signature)
Gastric & Gastro-
esophageal ERBB2 (HER2) amp
Melanoma BRAF mt KIT mt
GIST KIT mt PDGFRA mt
BRAF mt
Ovarian BRCA1/2 germline and somatic
NCCN 2016 Guideline Biomarkers in Solid Tumors
Cancer Type
Targetable Alterations
NSCLC EGFR mt BRAF mt ERBB2 mt ALK fusion
ROS1 fusion
RET fusion
MET amp and exon 14 skipping mt
PD-L1 exp
Colorectal KRAS mt exons 2,3,4
NRAS mt exons 2,3,4
BRAF mt MSI (or MMR IHC) if < 70 or older if relative with CRC < 50 or 2 relatives with CRC
Breast ERBB2 (HER2) amp
BRCA1/2 germline if: • early onset < 45 • triple negative breast cancer < 60 • male breast cancer at any age • dx at any age & family hx
ER, PR exp Proliferation
(Genomic signature)
Gastric & Gastro-
esophageal ERBB2 (HER2) amp
Melanoma BRAF mt KIT mt
GIST KIT mt PDGFRA mt
BRAF mt
Ovarian BRCA1/2 germline and somatic
NCCN 2016 Guideline Biomarkers in Solid Tumors
Cancer Type
Targetable Alterations
NSCLC EGFR mt BRAF mt ERBB2 mt ALK fusion
ROS1 fusion
RET fusion
MET amp and exon 14 skipping mt
PD-L1 exp
Colorectal KRAS mt exons 2,3,4
NRAS mt exons 2,3,4
BRAF mt MSI (or MMR IHC) if < 70 or older if relative with CRC < 50 or 2 relatives with CRC
Breast ERBB2 (HER2) amp
BRCA1/2 germline if: • early onset < 45 • triple negative breast cancer < 60 • male breast cancer at any age • dx at any age & family hx
ER, PR exp Proliferation
(Genomic signature)
Gastric & Gastro-
esophageal ERBB2 (HER2) amp
Melanoma BRAF mt KIT mt
GIST KIT mt PDGFRA mt
BRAF mt
Ovarian BRCA1/2 germline and somatic
Cuestión 3.
¿El conocimiento molecular cambia el
paradigma del tratamiento en el paciente
oncológico?
Cancer genetics is accelerating the time from 'driver mutation discovery' to
'clinical proof-of-concept' and the approval of new drugs
Chin, L et al. Nat Med 2013
Dawood et al. J Clin Oncol 2010;28:92–98
Biomarkers and targeted therapies changed the
evolution of disease in cancer patients
Dawood et al. J Clin Oncol 2010;28:92–98
Biomarkers and targeted therapies changed the
evolution of disease in cancer patients
Next Generation Sequencing Identifies Driver
Mutations and Enable Precision Medicine in
Cancer
Biankin, AV et al. Nature 2015
From histology to molecular definition of
cancer subtypes
Liquid Biopsy in Cancer
Diagnostic applications of
blood-based molecular testing
Early Detection
Diagnosis Prognosis
Monitoring Response
Response Prediction
Monitoring Resistance
Assessment of Molecular
Heterogeneity
Monitoring of Minimal
Residual Disease
T790M-mutant ctDNA
25 abstracts sobre estudio de
mutaciones en plasma
“…es imposible que una muestra de sangre recoja toda la complejidad de
las mutaciones de los tumores y permita conocer biomarcadores fiables
para que los oncólogos tomen decisiones…”
25 abstracts sobre estudio de
mutaciones en plasma
• Blood test to screen for diseases in their babies
• Unusual pattern identified on their cfDNA profile
• Following consultancy, they were diagnosed
with cancer
• Had surgery to remove cancer
• No signs of ctDNA in follow up at 7 month
pregnancy
Liquid biopsy in cancer
Diagnostic?
Liquid biopsy in cancer
Diagnostic?
Cuestión 4.
