Accepted Manuscript

Genetic risk factors associated with antiemetic efficacy of palonosetron, aprepitant,

and dexamethasone in Japanese breast cancer patients treated with anthracycline-
based chemotherapy

Satoshi Yokoyama, Satoshi Tamaru, Shinya Tamaki, Daisuke Nakanishi, Akiya

Mori, Tomokazu Yamakawa, Takaaki Ao, Yasuhiko Sakata, Toshiro Mizuno, Takuya
Iwamoto, Kenichi Watanabe, Makoto Simomura, Keiki Kawakami, Naomi Konishi,
Shinichi Kageyama, Shoichiro Ohtani, Tomomi Yamada, Susumu Ban, Kazuya Ooi
PII: S1526-8209(17)30142-8
DOI: 10.1016/j.clbc.2017.05.013
Reference: CLBC 626

To appear in: Clinical Breast Cancer

Received Date: 14 March 2017

Revised Date: 23 April 2017
Accepted Date: 22 May 2017

Please cite this article as: Yokoyama S, Tamaru S, Tamaki S, Nakanishi D, Mori A, Yamakawa T, Ao
T, Sakata Y, Mizuno T, Iwamoto T, Watanabe K, Simomura M, Kawakami K, Konishi N, Kageyama
S, Ohtani S, Yamada T, Ban S, Ooi K, Genetic risk factors associated with antiemetic efficacy of
palonosetron, aprepitant, and dexamethasone in Japanese breast cancer patients treated with
anthracycline-based chemotherapy, Clinical Breast Cancer (2017), doi: 10.1016/j.clbc.2017.05.013.

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 ACCEPTED MANUSCRIPT

Genetic risk factors associated with antiemetic efficacy of palonosetron,

aprepitant, and dexamethasone in Japanese breast cancer patients treated
with anthracycline-based chemotherapy

Running title: Genetic Risk Factor for Anthracycline-based Chemotherapy-induced

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Nausea and Vomiting

Satoshi Yokoyama,1* Satoshi Tamaru,2 Shinya Tamaki,3 Daisuke Nakanishi,4 Akiya

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Mori,5 Tomokazu Yamakawa,6 Takaaki Ao,7 Yasuhiko Sakata,8 Toshiro Mizuno,9 Takuya
Iwamoto,10 Kenichi Watanabe,11 Makoto Simomura,12 Keiki Kawakami,13 Naomi

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Konishi,14 Shinichi Kageyama,15 Shoichiro Ohtani,16 Tomomi Yamada,17 Susumu Ban,1
Kazuya Ooi1

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1
Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, 3500-3
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Minamitamagaki-cho, Suzuka, Mie 513-8670, Japan.
*Present affiliation: Department of Community Pharmacy, Gifu Pharmaceutical
University.
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2
Clinical Research Support Center, Mie University Hospital Hematology and Oncology,
Mie University Hospital, 2-174 Edobashi, Tsu, Mie 514-8507, Japan.
3
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Department of Pharmacy, Hokkaido Cancer Center, 4-2-3-54 Kikusui, Shiroishiku,

Sapporo 003-0804, Japan.
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4
Department of Pharmacy, Matsusaka City Hospital, 1550 Tono-machi, Matsusaka, Mie
515-8544, Japan.
5
Department of Pharmacy, Suzuka General Hospital, 1275-53 Yasuzuka-Yamanohana,
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Suzuka, Mie 513-8630, Japan.

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Department of Pharmacy, Mie Prefectural General Medical Center, 5450-132 Hinaga,
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Yokkaichi, Mie 510-0885, Japan.

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Division of Pharmacy, Suzuka Kaisei Hospital, 112 Kou, Suzuka, Mie 513-8505,
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Japan.
8
Department of Pharmacy, Hiroshima City Hiroshima Citizens Hospital, 7-33
Moto-machi, Naka-ku, Hiroshima 730-8518, Japan
9
Department of Hematology and Oncology, Mie University Graduate School of
Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan.
10
Department of Pharmacy, Mie University Hospital, 2-174 Edobashi, Tsu, Mie
514-8507, Japan.
11
Department of Breast Surgery, Hokkaido Cancer Center, 4-2-3-54 Kikusui,

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Shiroishiku, Sapporo 003-0804, Japan.

12
Department of Surgery, Matsusaka City Hospital, 1550 Tono-machi, Matsusaka, Mie
515-8544, Japan.
13
Division of Hematology/Oncology, Suzuka General Hospital, 1275-53
Yasuzuka-Yamanohana, Suzuka, Mie 513-8630, Japan.
14

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Department of Surgery, Mie Prefectural General Medical Center, 5450-132 Hinaga,
Yokkaichi, Mie 510-0885, Japan.
15
Department of Immuno-Gene Therapy, Mie University Graduate School of Medicine,

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2-174 Edobashi, Tsu, Mie 514-8507 Japan.
16
Department of Breast Surgery, Hiroshima City Hiroshima Citizens Hospital, 7-33

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Moto-machi, Naka-ku, Hiroshima 730-8518, Japan
17
Department of Medical Innovation, Osaka University Hospital, 2-2, Yamadaoka, Suita,
Osaka 565-0871, Japan.

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Correspondence: Satoshi Yokoyama Ph.D., Department of Community Pharmacy, Gifu
Pharmaceutical University. 1-108-3 Daigaku-Nishi, Gifu, Gifu 501-1113, Japan. Tel.:
+81-58-293-0220, Fax: +81-58-293-0221, E-mail: yokoyamas@gifu-pu.ac.jp
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Abstract

Poor control of chemotherapy-induced nausea and vomiting (CINV) is associated

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with poor clinical outcomes. We investigated genetic polymorphisms as risk factors

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for CINV in Japanese breast cancer patients receiving anthracycline-based

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chemotherapy. The ABCG2 (rs2231142) AA genotype was significantly associated

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with an increased risk of acute significant nausea. For patients with this genotype,
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a more effective antiemetic strategy is necessary.

Introduction: Breast cancer patients often receive anthracycline-based chemotherapy,

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and chemotherapy-induced nausea and vomiting (CINV) remains one of the most
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uncomfortable and distressing adverse reactions. Poor control of CINV reduces the
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relative dose intensity of chemotherapy agents, which is associated with poor clinical
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outcomes and shorter survival. The aim of the present study was to identify genetic risk
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factors associated with anthracycline-based CINV.

