NZ620345B2 - Responsiveness to angiogenesis inhibitors - Google Patents
Responsiveness to angiogenesis inhibitors Download PDFInfo
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- NZ620345B2 NZ620345B2 NZ620345A NZ62034512A NZ620345B2 NZ 620345 B2 NZ620345 B2 NZ 620345B2 NZ 620345 A NZ620345 A NZ 620345A NZ 62034512 A NZ62034512 A NZ 62034512A NZ 620345 B2 NZ620345 B2 NZ 620345B2
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Abstract
Disclosed is an in vitro method of determining whether a patient is suitably treated by a therapy comprising an angiogenesis inhibitor comprising bevacizumab or an antibody that binds essentially the same epitope on VEGF as bevacizumab, said method comprising: (a) determining in a sample derived from a patient suffering from cancer the genotype at polymorphism rs12505758 (SEQ ID NO. 2), and (b) identifying a patient as more or less suitably treated by a therapy with an angiogenesis inhibitor comprising bevacizumab or an antibody that binds essentially the same epitope on VEGF as bevacizumab based on said genotype, wherein the presence of each T allele at polymorphism rs12505758 (SEQ ID NO. 2) indicates an increased likelihood that said patient is more suitably treated, or the presence of each C allele at polymorphism rs12505758 (SEQ ID NO. 2) indicates an increased likelihood that said patient is less suitably treated. om a patient suffering from cancer the genotype at polymorphism rs12505758 (SEQ ID NO. 2), and (b) identifying a patient as more or less suitably treated by a therapy with an angiogenesis inhibitor comprising bevacizumab or an antibody that binds essentially the same epitope on VEGF as bevacizumab based on said genotype, wherein the presence of each T allele at polymorphism rs12505758 (SEQ ID NO. 2) indicates an increased likelihood that said patient is more suitably treated, or the presence of each C allele at polymorphism rs12505758 (SEQ ID NO. 2) indicates an increased likelihood that said patient is less suitably treated.
Description
Case 30615
Responsiveness to Angiogenesis Inhibitors
Field of the Invention
The t invention is directed to methods for identifying which patients will most benefit
from treatment with anti-cancer agents and monitoring patients for their sensitivity and
responsiveness to treatment with anti-cancer agents.
Background of the ion
Angiogenesis contributes to benign and malignant diseases such as cancer development and,
especially in cancer, is necessary for primary tumor , invasiveness and metastasis. In
order to grow, a tumor must undergo an angiogenic switch. Vascular endothelial growth factor
(VEGF) is required to induce this angiogenic switch. VEGF and the genes in the VEGF pathway
are considered important ors of cancer progression. The VEGF gene family includes the
VEGF gene, also referred to as VEGFA, homologues to VEGF including, placenta growth factor
(PlGF), VEGFB, VEGFC, VEGFD, the VEGF receptors, including VEGFR-1 and VEGFR-2
(also referred to as FLT1 and FLK1/KDR, respectively), the VEGF inducers, including hypoxiainducible
s HIF1α, HIF2 α, and the oxygen sensors PHD1, PHD2 and PHD3.
The importance of this pathway in cancer cell growth and metastasis has led to the development
of anti-angiogenesis agents for use in cancer therapy. These ies include, among others,
bevacizumab, pegaptanib, sunitinib, sorafenib and vatalanib. Despite significantly prolonged
survival obtained with angiogenesis inhibitors, such as bevacizumab, patients still succumb to
cancer. Further, not all patients respond to angiogenesis inhibitor therapy. The mechanism
ying the non-responsiveness s unknown. Moreover, angiogenesis inhibitor therapy
is associated with side effects, such as gastrointestinal perforation, thrombosis, bleeding,
hypertension and nuria.
AOK / 31.07.2012
Accordingly, there is a need for methods of determining which patients respond particular well
to angiogenesis inhibitor therapy and/or which patients are susceptible to side effects associated
with anti-angiogenesis treatments.
Summary of the Invention
Described herein is a method of determining r a patient is more suitably treated by a
therapy with an angiogenesis inhibitor, such as bevacizumab, by determing the genotype at
rs699946 (SEQ ID NO. 1) SNP, located in the VEGF promoter, which is associated with an
improved treatment . The t invention relates to a method of determining whether a
t is more suitably treated by a therapy with an angiogenesis inhibitor, such as zumab,
by determing the genotype at 5758 (SEQ ID NO. 2) SNP in VEGFR2, which is ated
with an improved treatment effect. Also described herein is a method of ining whether a
patient is more suitably treated by a therapy with an angiogenesis inhibitor, such as bevacizumab,
by determing the genotype at 3360 (SEQ ID NO. 5) SNP in VEGFR2, which is ated
with an improved ent effect. Also described is a ceutical ition comprising
an angiogenesis inhibitor, such as bevacizumab, for the treatment of a patient suffering from
cancer and having the genotype at rs699946 (SEQ ID NO. 1) SNP, rs12505758 (SEQ ID NO. 2)
SNP and/or rs11133360 (SEQ ID NO. 5) SNP associated with an improved treatment effect.
Also described is a method for improving the treatment effect of chemotherapy of a patient
suffering from cancer by adding an angiogenesis inhibitor, such as bevacizumab, based on the
genotype at rs699946 (SEQ ID NO. 1) SNP, rs12505758 (SEQ ID NO. 2) SNP and/or
rs11133360 (SEQ ID NO. 5) SNP associated with an improved treatment effect.
Described herein are methods of determining whether a patient is suitably treated by a therapy
comprising an angiogenesis inhibitor comprising bevacizumab or an antibody that binds
essentially the same epitope on VEGF as bevacizumab. The methods comprise: (a) determining
in a sample derived from a patient suffering from cancer the pe at polymorphism
rs699946 (SEQ ID NO. 1), and (b) identifying a patient as more or less suitably treated by a
therapy comprising an enesis inhibitor comprising bevacizumab or an antibody that binds
essentially the same epitope on VEGF as bevacizumab based on said genotype, wherein the
presence of each A allele at polymorphism rs699946 (SEQ ID NO. 1) indicates an increased
likelihood that said patient is more suitably treated, or the presence of each G allele at
polymorphism rs699946 (SEQ ID NO. 1) indicates an sed likelihood that said patient is
less suitably d. In some embodiments, the methods are in vitro methods. In some
embodiments, the therapy further comprises a chemotherapeutic agent or chemotherapy regimen.
In some embodiments, whether a patient is suitably treated by a therapy comprising an
enesis inhibitor is determined in terms of ssion-free survival. In some embodiments,
the angiogenesis inhibitor is administered with one or more agents selected from the group
ting of taxanes, interferon alpha, 5-fluorouracil, capecitabine, leucovorin, gemcitabine,
erlotinib and platinum-based chemotherapeutic agents. In some embodiments, the cancer is
pancreatic cancer, renal cell cancer, colorectal cancer, breast cancer or lung cancer. In some
embodiments, the sample is a blood sample. In some embodiments, the genotype is determined
by means of MALDI-TOF mass spectrometry. In some embodiments, the methods further
comprise administering the therapy to the t.
Also described are pharmaceutical compositions sing an angiogenesis inhibitor as defined
in above for the treatment of a patient in need thereof, wherein said patient has been determined
to be more suitably treated with the therapy comprising the angiogenesis inhibitor in accordance
with the method of any one of claims bed herein.
Also described are kits for carrying out the methods described herein. The kits comprise
oligonucleotides e of determining the genotype at polymorphism rs699946 (SEQ ID NO.
Also described are s for improving the treatment effect of a chemotherapeutic agent or
chemotherapy regimen of a patient suffering from cancer by adding an angiogenesis inhibitor
comprising bevacizumab or an antibody that binds essentially the same e on VEGF as
bevacizumab. The methods comprise (a) determining in a sample derived from a patient
suffering from cancer the genotype at polymorphism rs699946 (SEQ ID NO. 1); (b) identifying a
patient as more suitably treated by the addition of an enesis inhibitor sing
bevacizumab or an antibody that binds essentially the same e on VEGF as bevacizumab
based on said genotype, wherein the presence of each A allele at polymorphism 46 (SEQ
ID NO. 1) indicates an increased likelihood that said patient is more suitably treated; and (c)
administering said angiogenesis inhibitor in combination with a chemotherapeutic agent or
chemotherapy regimen to a patient identified as more suitably treated in accordance with (b). In
some embodiments, whether a patient is suitably d by a therapy comprising an
angiogenesis inhibitor is determined in terms of progression-free survival. In some embodiments,
the therapy further ses a chemotherapeutic agent or chemotherapy n. In some
embodiments, the angiogenesis inhibitor is administered with one or more agents selected from
the group consisting of taxanes, interferon alpha, 5-fluorouracil, capecitabine, leucovorin,
gemcitabine, erlotinib and platinum-based chemotherapeutic agents. In some embodiments, the
cancer is pancreatic cancer, renal cell cancer, colorectal cancer, breast cancer or lung cancer. In
some embodiments, the sample is a blood sample. In some embodiments, the genotype is
determined by means of MALDI-TOF mass spectrometry.
Also described herein are methods of treating a patient suffering from cancer. The methods
comprise administering to the patient therapy comprising an angiogenesis inhibitor comprising
bevacizumab or an dy that binds essentially the same e on VEGF as bevacizumab
wherein the patient genotype at polymorphism rs699946 (SEQ ID NO. 1) has been determined to
be an A allele.
In an embodiment, the invention es in vitro methods of determining whether a t is
suitably treated by a therapy comprising an angiogenesis inhibitor comprising bevacizumab or an
antibody that binds essentially the same epitope on VEGF as bevacizumab. The methods
comprise (a) determining in a sample derived from a patient suffering from cancer the genotype
at polymorphism rs12505758 (SEQ ID NO. 2), and (b) identifying a patient as more or less
suitably treated by a therapy with an angiogenesis inhibitor comprising bevacizumab or an
antibody that binds essentially the same epitope on VEGF as bevacizumab based on said
genotype, wherein the presence of each T allele at rphism rs12505758 (SEQ ID NO. 2)
indicates an increased likelihood that said t is more suitably d, or the presence of
each C allele at polymorphism rs12505758 (SEQ ID NO. 2) indicates an increased likelihood
that said t is less ly treated. In some embodiments, r a patient is suitably
d by a therapy comprising an enesis inhibitor is determined in terms of overall
survival. In some embodiments, the therapy further comprises a chemotherapeutic agent or
chemotherapy regimen. In some embodiments, the angiogenesis inhibitor is stered with
one or more agents selected from the group consisting of taxanes, interferon alpha, 5-fluorouracil,
capecitabine, leucovorin, gemcitabine, erlotinib and platinum-based chemotherapeutic agents. In
some embodiments, the cancer is pancreatic cancer, renal cell cancer, colorectal cancer, breast
cancer or lung cancer. In some embodiments, the sample is a blood . In some
embodiments, the genotype is determined by means of MALDI-TOF mass spectrometry. Also
described are methods that further comprise administering the therapy to the patient.
A further embodiment of the invention provides the use of an angiogenesis inhibitor comprising
bevacizumab or an antibody that binds essentially the same epitope on VEGF as bevacizumab
for the manufacture of a medicament for the treatment of cancer in a patient in need thereof,
wherein said patient has been determined to be more suitably treated with the angiogenesis
inhibitor in ance with the method of the invention.
Also described herein are pharmaceutical compositions comprising an angiogenesis inhibitor as
described above for the treatment of a patient in need thereof, wherein said patient has been
determined to be more ly treated with the angiogenesis inhibitor in accordance with the
methods described herein.
A further embodiment of the ion provides the use of an enesis inhibitor comprising
bevacizumab or an antibody that binds essentially the same epitope on VEGF as bevacizumab
for the manufacture of a medicament for treating cancer in a patient, wherein the t
genotype at polymorphism 5758 (SEQ ID NO. 2) has been determined to be a T allele.
Also described are kits for carrying out the method bed . The kits comprise
oligonucleotides capable of determining the genotype at polymorphism rs12505758 (SEQ ID
NO. 2).
A r embodiment of the invention provides the use of an angiogenesis tor comprising
bevacizumab or an antibody that binds essentially the same epitope on VEGF as bevacizumab,
for the manufacture of a medicament for the treatment of cancer in a patient in need thereof,
wherein the patient has been determined to be more suitably treated with the angiogenesis
inhibitor by an in vitro method comprising:
(a) determining in a sample derived from a patient suffering from cancer the genotype at
rphism rs12505758 (SEQ ID NO. 2); and
(b) identifying a patient as more suitably d by the addition of an angiogenesis
inhibitor comprising bevacizumab or an antibody that binds ially the same epitope on
VEGF as bevacizumab based on said genotype, wherein the presence of each T allele at
polymorphism rs12505758 (SEQ ID NO. 2) indicates an increased likelihood that said patient is
more suitably treated.
Also described herein are methods for improving the ent effect of a chemotherapeutic
agent or herapy n of a patient suffering from cancer by adding an angiogenesis
tor sing bevacizumab or an antibody that binds essentially the same epitope on
VEGF as bevacizumab. The methods comprise (a) determining in a sample derived from a
patient suffering from cancer the genotype at polymorphism rs12505758 (SEQ ID NO. 2); (b)
identifying a patient as more suitably d by the addition of an angiogenesis inhibitor
comprising bevacizumab or an antibody that binds essentially the same epitope on VEGF as
bevacizumab based on said genotype, wherein the presence of each T allele at polymorphism
rs12505758 (SEQ ID NO. 2) tes an increased likelihood that said patient is more suitably
treated; and (c) administering said angiogenesis inhibitor in combination with a
chemotherapeutic agent or chemotherapy regimen to a patient fied as more suitably treated
in accordance with (b). In some embodiments, whether a patient is suitably treated by a therapy
comprising an angiogenesis inhibitor is determined in terms of overall survival. In some
embodiments, the therapy further comprises a herapeutic agent or chemotherapy n.
In some embodiments, the angiogenesis inhibitor is administered with one or more agents
selected from the group consisting of taxanes, interferon alpha, 5-fluorouracil, capecitabine,
leucovorin, gemcitabine, nib and platinum-based chemotherapeutic agents. In some
embodiments, the cancer is pancreatic cancer, renal cell cancer, colorectal , breast cancer
or lung cancer. In some embodiments, the sample is a blood sample. In some embodiments, the
genotype is determined by means of MALDI-TOF mass spectrometry.
Also described herein are methods of treating a patient suffering from cancer. The methods
se administering to the patient therapy comprising an angiogenesis inhibitor comprising
bevacizumab or an antibody that binds essentially the same epitope on VEGF as zumab
n the patient genotype at polymorphism rs12505758 (SEQ ID NO. 2) has been determined
to be a T allele.
