Fear of cancer recurrence among breast cancer survivors could be controlled by prudent dietary modification with polyunsaturated fatty acids

Journal of Affective Disorders 245 (2019) 1114–1118

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Research paper

Fear of cancer recurrence among breast cancer survivors could be controlled by prudent dietary modification with polyunsaturated fatty acids

T

Ryo Okuboa, Hiroko Noguchia, Kei Hamazakib, Masayuki Sekiguchic, Takayuki Kinoshitad, ⁎ Noriko Katsumatae, Tomomi Narisawaa, Yasuhito Uezonof, Jinzhong Xiaoe, Yutaka J. Matsuokaa, a

Division of Health Care Research, Center for Public Health Sciences, National Cancer Center Japan, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan Department of Public Health, Faculty of Medicine, University of Toyama, 2630 Sugitani, Toyama City, Toyama 930-0194, Japan c Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi-cho, Kodaira City, Tokyo 187-8551, Japan d Department of Breast Surgery, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan e Next Generation Science Institute, Morinaga Milk Industry Co., Ltd, 5-1-83 Higashihara, Zama, Kanagawa 252-8583, Japan f Division of Cancer Pathophysiology, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan b

A R T I C LE I N FO

A B S T R A C T

Keywords: Fear of cancer recurrence Polyunsaturated fatty acids Nutrition Mental health Cancer survivorship Anxiety

Background: The pathophysiology of fear of cancer recurrence (FCR), the leading unmet psychological need of cancer survivors, may involve the dysfunctional processing of fear memory. n-3 polyunsaturated fatty acids (PUFAs) have beneficial effects on psychiatric disorders, including depressive disorder and anxiety disorders, and are involved in fear memory processing. We hypothesized that n-3 PUFA composition is associated with FCR in cancer survivors. Methods: We conducted a cross-sectional study to examine the relationship between n-3 PUFAs and FCR among breast cancer survivors. Adults who had been diagnosed with invasive breast cancer and were not undergoing chemotherapy were asked to participate. Blood PUFA composition was evaluated by using capillary blood. We directly administered the Concerns About Recurrence Scale (CARS) to assess the grade of FCR. Results: Among 126 participants used for the analysis, the mean age (SD) was 58 (11) years and 47% had stage I cancer. Multiple regression analysis controlling for possible confounders, depressive symptoms, and post-traumatic stress disorder (PTSD) symptoms revealed that the alpha-linolenic acid (ALA) level was significantly inversely associated with the average score on the CARS overall fear index (beta = −0.165, p = 0.04). No significant associations were found for other PUFAs. Limitations: Our findings were obtained from a cross-sectional study in a single institute. Conclusion: These findings provide the first evidence of a beneficial effect of ALA on FCR and indicate the need for prospective study of this association. FCR among breast cancer survivors might be controllable by prudent selection of ALA-containing cooking oil.

1. Introduction The need to support cancer survivors after treatment is rapidly increasing due to improved early detection and treatment of cancer. The psychological concerns of cancer survivors include fear of cancer recurrence (FCR), defined as “fear or worry that the cancer will return or progress in the same organ or in another part of the body” (Vickberg, 2003). FCR is the most frequently endorsed unmet need after initial treatment among cancer survivors (Okubo et al., 2018). Approximately half of cancer survivors have moderate-to-high FCR and 7% have severe FCR (Simard et al., 2013). Cancer survivors with high

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FCR tend to have psychological distress, to avoid reminders of cancer (e.g., television, newspapers, and conversations about cancer), and to adopt reassurance behavior (e.g., excessive body checking and unscheduled consults with physicians and emergency room staff) (Okubo et al., 2018; Simard et al., 2013). They also tend to have a low quality of life and social functioning (Simard et al., 2013). Although the FCR of some cancer survivors somewhat improves after the initial cancer treatment, the FCR of most survivors is typically relatively stable (Simard et al., 2013). When considering the pathophysiology of FCR, we can refer to that of post-traumatic stress disorder (PTSD), a condition that involves the

Corresponding author. E-mail address: [email protected] (Y.J. Matsuoka).

https://doi.org/10.1016/j.jad.2018.12.014 Received 2 October 2018; Received in revised form 22 November 2018; Accepted 8 December 2018 Available online 10 December 2018 0165-0327/ © 2018 Elsevier B.V. All rights reserved.