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Patients and Methods: We evaluated CINV attributable to anthracycline-based

chemotherapy in Japanese breast cancer patients treated with an antiemetic regimen that

included palonosetron, aprepitant, and dexamethasone. Further, we investigated the

associations between CINV and single nucleotide polymorphisms in six candidate

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genes.

Results: Emesis episodes were rarely observed in the 125 patients included in this

survey (7.2%, n = 9); however, significant nausea occurred in more than half of the

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patients (52.8%, n = 66). In particular, acute significant nausea was not effectively

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controlled. Multivariate logistic regression analysis revealed that the ABCG2

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(rs2231142) AA genotype is significantly associated with acute significant nausea (odds

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ratio: 4.87, 95% confidence interval: 1.01–23.60, p = 0.049).
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Conclusion: The findings of this study provide significant insights for developing

personalized antiemetic strategies for breast cancer patients receiving

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anthracycline-based chemotherapy.
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Keywords: Anthracycline, Chemotherapy-induced nausea and vomiting, Genetic risk

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factors, Antiemetics, Single nucleotide polymorphism.

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Introduction

Breast cancer patients often receive anthracycline-based chemotherapy, and

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chemotherapy-induced nausea and vomiting (CINV) remains one of the most

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uncomfortable and distressing adverse reactions observed in these patients. CINV leads

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to a decrease in appetite and body weight and decreases the quality of life (QOL).1 In

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addition, the administered dose of chemotherapy agents is reduced in patients with
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CINV, resulting in delayed treatment. Recent reports emphasize the importance of

sustaining the full-dose intensity of adjuvant chemotherapy.2,3 Therefore, it is important

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to control CINV to receive the maximum benefits of chemotherapy.

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Established guidelines for management of CINV recommend three types of drugs,

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including 5-hydroxytryptamine receptor antagonists (5-HT3RA), neurokinin 1 receptor

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antagonists (NK1RA), and corticosteroids.4 For highly emetogenic chemotherapy such

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as anthracycline-based chemotherapy, use of a triple antiemetic regimen that includes a

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5-HT3RA, a NK1RA, and corticosteroids is recommended.5 Palonosetron and aprepitant,

second generation 5-HT3RAs and NK1RAs, respectively, have recently been developed.

These two drugs are effective against CINV and have dramatically changed antiemetic

therapy for CINV.6

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The triple antiemetic regimen consisting of palonosetron, aprepitant, and

dexamethasone (PAD regimen) demonstrated better efficacy for preventing CINV in

breast cancer patients administered anthracycline-based chemotherapy7 than that of an

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earlier antiemetic regimen comprising first generation 5-HT3RAs such as ondansetron

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and granisetron, with or in the absence of aprepitant.8,9 However, clinical outcomes

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from the PAD regimen have not been satisfactory. Furthermore, the study7 reported by

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Hesketh et al. was conducted on a small scale and the subjects were not Asian; severe
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CINV tends to occur in Asian women with breast cancer.10 Therefore, one reason for the

failure of antiemetic treatment could be individual variations in genetic polymorphisms.

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Genetic variations in which single nucleotide polymorphisms (SNPs) play a key role
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might influence the therapeutic and adverse reactions of multiple drugs in different
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patients.11 Pharmacogenomic studies of CINV are few and focus primarily on

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polymorphisms associated with drug transporters in the cell membrane, drug

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metabolism enzymes, and the serotonin receptor.12 Previously, adenosine triphosphate

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binding cassette (ABC) transporters, cytochrome P450s, and 5-HT3 receptor subunits

have been the targets of interest.13 Several studies have examined antiemetic outcomes

of first generation 5-HT3RAs and genetic polymorphisms.8,14,15 However, there have

been few investigations examining the relation between genetic polymorphisms and the

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antiemetic effects of second generation 5-HT3RAs and NK1RAs.

The development of antiemetic agents has dramatically suppressed the incidence of

vomiting in cancer patients. However, control of nausea remains unsatisfactory, and

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severe nausea influences QOL and patient compliance with treatment. Therefore, this

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observational study evaluated the efficacy of the PAD regimen in naïve Japanese breast

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cancer patients receiving anthracycline-based chemotherapy, with a focus on severe

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nausea. The aim of this study was to identify genetic risk factors associated with
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anthracycline-based CINV.
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Patients and Methods

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Study design
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To investigate genetic polymorphisms as risk factors for CINV, we conducted a

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multi-institutional, prospective, observational, non-comparative study. The protocol was

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approved by the medical ethics review board of all the participating institutions, and
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signed consents were obtained from all patients. This study was performed in

accordance with the Declaration of Helsinki (Clinical Trial ID: UMIN000010423).

Inclusion criteria

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Patients eligible for inclusion were chemotherapy naïve Japanese female patients with

histologically confirmed breast cancer. Included patients were over 20 years old and

scheduled to receive their first cycle of anthracycline-based chemotherapy (combined

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anthracycline and cyclophosphamide ± fluorouracil [5-FU]). Additional criteria

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included an Eastern Cooperative Oncology Group performance status of 0–1 and

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adequate general health, including white blood cell count ≥ 3,000 /mm3, platelet count ≥

75,000/mm3, hemoglobin ≥ 8.0 g/dL, aspartate aminotransferase and alanine

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aminotransferase ≤ 3.0X the normal upper limit, blood bilirubin ≤ 1.5X the normal

upper limit, and creatinine ≤ 1.5X the normal upper limit.

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Exclusion criteria
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To eliminate the influence of co-medications on the genotype-phenotype correlations,

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patients with factors such as brain tumor, brain metastasis causing nausea and vomiting,
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and those who received a CYP3A4 inducer, CYP2D6 inhibitor, 5-HT3RA, and/or
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NK1RA within seven days before administration of the anticancer agents were excluded

from the study. Exclusion conditions also included radiation therapy within 14 days

before the administration of anticancer agents; hypersensitivity to palonosetron,

aprepitant, or dexamethasone; pregnancy; and unstable glycemic control. Patients were

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also excluded if they were unable to cooperate or were judged by an investigator to be

unfit for participation in the study.

