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Can the Lung Cancer Pie Be Divided into Angiogenic Slices?
Tina Cascone1 and John V. Heymach2,3
1
Division of Cancer Medicine, 2,3Departments of Thoracic, Head and Neck Medical
Oncology and Cancer Biology. The University of Texas MD Anderson Cancer Center,
Houston, Texas.
Corresponding Author: John V. Heymach, Departments of Thoracic, Head and Neck
Medical Oncology, and Cancer Biology, The University of Texas MD Anderson Cancer
Center, 1515 Holcombe Boulevard, Unit 432, Houston, TX 77030. Phone: 713-792-6363;
Fax: 713-792-1220; E-mail: [email protected]
Running Title: Predictive Markers for VEGF and EGFR Inhibition in NSCLC
Disclosure of Potential Conflicts of Interest
J.V. Heymach reports receiving commercial research grants from AstraZeneca, Bayer,
and GlaxoSmithKline, and is a consultant/advisory board member for AstraZeneca,
Boehringer Ingelheim, Eli Lilly, Exelixis, Genentech, GlaxoSmithKline, Novartis, and
Synta Pharmaceuticals. No potential conflicts of interest were disclosed by the other
author.
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Author Manuscript Published OnlineFirst on July 31, 2015; DOI: 10.1158/1078-0432.CCR-15-1180
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Summary
There are no validated markers for predicting benefit from angiogenesis inhibitors or
classifying tumors with distinct angiogenic phenotypes. In NSCLC patients treated with
bevacizumab and erlotinib, Franzini and colleagues find that angiogenesis- and hypoxiaassociated gene expression signatures predict tumor response and/or clinical outcome,
and may define distinct angiogenic patterns.
2
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In this issue of Clinical Cancer Research, Franzini and colleagues (1) investigate
the association between angiogenesis- and hypoxia-related gene expression signatures
and clinical outcome in non-squamous non-small cell lung cancer (NSCLC) patients
treated with the Vascular Endothelial Growth Factor (VEGF) inhibitor bevacizumab plus
the Epidermal Growth Factor Receptor (EGFR) inhibitor erlotinib. A remarkable advance
in the treatment of NSCLC, and other cancers, is the development of biomarker-defined
classifications that help define subgroups likely to benefit from particular targeted agents.
The major genomically-defined “slices of the pie” for NSCLC are now familiar, such as
those marked by EGFR, ALK, or BRAF alterations. Immunotherapy is rapidly moving in
a similar direction; emerging data already supports that tumors expressing varying
amounts of PD-L1 on tumor or immune cells may derive different degrees of benefit
from agents targeting the PD-1/PD-L1 axis, and more refined immune classifications are
no doubt on the way (2).
Given this progress, it is perhaps surprising that after about two decades of testing
angiogenesis inhibitors such as the anti-VEGF monoclonal antibody bevacizumab, we
still do not have clinically useful markers for classifying tumors based on their
angiogenic phenotype, or for predicting which patients are more likely to benefit from
these drugs. This is surely an important unmet need, given that only a minority of patients
derive significant benefit from bevacizumab, serious toxicities may occur, and resistance
inevitably occurs.
Bevacizumab significantly improves clinical outcomes when added to platinumbased chemotherapy in NSCLC (3). The addition of bevacizumab to erlotinib did not
prolong survival compared with erlotinib in the overall platinum- refractory NSCLC
3
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population, but two randomized phase III studies suggest that bevacizumab plus erlotinib
may be superior to erlotinib alone among EGFR mutation positive patients (4, 5). Outside
of EGFR mutation, there are currently no validated markers for identifying which
patients are more likely to benefit from bevacizumab when added to either chemotherapy
or erlotinib.
Franzini and colleagues (1) performed gene expression profiling on
bronchoscopic biopsies from 42 patients with stage IIIB/IV non-squamous NSCLC
enrolled in the Swiss Group for Clinical Cancer Research 19/05 phase II trial (6) and
treated with bevacizumab and erlotinib. Pretreatment gene expression profiles were
correlated with clinical outcomes (tumor shrinkage [TS], time to progression [TTP], and
OS) and then subjected to gene set enrichment analysis (GSEA) using a 43-gene core
angiogenesis signature and a 51-gene hypoxia signature, previously reported. GSEA
revealed that both angiogenic and hypoxic-associated signatures are enriched within
genes that associate with TTP under bevacizumab and erlotinib therapy. Further
unsupervised hierarchical clustering of the top 10-ranked angiogenesis-associated genes
revealed that patients with increased expression of angiogenic genes at baseline (low risk)
possess an improved median TTP (7.1 months) versus a 2.1 month median TTP in
patients with a decreased signature (high risk). Patients with a diminished hypoxiasignature (low-risk) had a prolonged median TTP (6.9 months) versus a 2.9 month
median TTP in patients with elevated levels (high risk).
Unlike the angiogenesis signature, increased expression of the hypoxia signature
was predictive of TS after 12 weeks of bevacizumab plus erlotinib, suggesting that it may
possess greater potential for assessing treatment response. Furthermore, both signatures
4
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were found to have prognostic value for OS, as the median OS for patients with elevated
hypoxia signature expression was 9.9 months versus 17.8 months in patients with
decreased levels. While hypoxia-inducible factor 1-alpha (HIF-1α) was not identified as
predictive for TTP, several of its downstream targets were components of the hypoxia
signature. These results agree with previously reported studies demonstrating that
hypoxia correlates with a more aggressive phenotype, perhaps by enhancing malignant
potential through increased genomic instability and by acting as selective pressure for
variants with diminished apoptotic potential (7).