Also described herein are methods of determining whether a patient is suitably treated by a
therapy sing an angiogenesis inhibitor comprising bevacizumab or an antibody that binds
essentially the same epitope on VEGF as bevacizumab. The methods comprise (a) determining
in a sample derived from a patient suffering from cancer the genotype at polymorphism
rs11133360 (SEQ ID NO. 5), and (b) identifying a patient as more or less suitably treated by a
therapy comprising an angiogenesis inhibitor comprising bevacizumab or an antibody that binds
essentially the same epitope on VEGF as bevacizumab based on said genotype, wherein the
presence of each T allele at polymorphism rs11133360 (SEQ ID NO. 5) indicates an increased
likelihood that said patient is more suitably treated, or the presence of each C allele at
polymorphism rs11133360 (SEQ ID NO. 5) indicates an increased likelihood that said patient is
less suitably treated. In some embodiments, the s are in vitro s. In some
embodiments, whether a patient is suitably treated by a therapy comprising an angiogenesis
tor is determined in terms of progression-free survival. In some embodiments, the therapy
further comprises a herapeutic agent or chemotherapy regimen. In some embodiments,
the angiogenesis inhibitor is administered with one or more agents selected from the group
ting of taxanes, eron alpha, 5-fluorouracil, capecitabine, leucovorin, gemcitabine,
erlotinib and platinum-based chemotherapeutic agents. In some embodiments, the cancer is
pancreatic cancer, renal cell cancer, colorectal cancer, breast cancer or lung cancer. In some
embodiments, the sample is a blood sample. In some ments, the pe is determined
by means of MALDI-TOF mass spectrometry. In some embodiments, the methods further
comprise adminstering the therapy to the subject.
Also bed are ceutical compositions comprising an enesis inhibitor as defined
in above for the treatment of a patient in need thereof, wherein said patient has been determined
to be more ly treated with the therapy comprising the angiogenesis inhibitor in accordance
with the method of any one of claims described herein.
Also described are kits for carrying out the method described herein. The kits comprise
oligonucleotides e of determining the genotype at rphism 3360 (SEQ ID
NO. 5).
Also described are methods for improving the treatment effect of a chemotherapeutic agent or
chemotherapy n of a patient suffering from cancer by administering an angiogenesis
inhibitor comprising bevacizumab or an antibody that binds essentially the same epitope on
VEGF as bevacizumab. The methods comprise (a) determining in a sample derived from a
patient suffering from cancer the genotype at polymorphism rs11133360 (SEQ ID NO. 5); (b)
identifying a patient as more suitably treated by the on of an angiogenesis tor
sing bevacizumab or an antibody that binds essentially the same epitope on VEGF as
zumab based on said genotype, n the presence of each T allele at polymorphism
rs11133360 (SEQ ID NO. 5) indicates an increased likelihood that said patient is more suitably
treated; and (c) stering said enesis inhibitor in combination with a
chemotherapeutic agent or chemotherapy regimen to a patient identified as more suitably treated
in accordance with (b). In some embodiments, whether a patient is suitably treated by a therapy
comprising an angiogenesis tor is ined in terms of progression-free survival. In
some embodiments, the therapy further comprises a chemotherapeutic agent or chemotherapy
regimen. In some embodiments, the angiogenesis inhibitor is administered with one or more
agents selected from the group ting of taxanes, interferon alpha, 5-fluorouracil,
capecitabine, leucovorin, gemcitabine, erlotinib and platinum-based chemotherapeutic agents. In
some ments, the cancer is pancreatic cancer, renal cell cancer, colorectal cancer, breast
cancer or lung cancer. In some embodiments, the sample is a blood sample. In some
embodiments, the genotype is determined by means of MALDI-TOF mass spectrometry.
Also described are methods of treating a patient suffering from cancer. The methods comprise
administering to the patient therapy comprising an angiogenesis inhibitor comprising
bevacizumab or an antibody that binds essentially the same epitope on VEGF as bevacizumab
wherein the patient genotype at rphism rs11133360 (SEQ ID NO. 5) has been determined
to be a T allele.
These and other embodiments are further described in the ed description that follows.
Brief Description of the Drawings
Figure 1: Endpoint distributions of clinical data. Kaplan-Meier plot of Progression-free Survival
(PFS).
Figure 2: Endpoint distributions of clinical data. Kaplan-Meier plot of Overall Survival (OS).
Figure 3: Endpoint butions of clinical data. Bar chart of Best Overall Response (BOR).
Rates of BOR were 49% in BEV-treated subjects and 46% in PBO-treated subjects.
Figure 4: Endpoint distributions of clinical data. Bar chart of Hypertension not unrelated to
study drug. Rates of hypertension were 18% in BEV-treated subjects and 7% in PBO-treated
Figure 5: Association analysis results for VEGFA and PFS in the Leuven efficacy panel analysis.
Figure 6: Forest plot for rs699946 (SEQ ID NO. 1) in VEGFA when tested for ation
against PFS.
Figure 7: Forest plot for the ation of rs12505758 (SEQ ID NO. 2) with OS in white BEV-
treated subjects.
Figure 8: Kaplan Meier plots for association between rs12505758 (SEQ ID NO. 2) and OS.
Figure 9: Hypertension ncies in correlation to rs2305949 (SEQ ID NO. 3) (KDR).
Figure 10: Forest plot for rs2305949 (SEQ ID NO. 3) in KDR, for ension in white BEV-
treated subjects.
Figure 11: Hypertension frequencies in correlation to rs4444903 (SEQ ID NO. 4) (EGF).
Figure 12: Forest plot for rs4444903 (SEQ ID NO. 4) in EGF and hypertension in PGx-SP-BEV-
White.
Figure 13: Forest plot for the ation of rs11133360 (SEQ ID NO. 5) with PFS in white
BEV-treated subjects.
Figure 14: Sequence of SNPs genotyped in the meta-analysis and associated with bevacizumab
outcome. SEQ ID NO.1 corresponds to 46, wherein position 51 is A or G. SEQ ID NO.2
corresponds to rs12505758, wherein position 51 is C or T. SEQ ID NO.3 corresponds to
949, wherein position 51 is C or T. SEQ ID NO.4 corresponds to rs4444903, wherein
position 51 is A or G. SEQ ID NO.5 corresponds to rs11133360, wherein on 51 is C or T.
Detailed Description of the Embodiments
1. Definitions
The term "administering" means the administration of a pharmaceutical composition, such as an
angiogenesis inhibitor, to the patient. For example, 2.5 mg/kg of body weight to 15 mg/kg of
body weight bevacizumab (Avastin®) can be administered every week, every 2 weeks or every 3
weeks, depending on the type of cancer being treated. Particular dosages include 5 mg/kg, 7.5
mg/kg, 10 mg/kg and 15 mg/kg. Even more particular dosages are 5 mg/kg every 2 weeks, 10
mg/kg every 2 weeks and 15 mg/kg every 3 weeks.
The term "angiogenesis inhibitor" in the context of the present invention refers to all agents that
alter angiogenesis (e.g. the process of forming blood vessels) and includes agents that inhibit the
angiogenesis, including, but not limited to, tumor angiogenesis. In this context, inhibition can
refer to blocking the formation of blood vessels and halting or slowing down the growth of blood
vessels. Examples of angiogenesis inhibitors include bevacizumab (also known as Avastin®),
pegaptanib, sunitinib, sorafenib and vatalanib. Bevacizumab is a recombinant humanized
monoclonal IgG1 dy that binds to and inhibits the biological activity of human VEGFA in
in vitro and in vivo assay system. The term "bevacizumab" encompass all corresponding anti-
VEGF antibodies that fulfill the ements necessary for obtaining a marketing authorization
as an cal or ilar product in a country or territory selected from the group of countries
consisting of the USA, Europe and Japan. In the context of the present invention, an
angiogenesis inhibitor includes an antibody that binds essentially the same epitope on VEGF as
bevacizumab, more ically an antibody that binds to the same epitope on VEGF as
zumab. An antibody binds "essentially the same epitope" as a nce antibody, when
the two antibodies ize identical or ally overlapping epitopes. The most widely used
and rapid methods for determining whether two epitopes bind to identical or sterically
overlapping es are competition assays, which can be configured in all number of different
formats, using either labeled antigen or labeled antibody. Usually, the antigen is immobilized on
a 96-well plate, and the ability of unlabeled antibodies to block the binding of labeled antibodies
is measured using radioactive or enzyme labels.
The term r” refers to the physiological condition in mammals that is typically
characterized by unregulated cell proliferation. es of cancer include but are not limited to,
carcinoma, lymphoma, ma, sarcoma and leukemia. More ular examples of such
cancers include squamous cell cancer, lung cancer (including small-cell lung cancer, non-small
cell lung cancer, adenocarcinoma of the lung, and squamous carcinoma of the lung), cancer of
the peritoneum, hepatocellular cancer, c or stomach cancer (including gastrointestinal
cancer), pancreatic cancer (including metastic pancreatic cancer), glioblastoma, cervical cancer,
ovarian cancer, liver , bladder cancer, hepatoma, breast cancer (including locally advanced,
recurrent or atic HER-2 ve breast cancer), colon cancer, colorectal cancer,
endometrial or uterine oma, salivary gland carcinoma, kidney or renal cancer, liver cancer,
prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma and various types of head and
neck cancer, as well as B-cell lymphoma (including low follicular non-Hodgkin's
lymphoma (NHL); small lymphocytic (SL) NHL; ediate follicular NHL;
intermediate grade diffuse NHL; high grade immunoblastic NHL; high grade lymphoblastic
NHL; high grade small non-cleaved cell NHL; bulky disease NHL; mantle cell lymphoma;
AIDS-related lymphoma; and Waldenstrom's Macroglobulinemia); chronic lymphocytic
leukemia (CLL); acute lymphoblastic leukemia (ALL); Hairy cell leukemia; chronic
myeloblastic leukemia; and post-transplant lymphoproliferative er (PTLD), as well as
abnormal vascular proliferation associated with phakomatoses, edema (such as that associated
with brain tumors), and Meigs' syndrome.
The term "chemotherapeutic agent" or "chemotherapy regimen" includes any active agent that
can provide an anticancer eutic effect and may be a chemical agent or a biological agent,
in particular, that are capable of interfering with cancer or tumor cells. Particular active agents
are those that act as eoplastic (chemotoxic or chemostatic) agents which inhibit or t
the development, maturation or proliferation of malignant cells. Examples of chemotherapeutic
agents include alkylating agents such as nitrogen mustards (e.g., mechlorethamine,
cyclophosphamide, ifosfamide, melphalan and chlorambucil), nitrosoureas (e.g., carmustine
, lomustine (CCNU), and semustine (methyl-CCNU)), ethylenimines/ methylmelamines
(e.g., thriethylenemelamine (TEM), ylene, thiophosphoramide (thiotepa),
hexamethylmelamine (HMM, altretamine)), alkyl sulfonates (e.g., busulfan), and triazines (e.g.,
dacarbazine (DTIC)); antimetabolites such as folic acid analogs (e.g., rexate, trimetrexate),
pyrimidine analogs (e.g., 5-fluorouracil, capecitabine, fluorodeoxyuridine, gemcitabine, cytosine
arabinoside (AraC, cytarabine), 5-azacytidine, 2,2′-difluorodeoxycytidine), and purine analogs
(e.g., 6-mercaptopurine, 6-thioguanine, azathioprine, 2′-deoxycoformycin (pentostatin),
erythrohydroxynonyladenine (EHNA), fludarabine phosphate, and 2-chlorodeoxyadenosine
(cladribine, 2-CdA)); antimitotic drugs developed from natural products (e.g., paclitaxel, vinca
alkaloids (e.g., vinblastine (VLB), vincristine, and vinorelbine), docetaxel, estramustine, and
estramustine phosphate), epipodophylotoxins (.e.g., etoposide, teniposide), antibiotics (.e.g,
actimomycin D, daunomycin omycin), daunorubicon, bicin, epirubicin,
ntrone, icin, bleomycins, plicamycin (mithramycin), mitomycinC, actinomycin),
enzymes (e.g., L-asparaginase), and biological response modifiers (e.g., interferon-alpha, IL-2,
G-CSF, GM-CSF); miscellaneous agents including platinum coordination complexes (e.g.,
cisplatin, carboplatin, oxaliplatin), cenediones (e.g., mitoxantrone), substituted urea (i.e.,
hydroxyurea), methylhydrazine derivatives (e.g., N-methylhydrazine (MIH), procarbazine),
adrenocortical suppressants (e.g., mitotane (o,p′-DDD), aminoglutethimide); hormones and
antagonists including adrenocorticosteroid antagonists (.e.g, prednisone and equivalents,
dexamethasone, aminoglutethimide), progestins (e.g., hydroxyprogesterone caproate,
medroxyprogesterone acetate, megestrol acetate), estrogens (e.g., diethylstilbestrol, ethinyl
estradiol and equivalents thereof); antiestrogens (e.g., tamoxifen), androgens (e.g., testosterone
propionate, fluoxymesterone and equivalents thereof), antiandrogens (e.g., flutamide,
gonadotropin-releasing hormone analogs, leuprolide), non-steroidal antiandrogens (e.g.,
flutamide), epidermal growth factor inhibitors (e.g., erlotinib, lapatinib, gefitinib) antibodies (e.g.,
trastuzumab), irinotecan and other agents such as leucovorin. For the treatment of metastatic
pancreatic cancer, chemotherapeutic agents for administration with bevacizumab include
gemcitabine and nib and combinations thereof (see also the examples herein ed). For
the treatment of renal cell cancer, herapeutic agents for administration with zumab
include eron alpha (see also the examples herein provided).
The term e” refers to a tide sequence variant of a gene of interest.
The term “genotype” refers to a ption of the alleles of a gene contained in an individual or
a sample. In the context of this invention, no distinction is made between the genotype of an
individual and the genotype of a sample originating from the individual. Although typically a
genotype is determined from samples of diploid cells, a genotype can be determined from a
sample of haploid cells, such as a sperm cell.
The terms nucleotide" and "polynucleotide" are used interchangeably and refer to a
molecule comprised of two or more deoxyribonucleotides or ribonucleotides, preferably more
than three. Its exact size will depend on many factors, which in turn depend on the ultimate
function or use of the oligonucleotide. An oligonucleotide can be derived synthetically or by
cloning. Chimeras of deoxyribonucleotides and ribonucleotides may also be in the scope of the
present invention.
The term orphism” refers to the occurrence of two or more genetically determined
alternative ces of a gene in a population. Typically, the first identified c form is
arily designated as the reference form and other allelic forms are designated as alternative
or variant alleles. The allelic form occurring most frequently in a selected population is
sometimes referred to as the wildtype form.
The term a “single nucleotide polymorphism” or “SNP” is a site of one nucleotide that varies
between alleles. Single nucleotide rphisms may occur at any region of the gene. In some
instances the polymorphism can result in a change in protein sequence. The change in protein
sequence may affect protein function or not.
The term "patient" refers to any single animal, more specifically a mammal (including such non-
human s as, for example, dogs, cats, , rabbits, zoo animals, cows, pigs, sheep, and
non-human primates) for which treatment is desired. Even more specifically, the patient herein is
a human. In the context of the present invention, the patient may be a white subject.
