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ZARDAVAS AND PICCART-GEBHART
TABLE 1. Molecular Aberrations Defining Administration of Approved Targeted Agents in Different Solid Tumor
Diagnoses
Cancer Type Molecular Target Aberration Method of Assessment Approved Targeted Agent
Breast Cancer ER Overexpression IHC Tamoxifen
AIs
Fulvestrant
PgR Overexpression IHC Tamoxifen
AIs
Fulvestrant
HER2 Overexpression and/or amplification IHC Trastuzumab
Pertuzumab
FISH
Lapatinib
T-DM1
Colorectal Cancer KRAS* Mutation DNA Cetuximab
Panitumumab
Gastric Cancer HER2 Overexpression and/or amplification IHC Trastuzumab
FISH
GIST KIT Mutation IHC Imatinib
Melanoma BRAF Mutation DNA Vemurafenib
Dabrafenib
Non-Small Cell Lung Cancer EGFR Mutation DNA Gefitinib
Erlotinib
ALK Rearrangement FISH Crizotinib
RET Rearrangement FISH Vandetanib
ROS Rearrangement FISH Crizotinib
Abbreviations: AI, aromatase inhibitor; ALK, anaplastic lymphoma kinase; EGFR, epidermal growth factor receptor; ER, estrogen receptor; FISH, fluorescent in situ hybridization; GIST,
gastrointestinal stromal tumor; HER2, human epidermal growth factor receptor 2; IHC, immunohistochemistry; PgR, progesterone receptor; T-DM1, trastuzumab DM1.
*KRAS mutations predict lack of benefit derived from EGFR-blocking agents.
the tumor microenvironment. An expanding arsenal of targeted
agents is currently under clinical development, aiming
to block specifıc molecular aberrations 9 ; however, the extended
tumor heterogeneity seen poses impediments to their
success. 10 The increasing number of targeted agents warranting
clinical assessment, coupled with the increasing molecular
fragmentation of breast cancer and thus the respective
decrease in prevalence of putative predictive biomarkers,
render the current clinical trial paradigm ineffıcient. New
study designs are needed to facilitate the successful clinical
development of targeted agents within specifıc molecular
niches of breast cancer. 11
KEY POINTS
The success stories of trastuzumab and endocrine
treatment for patients with HER2-positive and hormone
receptor-positive breast cancer exemplify the potential of
personalized cancer medicine.
High-throughput molecular profiling techniques reveal the
extensive molecular diversity of breast cancer, leading to
an increased molecular fragmentation.
There is an increasing number of targeted agents that
need to be assessed in the setting of breast cancer.
Clinical assessment of targeted agents within small
molecularly defined breast cancer segments poses
challenges to the design and conduct of clinical trials.
New, innovative study designs are being introduced to
overcome these challenges.
MOLECULAR PROFILING IN BREAST CANCER
The advent of gene-expression profıling analysis led to the
identifıcation of four intrinsic subtypes of breast cancer, associated
with different prognostication and sensitivity profıles
to treatment, 12 namely: (1) luminal A, being HR-positive
with low proliferation rates, (2) luminal B, HR-positive with
higher proliferation rates, (3) HER2-like, characterized by
amplifıcation of the ERBB2 gene as well as other genes in the
same amplicon, and (4) basal-like, largely showing a triple
phenotype with lack of expression of estrogen receptor, progesterone
receptor, and HER2. Of note, these subtypes show
distinct molecular profıles, as indicated by studies that coupled
gene expression profıling with genome copy number
analysis. 13,14 Subsequent studies, implementing this powerful
technique to larger collections of primary breast tumors,
have led to further molecular fragmentation of this common
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