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Chemotherapy

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All patients received doxorubicin (60 mg/m2) and cyclophosphamide (600 mg/m2)

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(AC regimen); epirubicin (90 mg/m2) and cyclophosphamide (600 mg/m2) (EC

regimen); or epirubicin (100 mg/m2), cyclophosphamide (500 mg/m2), and 5-FU (500

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mg/m2) (FEC regimen).
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Antiemetic treatment
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Patients receiving the AC, EC, or FEC regimens were administered either aprepitant
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or fosaprepitant meglumine prior to administration of the first emetogenic

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chemotherapy agent on day 1 of the first cycle. Aprepitant (day 1: 125 mg, days 2 and 3:
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80 mg), palonosetron (day 1: 0.75 mg), and dexamethasone (day 1: 9.9 mg, days 2–4:
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8.0 mg) were administered to patients receiving aprepitant. In Japan, doses of 0.25 mg

and 0.75 mg palonosetron were identified as effective and well tolerated;16 therefore, we

chose the 0.75 mg dose. Fosaprepitant meglumine (day 1: 150 mg), palonosetron (day

1: 0.75 mg), and dexamethasone (day 1: 9.9 mg, day 2: 8.0 mg, days 3 and 4: 8.0 mg

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b.i.d.) were administered to patients treated with fosaprepitant meglumine in accordance

with the guidelines for antiemetics in oncology prescribed by the Japanese Society of

Clinical Oncology (2010). Rescue medication was permitted.

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Assessment of nausea and vomiting

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To examine the occurrence of nausea and vomiting, patients were asked to fill in a

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diary on days 1–5 (0–120 h) of the first treatment cycle. All antiemetic efficacy
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endpoints were based on the diary data. Patient diaries contained data on the severity of

nausea, measured using a 100-mm horizontal visual analog scale (VAS) at 24-h
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intervals up to 120 h. The diary also contained information on any experience of

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retching/vomiting and the intake of rescue medication after the chemotherapy. The VAS
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scores (in mm) for nausea were categorized as follows: no nausea: < 5 mm, mild
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nausea: ≥ 5 mm and < 25 mm, significant nausea: ≥ 25 mm. The occurrence of anorexia
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was also evaluated. We defined significant anorexia as appetite suppression leading to

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lower food intake than that observed at baseline. In the observation period, which was

divided into three distinct phases after chemotherapy, namely overall (0–120 h), acute

(0–24 h), and delayed (24–120 h), we evaluated the proportion of patients achieving a

complete response (CR, defined as no emesis and no rescue medication) or complete

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control (CC, defined as no emesis, no significant nausea, and no rescue medication).

DNA extraction and genotyping

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A blood sample (5 mL) from each patient was collected in an

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ethylenediaminetetraacetic acid (EDTA)-containing storage tube, and the whole blood

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samples were stored at −20 °C for DNA extraction. DNA was purified from whole

blood samples using NucleoSpin® Blood QuickPure (Macherey Nagel, Duren,

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Germany). Laboratory genotyping analysis was performed on all samples for SNPs,

including ABCB1 (rs1128503, rs2032582, rs1045642), ABCG2 (rs2231142), CYP2D6

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(rs1065852), CYP3A5 (rs776746), HTR3C (rs6766410), and HTR3D (rs6443930).

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These candidate SNPs were previously reported to be either associated with antiemetic
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efficacy8,14–15,17 or known to influence drug efficacy.18,19 Genotyping for the SNPs was
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performed using the commercially available TaqMan® Assays-on-demand (Life

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Technologies Japan Ltd., Tokyo, Japan). Genotyping PCR assays were carried out using
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the Applied Biosystems StepOnePlus™ Real-Time PCR System (Life Technologies

Japan Ltd., Tokyo, Japan) according to the instructions provided in the TaqMan®

manual.

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Statistical analysis

Categorical variables are represented as frequencies and proportions, continuous

variables are represented as means ± standard deviation. Data distributions of

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continuous variables were checked for normality with the Shapiro–Wilk normality test.

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The Chi-square test (or Fisher’s exact test) was performed to test the association

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between patient characteristic and CINV outcomes. The association between genotypes

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and CINV was assessed by odds ratio and 95% confidence intervals from multivariate
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logistic regression analysis, with adjustments for age, alcohol habit, morning sickness,

and motion sickness. All tests were two-sided, and results with a p-value < 0.05 were
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considered significant. All statistical analyses were performed with EZR ver. 1.30
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(Saitama Medical Center, Jichi Medical University; Kanda, 2012), which is a graphical
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user interface for R (The R Foundation for Statistical Computing).20

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Results
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Patient characteristics

We enrolled 126 patients between April 2013 and March 2015. One patient was

excluded from the analyses because of erroneous administration of 80 mg aprepitant

instead of 125 mg on day 1. Table 1 shows the clinical characteristics of the enrolled

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patients (n = 125). The SNP allele frequencies of the target polymorphisms

(Supplementary Table A.1) were similar to those described elsewhere for Japanese

persons (SNP database; http://www.ncbi.nlm.nih.gov/snp), and all the SNPs were in

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Hardy-Weinberg equilibrium (p > 0.05).

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Antiemetic efficacy

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CR during the overall phase was achieved in 63.2% (79/125) of patients. CR rates in
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the acute and delayed phase were 75.2 (94/125) and 77.6% (97/125), respectively. CC

rates for the overall, acute, and delayed phases were 39.2 (49/125), 55.2 (69/125), and
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62.0% (73/125), respectively.

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The expression of emesis, significant nausea, and significant anorexia is shown in

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Supplementary Table A.2. The emesis rate, significant nausea rate, and significant
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anorexia rate for the overall phase were 7.2, 52.8, and 72.6%, respectively. During both
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the acute and delayed phase, emesis rates were very low. However, significant nausea
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rates were observed during the acute and delayed phase (39.2 and 36.0%, respectively).

Furthermore, significant anorexia rates were observed during the acute and delayed

phase (49.2 and 71.8%, respectively). Table 2 shows that acute significant nausea was

closely related to significant anorexia during all phases (p < 0.01).

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Change in the expression of nausea with time

Significant nausea plus mild nausea was observed in 64.8% (81/125) of patients on

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day 1. This percentage was gradually reduced to 34.4% (43/125) over a period of five

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days (Figure 1). In particular, the percentage of patients showing significant nausea on

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day 5 (15.2%) was less than half of those on day 1 (39.2%).

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Onset of the first significant nausea

During the overall phase, there were 66 patients who experienced significant nausea.
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Among these 66 patients, 74.3% patients (49/66) experienced the first significant nausea
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on day 1 (Figure 2).