¿Existen limitaciones en el diagnóstico
basado exclusivamente en el
conocimiento molecular?
Importance of selection of tissue sample for molecular diagnosis
Normal breast
Stroma
Invasive carcinoma
In situ carcinoma
Necrosis
Importance of selection of tissue sample for molecular diagnosis
Importance of selection of tissue sample for molecular diagnosis
DNA RNA DNA RNA
DNA RNA DNA RNA
1ng/ul 3ng/ul 8ng/ul 5ng/ul
76ng/ul 68ng/ul 112ng/ul 68ng/ul
Rojo, F. SPMM 2011
Elloumi, F. et al. BMC Med Genomics 2011
Systematic bias in genomic classification due to
non-neoplastic cell proportion in breast cancer
Turner, BM et al. Mod Pathol 2015
Acs, G et al. Mod Pathol 2012
Potential limitations of multigene plataforms: Role of cancer stroma
Increased stromal cellularity and presence of inflammatory cells are
associated with RS≥18
Elevated Ki67 in stroma predicts RS≥18
Andre, F et al. Lancet Oncol 2014
Limited role of targeted therapy based on
alterations, SAFIR01 and SHIVA trials
Phase 2 randomised molecularly targeted therapy based on
tumour molecular profiling versus conventional therapy for
advanced cancer trial (SHIVA)
Le Tourneau, C et al. Lancet Oncol 2015
Cuestión 5.
¿Cuál debe de ser el planteamiento futuro
en el diagnóstico oncológico?
Denkert, C et al. Mod Pathol 2016
Standardized methodology for pathological TILs evaluation
Ring studies for standardized evaluation of TILs in
breast cancer
Cuzick, J et al. J Clin Oncol 2011
Dowsett, M et al. J Clin Oncol 2013
Predicted time to distant recurrence for a node-negative
patient age ≥ 65 years with a poorly differentiated 1- to 2-
cm tumor treated with anastrozole
IHC4 = 94.7*(-0.100*ER10 – 0.079*PgR10 + 0.586*HER2 +
0.240*ln(1 +10*ki67)
Correlation between IHC4 and Magee equation with RS Recurrence score = 15.31385 + Nottingham score*1.4055 +
ERIHC*(-0.01924) + PRIHC*(-0.02925) + (0 for HER2
negative, 0.77681 for equivocal, 11.58134 for HER2 positive)
+ tumor size*0.78677 + Ki-67 index*0.13269
http://path.upmc.edu/onlineTools/MageeEquations.html
PPV: 0.86 for low risk RS and 1.0 for
high risk, and the NPV: 0.45 and 0.97,
respectively
Eliminating high and low risk cases,
between 5% and 23% of cases would
potentially not have been sent for
OncotypeDX testing, (potential cost
savings $56,550-282,750) Flanagan, MB et al. Mod Pathol 2008
Klein, ME et al. Mod Pathol 2013
Turner, BM et al. Mod Pathol 2015
Standardized evaluation of biomarkers in breast
cancer
Clasificación de los gliomas
(OMS 2016)
Louis, DN et al. Acta Neuropathol 2016
Clasificación de los gliomas
(OMS 2016)
¿Cuál es el papel del diagnóstico morfológico en la Era de la Oncología de
Precisión?
La información morfológica guía las decisiones clínicas y
aporta valor pronóstico y predictivo
¿Existen limitaciones al diagnóstico morfológico?
Las potenciales limitaciones deben de motivar la incorporación
de nuevas herramientas y mejorar la capacitación de los
profesionales
¿El conocimiento molecular cambia el paradigma del tratamiento en el paciente
oncológico?
Nos encontramos en la antesala de la Oncología de Precisión,
pero el conocimiento molecular necesita de la morfología
¿Cuál debe de ser el planteamiento futuro en el diagnóstico oncológico?
Necesidad de integrar el conocimiento morfológico y molecular:
Sumar y no sustituir