The term “subject” herein is any single human subject, including a patient, eligible for treatment
who is experiencing or has experienced one or more signs, symptoms, or other indicators of an
angiogenic er. Intended to be included as a t are any subjects ed in clinical
research trials not showing any clinical sign of disease, or subjects involved in epidemiological
studies, or subjects once used as controls. The subject may have been previously treated with an
anti-cancer agent, or not so treated. The subject may be naïve to an additional agent(s) being
used when the treatment herein is d, i.e., the subject may not have been previously treated
with, for example, an anti-neoplastic agent, a chemotherapeutic agent, a growth inhibitory agent,
a cytotoxic agent at “baseline” (i.e., at a set point in time before the administration of a first dose
of an anti-cancer in the treatment method herein, such as the day of screening the subject before
treatment is commenced). Such "naïve" subjects are generally considered to be ates for
treatment with such onal agent(s).
The term "a patient suffering from" refers to a patient showing al signs in respect to a
certain malignant disease, such as cancer, a disease ing physiological and pathological
angiogenesis and/or tumorous disease.
As used herein, “therapy” or “treatment” refers to clinical ention in an attempt to alter the
natural course of the individual or cell being treated, and can be med either for prophylaxis
or during the course of clinical pathology. Desirable effects of treatment e preventing
occurrence or recurrence of disease, alleviation of symptoms, diminishment of any direct or
ct pathological consequences of the disease, preventing asis, decreasing the rate of
disease ssion, amelioration or palliation of the e state, and remission or improved
prognosis.
The term "treatment effect" encompasses the terms "overall survival" and "progression-free
survival".
The term "overall al" refers to the length of time during and after treatment the patient
survives. As the skilled person will appreciate, a patient's overall survival is ed or
enhanced, if the patient belongs to a subgroup of patients that has a statistically significant longer
mean survival time as compared to another subgroup of patients.
The term "progression-free al" refers to the length of time during and after treatment
during which, according to the assessment of the treating physician or igator, the patient's
disease does not become worse, i.e., does not progress. As the skilled person will appreciate, a
patient's progression-free survival is improved or ed if the patient belongs to a subgroup
of patients that has a longer length of time during which the disease does not progress as
compared to the average or mean progression free survival time of a control group of similarly
situated patients.
The term "pharmaceutical composition" refers to a sterile preparation that is in such form as to
permit the biological activity of the medicament to be effective, and which contains no additional
components that are unacceptably toxic to a subject to which the formulation would be
administered.
2. Detailed Embodiments
In the present invention, variations in the VEGF promoter and/or VEGFR2 genes were
singly identified as markers/predictors for overall survival and/or progression-free survival
to treatment with an angiogenesis inhibitor. The terms "marker" and ctor" can be used
interchangeably and refer to specific allele variants of genes. The variation or marker may also
be referred to as a single nucleotide polymorphism (SNP).
In accordance with the methods of the present invention, a nalysis of SNPs was conducted
using the samples derived from five Phase II and Phase III trials with bevacizumab, i.e.
NO16966 (advanced primary colorectal cancer, see, Saltz et al., 2008, J. Clin. Oncol. 26:2013-
2019 and Hurwitz et al., 2004, N. Engl. J. Med. 350:2335-2342), AVITA (pancreatic cancer, see,
Van Cutsem, J. Clin. Oncol. 2009 27:2231-2237), AVAiL (non-small cell lung , see, Reck
et al., J. Clin. Oncol. 2009 27:1227), AVOREN (renal , see, Escudier et al., Lancet 2007
370:2103) and AVADO (breast cancer, see, Miles, J. Clin. Oncol. 2010 28:3239).
As shown in the examples, the rs699946 (SEQ ID NO. 1) SNP, located in the VEGFA promoter,
was associated with improved progression-free al (PFS) in bevacizumab-treated ts.
Relative to AA carriers, HR for rs699946 (SEQ ID NO. 1) AG carriers was 1.26 (95% CI 1.07–
1.48, p=0.005). This means that each additional G allele was associated with 26% increase in
risk of progression or death. No effect was seen in placebo subjects, suggesting that rs699946
(SEQ ID NO. 1) may be a predictive marker for favourable outcome with bevacizumab treatment.
Further, as shown in the examples, the rs12505758 (SEQ ID NO. 2) SNP in VEGFR2 was
ated with improved overall al (OS) in zumab-treated patients. Relative to TT
carriers, HR for rs12505758 (SEQ ID NO. 2) TC carrier was 1.50, 95% CI 1.21–1.86
( p=0.0002). This means that each additional C allele was ated with 50% increase in risk of
death. No effects for rs12505758 (SEQ ID NO. 2) were seen in placebo patients.
Further, as shown in the examples, the rs11133360 (SEQ ID NO. 5) SNP, located in the
VEGFR2, was associated with improved PFS in bevacizumab-treated subjects. Relative to TT
carriers, HR for rs11133360 (SEQ ID NO. 5) CT carriers was 1.15 (95% CI 1.02–1.30, p=0.02).
This means that each additional C allele was associated with 15% increase in risk of progression
or death.
Accordingly, described herein is an in vitro method of determining r a patient is suitably
treated by a therapy with an angiogenesis inhibitor comprising bevacizumab or an antibody that
binds essentially the same epitope on VEGF as bevacizumab, said method comprising:
(a) determining in a sample derived from a t suffering from cancer the genotype at
polymorphism rs699946 (SEQ ID NO. 1), and
(b) identifying a patient as more or less suitably treated by a therapy with an angiogenesis
inhibitor comprising bevacizumab or an antibody that binds essentially the same e on
VEGF as bevacizumab based on said genotype, wherein the presence of each A allele at
polymorphism rs699946 (SEQ ID NO. 1) indicates an increased likelihood that said patient is
more suitably treated, or the presence of each G allele at polymorphism rs699946 (SEQ ID NO.
1) indicates an increased likelihood that said patient is less suitably treated. In an embodiment,
whether a patient is suitably treated by a therapy with an angiogenesis inhibitor is determined in
terms of progression-free al. In an embodiment, cancer is selected from the group
consisting of colorectal cancer, glioblastoma, renal cancer, ovarian cancer, breast cancer,
pancreatic cancer, gastric cancer and lung cancer, more specifically colorectal , renal
cancer, breast cancer, pancreatic cancer and lung , even more specifically colorectal
cancer, breast cancer, pancreatic cancer and lung cancer.
More specifically, described herein is an in vitro method of determining whether a patient is
suitably treated by a therapy with an angiogenesis tor comprising bevacizumab or an
antibody that binds essentially the same epitope on VEGF as zumab, said method
comprising:
(a) determining in a sample derived from a patient suffering from cancer the genotype at
polymorphism rs699946 (SEQ ID NO. 1), and
(b) identifying a patient as more or less suitably treated by a therapy with an angiogenesis
inhibitor comprising bevacizumab or an antibody that binds essentially the same epitope on
VEGF as bevacizumab based on said genotype, wherein the presence of AA or AG genotype at
polymorphism rs699946 (SEQ ID NO. 1) indicates that said t is more suitably treated than
a patient having a genotype of GG at polymorphism rs699946 (SEQ ID NO. 1), or the presence
of GG genotype at polymorphism rs699946 (SEQ ID NO. 1) indicates that said patient is less
suitably treated than a patient having a genotype of AA or AG at rphism rs699946 (SEQ
ID NO. 1), or
(b’) identifying a t as more suitably treated by a therapy with an angiogenesis
inhibitor sing zumab or an antibody that binds essentially the same epitope on
VEGF as bevacizumab based on said genotype, wherein the ce of AA genotype at
polymorphism rs699946 (SEQ ID NO. 1) indicates that said patient is more suitably treated than
a patient having a pe of AG or GG at polymorphism rs699946 (SEQ ID NO. 1), or the
presence of AG or GG genotype at rphism rs699946 (SEQ ID NO. 1) indicates that said
patient is less suitably treated than a patient having a genotype of AA at polymorphism rs699946
(SEQ ID NO. 1). In an embodiment, whether a patient is suitably d by a therapy with an
angiogenesis tor is determined in terms of ssion-free survival. In an embodiment,
cancer is selected from the group consisting of colorectal , glioblastoma, renal cancer,
ovarian cancer, breast cancer, pancreatic , gastric cancer and lung cancer, more
specifically colorectal cancer, renal cancer, breast cancer, pancreatic cancer and lung cancer,
even more specifically colorectal cancer, breast cancer, pancreatic cancer and lung .
Also described herein is a ceutical ition comprising an angiogenesis inhibitor that
comprises bevacizumab or an antibody that binds essentially the same epitope on VEGF as
bevacizumab, for the treatment of a patient in need thereof, wherein said patient has been
determined to be more suitable treated with the angiogenesis inhibitor by an in vitro method
comprising:
(a) determining in a sample derived from a patient suffering from cancer the genotype at
polymorphism rs699946 (SEQ ID NO. 1), and
(b) identifying a patient as more or less suitably treated by a therapy with an angiogenesis
tor comprising bevacizumab or an antibody that binds essentially the same epitope on
VEGF as bevacizumab based on said pe, wherein the presence of each A allele at
polymorphism rs699946 (SEQ ID NO. 1) indicates an increased likelihood that said patient is
more suitably treated, or the presence of each G allele at polymorphism rs699946 (SEQ ID NO.
1) indicates an increased likelihood that said patient is less suitably treated. In an embodiment,
r a t is suitably treated by a therapy with an angiogenesis inhibitor is determined in
terms of progression-free survival. In an embodiment, cancer is selected from the group
consisting of ctal cancer, glioblastoma, renal cancer, ovarian cancer, breast cancer,
pancreatic cancer, gastric cancer and lung cancer, more specifically colorectal cancer, renal
cancer, breast cancer, pancreatic cancer and lung cancer, even more specifically colorectal
cancer, breast cancer, pancreatic cancer and lung cancer.
Also described herein is a pharmaceutical composition comprising an angiogenesis inhibitor that
comprises bevacizumab or an antibody that binds essentially the same epitope on VEGF as
bevacizumab, for the treatment of a t in need thereof, wherein said patient has been
determined to be more suitable treated with the enesis inhibitor by an in vitro method
comprising:
(a) determining in a sample derived from a patient suffering from cancer the genotype at
polymorphism rs699946 (SEQ ID NO. 1), and
(b) fying a patient as more or less suitably treated by a therapy with an angiogenesis
tor comprising bevacizumab or an antibody that binds essentially the same epitope on
VEGF as bevacizumab based on said genotype, wherein the presence of AA or AG genotype at
polymorphism rs699946 (SEQ ID NO. 1) indicates that said patient is more suitably treated than
a patient having a genotype of GG at polymorphism rs699946 (SEQ ID NO. 1), or the presence
of GG genotype at polymorphism rs699946 (SEQ ID NO. 1) indicates that said t is less
suitably treated than a patient having a genotype of AA or AG at polymorphism rs699946 (SEQ
ID NO. 1), or
(b’) identifying a patient as more suitably treated by a therapy with an angiogenesis
inhibitor comprising bevacizumab or an antibody that binds essentially the same epitope on
VEGF as zumab based on said genotype, wherein the presence of AA genotype at
polymorphism rs699946 (SEQ ID NO. 1) indicates that said patient is more suitably treated than
a patient having a genotype of AG or GG at polymorphism rs699946 (SEQ ID NO. 1), or the
ce of AG or GG pe at polymorphism 46 (SEQ ID NO. 1) indicates that said
patient is less ly treated than a patient having a genotype of AA at polymorphism rs699946
(SEQ ID NO. 1). In an embodiment, whether a patient is ly treated by a therapy with an
angiogenesis inhibitor is determined in terms of progression-free survival. In an embodiment,
cancer is selected from the group consisting of colorectal , glioblastoma, renal cancer,
ovarian cancer, breast cancer, pancreatic cancer, gastric cancer and lung , more
specifically colorectal , renal cancer, breast cancer, pancreatic cancer and lung cancer,
even more specifically ctal cancer, breast cancer, pancreatic cancer and lung cancer.
Also described herein is a method for improving the treatment effect of a chemotherapeutic
agent or chemotherapy n of a patient suffering from cancer by adding an angiogenesis
inhibitor comprising zumab or an antibody that binds essentially the same epitope on
VEGF as bevacizumab, said method sing:
(a) determining in a sample derived from a patient suffering from cancer the genotype at
polymorphism rs699946 (SEQ ID NO. 1);
(b) identifying a patient as more suitably treated by the addition of an angiogenesis
inhibitor comprising bevacizumab or an antibody that binds essentially the same epitope on
VEGF as bevacizumab based on said genotype, wherein the presence of each A allele at
polymorphism rs699946 (SEQ ID NO. 1) indicates an increased likelihood that said patient is
more suitably treated; and
(c) administering said angiogenesis inhibitor in combination with a herapeutic
agent or chemotherapy regimen to a patient identified as more suitably treated in accordance
with (b). In an ment, the treatment effect is determined in terms of progression-free
survival. In an embodiment, cancer is selected from the group consisting of colorectal cancer,
glioblastoma, renal cancer, ovarian cancer, breast , pancreatic cancer, gastric cancer and
lung cancer, more specifically colorectal cancer, renal cancer, breast cancer, pancreatic cancer
and lung cancer, even more specifically colorectal cancer, breast cancer, pancreatic cancer and
lung cancer.
Also described herein is a method for improving the treatment effect of a chemotherapeutic
agent or chemotherapy regimen of a patient ing from cancer by adding an angiogenesis
inhibitor comprising bevacizumab or an antibody that binds essentially the same epitope on
VEGF as bevacizumab, said method comprising:
(a) determining in a sample derived from a patient suffering from cancer the genotype at
rphism rs699946 (SEQ ID NO. 1);
(b) fying a patient as more or less suitably treated by a therapy with an angiogenesis
inhibitor comprising zumab or an antibody that binds essentially the same e on
VEGF as bevacizumab based on said genotype, wherein the presence of AA or AG genotype at
polymorphism rs699946 (SEQ ID NO. 1) indicates that said patient is more ly treated than
a patient having a genotype of GG at polymorphism rs699946 (SEQ ID NO. 1), or the presence
of GG genotype at polymorphism rs699946 (SEQ ID NO. 1) indicates that said patient is less
suitably treated than a patient having a genotype of AA or AG at polymorphism rs699946 (SEQ
ID NO. 1), or
(b’) identifying a t as more suitably treated by a therapy with an angiogenesis
inhibitor comprising bevacizumab or an antibody that binds essentially the same e on
VEGF as bevacizumab based on said genotype, n the presence of AA pe at
polymorphism rs699946 (SEQ ID NO. 1) indicates that said patient is more suitably treated than
a patient having a genotype of AG or GG at polymorphism 46 (SEQ ID NO. 1), or the
presence of AG or GG genotype at polymorphism rs699946 (SEQ ID NO. 1) indicates that said
patient is less suitably d than a patient having a genotype of AA at polymorphism rs699946
(SEQ ID NO. 1); and
(c) administering said angiogenesis inhibitor in combination with a chemotherapeutic
agent or herapy regimen to a patient identified as more suitably treated in accordance
with (b) or (b’). In an embodiment, the treatment effect is determined in terms of progressionfree
survival. In an embodiment, cancer is selected from the group consisting of colorectal
cancer, glioblastoma, renal cancer, n cancer, breast cancer, pancreatic cancer, gastric
cancer and lung cancer, more specifically colorectal cancer, renal cancer, breast ,
pancreatic cancer and lung cancer, even more specifically ctal cancer, breast cancer,
pancreatic cancer and lung cancer.