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Characteristics and treatment parameters of patients showing acute significant

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nausea
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In the present study, the frequency of emesis episodes was very low. However,

significant nausea during the overall phase was observed in more than half of the

patients. The percentage of patients showing significant nausea on day 1 was higher

than that on other days. To understand the relation between significant nausea and

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patient characteristics, we analyzed the clinical and treatment parameters in patients

showing acute significant nausea (Table 3). Youth (the cutoff age for defining youth was

determined from the receiver operating characteristics curve) was significantly

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associated with an increase in acute significant nausea (p = 0.002). There were no

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significant associations between previously known risk factors (i.e., motion sickness,

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morning sickness, or alcohol habit) and acute significant nausea. Moreover, no

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significant associations were observed between patient characteristics and delayed
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significant nausea (Supplementary Table A.3).
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Genetic polymorphisms as risk factors for significant nausea in the acute phase
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We performed univariate analysis to explore the association between SNPs and acute
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significant nausea. Results of the univariate analysis suggest that ABCG2 (421C > A, p
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= 0.13) and CYP2D6 (100C > T, p = 0.15) SNPs influence the expression of acute
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significant nausea (Supplementary Table A.4). Based on a previous report,21 we next

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classified ABCB1 polymorphisms into genotype groups (TT and nonTT). In addition,

we classified other polymorphisms into homozygous minor allele or other genotype

groups (Table 4). Univariate analysis indicated an association between acute significant

nausea and a homozygous minor allele of ABCG2 (421C > A, p = 0.048) or CYP2D6

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(100C > T, p = 0.07). Multivariate logistic regression analysis adjusted for age, alcohol

habit, motion sickness, and morning sickness demonstrated that the ABCG2 (rs2231142)

AA genotype is significantly associated with an increased risk of acute significant

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nausea (odds ratio: 4.87, 95% confidence interval: 1.01–23.60, p = 0.049). Associations

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between the CYP2D6 (rs1065852) TT genotype and acute significant nausea did not

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reach statistical significance (odds ratio: 2.87, 95% confidence interval: 0.77–10.60, p =

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0.12) (Table 5). No significant correlations were noted between acute significant nausea
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and the presence of other SNPs, except ABCG2 (rs2231142), during the acute phase.

During the delayed phase, no associations were noted between significant nausea and
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the SNPs investigated in this study (Supplementary Table A.5).

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Discussion
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This study is the first pharmacogenomic study to explore genetic risk factors
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associated with the treatment of CINV by evaluating the detailed antiemetic efficacy of
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the PAD regimen in Japanese breast cancer patients receiving anthracycline-based

chemotherapy.

Before the introduction of palonosetron and aprepitant to the market, the combination

of first generation 5-HT3RAs and dexamethasone was the antiemetic regimen of choice.

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Emesis control rates when using this antiemetic regimen were very low (approximately

50%).9 The introduction of aprepitant as an antiemetic to the regimen improved the

control rate of emesis.22,23 Furthermore, a small scale study using the PAD regimen

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exhibited no emesis in greater than 90% of patients.24,25 Despite the rarity of emesis,

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these studies indicated that the CR rate was 50–60%. The reason for a low CR rate was

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the use of rescue medication to treat nausea; breast cancer patients tend to experience

nausea during the early phase.25 Our results also show that acute significant nausea was

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not well controlled, which is an important issue because of the strong association

between significant nausea and anorexia. Therefore, it is necessary to develop a more

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comprehensive antiemetic strategy by clarifying the risk factors for acute significant
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nausea. It has been reported that the clinical condition of patients, such as age, female
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gender, motion sickness, morning sickness, and alcohol habit might contribute to
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antiemetic effects.10,26-28 In the present study, we investigated genetic polymorphisms as

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risk factors for acute significant nausea.

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ABC transporters are expressed in various tissues and play a role in drug efflux or

drug resistance. Previous clinical studies using first generation 5HT3RAs showed that

the ABCB1 polymorphisms, 3435C > T or 2677G > T/A, are significantly associated

with CINV during the acute phase.8,29 However, our results indicate no significant

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association between these ABCB1 polymorphisms and acute significant nausea.

Differences in our results from those of past reports may be attributable to differing

antiemetics, anticancer agents, subjects, race/ethnicity, and endpoints. However,

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multivariate analysis of our study showed a significant association between the ABCG2

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(rs2231142) AA genotype and acute significant nausea, although there have been no

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previous reports regarding the association between CINV and ABCG2 polymorphisms.

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C to A nucleotide substitution at position 421 results in amino acid substitutions that
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induce changes in activity,18,30-32 and thus might result in altered antiemetic

pharmacokinetics.
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The HTR3C (rs6766410) CC genotype was significantly associated with a higher

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percentage of emesis expression in ondansetron-treated patients.15 Further, the study by

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Fasching et al. showed an increased risk of emesis during the acute phase in patients
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with an HTR3D containing a G allele (rs6443930).17 In our study, the PAD regimen
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greatly suppressed the onset of emesis during the acute phase, and the HTR3C or
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HTR3D polymorphisms included in our study were significantly association with

emesis or nausea during the acute phase.

In vitro studies have suggested that CYP2D6 and CYP3A are involved in the

metabolism of palonosetron.33 Aprepitant undergoes hepatic metabolism with the

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involvement of CYP3A.34 CYP2D6 is highly polymorphic and has many allelic variants.

These CYP2D6 polymorphisms are likely the cause of large differences in the activities

among individuals.35 The existence of a T allele in CYP2D6 (rs1065852) causes lower

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CYP2D6-dependent metabolism. Japanese patients are primarily divided into

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intermediate or extensive metabolizers.36,37 The CYP2D6 (rs1065852) TT genotype is

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present in intermediate metabolizers.38 Kaiser et al. reported that ultra-rapid

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metabolizers have a significantly higher mean number of acute emesis episodes than
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that of all other patients when treated with tropisetron, a first generation 5-HT3RA.14 In

our study, univariate analysis showed that the possibility of significant nausea during
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the acute phase increases in patients with the CYP2D6 (rs1065852) TT genotype.
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However, multivariate analysis revealed that the CYP2D6 C100T polymorphism is not a
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predictor of acute significant nausea. The label information for palonosetron (Aloxi®)
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published by the Food and Drug Administration reports that the clinical
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pharmacokinetic parameters of palonosetron are not significantly different between poor

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and extensive metabolizers of CYP2D6 substrate, which supports our results.

