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Molecular Pathology of Lung Cancer
Angelo Paolo Dei Tos M.D. Departments of Pathology & Oncology
Treviso, ITALY
WHO 2015
• Personalized medicine • Therapeutic decisions based on specific
histologic and genetic characteristics of tumor • Pathologists to classify NSCLC into specific
pathologic subtypes – adenocarcinoma versus squamous cell
carcinoma) • Eligibility for molecular testing and
consequent therapeutic strategies.
Molecular Testing in Lung Cancer
• Identification of molecular abnormalities in tumor specimens is required for therapy
• Limit the use of diagnostic immunohistochemical markers
• Pathology should determine the adequacy of specimens for molecular testing
Oncogene Addiction
• Tumor cells have many genetic abnormalities
• Driver mutations determines tumor cell survival
• Inactivation of upregulated oncogenic pathways
results in cancer cell death
MET
Driver Mutations in Lung Cancer (lung adenocarcinoma)
• EGFR, KRAS and ALK/ROS1/RET
• EGFR and/or ALK non smokers
• KRAS/BRAF smokers
EGFR-mutations in Adenocarcinoma
• 10-20% European area
• 50% East Asian area
• Randomized trials in patients with
advanced disease have shown
benefits for first-line treatment with
gefitinib, erlotinib and afatinib
EGFR-I mutations are not alike
Determination of EGFR mutations in NSCLC
• Adenocarcinoma
• Large cell carcinoma
• Mixed tumor with adenocarcinoma
• NSCLC NAS
Secondary Resistance to EGFR-I
• Additional somatic mutation in EGFR
(T790M)
• Amplification MET or ERBB2
• EGFR-I, EGFR antibodies and T790M
specific inhibitors under investigation
KRAS mutation adenocarcinoma
• 30% caucasian; 10% East Asian
population
• No response to EGFR-target agents
• Impact on overall survival remains
controversial
ALK rearrangements in NSCLC
ALK fusion protein in NSCLC
ALK/MET/ROS1 inhibitor crizotinib
ALK activating rearrangements
• 3-7% lung adenocarcinomas
• Good responder to ALK/MET/ROS1
inhibitor crizotinib
• Immunohistochemistry is a sensitive and
specific tool
• Vysis ALK Break-Apart FISH Probe Kit
• IHC = good surrogate biomarker
Crizotinib Resistant ALK + NSCLC
ROS and RET activating rearrangements
• 1% lung adenocarcinomas
• Good responder to ALK/MET/ROS1
inhibitor crizotinib
ERBB2 (HER2) mutations
• 1-5% lung adenocarcinomas
• Preclinical studies suggest that
ERBB2 inhibitors could be effective
BRAF mutation in NSCLC
• 2-10% lung adenocarcinomas
• The proportion of non-V600E
mutations is higher in lung cancer than
in other histotype
Squamous Cell Lung Carcinoma
Immunohistochemistry & ALK (Mino-Kenudson et al, CCR 2010)
• With the D5F3 clone high rates of sensitivity and specificity can be achieved (in experienced hands?)
• IHC remains a preferred technique for screening and diagnosis in
routine surgical pathology practice
• IHC-based screening can be used to identify lung adk harboring ALK
rearrangements
• *rabbit monoclonal anti-human CD246, Cell Signaling Technology
Our Approach
Diagnosis
adenocarcinoma
EGFR/KRAS molecular analysis + ALK/ROS IHC
• IHC 0 = negative
• IHC 1+/2 + = FISH
• IHC 3+ = positive
ALK
ALK
ROS
ROS
Int. J. Mol. Sci. 2015, 16, 14122-14142; doi:10.3390/ijms160614122
International Journal of Molecular Sciences
ISSN 1422-0067 www.mdpi.com/journal/ijms
Review
Circulating Cell-Free Tumour DNA in the Management of Cancer
Glenn Francis 1,2,3,* and Sandra Stein 4
1 Director Pathology, Genomics for Life, Herston 4006, Australia 2 School of Medicine, Griffith University, Gold Coast 4215, Australia 3 Australian Institute for Bioengineering and Nanotechnology, University of Queensland,
St Lucia 4067, Australia 4 Laboratory Director, Genomics for Life, Herston 4006, Australia;
E-Mail: [email protected]
* Author to whom correspondence should be addressed; E-Mail: [email protected]; Tel.: +61-1800-445-433.
Academic Editor: Camile S. Farah
Received: 22 February 2015 / Accepted: 26 May 2015 / Published: 19 June 2015
Abstract: With the development of new sensitive molecular techniques, circulating cell-free tumour DNA containing mutations can be identified in the plasma of cancer patients. The applications of this technology may result in significant changes to the care and management of cancer patients. Whilst, currently, these “liquid biopsies” are used to supplement the histological diagnosis of cancer and metastatic disease, in the future these assays may replace the need for invasive procedures. Applications include the monitoring of tumour burden, the monitoring of minimal residual disease, monitoring of tumour heterogeneity, monitoring of molecular resistance and early diagnosis of tumours and metastatic disease.
Keywords: cell-free DNA; cell-free tumour DNA; non-small cell lung cancer; melanoma; colorectal carcinoma; minimal residual disease; liquid biopsy
1. Introduction
A biomarker is a chemical or biological compound that can be used to diagnose or monitor disease. For cancer, the aims of a sensitive biomarker are to enable early detection of cancer, monitoring of disease progression and response to treatment. Biomarkers can be broadly grouped into predictive
OPEN ACCESS
Conclusions
• Multiprofessional approch
• Morphology still very important
• Molecular tools predict response and
resistance to targeted therapies
• IHC good surrogate for molecular
analysis of ALK/ROS1
• NGS approches