The present invention also provides an in vitro method of determining whether a t is
suitably treated by a y with an enesis inhibitor comprising bevacizumab or an
antibody that binds essentially the same epitope on VEGF as bevacizumab, said method
comprising:
(a) determining in a sample derived from a patient suffering from cancer the genotype at
polymorphism rs12505758 (SEQ ID NO. 2), and
(b) identifying a patient as more or less suitably treated by a therapy with an angiogenesis
tor comprising bevacizumab or an antibody that binds essentially the same epitope on
VEGF as bevacizumab based on said pe, wherein the presence of each T allele at
polymorphism rs12505758 (SEQ ID NO. 2) indicates an sed likelihood that said patient is
more suitably treated, or the presence of each C allele at polymorphism rs12505758 (SEQ ID
NO. 2) indicates an increased likelihood that said patient is less suitably treated. In an
embodiment, whether a patient is suitably treated by a therapy with an angiogenesis inhibitor is
determined in terms of overall survival. In an ment, cancer is ed from the group
ting of colorectal cancer, glioblastoma, renal cancer, ovarian cancer, breast cancer,
pancreatic cancer, gastric cancer and lung cancer, more specifically colorectal cancer, renal
cancer, breast cancer, pancreatic cancer and lung cancer, even more specifically colorectal
cancer and renal cancer.
More specifically, the present invention provides an in vitro method of determining whether a
t is suitably treated by a therapy with an angiogenesis inhibitor comprising bevacizumab or
an antibody that binds essentially the same epitope on VEGF as bevacizumab, said method
comprising:
(a) determining in a sample derived from a patient suffering from cancer the genotype at
rphism rs12505758 (SEQ ID NO. 2), and
(b) identifying a patient as more or less suitably treated by a therapy with an angiogenesis
inhibitor comprising bevacizumab or an antibody that binds essentially the same epitope on
VEGF as bevacizumab based on said genotype, wherein the presence of TT or TC genotype at
polymorphism rs12505758 (SEQ ID NO. 2) indicates that said t is more suitably treated
than a patient having a genotype of CC at polymorphism rs12505758 (SEQ ID NO. 2), or the
presence of CC genotype at polymorphism 5758 (SEQ ID NO. 2) indicates that said
patient is less suitably d than a patient having a genotype of TT or TC at polymorphism
rs12505758 (SEQ ID NO. 2), or
(b’) identifying a patient as more or less suitably treated by a therapy with an
enesis tor comprising bevacizumab or an dy that binds essentially the same
epitope on VEGF as bevacizumab based on said genotype, wherein the presence of TT genotype
at polymorphism rs12505758 (SEQ ID NO. 2) indicates that said t is more suitably d
than a patient having a genotype of TC or CC at polymorphism rs12505758 (SEQ ID NO. 2), or
the presence of TC or CC genotype at polymorphism rs12505758 (SEQ ID NO. 2) indicates that
said patient is less suitably treated than a patient having a genotype of TT at polymorphism
rs12505758 (SEQ ID NO. 2). In an embodiment, whether a patient is suitably treated by a
therapy with an angiogenesis tor is determined in terms of overall survival. In an
embodiment, cancer is selected from the group consisting of colorectal cancer, glioblastoma,
renal cancer, ovarian cancer, breast cancer, atic cancer, gastric cancer and lung cancer,
more specifically colorectal cancer, renal cancer, breast cancer, pancreatic cancer and lung
cancer, even more specifically colorectal cancer and renal cancer.
The present invention further provides the use of an angiogenesis inhibitor that comprises
zumab or an antibody that binds essentially the same epitope on VEGF as bevacizumab,
for the manufacture of a medicament for the treatment of cancer in a patient in need f,
wherein said patient has been determined to be more suitably treated with the angiogenesis
inhibitor by an in vitro method comprising:
(a) determining in a sample derived from a patient suffering from cancer the genotype at
polymorphism 5758 (SEQ ID NO. 2), and
(b) identifying a patient as more or less suitably treated by a therapy with an enesis
inhibitor sing bevacizumab or an antibody that binds essentially the same epitope on
VEGF as bevacizumab based on said genotype, wherein the presence of each T allele at
polymorphism rs12505758 (SEQ ID NO. 2) indicates an increased likelihood that said patient is
more suitably treated, or the presence of each C allele at polymorphism rs12505758 (SEQ ID
NO. 2) tes an increased likelihood that said patient is less suitably treated. In an
embodiment, whether a patient is ly treated by a therapy with an angiogenesis inhibitor is
determined in terms of l survival. In an embodiment, cancer is selected from the group
ting of ctal cancer, glioblastoma, renal cancer, ovarian cancer, breast cancer,
pancreatic cancer, gastric cancer and lung cancer, more specifically colorectal cancer, renal
cancer, breast cancer, pancreatic cancer and lung cancer, even more specifically colorectal
cancer and renal cancer.
More specifically, the t invention provides the use of an angiogenesis inhibitor that
comprises bevacizumab or an antibody that binds essentially the same epitope on VEGF as
zumab, for the manufacture of a medicament for the treatment of cancer in a patient in
need thereof, wherein said patient has been determined to be more suitably treated with the
angiogenesis inhibitor by an in vitro method comprising:
(a) ining in a sample derived from a patient suffering from cancer the genotype at
rphism rs12505758 (SEQ ID NO. 2), and
(b) identifying a patient as more or less suitably treated by a therapy with an angiogenesis
inhibitor comprising bevacizumab or an antibody that binds ially the same epitope on
VEGF as bevacizumab based on said genotype, wherein the presence of TT or TC genotype at
polymorphism rs12505758 (SEQ ID NO. 2) indicates that said patient is more suitably d
than a patient having a genotype of CC at polymorphism rs12505758 (SEQ ID NO. 2), or the
presence of CC genotype at polymorphism rs12505758 (SEQ ID NO. 2) indicates that said
patient is less suitably treated than a patient having a genotype of TT or TC at polymorphism
rs12505758 (SEQ ID NO. 2), or
(b’) fying a patient as more or less suitably treated by a therapy with an
angiogenesis inhibitor comprising bevacizumab or an antibody that binds essentially the same
epitope on VEGF as zumab based on said genotype, wherein the presence of TT genotype
at polymorphism rs12505758 (SEQ ID NO. 2) indicates that said patient is more suitably d
than a patient having a genotype of TC or CC at rphism rs12505758 (SEQ ID NO. 2), or
the presence of TC or CC genotype at polymorphism rs12505758 (SEQ ID NO. 2) indicates that
said patient is less suitably treated than a patient having a pe of TT at polymorphism
rs12505758 (SEQ ID NO. 2). In an embodiment, whether a patient is suitably treated by a
therapy with an angiogenesis inhibitor is determined in terms of overall survival. In an
embodiment, cancer is selected from the group consisting of ctal cancer, glioblastoma,
renal cancer, ovarian cancer, breast cancer, atic cancer, gastric cancer and lung cancer,
more specifically colorectal cancer, renal cancer, breast cancer, pancreatic cancer and lung
cancer, even more specifically colorectal cancer and renal cancer.
Also described herein is a method for improving the treatment effect of a chemotherapeutic
agent or chemotherapy regimen of a patient suffering from cancer by adding an angiogenesis
inhibitor comprising bevacizumab or an antibody that binds ially the same epitope on
VEGF as zumab, said method comprising:
(a) determining in a sample derived from a t suffering from cancer the genotype at
polymorphism rs12505758 (SEQ ID NO. 2);
(b) identifying a patient as more suitably treated by the addition of an angiogenesis
inhibitor sing bevacizumab or an antibody that binds essentially the same epitope on
VEGF as bevacizumab based on said genotype, n the presence of each T allele genotype
at polymorphism rs12505758 (SEQ ID NO. 2) indicates an increased likelihood that said patient
is more suitably treated; and
(c) administering said angiogenesis inhibitor in combination with a chemotherapeutic
agent or chemotherapy regimen to a patient identified as more suitably d in accordance
with (b). In an embodiment, the treatment effect is determined in terms of l survival. In an
embodiment, cancer is selected from the group consisting of colorectal cancer, glioblastoma,
renal cancer, ovarian cancer, breast cancer, pancreatic cancer, gastric cancer and lung cancer,
more specifically colorectal , renal cancer, breast , pancreatic cancer and lung
cancer, even more ically colorectal cancer and renal cancer.
More specifically, described herein is a method for ing the treatment effect of a
chemotherapeutic agent or herapy regimen of a patient suffering from cancer by adding
an angiogenesis inhibitor comprising bevacizumab or an antibody that binds essentially the same
epitope on VEGF as bevacizumab, said method comprising:
(a) determining in a sample derived from a patient suffering from cancer the genotype at
rphism rs12505758 (SEQ ID NO. 2);
(b) identifying a t as more or less suitably treated by a therapy with an angiogenesis
tor sing bevacizumab or an antibody that binds essentially the same epitope on
VEGF as bevacizumab based on said genotype, wherein the presence of TT or TC genotype at
polymorphism rs12505758 (SEQ ID NO. 2) indicates that said patient is more suitably treated
than a patient having a genotype of CC at polymorphism rs12505758 (SEQ ID NO. 2), or the
presence of CC genotype at polymorphism rs12505758 (SEQ ID NO. 2) indicates that said
patient is less suitably treated than a patient having a genotype of TT or TC at polymorphism
rs12505758 (SEQ ID NO. 2), or
(b’) identifying a patient as more or less suitably treated by a therapy with an
angiogenesis inhibitor comprising bevacizumab or an dy that binds essentially the same
epitope on VEGF as zumab based on said genotype, wherein the presence of TT genotype
at polymorphism rs12505758 (SEQ ID NO. 2) indicates that said patient is more suitably treated
than a t having a genotype of TC or CC at polymorphism rs12505758 (SEQ ID NO. 2), or
the presence of TC or CC genotype at polymorphism rs12505758 (SEQ ID NO. 2) indicates that
said patient is less suitably treated than a patient having a genotype of TT at polymorphism
rs12505758 (SEQ ID NO. 2); and
(c) administering said angiogenesis inhibitor in combination with a chemotherapeutic
agent or chemotherapy regimen to a patient identified as more suitably d in accordance
with (b) or (b’). In an embodiment, the treatment effect is ined in terms of overall al.
In an ment, cancer is selected from the group consisting of colorectal cancer,
glioblastoma, renal cancer, ovarian cancer, breast , pancreatic cancer, gastric cancer and
lung cancer, more specifically colorectal cancer, renal cancer, breast cancer, pancreatic cancer
and lung cancer, even more specifically colorectal cancer and renal cancer.
Also bed herein is an in vitro method of determining whether a patient is ly treated
by a therapy with an angiogenesis inhibitor comprising bevacizumab or an antibody that binds
essentially the same epitope on VEGF as bevacizumab, said method comprising:
(a) determining in a sample derived from a patient suffering from cancer the pe at
polymorphism rs11133360 (SEQ ID NO. 5), and
(b) identifying a patient as more or less suitably treated by a therapy with an angiogenesis
inhibitor comprising bevacizumab or an antibody that binds essentially the same epitope on
VEGF as bevacizumab based on said genotype, wherein the presence of each T allele at
polymorphism rs11133360 (SEQ ID NO. 5) indicates an increased likelihood that said patient is
more suitably treated, or the presence of each C allele at polymorphism rs11133360 (SEQ ID
NO. 5) indicates an increased hood that said patient is less suitably treated. In an
ment, r a patient is suitably treated by a therapy with an angiogenesis inhibitor is
determined in terms of progression-free survival. In an embodiment, cancer is selected from the
group consisting of colorectal cancer, glioblastoma, renal cancer, ovarian cancer, breast cancer,
pancreatic cancer, gastric cancer and lung cancer, more specifically colorectal cancer, renal
cancer, breast cancer, pancreatic cancer and lung cancer.
More specifically, described herein is an in vitro method of determining whether a patient is
suitably treated by a therapy with an angiogenesis inhibitor comprising bevacizumab or an
antibody that binds essentially the same epitope on VEGF as bevacizumab, said method
comprising:
(a) determining in a sample derived from a patient suffering from cancer the genotype at
polymorphism rs11133360 (SEQ ID NO. 5), and
(b) identifying a patient as more or less suitably treated by a therapy with an angiogenesis
tor comprising bevacizumab or an antibody that binds essentially the same epitope on
VEGF as bevacizumab based on said genotype, wherein the ce of TT or CT genotype at
polymorphism rs11133360 (SEQ ID NO. 5) indicates that said t is more suitably treated
than a patient having a genotype of CC at rphism rs11133360 (SEQ ID NO. 5), or the
presence of CC genotype at polymorphism rs11133360 (SEQ ID NO. 5) indicates that said
patient is less suitably d than a t having a genotype of TT or CT at polymorphism
rs11133360 (SEQ ID NO. 5), or
(b’) identifying a patient as more suitably treated by a therapy with an angiogenesis
inhibitor comprising bevacizumab or an antibody that binds essentially the same epitope on
VEGF as bevacizumab based on said pe, wherein the presence of TT genotype at
polymorphism rs11133360 (SEQ ID NO. 5) indicates that said patient is more suitably treated
than a patient having a genotype of CT or CC at polymorphism rs11133360 (SEQ ID NO. 5), or
the presence of CT or CC genotype at polymorphism rs11133360 (SEQ ID NO. 5) indicates that
said patient is less suitably treated than a patient having a genotype of TT at polymorphism
rs11133360 (SEQ ID NO. 5). In an embodiment, whether a t is suitably treated by a
therapy with an enesis inhibitor is determined in terms of progression-free survival. In an
embodiment, cancer is selected from the group ting of colorectal cancer, astoma,
renal , ovarian cancer, breast cancer, pancreatic cancer, gastric cancer and lung cancer,
more specifically colorectal cancer, renal cancer, breast cancer, pancreatic cancer and lung
cancer.
Also bed herein is a pharmaceutical composition comprising an angiogenesis inhibitor that
comprises bevacizumab or an antibody that binds essentially the same epitope on VEGF as
bevacizumab, for the treatment of a patient in need thereof, wherein said patient has been
determined to be more suitable treated with the angiogenesis inhibitor by an in vitro method
comprising:
(a) determining in a sample derived from a patient suffering from cancer the pe at
polymorphism rs11133360 (SEQ ID NO. 5), and
(b) identifying a t as more or less suitably treated by a therapy with an angiogenesis
inhibitor comprising bevacizumab or an antibody that binds essentially the same epitope on
VEGF as bevacizumab based on said genotype, wherein the presence of each T allele at
polymorphism rs11133360 (SEQ ID NO. 5) indicates an increased likelihood that said patient is
more ly d, or the ce of each C allele at polymorphism rs11133360 (SEQ ID
NO. 5) indicates an increased likelihood that said patient is less suitably treated. In an
embodiment, whether a patient is suitably d by a therapy with an angiogenesis inhibitor is
determined in terms of progression-free survival. In an embodiment, cancer is selected from the
group consisting of colorectal cancer, glioblastoma, renal cancer, ovarian cancer, breast cancer,
pancreatic cancer, gastric cancer and lung cancer, more specifically colorectal , renal
cancer, breast , pancreatic cancer and lung cancer.