CYP3A5 and CYP3A4 proteins are highly homologous and frequently metabolize the

same substrates.39 The CYP3A5 6986G > A (rs776746) polymorphism causes decreased

activity, and a close linkage has been found between rs776746 and CYP3A4 SNPs in the

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Japanese population.40 Therefore, we suggest that rs776746 in CYP3A5 led to the

differences observed among individuals by changing the total metabolic activity of

CYP3A. However, our data indicate that rs776746 in CYP3A5 is not a significant risk

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factor for acute significant nausea. The pharmacokinetic study of aprepitant in Japanese

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patients performed by Motohashi et al. revealed that the AUC for aprepitant does not

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correlate with rs776746 in CYP3A5.41 Further, CYP3A5 6986G > A does not appear to

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influence the antiemetic efficacy of the PAD regimen.
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Genetic variants might alter the pharmacokinetics and pharmacodynamics of

anticancer and antiemetic drugs and in doing so influence their propensity to cause
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CINV.12 Some transporters and drug-metabolizing enzymes are shared by both

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antiemetic drugs and anticancer drugs.42 The anthracycline agents, doxorubicin and
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epirubicin, are also substrates of ABCB1 and ABCG2,43,44 and cyclophosphamide is

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metabolized by CYP3A. Genetic polymorphisms of ABC transporters or CYP450s

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contribute to the individual differences in pharmacokinetics of anticancer drugs. In fact,

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the efficacy or toxicity of anthracycline-based chemotherapy is related to genetic

polymorphisms of ABC transporters or CYP450s.45-47 SNP in ABCG2 (rs2231142) has

been associated with decreased levels of ABCG2 protein expression and/or activity,

which might result in hypersensitivity against ABCG2 substrates in Asian

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populations.33,48 Enhancement of CINV in rs2231142, as observed in our study, is likely

caused by the delayed efflux of anthracycline agents. We suggest that the substrate

specificity of anticancer and antiemetic agents influences the antiemetic efficacy. In

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clinical practice, other antiemetics such as olanzapine should be added to triple

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antiemetic regimens in patients with the AA genotype (rs2231142). Furthermore,

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lorazepam and H2 blockers or proton pump inhibitors as adjuvants may be added to this

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antiemetic regimen; such changes in antiemetic treatment may lead to improvements in
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QOL and clinical outcomes. The advantages of a personalized antiemetic strategy based

on genotype are clear when compared with the cost of regular testing.
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In our study, there were no significant relations between delayed significant nausea
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and genetic polymorphisms. Figure 1 shows that patients had a high expression rate of
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significant nausea on day 1. However, some patients experienced their first significant
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nausea episode on day 4 or 5. The expression mechanism of this delayed nausea is

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thought to differ from that of acute nausea. Differences in the expression mechanism
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appear to involve other 5-HT3 receptor subunit polymorphisms or NK1 receptor

polymorphisms.

The present study has some limitations, including an inadequate sample size,

confounding factors, and use of a single race/ethnicity. The small sample size of patients

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with AA homozygous ABCG2 C421A was a major limitation of this study. The power

for 125 patients receiving the PAD regimen (proportions of acute significant nausea:

7/10 = 0.7 and 42/115 = 0.37 for AA and non-AA in ABCG2 421C > A, respectively),

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calculated based on a two-sided chi-square test at 0.05 significance level, was 0.40. To

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reach adequate statistical power, twice the number of cases as that used in our study

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would be required. Further, we did not perfectly consider all confounding factors, such

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as possible psychological aspects; for example, anxiety could be associated with acute
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nausea.49 Our data provide preliminary information about the Japanese population and

can likely be translated to Asian populations. A future basic study focusing on the
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influence of genetic polymorphisms on membrane transport and pharmacokinetics of

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palonosetron or aprepitant is necessary. Thus, CINV risk factors associated with genetic
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polymorphisms in breast cancer patients administered anthracycline-based

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chemotherapy should be further investigated.

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Conclusion

In conclusion, our findings suggest that breast cancer patients with the ABCG2

(rs2231142) AA genotype receiving anthracycline-based chemotherapy experience more

episodes of acute significant nausea than that of other patients. For patients with this

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genetic risk factor, a more effective antiemetic strategy for acute significant nausea

might be necessary. Further large-scale studies are needed to confirm these results and

assist in the development of personalized antiemetic strategies.

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Clinical Practice Points

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Breast cancer patients often receive anthracycline-based chemotherapy.

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Chemotherapy-induced nausea and vomiting remains one of the most
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uncomfortable and distressing consequences, despite significant advances in

antiemetic treatments.
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It has been reported that the clinical condition of patients, such as age and female
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gender, might contribute to antiemetic effects. However, there have been few
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studies regarding the relation between genetic polymorphisms and antiemetic

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efficacy.
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We evaluated the efficacy of the palonosetron, aprepitant, and dexamethasone

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combined antiemetic regimen in naïve Japanese breast cancer patients receiving

anthracycline-based chemotherapy. Emesis episodes were rarely observed in the

125 patients included in this survey; however, significant nausea occurred in more

than half of the patients. Acute significant nausea was closely related to significant

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anorexia.

Multivariate logistic regression analysis demonstrated that the ABCG2 (rs2231142)

AA genotype was significantly associated with an increased risk of acute significant

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nausea.

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For breast cancer patients with the ABCG2 (rs2231142) AA genotype who are

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receiving anthracycline-based chemotherapy, a more effective antiemetic strategy

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might be necessary. AN
Acknowledgments
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We thank Mr. Shinya Takada (Department of Pharmacy, Hokkaido Cancer Center,

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Sapporo, Japan) for his assistance in this work. We also thank all patients and medical
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staff who participated in this study.

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Disclosure
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The authors declare no conflict of interest.

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References

1. Cohen L, de Moor CA, Eisenberg P, et al. Chemotherapy-induced nausea and

vomiting: incidence and impact on patient quality of life at community oncology

PT
settings. Support Care Cancer 2007; 15: 497–503.

RI
2. Budman DR, Berry DA, Cirrincione CT, et al. Dose and dose intensity as

SC
determinants of outcome in the adjuvant treatment of breast cancer. The Cancer and

U
Leukemia Group B. J Natl Cancer Inst 1998; 90: 1205–11.
AN
3. Lyman GH, Dale DC, Crawford J. Incidence and predictors of low dose-intensity in

adjuvant breast cancer chemotherapy: a nationwide study of community practices. J

M

Clin Oncol 2003; 21: 4524–31.