Assuming the associations described between the angiogenic and hypoxia
response signatures are robust, important issues would need to be addressed before they
could be used in selecting therapy. In the absence of a control arm, it is not possible to
determine whether the signatures are predictive of benefit for bevacizumab plus erlotinib
compared with another therapy, or merely prognostic. Caution should be used in
assuming that markers associated with improved clinical outcome in a single arm study
will be predictive of greater relative benefit compared with another drug in a randomized
study. For example, we previously observed that high circulating IL-6 is a negative
prognostic marker in metastatic renal cell cancer, but predicts greater relative benefit for
patients receiving pazopanib compared with placebo control (8). Such observations
would not be evident in a single arm study.
Clinically useful predictive biomarkers typically help inform the choice between
different therapies. It remains to be seen whether the angiogenic or hypoxia signatures
could be used to predict, for example, which patients benefit from bevacizumab in
combination with chemotherapy compared with chemotherapy alone. Interestingly, the
5
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authors report an association between the hypoxia signature and PFS in the sorafenib, but
not erlotinib, arm of the BATTLE study, suggesting the signature may have utility for
other drugs targeting the VEGF pathway (9, 10).
Given the current NSCLC landscape, it would also be important to assess whether
the signatures are predictive of benefit within the standard molecularly defined subgroups.
As noted above, bevacizumab appears to add greater benefit in the EGFR mutation
positive subgroup (4, 5). It would therefore be important to assess the signatures in the
EGFR-mutant and wild-type groups separately. The mechanism underlying the
apparently increased sensitivity of EGFR mutant tumors to VEGF blockade is not well
understood, but it is noteworthy that constitutive EGFR pathway activation results in
upregulation of VEGF and the HIF-1α pathway (11), suggesting there may be overlap
between EGFR and VEGF pathway dependence.
The authors suggest that the signatures are associated with distinct vascular
patterns; for example, vessels from tumors most likely to respond to bevacizumab and
erlotinib appear to possess a greater level of integrity and are less permeable compared
with vessels supplying less responsive tumors. It is known that expression levels of genes
encoding proteins critical to endothelial barrier function and vessel integrity are elevated
in tumors of patients with improved response to bevacizumab and erlotinib. The authors
conclude that when angiogenesis-associated genes are diminished, tumor angiogenesis is
dysregulated, resulting in hyperpermeable vasculature, increased hypoxia and earlier
disease progression (Fig. 1). Previous studies illustrate that different angiogenic
phenotypes impact tumor response to angiogenesis inhibition. For example, we
previously showed (12) that NSCLC xenografts which were less responsive to prolonged
6
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bevacizumab are supplied by tortuous and pericyte-devoid tumor-associated vessels,
whereas a more normalized revascularization characterizes NSCLC xenografts with
acquired resistance to long-term treatment.
It is now widely accepted that genomic phenotypes of a variety of cancers, such
as EGFR mutant NSCLC or BRAF mutant melanoma, impact the response to targeted
therapeutic strategies in distinct subgroups of patients. However, the search for
biomarkers capable of defining distinct angiogenic phenotypes, and identifying NSCLC
patients most likely to derive clinical benefit from anti-angiogenic therapies, has proved
challenging. The findings reported by Franzini and colleagues (1), while not ready for
immediate clinical application, may be a promising step forward towards addressing our
collective hunger for angiogenic slices of the NSCLC pie.
Grant Support
J.V. Heymach is supported in part by the UT Lung Spore (P50CA070907); an NIH
Cancer Center Support Grant (P30CA16672); an NCI R01 award (R01CA168484); the V
Foundation for Cancer Research; the LUNGevity Foundation; Uniting Against Lung
Cancer; the Lung Cancer Research Foundation; and generous philanthropic contributions
to The University of Texas MD Anderson Lung Moon Shot Program, the Dell Fund
honoring Lorraine Dell, Rexanna’s Foundation for Fighting Lung Cancer, and the Bruton
Endowment for Tumor Biology.
Acknowledgments
The authors thank Emily B. Roarty, PhD, for providing expert editorial assistance.
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Figure 1. Angiogenesis- and hypoxia-associated gene expression signatures predict
response of NSCLC tumors to combined bevacizumab and erlotinib therapy. Patients
with tumors characterized by a robust angiogenesis gene signature and a decreased
hypoxia-associated gene signature (upper panel) display increased tumor shrinkage and
improved outcome. Gene expression data predict that tumor-associated vascular bed of
these tumors is formed through controlled, sustained angiogenesis and that the
vasculature is less permeable compared with the vascular network supplying highly
hypoxic tumors, which are less responsive to therapy (lower panel). Abbreviations: OS,
overall survival; pO2: partial pressure of oxygen; TS, tumor shrinkage; TTP, time to
tumor progression; VEGF, vascular endothelial growth factor.
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Figure 1:
i TS
i TTP
pO2
i OS
pO2
k TS
k TTP
Tumor cell
k OS
Pericyte
Endothelial cell
Macromolecule
VEGF
Bevacizumab
Erlotinib
© 2015 American Association for Cancer Research
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Can the Lung Cancer Pie Be Divided into Angiogenic Slices?
Tina Cascone and John V. Heymach
Clin Cancer Res Published OnlineFirst July 31, 2015.
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