Also described herein is a pharmaceutical composition comprising an angiogenesis inhibitor that
comprises bevacizumab or an antibody that binds essentially the same epitope on VEGF as
bevacizumab, for the treatment of a patient in need f, wherein said patient has been
determined to be more suitable treated with the angiogenesis inhibitor by an in vitro method
comprising:
(a) determining in a sample d from a patient suffering from cancer the pe at
polymorphism rs11133360 (SEQ ID NO. 5), and
(b) fying a t as more or less suitably treated by a therapy with an angiogenesis
inhibitor comprising bevacizumab or an antibody that binds essentially the same epitope on
VEGF as bevacizumab based on said genotype, wherein the presence of TT or CT genotype at
polymorphism rs11133360 (SEQ ID NO. 5) indicates that said patient is more suitably treated
than a patient having a genotype of CC at polymorphism 3360 (SEQ ID NO. 5), or the
presence of CC genotype at polymorphism rs11133360 (SEQ ID NO. 5) indicates that said
t is less suitably treated than a patient having a genotype of TT or CT at polymorphism
rs11133360 (SEQ ID NO. 5), or
(b’) identifying a patient as more suitably treated by a therapy with an angiogenesis
inhibitor comprising bevacizumab or an antibody that binds essentially the same epitope on
VEGF as bevacizumab based on said genotype, wherein the presence of TT genotype at
polymorphism rs11133360 (SEQ ID NO. 5) indicates that said patient is more suitably treated
than a patient having a genotype of CT or CC at polymorphism rs11133360 (SEQ ID NO. 5), or
the presence of CT or CC genotype at polymorphism rs11133360 (SEQ ID NO. 5) indicates that
said patient is less suitably treated than a patient having a genotype of TT at polymorphism
rs11133360 (SEQ ID NO. 5). In an embodiment, whether a patient is suitably treated by a
therapy with an angiogenesis inhibitor is determined in terms of progression-free al. In an
embodiment, cancer is selected from the group ting of colorectal cancer, glioblastoma,
renal cancer, n cancer, breast cancer, pancreatic cancer, gastric cancer and lung cancer,
more specifically ctal cancer, renal , breast cancer, atic cancer and lung
cancer.
The present invention further provides a method for improving the treatment effect of a
chemotherapeutic agent or chemotherapy regimen of a patient suffering from cancer by adding
an angiogenesis inhibitor sing bevacizumab or an antibody that binds essentially the same
epitope on VEGF as bevacizumab, said method sing:
(a) determining in a sample derived from a patient suffering from cancer the genotype at
polymorphism rs11133360 (SEQ ID NO. 5);
(b) identifying a patient as more ly d by the addition of an angiogenesis
tor comprising bevacizumab or an antibody that binds essentially the same epitope on
VEGF as bevacizumab based on said genotype, wherein the presence of each T allele at
polymorphism rs11133360 (SEQ ID NO. 5) indicates an increased likelihood that said patient is
more suitably treated; and
(c) administering said angiogenesis inhibitor in combination with a chemotherapeutic
agent or chemotherapy n to a patient identified as more suitably treated in accordance
with (b). In an embodiment, the treatment effect is determined in terms of ssion-free
survival. In an embodiment, cancer is ed from the group consisting of colorectal cancer,
glioblastoma, renal cancer, ovarian cancer, breast cancer, pancreatic cancer, gastric cancer and
lung cancer, more specifically colorectal cancer, renal cancer, breast cancer, atic cancer
and lung cancer.
Also described herein is a method for improving the treatment effect of a chemotherapeutic
agent or chemotherapy regimen of a patient suffering from cancer by adding an enesis
inhibitor comprising bevacizumab or an antibody that binds essentially the same epitope on
VEGF as bevacizumab, said method sing:
(a) determining in a sample derived from a patient suffering from cancer the genotype at
polymorphism rs11133360 (SEQ ID NO. 5);
(b) identifying a t as more or less suitably treated by a therapy with an angiogenesis
inhibitor comprising bevacizumab or an antibody that binds essentially the same epitope on
VEGF as bevacizumab based on said genotype, wherein the presence of TT or CT genotype at
polymorphism rs11133360 (SEQ ID NO. 5) indicates that said t is more suitably treated
than a patient having a genotype of CC at polymorphism rs11133360 (SEQ ID NO. 5), or the
presence of CC genotype at polymorphism 3360 (SEQ ID NO. 5) indicates that said
patient is less suitably treated than a patient having a genotype of TT or CT at polymorphism
rs11133360 (SEQ ID NO. 5), or
(b’) fying a patient as more suitably treated by a therapy with an angiogenesis
inhibitor comprising bevacizumab or an antibody that binds essentially the same epitope on
VEGF as bevacizumab based on said genotype, wherein the presence of TT genotype at
polymorphism rs11133360 (SEQ ID NO. 5) indicates that said patient is more suitably treated
than a patient having a genotype of CT or CC at polymorphism rs11133360 (SEQ ID NO. 5), or
the presence of CT or CC pe at polymorphism rs11133360 (SEQ ID NO. 5) indicates that
said patient is less ly treated than a t having a genotype of TT at polymorphism
rs11133360 (SEQ ID NO. 5); and
(c) administering said angiogenesis inhibitor in ation with a chemotherapeutic
agent or chemotherapy regimen to a patient identified as more suitably treated in ance
with (b) or (b’). In an embodiment, the treatment effect is determined in terms of progression-
free survival. In an embodiment, cancer is selected from the group consisting of colorectal
cancer, glioblastoma, renal , ovarian , breast cancer, pancreatic cancer, gastric
cancer and lung cancer, more specifically colorectal cancer, renal cancer, breast cancer,
atic cancer and lung cancer.
In an embodiment, the angiogenesis tor is administered as a co-treatment with a
chemotherapeutic agent or chemotherapy regimen. In a further embodiment, the angiogenesis
inhibitor is stered with one or more agents selected from the group consisting of taxanes
such as docetaxel and paclitaxel, interferon alpha, 5-fluorouracil, leucovorin, gemcitabine,
erlotinib and platinum-based chemotherapeutic agents such as carboplatin, cisplatin and
oxaliplatin. Further, the angiogenesis inhibitor may be administered as a atment with
radiotherapy.
In the context of the present invention, the sample is a biological sample and may be a blood
and/or tissue . In an embodiment, the sample is a blood sample, more ically a
peripheral blood sample. In the context of the present invention, the sample is a DNA sample.
The DNA sample may be ne DNA or somatic DNA, more specifically germline DNA.
In one embodiment, the pe is ined by means of MALDI-TOF mass spectrometry.
In addition to the detailed description of the detection of SNPs below, the following reference
provides guidance for MALDI-TOF mass ometry-based SNP genotyping, e.g. Storm et al.,
Methods Mol. Biol. 212:241-62, 2003.
3. Detection of Nucleic Acid Polymorphisms
Detection techniques for evaluating nucleic acids for the presence of a SNP involve procedures
well known in the field of molecular genetics. Many, but not all, of the methods involve
amplification of nucleic acids. Ample guidance for ming amplification is provided in the
art. Exemplary nces include manuals such as PCR Technology: Principles and
Applications for DNA Amplification (ed. H. A. , Freeman Press, NY, N.Y., 1992); PCR
Protocols: A Guide to Methods and Applications (eds. Innis, et al., Academic Press, San Diego,
, 1990); Current Protocols in Molecular Biology, Ausubel, 1994-1999, including
supplemental updates through April 2004; Sambrook & Russell, Molecular Cloning, A
Laboratory Manual (3rd Ed, 2001). General methods for detection of single nucleotide
polymorphisms are disclosed in Single Nucleotide Polymorphisms: Methods and Protocols, Pui-
Yan Kwok, ed., 2003, Humana Press.
Although the methods lly employ PCR steps, other amplification protocols may also be
used. Suitable amplification methods include ligase chain on (see, e.g., Wu & Wallace,
Genomics 4:560-569, 1988); strand displacement assay (see, e.g. Walker et al., Proc. Natl. Acad.
Sci. USA -396, 1992; U.S. Pat. No. 5,455,166); and several transcription-based
amplification systems, including the s described in U.S. Pat. Nos. 5,437,990; 5,409,818;
and 5,399,491; the transcription amplification system (TAS) (Kwoh et al., Proc. Natl. Acad. Sci.
USA 86:1173-1177, 1989); and self-sustained sequence replication (3SR) (Guatelli et al., Proc.
Natl. Acad. Sci. USA 87:1874-1878, 1990; WO 92/08800). Alternatively, methods that amplify
the probe to able levels can be used, such as licase amplification (Kramer & Lizardi,
Nature 339:401-402, 1989; Lomeli et al., Clin. Chem. 35:1826-1831, 1989). A review of known
amplification methods is provided, for example, by Abramson and Myers in Current Opinion in
hnology 4:41-47, 1993.
ion of the genotype, haplotype, SNP, microsatellite or other polymorphism of an
dual can be performed using oligonucleotide primers and/or probes. Oligonucleotides can
be prepared by any suitable method, usually chemical synthesis. ucleotides can be
synthesized using commercially available reagents and instruments. Alternatively, they can be
sed h commercial sources. Methods of synthesizing oligonucleotides are well
known in the art (see, e.g, Narang et al., Meth. Enzymol. 68:90-99, 1979; Brown et al., Meth.
Enzymol. 68:109-151, 1979; Beaucage et al., Tetrahedron Lett. 22:1859-1862, 1981; and the
solid support method of U.S. Pat. No. 4,458,066). In addition, modifications to the abovedescribed
methods of synthesis may be used to desirably impact enzyme behavior with respect to
the synthesized oligonucleotides. For example, incorporation of modified phosphodiester
linkages (e.g., phosphorothioate, methylphosphonates, phosphoamidate, or boranophosphate) or
linkages other than a phosphorous acid tive into an oligonucleotide may be used to prevent
cleavage at a selected site. In addition, the use of 2’-amino modified sugars tends to favor
displacement over digestion of the oligonucleotide when hybridized to a nucleic acid that is also
the te for synthesis of a new nucleic acid strand.
The genotype of an individual can be determined using many detection methods that are well
known in the art. Most assays entail one of several general ols: hybridization using allelespecific
oligonucleotides, primer extension, allele-specific ligation, sequencing, or
electrophoretic separation techniques, e.g., single-stranded conformational polymorphism (SSCP)
and heteroduplex is. Exemplary assays include 5’-nuclease assays, template-directed dyeterminator
incorporation, molecular beacon -specific oligonucleotide assays, single-base
extension , and SNP scoring by real-time pyrophosphate sequences. Analysis of amplified
sequences can be performed using various logies such as microchips, scence
polarization assays, and MALDI-TOF (matrix assisted laser desorption ionization-time of flight)
mass spectrometry. Two methods that can also be used are assays based on invasive cleavage
with Flap nucleases and methodologies employing padlock probes.
ination of the presence or absence of a ular allele is generally med by
analyzing a nucleic acid sample that is obtained from the individual to be analyzed. Often, the
nucleic acid sample comprises genomic DNA. The genomic DNA is typically obtained from
blood samples, but may also be obtained from other cells or tissues.
It is also possible to analyze RNA samples for the presence of polymorphic s. For example,
mRNA can be used to determine the genotype of an dual at one or more polymorphic sites.
In this case, the nucleic acid sample is obtained from cells in which the target nucleic acid is
expressed, e.g., adipocytes. Such an analysis can be performed by first reverse-transcribing the
target RNA using, for example, a viral e transcriptase, and then amplifying the resulting
cDNA; or using a combined high-temperature e-transcription-polymerase chain reaction
(RT-PCR), as described in U.S. Pat. Nos. 5,310,652; 770; 5,561,058; 5,641,864; and
,693,517.
Frequently used methodologies for analysis of nucleic acid samples to detect SNPs are briefly
described. However, any method known in the art can be used in the invention to detect the
presence of single nucleotide substitutions.
a. Allele-Specific Hybridization
This technique, also commonly referred to as allele specific oligonucleotide hybridization (ASO)
(e.g., Stoneking et al., Am. J. Hum. Genet. 48:70-382, 1991; Saiki et al., Nature 324, 163-166,
1986; EP 235,726; and WO 89/11548), relies on distinguishing between two DNA molecules
differing by one base by hybridizing an oligonucleotide probe that is specific for one of the
variants to an amplified product obtained from amplifying the nucleic acid sample. This method
typically employs short oligonucleotides, e.g. 15-20 bases in length. The probes are designed to
entially hybridize to one variant versus another. Principles and guidance for designing such
probe is available in the art, e.g. in the references cited herein. Hybridization conditions should
be iently stringent that there is a significant difference in hybridization intensity between
alleles, and producing an essentially binary response, whereby a probe hybridizes to only one of
the alleles. Some probes are designed to hybridize to a segment of target DNA such that the
polymorphic site aligns with a central position (e.g., in a 15-base oligonucleotide at the 7
position; in a 16-based oligonucleotide at either the 8 or 9 position) of the probe, but this design
is not required.
The amount and/or ce of an allele is ined by measuring the amount of allelespecific
oligonucleotide that is hybridized to the sample. Typically, the oligonucleotide is d
with a label such as a fluorescent label. For example, an allele-specific oligonucleotide is applied
to immobilized oligonucleotides representing SNP sequences. After stringent hybridization and
washing conditions, fluorescence intensity is measured for each SNP oligonucleotide.
In one embodiment, the tide present at the polymorphic site is identified by hybridization
under sequence-specific hybridization conditions with an oligonucleotide probe or primer
exactly complementary to one of the polymorphic alleles in a region encompassing the
polymorphic site. The probe or primer hybridizing sequence and sequence-specific hybridization
conditions are ed such that a single mismatch at the polymorphic site destabilizes the
hybridization duplex sufficiently so that it is effectively not formed. Thus, under sequencespecific
hybridization ions, stable duplexes will form only between the probe or primer
and the exactly complementary allelic sequence. Thus, ucleotides from about 10 to about
35 tides in length, usually from about 15 to about 35 nucleotides in length, which are
y complementary to an allele sequence in a region which encompasses the polymorphic
site are within the scope of the invention.
In an alternative embodiment, the nucleotide present at the polymorphic site is identified by
hybridization under sufficiently stringent hybridization conditions with an oligonucleotide
ntially complementary to one of the SNP alleles in a region encompassing the polymorphic
site, and exactly complementary to the allele at the polymorphic site. Because mismatches which
occur at non-polymorphic sites are mismatches with both allele sequences, the difference in the
number of mismatches in a duplex formed with the target allele sequence and in a duplex formed
with the corresponding non-target allele sequence is the same as when an oligonucleotide exactly
mentary to the target allele sequence is used. In this embodiment, the hybridization
conditions are relaxed sufficiently to allow the formation of stable duplexes with the target
sequence, while maintaining sufficient stringency to preclude the formation of stable duplexes
with non-target sequences. Under such sufficiently stringent hybridization conditions, stable
duplexes will form only between the probe or primer and the target allele. Thus, ucleotides
from about 10 to about 35 nucleotides in length, usually from about 15 to about 35 nucleotides in
, which are substantially complementary to an allele sequence in a region which
encompasses the rphic site, and are exactly complementary to the allele sequence at the
polymorphic site, are within the scope of the invention.