D

4. Basch E, Prestrud AA, Hesketh PJ, et al. Antiemetics: American Society of Clinical
TE

Oncology clinical practice guideline update. J Clin Oncol 2011; 29: 4189–98.
EP

5. Roila F, Herrstedt J, Aapro M, et al. Guideline update for MASCC and ESMO in
C

the prevention of chemotherapy- and radiotherapy-induced nausea and vomiting:

AC

results of the Perugia consensus conference. Ann Oncol 2010; 21 Suppl 5: v232–43.

6. Oo TH, Hesketh PJ. Drug insight: New antiemetics in the management of

chemotherapy-induced nausea and vomiting. Nat Clin Pract Oncol 2005; 2: 196–

201.

26
 ACCEPTED MANUSCRIPT

7. Hesketh PJ, Sanz-Altamira P. Aprepitant, dexamethasone, and palonosetron in the

prevention of doxorubicin/cyclophosphamide-induced nausea and vomiting.

Support Care Cancer 2012; 20: 653–6.

PT
8. Tsuji D, Kim YI, Nakamichi H, et al. Association of ABCB1 polymorphisms with

RI
the antiemetic efficacy of granisetron plus dexamethasone in breast cancer patients.

SC
Drug Metab Pharmacokinet 2013; 28: 299–304.

U
9. Yeo W, Mo FK, Suen JJ, et al. A randomized study of aprepitant, ondansetron and
AN
dexamethasone for chemotherapy-induced nausea and vomiting in Chinese breast

cancer patients receiving moderately emetogenic chemotherapy. Breast Cancer Res

M

Treat 2009; 113: 529–35.

D

10. Bourdeanu L, Frankel P, Yu W, et al. Chemotherapy-induced nausea and vomiting

TE

in Asian women with breast cancer receiving anthracycline-based adjuvant

EP

chemotherapy. J Support Oncol 2012; 10: 149–54.

C

11. Kurose K, Sugiyama E, Saito Y. Population differences in major functional

AC

polymorphisms of pharmacokinetics/pharmacodynamics-related genes in Eastern

Asians and Europeans: implications in the clinical trials for novel drug

development. Drug Metab Pharmacokinet 2012; 27: 9–54.

12. Sugino S, Janicki PK. Pharmacogenetics of chemotherapy-induced nausea and

27
 ACCEPTED MANUSCRIPT

vomiting. Pharmacogenomics 2015; 16: 149–60.

13. Perwitasari DA, Gelderblom H, Atthobari J, et al. Anti-emetic drugs in oncology:

pharmacology and individualization by pharmacogenetics. Int J Clin Pharm 2011;

PT
33: 33–43.

RI
14. Kaiser R, Sezer O, Papies A, et al. Patient-tailored antiemetic treatment with

SC
5-hydroxytryptamine type 3 receptor antagonists according to cytochrome P-450

U
2D6 genotypes. J Clin Oncol 2002; 20: 2805–11.
AN
15. Fasching PA, Kollmannsberger B, Strissel PL, et al. Polymorphisms in the novel

serotonin receptor subunit gene HTR3C show different risks for acute
M

chemotherapy-induced vomiting after anthracycline chemotherapy. J Cancer Res

D

Clin Oncol 2008; 134: 1079–86.

TE

16. Maemondo M, Masuda N, Sekine I, et al. A phase II study of palonosetron

EP

combined with dexamethasone to prevent nausea and vomiting induced by highly

C

emetogenic chemotherapy. Ann Oncol 2009; 20: 1860-6.

AC

17. Hammer C, Fasching PA, Loehberg CR, et al. Polymorphism in HTR3D shows

different risks for acute chemotherapy-induced vomiting after anthracycline

chemotherapy. Pharmacogenomics 2010; 11: 943–50.

18. Mizuno T, Terada T, Kamba T, et al. ABCG2 421C>A polymorphism and high

28
 ACCEPTED MANUSCRIPT

exposure of sunitinib in a patient with renal cell carcinoma. Ann Oncol 2010; 21:

1382–3.

19. Takashina Y, Naito T, Mino Y, et al. Impact of CYP3A5 and ABCB1 gene

PT
polymorphisms on fentanyl pharmacokinetics and clinical responses in cancer

RI
patients undergoing conversion to a transdermal system. Drug Metab

SC
Pharmacokinet 2012; 27: 414–21.

U
20. Kanda Y. Investigation of the freely available easy-to-use software 'EZR' for
AN
medical statistics. Bone Marrow Transplant 2013; 48: 452–8.

21. Tsuji D, Yokoi M, Suzuki K, et al. Influence of ABCB1 and ABCG2

M

polymorphisms on the antiemetic efficacy in patients with cancer receiving

D

cisplatin-based chemotherapy: a TRIPLE pharmacogenomics study.

TE

Pharmacogenomics J 2016; doi: 10.1038/tpj.2016.38.

EP

22. Rapoport BL, Jordan K, Boice JA, et al. Aprepitant for the prevention of
C

chemotherapy-induced nausea and vomiting associated with a broad range of

AC

moderately emetogenic chemotherapies and tumor types: a randomized,

double-blind study. Support Care Cancer 2010; 18: 423–31.

23. Warr DG, Hesketh PJ, Gralla RJ, et al. Efficacy and tolerability of aprepitant for the

prevention of chemotherapy-induced nausea and vomiting in patients with breast

29
 ACCEPTED MANUSCRIPT

cancer after moderately emetogenic chemotherapy. J Clin Oncol 2005; 23: 2822–

30.

24. Meattini I, Francolini G, Scotti V, et al. Aprepitant as prophylaxis of

PT
chemotherapy-induced nausea and vomiting in anthracyclines and

RI
cyclophosphamide-based regimen for adjuvant breast cancer. Med Oncol 2015; 32:

SC
80.

U
25. Grunberg SM, Dugan M, Muss H, et al. Effectiveness of a single-day three-drug
AN
regimen of dexamethasone, palonosetron, and aprepitant for the prevention of acute

and delayed nausea and vomiting caused by moderately emetogenic chemotherapy.

M

Support Care Cancer 2009; 17: 589–94.

D

26. Tamura K, Aiba K, Saeki T, et al. Testing the effectiveness of antiemetic guidelines:
TE

results of a prospective registry by the CINV Study Group of Japan. Int J Clin
EP

Oncol 2015; 20: 855–65.