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electronic medical records. Capillary blood was obtained using a drop of blood from the thumb of each participant. All procedures were approved by the Institutional Review Board of the National Cancer Center Japan.

dysfunctional processing of fear memory. One meta-analysis found that 13.8% of cancer survivors considered both cancer diagnosis and treatment to be traumatic and reported clinically significant cancer-related PTSD symptoms (Abbey et al., 2015). As in PTSD, reminders of cancer trigger negative interpretations and recollection of fear memories in individuals with FCR (Simonelli et al., 2017). Additionally, the degree of the FCR is strongly associated with intrusive thoughts, as in PTSD (White and Gumley, 2009). Research exploring the pathology of PTSD from the viewpoint of dysfunctional fear memory processing, such as enhanced consolidation of trauma-related fear memory (LeDoux, 2000) and impaired fear memory extinction (Rauch et al., 2006), have also implicated dysfunctional fear memory processing in the pathophysiology of FCR. Extensive research suggests that polyunsaturated fatty acids (PUFAs) are essential for fear memory processing (Mathieu et al., 2011; McNamara and Carlson, 2006; Noguchi et al., 2017; Ross, 2009). The main component of mammalian brain tissue is lipid, which itself comprises various fatty acids (saturated fatty acids, monounsaturated fatty acids, and PUFAs). Our previous research has suggested that n-3 PUFAs could attenuate PTSD symptoms, which involve dysfunctional processing of fear memory, in a prospective cohort study of accident survivors (Matsuoka et al., 2013) and a randomized control trial of female rescue workers following the Great East Japan Earthquake (Nishi et al., 2012). Yamada et al. (2014, 2016) found that an increased concentration of dietary n-3 PUFAs helps to control fear memory processing via CB1 receptor activation. Based on a review of these previous studies and other studies suggesting that n-3 PUFA interventions might be able to ameliorate dysfunctional fear memory processing via anti-inflammation/immunomodulation (Logan, 2003) or by augmenting brain-derived neurotrophic factor (BDNF) (Andero and Ressler, 2012; Dell'Osso et al., 2009; Wu et al., 2004) or adult neurogenesis (Beltz et al., 2007), we recently proposed the hypothetical effects of n-3 PUFAs on FCR in cancer survivors (Okubo et al., 2018). Few studies have addressed the biological risk factors of FCR, and no studies have examined the relationship between FCR and PUFAs in cancer survivors. A systematic review identified younger age and history of chemotherapy as risk factors for high FCR (Simard et al., 2013). In addition, FCR has been positively correlated with depressive symptoms and PTSD symptoms (Simard et al., 2013). Because depressive and PTSD symptoms can be influenced by PUFAs (Hallahan et al., 2016; Simard et al., 2013), we need to rule out spurious correlations in order to clarify the relationship between n-3 PUFAs and FCR. Thus, the present study investigated the relationship between n-3 PUFAs and FCR using multivariate regression analysis controlling for possible confounders such as age and history of chemotherapy, depressive symptoms, and PTSD symptoms.

2.2. Measurement Blood PUFAs were assessed from capillary whole blood using a capillary dried blood spot (DBS) system capable of protecting long-chain PUFAs from oxidation for up to 2 months at room temperature, as described elsewhere (Liu et al., 2014). A drop of capillary blood (approximately 80 μL) was spotted onto blood collection paper (Liu et al., 2014) and dried in air at room temperature. The dried blood spot was assessed within 4 weeks of storage at room temperature. The fatty acid composition was calculated by gas chromatography using the DBS system (Liu et al., 2014). FCR was directly assessed by researchers using the overall fear index of the Concerns About Recurrence Scale (CARS) (Momino et al., 2014; Vickberg, 2003), which contains 4 items scored on a 6-point Likert scale ranging from 1 to 6. The average score (1–6) reflects the FCR severity, with a higher score indicating more severe FCR. The Cronbach's alpha coefficient of the CARS score of the study participants was 0.86, indicating good internal consistency. Depressive symptoms were assessed by the self-administered Hospital Anxiety and Depression Scale (HADS) (Kugaya et al., 1998; Zigmond and Snaith, 1983), which consists of 14 items scored on a 4-point Likert scale ranging from 0 to 3. We used the total score (0–42) to indicate the severity of depressive symptoms, with higher scores indicating more severe symptoms. Cancer-related PTSD symptoms were assessed by the Impact of Event Scale-Revised (IES-R) (Asukai et al., 2002), which consists of 22 items scored on a 5-point Likert scale ranging from 0 to 4. We used the total score (0–88) to indicate the severity of cancer-related PTSD symptoms, with higher scores indicating more severe symptoms. 2.3. Statistical analyses We conducted multiple regression analysis for the average score of the CARS overall fear index as a dependent variable using three models. Model 1 used each of the PUFAs and adjusted variables such as age (years, continuous), living alone (yes/no), relative who died of cancer (yes/no), history of chemotherapy (yes/no), duration from diagnosis (years, continuous), and cancer stage (I–III). Model 2 used the variables of Model 1 and the total HADS score. Model 3 used the variables of Model 2 and the total IES-R score. Analysis was performed using R 3.2.1 software and statistical significance was set at p < 0.05 (two-tailed). 3. Results