The use of substantially, rather than exactly, complementary oligonucleotides may be desirable
in assay formats in which zation of hybridization conditions is limited. For example, in a
l multi-target immobilized-oligonucleotide assay , probes or primers for each target
are immobilized on a single solid support. Hybridizations are carried out simultaneously by
contacting the solid support with a solution containing target DNA. As all hybridizations are
carried out under identical ions, the hybridization conditions cannot be separately
optimized for each probe or primer. The incorporation of mismatches into a probe or primer can
be used to adjust duplex stability when the assay format precludes adjusting the hybridization
conditions. The effect of a ular uced mismatch on duplex stability is well known, and
the duplex stability can be routinely both estimated and empirically determined, as described
above. Suitable hybridization conditions, which depend on the exact size and sequence of the
probe or primer, can be selected cally using the guidance provided herein and well known
in the art. The use of oligonucleotide probes or primers to detect single base pair differences in
sequence is described in, for example, Conner et al., 1983, Proc. Natl. Acad. Sci. USA 80:278-
282, and U.S. Pat. Nos. 5,468,613 and 5,604,099, each incorporated herein by reference.
The proportional change in stability between a perfectly matched and a single-base mismatched
hybridization duplex s on the length of the hybridized oligonucleotides. Duplexes formed
with shorter probe sequences are destabilized proportionally more by the presence of a mismatch.
Oligonucleotides between about 15 and about 35 nucleotides in length are often used for
sequence-specific detection. rmore, e the ends of a hybridized oligonucleotide
undergo continuous random dissociation and re-annealing due to thermal energy, a mismatch at
either end destabilizes the hybridization duplex less than a mismatch ing internally. For
discrimination of a single base pair change in target sequence, the probe sequence is ed
which hybridizes to the target sequence such that the polymorphic site occurs in the interior
region of the probe.
The above criteria for selecting a probe ce that hybridizes to a specific allele apply to the
hybridizing region of the probe, i.e., that part of the probe which is involved in hybridization
with the target sequence. A probe may be bound to an additional nucleic acid sequence, such as a
poly-T tail used to immobilize the probe, without significantly altering the hybridization
characteristics of the probe. One of skill in the art will ize that for use in the t
methods, a probe bound to an additional nucleic acid sequence which is not complementary to
the target sequence and, thus, is not involved in the hybridization, is essentially equivalent to the
unbound probe.
Suitable assay formats for detecting hybrids formed between probes and target nucleic acid
sequences in a sample are known in the art and include the immobilized target (dot-blot) format
and lized probe (reverse dot-blot or line-blot) assay formats. Dot blot and reverse dot blot
assay formats are described in U.S. Pat. Nos. 5,310,893; 5,451,512; 5,468,613; and 5,604,099;
each incorporated herein by reference.
In a dot-blot format, amplified target DNA is immobilized on a solid support, such as a nylon
membrane. The membrane-target complex is incubated with labeled probe under suitable
hybridization conditions, idized probe is d by washing under suitably stringent
conditions, and the ne is monitored for the presence of bound probe.
In the reverse dot-blot (or line-blot) format, the probes are immobilized on a solid support, such
as a nylon membrane or a microtiter plate. The target DNA is labeled, typically during
amplification by the oration of labeled primers. One or both of the primers can be labeled.
The membrane-probe complex is incubated with the d amplified target DNA under suitable
ization conditions, unhybridized target DNA is removed by g under suitably
stringent conditions, and the membrane is monitored for the presence of bound target DNA. A
reverse line-blot detection assay is described in the example.
An allele-specific probe that is specific for one of the polymorphism ts is often used in
conjunction with the allele-specific probe for the other polymorphism variant. In some
embodiments, the probes are immobilized on a solid support and the target sequence in an
individual is ed using both probes simultaneously. Examples of nucleic acid arrays are
described by WO 95/11995. The same array or a different array can be used for analysis of
characterized polymorphisms. WO 95/11995 also describes subarrays that are optimized for
detection of variant forms of a pre-characterized rphism. Such a subarray can be used in
detecting the presence of the polymorphisms described .
b. Allele-Specific Primers
Polymorphisms are also commonly detected using allele-specific amplification or primer
extension methods. These reactions lly involve use of primers that are ed to
specifically target a polymorphism via a mismatch at the 3’-end of a primer. The presence of a
mismatch effects the ability of a polymerase to extend a primer when the polymerase lacks errorcorrecting
activity. For example, to detect an allele sequence using an -specific
ication- or extension-based , a primer complementary to one allele of a
polymorphism is designed such that the 3’-terminal nucleotide hybridizes at the polymorphic
position. The presence of the particular allele can be determined by the ability of the primer to
te extension. If the 3’-terminus is mismatched, the extension is impeded.
In some embodiments, the primer is used in conjunction with a second primer in an amplification
reaction. The second primer hybridizes at a site unrelated to the polymorphic on.
Amplification proceeds from the two primers g to a detectable product signifying the
particular allelic form is present. Allele-specific amplification- or extension-based methods are
described in, for example, WO 93/22456; U.S. Pat. Nos. 5,137,806; 5,595,890; 5,639,611; and
U.S. Pat. No. 4,851,331.
Using allele-specific amplification-based genotyping, identification of the alleles requires only
detection of the presence or absence of amplified target sequences. Methods for the detection of
amplified target sequences are well known in the art. For example, gel electrophoresis and probe
hybridization assays described are often used to detect the presence of nucleic acids.
In an alternative probe-less method, the amplified nucleic acid is ed by monitoring the
increase in the total amount of double-stranded DNA in the reaction mixture, is described, e.g. in
U.S. Pat. No. 5,994,056; and European Patent Publication Nos. 487,218 and 512,334. The
detection of double-stranded target DNA relies on the increased fluorescence various DNA-
g dyes, e.g., SYBR Green, exhibit when bound to double-stranded DNA.
As appreciated by one in the art, allele-specific amplification methods can be med in
reaction that employ multiple allele-specific primers to target particular alleles. Primers for such
multiplex applications are generally labeled with guishable labels or are selected such that
the amplification products produced from the alleles are distinguishable by size. Thus, for
example, both alleles in a single sample can be identified using a single amplification by gel
analysis of the amplification t.
As in the case of allele-specific probes, an allele-specific oligonucleotide primer may be exactly
complementary to one of the polymorphic alleles in the hybridizing region or may have some
mismatches at positions other than the 3’-terminus of the oligonucleotide, which mismatches
occur at non-polymorphic sites in both allele sequences.
c. Detectable Probes
i) 5’-Nuclease Assay Probes
Genotyping can also be med using a “TaqMan®” or “5’-nuclease assay” , as
described in U.S. Pat. Nos. 5,210,015; 5,487,972; and 5,804,375; and Holland et al., 1988, Proc.
Natl. Acad. Sci. USA 88:7276-7280. In the TaqMan® assay, d detection probes that
ize within the amplified region are added during the amplification reaction. The probes are
modified so as to prevent the probes from acting as primers for DNA synthesis. The
amplification is performed using a DNA polymerase having 5’- to 3’-exonuclease activity.
During each synthesis step of the amplification, any probe which hybridizes to the target nucleic
acid downstream from the primer being extended is ed by the 5’- to nuclease
activity of the DNA polymerase. Thus, the synthesis of a new target strand also results in the
degradation of a probe, and the accumulation of degradation product provides a measure of the
synthesis of target sequences.
The hybridization probe can be an allele-specific probe that discriminates between the SNP
alleles. Alternatively, the method can be performed using an allele-specific primer and a labeled
probe that binds to amplified product.
Any method le for detecting degradation product can be used in a 5’-nuclease assay. Often,
the detection probe is labeled with two fluorescent dyes, one of which is capable of quenching
the fluorescence of the other dye. The dyes are attached to the probe, y one attached to the
’-terminus and the other is attached to an internal site, such that quenching occurs when the
probe is in an unhybridized state and such that cleavage of the probe by the 5’- to 3’-exonuclease
activity of the DNA polymerase occurs in between the two dyes. Amplification results in
cleavage of the probe n the dyes with a concomitant elimination of quenching and an
increase in the fluorescence observable from the initially quenched dye. The accumulation of
ation t is monitored by measuring the increase in on fluorescence. U.S. Pat.
Nos. 5,491,063 and 5,571,673, both incorporated herein by reference, describe alternative
methods for detecting the degradation of probe which occurs concomitant with ication.
ii) Secondary Structure Probes
Probes detectable upon a secondary structural change are also suitable for detection of a
rphism, including SNPs. Exemplified secondary structure or stem-loop structure probes
include molecular beacons or Scorpion® primer/probes. Molecular beacon probes are single-
stranded oligonucleic acid probes that can form a hairpin ure in which a fluorophore and a
quencher are usually placed on the opposite ends of the oligonucleotide. At either end of the
probe short complementary sequences allow for the formation of an intramolecular stem, which
enables the fluorophore and the quencher to come into close proximity. The loop portion of the
molecular beacon is complementary to a target nucleic acid of interest. Binding of this probe to
its target nucleic acid of interest forms a hybrid that forces the stem apart. This causes a
conformation change that moves the fluorophore and the quencher away from each other and
leads to a more e fluorescent signal. lar beacon probes are, however, highly
sensitive to small sequence variation in the probe target (Tyagi S. and Kramer F. R., Nature
Biotechnology, Vol. 14, pages 8 (1996); Tyagi et al., Nature Biotechnology, Vol. 16,
pages 49-53(1998); Piatek et al., Nature hnology, Vol. 16, pages 359-363 (1998); Marras
S. et al., Genetic Analysis: Biomolecular ering, Vol. 14, pages 151-156 (1999); Tpp I. et
al, BioTechniques, Vol 28, pages 732-738 (2000)). A Scorpion® primer/probe comprises a stem-
loop structure probe covalently linked to a primer.
d. DNA Sequencing and Single Base Extensions
SNPs can also be ed by direct sequencing. Methods include e.g. dideoxy sequencing-based
methods and other methods such as Maxam and Gilbert sequence (see, e.g. Sambrook and
Russell, supra).
Other detection methods include Pyrosequencing™ of oligonucleotide-length products. Such
methods often employ amplification ques such as PCR. For example, in pyrosequencing, a
sequencing primer is hybridized to a single ed, PCR-amplified, DNA template; and
incubated with the enzymes, DNA polymerase, ATP sulfurylase, rase and apyrase, and the
substrates, adenosine 5’ osulfate (APS) and luciferin. The first of four deoxynucleotide
triphosphates (dNTP) is added to the reaction. DNA polymerase catalyzes the incorporation of
the deoxynucleotide triphosphate into the DNA strand, if it is complementary to the base in the
template strand. Each incorporation event is accompanied by release of pyrophosphate (PPi) in a
quantity equimolar to the amount of incorporated nucleotide. ATP sulfurylase quantitatively
converts PPi to ATP in the presence of adenosine 5’ phosphosulfate. This ATP drives the
luciferase-mediated conversion of luciferin to oxyluciferin that generates visible light in amounts
that are proportional to the amount of ATP. The light produced in the rase-catalyzed
reaction is detected by a charge d device (CCD) camera and seen as a peak in a
Pyrogram™. Each light signal is proportional to the number of nucleotides incorporated.
Apyrase, a nucleotide degrading enzyme, continuously degrades unincorporated dNTPs and
excess ATP. When degradation is complete, another dNTP is added.
r similar method for characterizing SNPs does not require use of a complete PCR, but
typically uses only the extension of a primer by a single, scence-labeled
dideoxyribonucleic acid molecule (ddNTP) that is complementary to the nucleotide to be
investigated. The nucleotide at the polymorphic site can be identified via detection of a primer
that has been extended by one base and is fluorescently labeled (e.g., Kobayashi et al, Mol. Cell.
Probes, 9:175-182, 1995).
e. Electrophoresis
Amplification products generated using the polymerase chain reaction can be analyzed by the
use of denaturing gradient gel electrophoresis. Different alleles can be fied based on the
different sequence-dependent melting properties and electrophoretic migration of DNA in
solution (see, e.g. Erlich, ed., PCR logy, ples and ations for DNA
ication, W. H. Freeman and Co, New York, 1992, Chapter 7).
Distinguishing of microsatellite polymorphisms can be done using capillary electrophoresis.
Capillary electrophoresis conveniently allows identification of the number of repeats in a
particular microsatellite allele. The application of capillary electrophoresis to the analysis of
DNA polymorphisms is well known to those in the art (see, for example, Szantai, et al, J
Chromatogr A. (2005) 1079(1-2):41-9; Bjorheim and Ekstrom, Electrophoresis (2005)
26(13):2520-30 and Mitchelson, Mol Biotechnol. (2003) 24(1):41-68).
f. Single-Strand Conformation Polymorphism Analysis
Alleles of target sequences can be differentiated using single-strand conformation rphism
analysis, which identifies base differences by alteration in electrophoretic migration of single
stranded PCR products, as described, e.g, in Orita et al., Proc. Nat. Acad. Sci. 86, 2766-2770
(1989). Amplified PCR products can be ted as described above, and heated or otherwise
denatured, to form single stranded amplification products. Single-stranded c acids may
refold or form secondary structures which are partially dependent on the base sequence. The
ent electrophoretic mobilities of single-stranded amplification products can be related to
base-sequence difference between alleles of target
SNP detection methods often employ d ucleotides. Oligonucleotides can be labeled
by incorporating a label detectable by spectroscopic, photochemical, biochemical,
chemical, or chemical means. Useful labels include fluorescent dyes, radioactive labels,
e.g. 32P, electron-dense reagents, enzyme, such as peroxidase or alkaline atase, biotin, or
haptens and proteins for which ra or monoclonal antibodies are available. Labeling
ques are well known in the art (see, e.g. Current Protocols in Molecular Biology, supra;
Sambrook & Russell, supra).
4. Methods of Treatment
Dosages of with bevacizumab (Avastin®) for treatments of specific cancers, ing to the
EMEA, are as follows. For metastatic oma of the colon or rectum (mCRC) recommended
dosages are 5 mg/kg or 10 mg/kg of body weight given once every 2 weeks or 7.5 mg/kg or 15
mg/kg of body weight given once every 3 weeks, for metastatic breast cancer (mBC)
recommended dosages are 10 mg/kg of body weight given once every 2 weeks or 15 mg/kg of
body weight given once every 3 weeks as an intravenous infusion, and for non-small cell lung
cancer (NSCLC) recommended dosages are 7.5 mg/kg or 15 mg/kg of body weight given once
every 3 weeks as an intravenous on. Clinical benefit in NSCLC patients has been
demonstrated with both 7.5 mg/kg and 15 mg/kg doses. For details refer to section 5.1
Pharmacodynamic Properties, all cell lung cancer (NSCLC). For advanced and/or
metastatic Renal Cell Cancer (mRCC) preferred dosages are 10 mg/kg of body weight given
once every 2 weeks as an intravenous infusion(in addition to platinum-based chemotherapy for
up to 6 cycles of ent followed by bevacizumab (Avastin®) as a single agent until disease
progression). For gliablastoma a particular dosage is 10 mg/kg every 2 weeks.