C

27. Osoba D, Zee B, Pater J, et al. Determinants of postchemotherapy nausea and

AC

vomiting in patients with cancer. Quality of Life and Symptom Control Committees

of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol

1997; 15: 116–23.

28. Hesketh PJ, Aapro M, Street JC, et al. Evaluation of risk factors predictive of

30
 ACCEPTED MANUSCRIPT

nausea and vomiting with current standard-of-care antiemetic treatment: analysis of

two phase III trials of aprepitant in patients receiving cisplatin-based chemotherapy.

Support Care Cancer 2010; 18: 1171–7.

PT
29. Babaoglu MO, Bayar B, Aynacioglu AS, et al. Association of the ABCB1 3435C>T

RI
polymorphism with antiemetic efficacy of 5-hydroxytryptamine type 3 antagonists.

SC
Clin Pharmacol Ther 2005; 78: 619–26.

U
30. Furukawa T, Wakabayashi K, Tamura A, et al. Major SNP (Q141K) variant of
AN
human ABC transporter ABCG2 undergoes lysosomal and proteasomal

degradations. Pharm Res 2009; 26: 469–79.

M

31. Morisaki K, Robey RW, Ozvegy-Laczka C, et al. Single nucleotide polymorphisms

D

modify the transporter activity of ABCG2. Cancer Chemother Pharmacol 2005; 56:
TE

161–72.
EP

32. Kim HR, Park HS, Kwon WS, et al. Pharmacogenetic determinants associated with
C

sunitinib-induced toxicity and ethnic difference in Korean metastatic renal cell

AC

carcinoma patients. Cancer Chemother Pharmacol 2013; 72: 825–35.

33. Janicki PK. Cytochrome P450 2D6 metabolism and 5-hydroxytryptamine type 3

receptor antagonists for postoperative nausea and vomiting. Med Sci Monit 2005;

11: RA322–8.

31
 ACCEPTED MANUSCRIPT

34. Sanchez RI, Wang RW, Newton DJ, et al. Cytochrome P450 3A4 is the major

enzyme involved in the metabolism of the substance P receptor antagonist

aprepitant. Drug Metab Dispos 2004; 32: 1287–92.

PT
35. Ozawa S, Soyama A, Saeki M, et al. Ethnic differences in genetic polymorphisms

RI
of CYP2D6, CYP2C19, CYP3As and MDR1/ABCB1. Drug Metab Pharmacokinet

SC
2004; 19: 83–95.

U
36. Tateishi T, Chida M, Ariyoshi N, et al. Analysis of the CYP2D6 gene in relation to
AN
dextromethorphan O-demethylation capacity in a Japanese population. Clin

Pharmacol Ther 1999; 65: 570–5.

M

37. Kubota T, Yamaura Y, Ohkawa N, et al. Frequencies of CYP2D6 mutant alleles in a

D

normal Japanese population and metabolic activity of dextromethorphan

TE

O-demethylation in different CYP2D6 genotypes. Br J Clin Pharmacol 2000; 50:

EP

31–4.
C

38. Sakuyama K, Sasaki T, Ujiie S, et al. Functional characterization of 17 CYP2D6

AC

allelic variants (CYP2D6.2, 10, 14A-B, 18, 27, 36, 39, 47-51, 53-55, and 57). Drug

Metab Dispos 2008; 36: 2460–7.

39. Tseng E, Walsky RL, Luzietti RA Jr, et al. Relative contributions of cytochrome

CYP3A4 versus CYP3A5 for CYP3A-cleared drugs assessed in vitro using a

32
 ACCEPTED MANUSCRIPT

CYP3A4-selective inactivator (CYP3cide). Drug Metab Dispos 2014; 42: 1163–73.

40. Fukushima-Uesaka H, Saito Y, Watanabe H, et al. Haplotypes of CYP3A4 and their

close linkage with CYP3A5 haplotypes in a Japanese population. Hum Mutat 2004;

PT
23: 100.

RI
41. Motohashi S, Mino Y, Hori K, et al. Interindividual variations in aprepitant plasma

SC
pharmacokinetics in cancer patients receiving cisplatin-based chemotherapy for the

U
first time. Biol Pharm Bull 2013; 36: 676–81.
AN
42. Deenen MJ, Cats A, Beijnen JH, et al. Part 2: pharmacogenetic variability in drug

transport and phase I anticancer drug metabolism. Oncologist 2011; 16: 820–34.
M

43. Doyle L, Ross DD. Multidrug resistance mediated by the breast cancer resistance
D

protein BCRP (ABCG2). Oncogene 2003; 22: 7340–58.

TE

44. Higgins CF. Multiple molecular mechanisms for multidrug resistance transporters.
EP

Nature 2007; 446: 749–57.

C

45. Lal S, Wong ZW, Sandanaraj E, et al. Influence of ABCB1 and ABCG2
AC

polymorphisms on doxorubicin disposition in Asian breast cancer patients. Cancer

Sci 2008; 99: 816–23.

46. Bray J, Sludden J, Griffin MJ, et al. Influence of pharmacogenetics on response and

toxicity in breast cancer patients treated with doxorubicin and cyclophosphamide.

33
 ACCEPTED MANUSCRIPT

Br J Cancer 2010; 102: 1003–9.

47. Petros WP, Hopkins PJ, Spruill S, et al. Associations between drug metabolism

genotype, chemotherapy pharmacokinetics, and overall survival in patients with

PT
breast cancer. J Clin Oncol 2005; 23: 6117–25.

RI
48. Imai Y, Nakane M, Kage K, et al. C421A polymorphism in the human breast cancer

SC
resistance protein gene is associated with low expression of Q141K protein and

U
low-level drug resistance. Mol Cancer Ther 2002; 1: 611–6.
AN
49. Shih V, Wan HS, Chan A. Clinical predictors of chemotherapy-induced nausea and

vomiting in breast cancer patients receiving adjuvant doxorubicin and

M

cyclophosphamide. Ann Pharmacother 2009; 43: 444–52.

D
TE
C EP
AC

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Figure captions

Figure 1

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Time course of the percentage of patients with no nausea, mild nausea, and significant

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nausea (in 24 h). No nausea: VAS score < 5 mm, mild nausea: VAS score ≥ 5 mm and <

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25 mm, significant nausea: VAS score ≥ 25 mm, n = 125.