2. Methods Of 201 eligible outpatients invited to participate, 130 were enrolled. After the exclusion of 2 participants who did not answer the questionnaire and 2 whose PUFA levels could not be assessed properly due to insufficient sample quantity, data from 126 participants were used for analysis. As shown in Table 1, all participants were female except one, and the mean age (SD) was 58 (11) years; 47% had stage I cancer. Multiple regression analysis revealed that the alpha-linolenic acid (ALA) level was significantly inversely associated with the average score on the CARS overall fear index (beta = − 0.169, p = 0.046 for Model 1; beta = –0.176, p = 0.03 for Model 2; beta = −0.165, p = 0.04 for Model 3) (Table 2). No significant associations were found for other n-3 and n-6 PUFAs.

2.1. Participants and procedure We conducted a cross-sectional study that examined the relationship between FCR and PUFAs among breast cancer survivors. Study participants were consecutively selected from outpatients who attended regularly scheduled consultations between November 2017 and May 2018. Inclusion criteria were outpatients aged ≥20 years who had been diagnosed with invasive breast cancer >1 year earlier. The exclusion criteria were as follows: cognitive impairment or disturbance of consciousness; current receipt of chemotherapy; with recurrence; and inability to participate in the study as determined by the physician in charge of the study. We obtained written informed consent from all study participants. We administered questionnaires on FCR, depressive symptoms, and cancer-related PTSD symptoms and demographic data such as age, sex, living alone, and existence of a relative who died of cancer, and also extracted the participants’ clinical data, such as cancer stage, history of chemotherapy, and duration from diagnosis, from the

4. Discussion Our study suggests that a higher peripheral blood level of ALA is significantly associated with lower FCR, independent of depressive symptoms and cancer-related PTSD symptoms. These results indicate a 1115