In the context of the present invention, the angiogenesis inhibitor may be stered in
addition to or as a co-therapy or a co-treatment with one or more chemotherapeutic agents
administered as part of standard chemotherapy regimen as known in the art. Examples of agents
included in such standard chemotherapy regimens include 5-fluorouracil, leucovorin, irinotecan,
gemcitabine, erlotinib, capecitabine, taxanes, such as docetaxel and paclitaxel, interferon alpha,
lbine, and platinum-based chemotherapeutic agents, such as paclitaxel, latin,
cisplatin and oxaliplatin. Examples of co-treatments for metastatic pancreatic cancer include
gemcitabine-erlotinib plus bevacizumab at a dosage of 5mg/kg or 10 mg/kg of body weight
given once every two weeks or 7.5 mg/kg or 15 mg/kg of body weight given once every three
weeks. es of co-treatments for renal cell cancer include interferon alpha plus
bevacizumab at a dosage of or 10 mg/kg of body weight given once every two weeks. Further, a
patient may be co-treated with a combination of irinotecan, 5-fluorouracil, leucovorin, also
referred to as IFL, as, for example, a bolus-IFL, with a ation of oxaliplatin, leucovorin,
and 5-fluorouracil, also referred to a FOLFOX4 regimen, or with a combination of capecitabine
and oxaliplatin, also referred to as XELOX. Accordingly, in a further embodiment of the
invention, the patient suffering from a malignant disease or a disease involving logical and
pathological angiogenesis is being treated with one or more chemotherapeutic agents such as
-fluorouracil, leucovorin, irinotecan, gemcitabine-erlotinib, capecitabine and/or platinum-based
chemotherapeutic agents, such as paclitaxel, latin and oxaliplatin. Examples of cotherapy
or co-treatment include 5 mg/kg bevacizumab (Avastin®) every two week with bolus-
IFL or 10 mg/kg bevacizumab (Avastin®) every 2 weeks with FOLFOX4 for metastatic
colorectal cancer, 15 mg/kg bevacizumab in®) every 3 weeks with caboplatis/paclitaxel
for non-squamous non-small cell lung , and 10 mg/kg bevacizumab in®) every 2
weeks with paclitaxel for metastatic breast cancer. Further, the angiogenesis inhibitor to be
administered may be administered as a co-therapy or a co-treatment with herapy.
5. Kit
Also described herein is a stic composition or kit comprising any of the mentioned
oligonucleotides and optionally suitable means for ion.
The kit may advantageously be used for carrying out a method of the ion and could be,
inter alia, employed in a variety of applications, e.g., in the diagnostic field or as a research tool.
The parts of the kit of the invention can be es individually in vials or in combination in
containers or multicontainer units. Manufacture of the kit follows preferably standard procedures
which are known to the person skilled in the art. The kit or diagnostic compositions may be used
for ion of the one or more t s in accordance with the herein-described methods
of the invention, employing, for example, amplification techniques as described herein.
Accordingly, also described herein is a kit useful for carrying out the methods herein described,
comprising oligonucleotides or polynucleotides capable of determining the genotype of one or
more SNPs. The oligonucleotides or polynucleotides may comprise primers and/or probes.
The present invention is further described by reference to the following non-limited figures and
examples.
Examples
Example 1:
Genetic determination can influence sensitivity of the endothelium to VEGF. In accordance with
this and in context of this invention, we explored genetic variability in underlying signaling
pathways in order to discover tive patterns for anti angiogenic treatment and the
development of hypertension under this therapy regimen. In this analysis, the correlation of
c variability in the VEGF-A ing pathway with clinical e of patients with
different advanced primary cancers was assessed in 5 different trials. All five were randomised
el trials to investigate the efficacy and safety of BEV (bevacizumab) in subjects with
metastatic colorectal cancer (NO16966), metastatic pancreatic cancer (AVITA), advanced or
recurrent non-squamous non-small-cell lung cancer (AVAIL), metastatic renal cancer
(AVOREN) and HER2-negative metastatic breast cancer (AVADO).
In all five trials, optional DNA ker sampling was included for SNP analysis. In total,
germline DNA was available from 1346 patients. Common single nucleotide polymorphisms
(SNPs) located in the hypoxia-inducible factor-1α and -2α, VEGF-A, its receptors (VEGFR-1
and -2) and other relevant genes were ed based on literature and using a SNP tagging
approach (f≥0.1 and r2 ≤ 0.8). 157 SNPs were successfully genotyped using MALDI-TOF mass
spectrometry. Risk and survival estimates were calculated using Cox regression analyses.
Two types of analyses were performed.
1. Correlation of genetic markers to PFS and OS.
2. Correlaton of genetic markers to hypertension, not fied as “unrelated to study drug”
The rs699946 (SEQ ID NO. 1) SNP, located in the VEGF-A promoter, was associated with
improved PFS in bev-treated subjects with an c HR of 1.26 (95% CI .48, p=0.005).
No effect was seen in placebo subjects, suggesting that rs699946 (SEQ ID NO. 1) may be a
predictive marker for favourable outcome with bevacizumab treatment. Further, the rs11133360
(SEQ ID NO. 5) SNP, located in the VEGFR2, was associated with improved PFS in
bevacizumab-treated subjects with an c HR of 1.15 (95% CI 1.02–1.30, p=0.02). In terms of
OS, the rs12505758 (SEQ ID NO. 2) SNP in VEGFR2 was most icantly ated with
improved OS in bev-treated pts (allelic HR 1.50, 95% CI 1.21–1.86, 02). No effects for
rs12505758 (SEQ ID NO. 2) were seen in placebo pts.
Ten SNPs were associated with zumab-induced hypertension (p<0.05), but none of these
surpassed the old for multiple testing (p<0.0003). The two SNPs showing the strongest
association (p<0.01) were: rs2305949 (SEQ ID NO. 3) in KDR (allelic OR 0.93, 95% CI 0.88–
0.98, 67), and rs4444903 (SEQ ID NO. 4) in EGF (allelic OR 1.06, 95% CI 1.02–1.11,
p=0.0052). Interestingly, rs2305949 (SEQ ID NO. 3) and rs4444903 (SEQ ID NO. 4) were
closely linked to amino acid changes occurring on position 273 and 708 of KDR and EGF,
suggesting that these changes may functionally affect both genes and thereby contribute to
hypertension. Notably, rs11064560 in WNK1 was also ated with bevacizumab-induced
hypertension (allelic OR 1.06, 95% CI 1.01–1.10, p=0.02), thereby supporting previous
observations in a limited number of ts [Frey et al. J Clin Oncol 26: 2008 (May 20 suppl;
abstr 11003)].
PATIENTS AND METHODS
Samples
All 5 trial protocols were approved by the institutional review board at each site and were
conducted in accordance with the Declaration of Helsinki, current US Food and Drug
Administration Good Clinical ces, and local ethical and legal ements. In total, 1346
subjects were genotyped. Among these subjects, 1225 were white and 121 were non-white. As
non-white patients are genetically distinct from white ts and SNP frequencies may differ
between both ethnic groups, non-white patients were omitted from further analysis. All ts
provided separate written informed consent for genetic biomarker g.
Assessments
Patients were assessed according to the study protocol as described in the following references:
- AVITA: Van Cutsem et al., J. Clinc. Oncol. 27, 2231-7 (2009)
- AVAIL: Reck M, von Pawel J, Zatloukal P, et al. Phase III trial of cisplatin plus gemcitabine
with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung
cancer: AVAiL. J Clin Oncol 2009;27(8):1227–34
- AVOREN: er B, Pluzanska A, Koralewski P, Ravaud A, da S, Szczylik C, et al.
Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a
randomised, double-blind phase III trial. Lancet. 2007;370(9605):2103-2111
- AVADO: Miles DW, et al., J Clin Oncol 2010a;28(20):3239–47
- NO16966: Saltz LB, Clarke S, Diaz-Rubio E, et al. Bevacizumab in combination with
oxaliplatin-based herapy as first-line therapy in metastatic colorectal cancer: a
randomized phase III study. J Clin Oncol 2008;26(12):2013-2019
Single Nucleotide Polymorphism Selection
Two marker panels were ered for analysis: The Roche panel and Leuven panel. The Roche
panel consists of 35 genetic polymorphisms selected by literature review for potential relevance
to BEV ent. The panel is made up of SNPs and repeat polymorphisms lying in the
following genes: VEGFA, NOS3, FLT1 (VEGFR1), KDR (VEGFR2), WNK1, IL8, IL8R and
IFNAR2. The Leuven panel ts of 186 tag SNPs from the VEGF signalling cascade or from
candidate genes for known side-effects, hypertension or thrombosis and includes the following
genes: the VEGF ligand, the VEGF homologues (placental growth factor or PlGF, VEGF-B and
-C, as well as VEGF-D or FlGF), the VEGF receptor-2 (KDR or VEGFR-2) and VEGF receptor-
1 (FLT1 or VEGFR-1). Genomic sequences 5 kb upstream of the translation start site up to 3’
poly-A adenylation site of each gene, were used to select SNPs from the HapMap database
(HapMap Data Rel 24/phaseII Nov08, on NCBI B36 assembly, dbSNP b126). Tagging SNPs
were selected using the Tagger , I., et al., Nat. Genet. 38, 663-7 (2006)) as provided in the
HAPLOVIEW software package (Barrett, J.C., et al., Bioinformatics. 21, 263-5 (2005)). Only
SNPs occurring commonly, i.e., with a minor allele frequency f≥0.1 and a minimum r2 threshold
≥0.8 were ered. In total, 167 tagging SNPs were selected following these criteria.
Additionally, 11 SNPs located in exonic sequences and inducing nonymous amino-acid
changes at a frequency f≥0.1 were selected from the dbSNP database, as well as 4 SNPs in
VEGF (rs699947, rs833061, rs2010963 and 039), 1 SNP in 1 (rsTP53_R-1) and
1 SNP in VEGFR-2 (rs2071559), which previously have been reported to affect function or
expression of these genes.
There is some p n markers in the two panels, and the size of the panels has
increased slightly over the duration of the six trials, so fewer markers are available for earlier
trials. The current meta-analysis is confined to markers for which genotyping was conducted in
at least two trials under study.
Four marker sets were defined as follows:
• ‘All Markers’ consists of all markers assayed for which at least one genotype was obtained.
• ‘Roche Markers’ consists of s from the Roche panel, which passed quality checks (see
below) and had frequency greater than 1% in white subjects.
• ‘Leuven Efficacy Markers’ consists of those markers from the Leuven panel, which lie in loci
implicated in the VEGF pathway, which passed quality checks (see below) and which had
frequency greater than 1% in white subjects.
• ‘Leuven Safety Markers’ consists of those markers from the Leuven panel which lie in
candidate genes for involvement in hypertension or thrombosis, which passed quality checks (see
below) and which had frequency greater than 1% in white subjects.
Genotyping
Peripheral blood was sampled in K2EDTA plastic iner tubes. After centrifugation, germline
DNA was extracted from the precipitated leucocyte cell fraction according to standard
procedures.
For SNPs of the Roche panel, Genotyping was carried out in a blinded manner at the Roche
Translational Research Sciences Genetics laboratories , Switzerland) using Allele Specific
PCR ication, Sanger sequencing and Fragment is platforms (AVAIL, AVITA,
AVOREN, AVADO, NO16966).
For SNPs of the Leuven panel, genotyping was carried out in a blinded manner at the Vesalius
Research Center (Leuven, Belgium) using the Sequenom iPLEX platform (Sequenom Inc, San
Diego, CA, USA). Any SNP that failed to provide a robust genotype in the first genotyping
round was redesigned using a different set of rase chain reaction primers and ed.
Overall, 157 (85.3%) were successfully genotyped with an overall success rate of 98.5%. The 27
SNPs that also failed the second design were ered failures.
The following amplification s were designed for SNPs rs699946 (SEQ ID NO. 1),
rs12505758 (SEQ ID NO. 2), rs2305949 (SEQ ID NO. 3), rs4444903 (SEQ ID NO. 4) and
rs11133360 (SEQ ID NO. 5). For rs699946 (SEQ ID NO. 1),
ACGTTGGATGCTACCACTAGTGTTGGCTTG (SEQ ID NO. 6) and
ACGTTGGATGTGAGCTCCACACTGCCTTC (SEQ ID NO. 7) were used. For SNP
rs12505758 (SEQ ID NO. 2), ACGTTGGATGCTTTACTCTGCCAAATCTATG (SEQ ID NO.
8) and ACGTTGGATGGCTAATAAGCTTATACATTTG (SEQ ID NO. 9) were used. For
rs2305949 (SEQ ID NO. 3), ACGTTGGATGATCCTATACCCTAGAGCAAG (SEQ ID NO.
) and ACGTTGGATGATCTGTGCAAAGTTATAGGC (SEQ ID NO. 11) were used. For
903 (SEQ ID NO. 4), ACGTTGGATGTCTTCTTTCAGCCCCAATCC (SEQ ID NO. 12)
and ACGTTGGATGAAGAAAGGAAGAACTGATGG (SEQ ID NO. 13) were used. For
rs11133360 (SEQ ID NO. 5), ACGTTGGATGTTTCACATTGCTATGCCCAA (SEQ ID NO.
14) and ACGTTGGATGCTCTTTCTTCACTTTGACTG (SEQ ID NO. 15) were used.
The following unextended primers (probes) were designed for SNPs rs699946 (SEQ ID NO. 1),
rs12505758 (SEQ ID NO. 2), rs2305949 (SEQ ID NO. 3), rs4444903 (SEQ ID NO. 4) and
rs11133360 (SEQ ID NO. 5). For rs699946 (SEQ ID NO. 1),
ATTAGTCAATTCTCTGACAGAGACA (SEQ ID NO. 16) was used. For rs12505758 (SEQ ID
NO. 2), TTACTCTGCCAAATCTATGATGCCA (SEQ ID NO. 17) was used. For rs2305949
(SEQ ID NO. 3), CTAGAGCAAGTAAATTGAAAAAA (SEQ ID NO. 18) was used. For
rs4444903 (SEQ ID NO. 4), GCATCTCCAATCCAAGGGTTGT (SEQ ID NO. 19) was used.
For rs11133360 (SEQ ID NO. 5), CACATTGCTATGCCCAACACATC (SEQ ID NO. 20) was
used.
Quality ng
Data were checked for quality as follows:
• Uniformity of assay strand was ensured
• Levels of missing data were summarised
• s with minor allele frequency (MAF<1%) were excluded
• Markers failing a test of homogeneity of allele frequency were ed
• Tests of Hardy Weinberg Equilibrium (HWE) were conducted to assist interpretation
After quality check, 25 Roche Markers, 133 Leuven Efficacy s and 22 Leuven Safety
Markers were subjected to pooled ation analysis.
Statistical analysis
A pooled analysis of individual patient data, stratified by study was applied to all markers with
homogeneous frequency. Candidate markers for efficacy were tested for ation to PFS and
OS using Cox Proportional Hazards Regression. ate markers for safety were tested for
association to Hypertension using logistic regression. The primary analysis involved white
BEV-treated subjects from the ITT (for efficacy endpoints) and SP tension), as appropriate.