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Figure 2

Percentage of patients experiencing their first significant nausea. Most patients

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experienced the first significant nausea 0–24 h (day 1) after receiving chemotherapy (n
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= 49/66).
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Table 1. Characteristics of patients (n=125)
Characteristics Number of Patients (%)
Age
mean ± S.D. 52.6 ± 10.9
Postmenopausal 64 (51.2)
Height (cm)
mean ± S.D. 156.3 ± 5.7

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Weight (kg)
mean ± S.D. 54.9 ± 9.3

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BMI (kg/m )
mean ± S.D. 22.5 ± 3.56

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BSA (m2)
mean ± S.D. 1.53 ± 0.10

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ECOG PS
0 124 (99.2)
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1 1 (0.8)
Cancer stage
I 33 (26.4)
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II 66 (52.8)
III 23 (18.4)
IV 3 (2.4)
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Chemotherapy regimen
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AC 36 (28.8)
EC 46 (36.8)
FEC 43 (34.4)
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Chemotherapy dosage (mg)

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DXR (mean ± S.D.) 93.7 ± 7.1
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CPA (mean ± S.D.) 937.7 ± 71.1

EC
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EPI (mean ± S.D.) 131.0 ± 13.0

CPA (mean ± S.D.) 883.5 ± 84.2
FEC
EPI (mean ± S.D.) 154.0 ± 12.4
CPA (mean ± S.D.) 770.5 ± 61.9
5-FU (mean ± S.D.) 770.7 ± 61.9
Purpose of chemotherapy
Adjuvant 92 (73.6)
Neoadjuvant 30 (24.0)
Metastatic breast cancer 3 (2.4)
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NK1RA
Aprepitant 112 (89.6)
Fosaprepitant 13 (10.4)
Alcohol habit
Yes 37 (29.6)
No 88 (70.4)
Tobacco use
Non- or ex- smoker 117 (93.6)

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Current smoker 8 (6.4)
History of motion sickness
Yes 33 (26.4)

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No 92 (73.6)
Morning sickness

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Yes 25 (20.0)
No 73 (58.4)
N.A. 27 (21.6)

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S.D.: standard deviation, BMI: body mass index, BSA: body surface area,
ECOG PS: eastern Cooperative Oncology Group performance status,
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DXR: doxorubicin, CPA: cyclophosphamide, EPI: epirubicin, 5-FU: 5-
fluorouracil, NK1RA: neurokinin-1 receptor antagonist, N.A.: not
available.
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Table 2. Univariate analysis of acute nausea associated with significant anorexia

Significant anorexia
Overall Acute Delayed
OR (95% CI) p -value OR (95% CI) p -value OR (95% CI) p -value
Acute nausea
(significant + mild)
Yes vs. No 2.79 (1.15-6.86) 0.02 6.00 (2.47-15.70) <0.01 2.58 (1.08-6.29) 0.02

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Acute significant nausea
Yes vs. No 7.23 (2.28-30.55) <0.01 16.33 (6.05-50.40) <0.01 10.96 (3.09-59.98) <0.01

OR: odds ratio, CI: confidential interval, vs.: versus.

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Table 3. 　Univariate analysis of characteristics of patients and treatment parameters associated with significant nausea in acute ph

Variable Significant nausea (acute) No significant nausea (acute) p -value

n (%) n (%)
Age (years) 55< 12 (24.5) 41 (53.9) <0.01
55≧ 37 (75.5) 35 (46.1)

BMI (kg/m2) <18.5 5 (10.2) 8 (10.5) 0.34

18.5≦, <25.0 37 (75.5) 49 (64.5)
25.0≦ 7 (14.3) 19 (25.0)

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Alcohol habit Yes 13 (26.5) 24 (31.6) 0.55
No 36 (73.5) 52 (68.4)

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Motion sickness Yes 16 (32.7) 17 (22.4) 0.20
No 33 (67.3) 59 (77.6)
Morning sickness Yes 12 (32.4) 13 (21.3) 0.22

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No 25 (67.6) 48 (78.7)
Smoking Non or Ex 47 (95.9) 70 (92.1) 0.48
Current 2 (4.1) 6 (7.9)

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NK1RA Aprepitant 45 (91.8) 67 (88.2) 0.57
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Fosaprepitant 4 (8.2) 　9 (11.8)
Regimen AC 14 (28.6) 22 (28.9) 1.00
EC 18 (36.7) 28 (36.9)
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FEC 17 (34.7) 26 (34.2)

BMI: body mass index, NK1RA: neurokinin 1 receptor antagonist.
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genotype group with significant nausea in acute phase

SNPs Genotype group Significant nausea (acute) No significant nausea (acute) p -value
n (%) n (%)
ABCB1 1236C>T TT 24 (49.0) 34 (44.7) 0.64
rs1128503 CC+CT 25 (51.0) 42 (55.3)
ABCB1 2677G>T/A TT 10 (20.4) 18 (23.7) 0.67
rs2032582 Non-TT 39 (79.6) 58 (76.3)
ABCB1 3435C>T TT 10 (20.4) 16 (21.1) 0.93
rs1045642 CC+CT 39 (79.6) 60 (78.9)

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ABCG2 421C>A AA 7 (14.3) 3 (3.9) <0.05
rs2231142 CC+CA 42 (85.7) 73 (96.1)
CYP2D6 100C>T TT 11 (22.4) 8 (10.5) 0.07
rs1065852 CC+CT 38 (77.6) 68 (89.5)

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CYP3A5 6986G>A AA 4 (8.2) 6 (7.9) 1.00
rs776746 GG+GA 45 (91.8) 70 (92.1)

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HTR3C 489C>A CC 9 (18.4) 16 (21.1) 0.82
rs6766410 AA+AC 40 (81.6) 60 (78.9)
HTR3D 107G>C GG 9 (18.4) 12 (15.8) 0.71
rs6443930 CC+CG 40 (81.6) 64 (84.2)

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Table 5. Maltivariate analysis of risk factors for significant nausea in acute phase

SNPs Genotype group Significant nausea (acute) No significant nausea (acute) Multivariate analysis
n (%) n (%) OR 95%CI p -value
ABCG2 421C>A AA 7 (14.3) 3 (3.9) 4.87 1.01-23.60 <0.05
rs2231142 CC+CA 42 (85.7) 73 (96.1)

CYP2D6 100C>T TT 11 (22.4) 8 (10.5) 2.87 0.77-10.60 0.12

rs1065852 CC+CT 38 (77.6) 68 (89.5)
SNP: single nucleotide polymorphism, OR: odds ratio, CI: confidence interval.

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