Adjustments were made in all association tests for the following covariates: Region, study and
dose and background chemotherapy regimen. A subset of the following les, selected by
endpoint using backwards stepwise regression, were adjusted for as well: ECOG performance
status (0 vs. 1), gender (male vs. female), age, LDH, alkaline phosphatase level (within normal
range vs. above normal range), serum albumin (<2.9g/dL vs. >=2.9g/dL) and baseline number of
metastatic sites (>2 vs. <=2). In order to investigate whether any detected associations reflected
temporal rather than treatment effects, association testing was also conducted in white placebotreated
subjects. In order to further characterise any detected associations, Genotype x
Treatment interaction analysis was conducted in white subjects.
Data
26 Roche Markers, 136 Leuven cy Markers and 22 Leuven Safety Markers passed y
checking and were subjected to homogeneity analysis. Table 1 shows the number of subjects to
be orated into the meta-analysis. It is noted that 3 subjects in the ITT were not in the SP
and 3 subjects had missing values for randomised weekly dose ).
Table 1: Subject sets and sizes for analysis
Analysis Population Count
PGx-ITT-All Arms-All Ethnicities 1346
PGx-ITT-All Arms-White 1225
PGx-ITT-BEV-All Ethnicities 668
PGx-ITT-BEV-White 629
T-PBO-White 593
-All Arms-White 1223
PGx- SP -BEV-All ities 667
PGx- SP -BEV-White 628
PGx- SP -PBO-White 592
Clinical Characteristics of genetic patient population
Demographic and endpoint characteristics are tabulated in Table 2 by clinical trial and overall
for subjects in PGx-ITT-BEV-All ities. Endpoint butions are portrayed graphically in
Figure 1-4.
Table 2: Summary of demographic and endpoint data
AVAIL AVOREN AVITA AVADO All
4 BO17705 BO17706 BO17708 NO16966
Cancer-type NSCLC Renal Pancreatic Breast Colorectal
N 119 108 161 350 610 1348
BEV 83 59 79 238 210 669
PBO 36 49 81 110 400 676
Male 0.71 0.72 0.64 0 0.61 0.47
Age (yr) (SD) 57.39 59.7 61.7 54.73 59.56 58.38
(9.85) (10.57) (9.59) (10.84) (11.46) (11.13)
White 0.92 0.99 0.95 0.96 0.85 0.91
OS (Median) 424 1011 213 873.5 636 614
Cens. (OS) 0.36 0.47 0.09 0.37 0.19 0.26
PFS n) 197 413 150 256 267.5 250
Cens. (PFS) 0.03 0.11 0.04 0.07 0.04 0.05
BOR (PR/CR) 0.42 0.37 0.14 0.49 0.51 0.44
ension 0.21 0.2 0.14 0.15 0.08 0.13
Clinical data was available for 1348 subjects from 5 trials, with approximately equal numbers
overall on treated and placebo. In contrast to the other trials, no males participated in BO17708
(AVADO), which was a trial of advanced breast cancer. The age distributions and the
proportions white were broadly homogeneous, except for a slightly lower proportion of white
subjects in the largest trial, NO16966. The median lengths of OS and PFS varied widely as did
the rates of censoring. As expected, censoring for OS was far greater than for PFS and in
statistical terms, the effect will be to reduce power to detect association to OS compared to PFS.
Rates of BOR were 49% in BEV-treated subjects and 46% in PBO-treated subjects. Rates of
hypertension were 18% in BEV-treated subjects and 7% in eated ts (Figure 4).
For PFS there were 592 events and for OS, there were 438 events out of 629 white BEV-treated
subjects in the PGx-ITT. For Hypertension, there were 113 events out of a total of 628 white
BEV-treated subjects in PGx-SP. Table 3 shows the number of white subjects to be orated
into the meta-analysis.
Table 3: Subject counts for pharmacogenetic meta-analysis of white ts
Population Treatment Count
ITT BEV 629
ITT PBO 593
SP BEV 628
SP PBO 592
ITT: intent-to-treat population
SP: safety population
Results Efficay
Progression Free Survival
Analysis in the oup of patients treated with Bevacizumab
The strongest association in VEGF-A with PFS was for rs699946 (SEQ ID NO. 1) (p=0.005).
Although the result would not be significant after adjustment for multiple-testing, it provides
tent upstream signal with marker rs699947, published by Schneider et al. J Clin Oncol
2008 26:4672. A scatter plot of association across the whole gene is given in Figure 5.
Marker Chr BP MAF N HR 95% CI p-value Gene
rs699946 Chr6 69 0.18 542 1.26 (1.07,1.48) 0.0047 VEGFA
Relative to AA carriers, HR for rs699946 (SEQ ID NO. 1) AG carriers was 1.26 (95% CI 1.07–
1.48, p=0.005). This means that each additional G allele was associated with 27% increase in
risk of progression or death. No effect was seen in placebo ts, suggesting that rs699946
(SEQ ID NO. 1) may be a predictive marker for favourable outcome with bevacizumab treatment.
As shown in Figure 6, consistent effects for rs699946 (SEQ ID NO. 1) were seen for all studies
except AVOREN/BO17705 (renal cancer), the smallest study under consideration.
Further, the rs11133360 (SEQ ID NO. 5) was weakly associated (p=0.02) to PFS (Figure 13).
Marker Chr BP MAF N HR 95% CI p-value Gene
rs11133360 Chr4 55982752 0.45 579 1.15 1.30) 0.02 KDR
Relative to TT carriers, HR for rs11133360 (SEQ ID NO. 5) CT carriers was 1.15 (95% CI 1.02–
1.30, ). This means that each additional C allele was associated with 15% increase in risk
of progression or death.
Overall Survival Analysis
Analysis in the sub-group of patients treated with Bevacizumab
In association analysis for OS, 6/133 markers had p<0.05 in white d subjects. One of these,
rs12505758 (SEQ ID NO. 2) is significant after Bonferroni adjustment for 158 tests. The marker
is an intronic SNP in KDR (Kinase Insert Domain Receptor; VEGFR2; FLK1) and it is in LD
(r2=0.31) with another intronic SNP, rs1531289 in the gene (source: HapMap release 22; the
marker not available in HapMap v3 release 2). The marker is not associated in white placebo-
treated subjects therefore it may be said to have predictive as d to prognostic qualities. An
tion of the forest plot (Figure 7) shows that the effect is driven primarily by 6
(colorectal cancer) and BO17705 (AVOREN; renal cancer). The effect is either weak or absent
in the other three studies.
Marker Chr BP MAF N HR 95% CI p-value Gene
rs12505758 Chr4 55966898 0.12 581 1.50 (1.21, 1.86) 2.00E-04 KDR
Relative to TT carriers, HR for rs12505758 (SEQ ID NO. 2) TC carrier was (allelic HR 1.50,
95% CI 1.21–1.86 (, p=0.0002). This means that each additional C allele was associated with
50% se in risk of death. No effects for rs12505758 (SEQ ID NO. 2) were seen in placebo
patients.
The Kaplan Meier plots show increasing estimated hazard ratio with sing number of copies
of the minor allele (Figure 8).
Additional information on SNPs
Since the rs699946 (SEQ ID NO. 1) SNP is located in the VEGF promoter, we examined its
effect on VEGF-A expression in human plasma samples. We found that GG carriers have a 27%
increased median VEGF expression compared to AG and AA (wildtype) rs. The minor
allele of rs699946 (SEQ ID NO. 1) was in linkage with the minor allele of rs699947 (D’ 0.98;
r2=0.23), which is another VEGF promoter SNP previously shown to associate with response to
bevacizumab therapy [Schneider et al, J Clin Oncol 2008 26:4672]. Furthermore, rs699946 (SEQ
ID NO. 1) is also in linkage with rs833058 (-6589 C>T), which emerged as the second hit in
VEGF for PFS in the meta-analysis (D’=0.95, r2=0.35).
Conclusion of additional research: We trated that the G allele of rs699946 (SEQ ID NO.
1) in the VEGF-A promoter is associated with an increased plasma VEGF-A expression and that
rs699946 (SEQ ID NO. 1) is in linkage with rs699947, another VEGF-A promoter SNP
previously shown to associate with se to bevacizumab by Schneider et al.
The rs11133360 (SEQ ID NO. 5) in VEGFR-2 is an intronic SNP located between the exons
that encode the extracellular domains of the VEGFR-2 protein. We found that HUVECs
homozygous for the minor C allele have sed proliferation upon VEGF stimulation
compared to CT and TT carriers. Importantly, rs11133360 is also in strong linkage with
rs2305948 (D’= 1), a nonsynonymous SNP that induces the Val297Ile substitution and which
has been ed to affect the binding of VEGF to VEGFR-2.
Results Hypertension
The two SNPs g the strongest association (p<0.01) were: rs2305949 (SEQ ID NO. 3) in
KDR (allelic OR 0.93, 95% CI 0.88–0.98, 67), rs4444903 (SEQ ID NO. 4) in EGF (allelic
OR 1.06, 95% CI 1.02–1.11, p=0.0052); see table 4, but none of these surpassed the threshold for
multiple testing (p<0.0003). Interestingly, rs2305949 (SEQ ID NO. 3) and rs4444903 (SEQ ID
NO. 4) were closely linked to amino acid changes occurring on on 273 and 708 of KDR
and EGF, suggesting that these changes may functionally affect both genes and thereby
bute to hypertension.
Table 4 Association results for SNP markers with Hypertension
Marker Chr BP MAF N OR 95% CI p-value Gene
rs2305949 4 55980456 0.22 578 0.93 (0.88,0.98) 0.0067 KDR
rs4444903 4 111053559 0.43 609 1.06 (1.02,1.11) 0.005 EGF
Chr = chromosome; MAF: Minor Allele Freqeuncy; OR = Odds ratio
rs2305949 (SEQ ID NO. 3) (KDR)
As shown in Figure 9, higher ncy of ension was seen for the CC carrier. Figure 10
shows that three studies, (NO16966, AVAIL/BO17704 and AVOREN/BO17705) drive the
association. The forest plot for white o-treated subjects (not shown) shows the mean effect
across studies is weakly in the opposite direction, so the marker may be concluded to have
predictive characteristics.
rs4444903 (SEQ ID NO. 4) (EGF)
As shown in Figure 11, higher frequency of hypertension was seen for the GA carrier, with
lowest ncy for the AA carriers, while the frequency of the GG carrier was in between. For
marker rs4444903 (SEQ ID NO. 4) in EGF, examination of the forest plot (Figure 12) shows
reasonable consistency across studies, with weakest effect observed inBO17708/ AVADO
(breast cancer). The forest plot for subjects in the placebo arm (not shown) shows that the marker
has predictive as opposed to stic characteristics.
Claims (17)
1. An in vitro method of determining whether a patient is suitably d by a therapy comprising an angiogenesis inhibitor sing bevacizumab or an antibody that binds essentially the same epitope on VEGF as bevacizumab, said method comprising: 5 (a) determining in a sample derived from a t suffering from cancer the genotype at polymorphism rs12505758 (SEQ ID NO. 2), and (b) identifying a patient as more or less suitably treated by a therapy with an angiogenesis inhibitor comprising bevacizumab or an dy that binds essentially the same epitope on VEGF as bevacizumab based on said genotype, wherein the presence of each T allele at 10 polymorphism rs12505758 (SEQ ID NO. 2) indicates an increased likelihood that said patient is more suitably treated, or the presence of each C allele at rphism rs12505758 (SEQ ID NO. 2) indicates an increased likelihood that said patient is less suitably treated.
2. The method of claim 1, wherein whether a patient is suitably treated by a therapy 15 comprising an angiogenesis inhibitor is determined in terms of overall survival.
3. The method of any one of claims 1 to 2, wherein the therapy further comprises a chemotherapeutic agent or herapy regimen. 20
4. The method of any one of claims 1 to 3, wherein the therapy comprises tration of the angiogenesis inhibitor with one or more agents selected from the group consisting of taxanes, interferon alpha, 5-fluorouracil, capecitabine, leucovorin, gemcitabine, erlotinib and um-based chemotherapeutic . 25
5. The method of any one of claims 1 to 4, wherein the cancer is pancreatic cancer, renal cell cancer, colorectal cancer, breast cancer or lung cancer.
6. The method of any one of claims 1 to 5, n the sample is a blood sample. 30
7. The method of any one of claims 1 to 6, wherein the genotype is determined by means of MALDI-TOF mass spectrometry.
8. The use of an angiogenesis inhibitor comprising bevacizumab or an antibody that binds essentially the same epitope on VEGF as bevacizumab for the manufacture of a medicament for the treatment of cancer in a patient in need thereof, wherein said patient has been determined to be more suitably treated with the angiogenesis inhibitor in accordance with the 5 method of any one of claims 1 to 7.
9. The use of an angiogenesis inhibitor comprising bevacizumab or an antibody that binds essentially the same epitope on VEGF as bevacizumab, for the manufacture of a medicament for the treatment of cancer in a patient in need thereof, wherein the patient has been
10 determined to be more suitably treated with the angiogenesis inhibitor by an in vitro method comprising: (a) determining in a sample derived from a patient suffering from cancer the genotype at polymorphism rs12505758 (SEQ ID NO. 2); and (b) identifying a patient as more suitably treated by the addition of an angiogenesis 15 inhibitor comprising zumab or an antibody that binds essentially the same e on VEGF as bevacizumab based on said genotype, wherein the presence of each T allele at rphism rs12505758 (SEQ ID NO. 2) tes an increased likelihood that said patient is more suitably treated. 20 10. The use of claim 9, wherein whether a t is suitably treated by a y comprising an angiogenesis tor is determined in terms of overall survival.
11. The use of any one of claims 9 to 10, wherein the therapy comprises administration of the angiogenesis inhibitor with one or more agents selected from the group 25 ting of taxanes, interferon alpha, 5-fluorouracil, capecitabine, orin, gemcitabine, erlotinib and platinum-based chemotherapeutic agents.
12. The use of any one of claims 9 to 11, wherein the cancer is atic cancer, renal cell cancer, colorectal , breast cancer or lung cancer.
13. The use of any one of claims 9 to 12, wherein the sample is a blood sample.
14. The use of any one of claims 9 to 13, wherein the genotype is determined by means of TOF mass spectrometry.
15. The use of an enesis inhibitor comprising bevacizumab or an antibody that 5 binds essentially the same epitope on VEGF as bevacizumab for the manufacture of a medicament for treating cancer in a patient, wherein the patient genotype at polymorphism rs12505758 (SEQ ID NO. 2) has been determined to be a T allele.
16. A method according to any one of claims 1 to 7 substantially as herein described 10 with reference to any example thereof.
17. The use according to any one of claims 8 to 15 substantially as herein described with nce to any example thereof.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP11179498 | 2011-08-31 | ||
EP11179498.8 | 2011-08-31 | ||
PCT/EP2012/066630 WO2013030167A1 (en) | 2011-08-31 | 2012-08-28 | Responsiveness to angiogenesis inhibitors |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ620345A NZ620345A (en) | 2016-06-24 |
NZ620345B2 true NZ620345B2 (en) | 2016-09-27 |
Family
ID=
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