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symptoms, we needed to rule out a spurious correlation in order to clarify the relationship between n-3 PUFAs and FCR. Furthermore, although we assumed that cancer-related PTSD symptoms affect the relationship between PUFAs and FCR, we failed to find the effects of cancer-related PTSD symptoms on the relationship between ALA and FCR. This result implied that the mechanism underlying the relationship between PUFAs and FCR was different from that between PUFAs and PTSD. FCR has a distinct clinical presentation from PTSD. FCR is characterized by catastrophic prediction about what could happen if the cancer recurs, stimulated by daily reminders of cancer (e.g., television, newspapers, and conversations about cancer) (Simard et al., 2013), whereas PTSD symptoms are the reaction to a discrete past event with significant threat (Simonelli et al., 2017). Further studies should investigate the biological mechanisms of FCR including the mechanism underlying the relationship between FCR and PUFAs. We failed to find the associations of EPA and DHA with FCR. We hypothesized that such an association existed based on our recent metaanalysis of 19 randomized controlled trials showing that n-3 PUFAs could attenuate anxiety symptoms (Su et al., 2018). This discrepancy might be related to the characteristics of the study participants and their eating habits. According to the meta-analysis, none of the three relevant randomized control studies conducted for Japanese participants was able to find significant effects of EPA and DHA on anxiety symptoms (Matsuoka et al., 2015; Nishi et al., 2013; Watanabe et al., 2018). A systematic analysis of nutrition surveys showed that Japanese people consumed 718 mg/day of seafood omega 3 fats such as EPA and DHA, comparing with world mean consumption 163 mg/day in 2010 (Micha et al., 2014). This results implied that the effect of EPA and DHA on anxiety symptoms might reach a plateau in Japanese. On the contrary, Japanese mean consumption of plant omega 3 fats such as ALA were similar with world mean consumption 1371 mg/day (Micha et al., 2014). ALA could play an important role in biological mechanisms of fear memory processing being independent of EPA and DHA. Therefore, blood ALA level might be related to FCR in this study. Emerging evidence has indicated the effects of ALA on fear memory processing. Fear memory processing depends on neuronal activities in the ventromedial prefrontal cortex and hippocampus (Kanoski et al., 2007, 2010) and the extinction of fear requires inhibitory learning of the original fear memory. Some studies have indicated that diets such as a western-style diet high in saturated fatty acids affect these neuronal activities involving fear memory processing (Francis and Stevenson, 2013) and induce poorer inhibitory learning of the original fear memory (Asem and Holland, 2012; Thiebaud et al., 2014). In contrast to such a diet, the consumption of a diet rich in ALA facilitates inhibitory learning of original fear memories more than a diet rich in linolenic acids, one of the n-6 PUFAs in the rat (Yamamoto et al., 1988). Recent work showed that an ALA-rich chocolate milkshake facilitated inhibitory learning of original fear memories in healthy individuals (Miller et al., 2018). The relationship between ALA and FCR could be explained by these effects of ALA on fear memory processing. Although the mechanisms underlying the relationship between ALA and FCR have not been fully understood, BDNF could play an important role in the relationship. BDNF supports the production, growth, differentiation, and survival of neurons (Park and Poo, 2013) and are necessary for the normal processing of fear memory such as formation and extinction of fear memories in the amygdala, hippocampus, and prefrontal cortex (Andero and Ressler, 2012). Lower plasma levels of BDNF were reported in patients with PTSD.(Angelucci et al., 2014; Dell'Osso et al., 2009) Similarly, mRNA levels of BDNF in the hippocampus were decreased in animal models of PTSD (Roth et al., 2011). Stimulation of BDNF signaling inhibits the return of fear after extinction training (Baker-Andresen et al., 2013). Furthermore, plasma levels of BDNF were increased by oral consumption of ALA in healthy adults (Hadjighassem et al., 2015). These previous studies and our results suggested that ALA increased BDNF, then could influence fear memory processing and FCR in cancer survivors. As other mechanisms

Table 1 Participant characteristics (n = 126). Characteristics

Number or mean (SD)

Age, years Sex (female:male) History of family cancer history (yes:no) Living alone (yes:no) Cancer stage I ▓▓▓▓▓▓▓▓▓▓▓II ▓▓▓▓▓▓▓▓▓▓▓III History of chemotherapy (yes:no) Duration from cancer diagnosis (year) Hospital Anxiety and Depression Scale Concerns About Recurrence Scale Polyunsaturated fatty acids, % ▓Total n-3 PUFAs ▓ALA ▓EPA ▓DHA ▓Total n-6 PUFAs ▓LA ▓AA ▓n-6/n-3 ratio

58 (11) 125:1 95:31 20:106 59 59 8 57:69 5 (3) 7.8 (5.6) 3.1 (1.1) 6.0 (1.9) 0.5 (0.2) 1.9 (1.0) 2.7 (0.8) 23.3 (4.3) 16.1 (3.1) 4.9 (1.3) 4.2 (1.2)

Abbreviations: EPA, eicosapentaenoic acid; DHA, docosahexaenoic acid; ALA, alpha-linolenic acid; LA, linoleic acid; AA, arachidonic acid. Table 2 Results of multiple regression analyses between PUFAs and the Concerns About Recurrence Scale (CARS) (n = 126). Independent variables Model 1 Total n-3 PUFAs ALA EPA DHA Total n-6 PUFAs LA AA n-6/n-3 ratio Model 2 Total n-3 PUFAs ALA EPA DHA Total n-6 PUFAs LA AA n-6/n-3 ratio Model 3 Total n-3 PUFAs ALA EPA DHA Total n-6 PUFAs LA AA n-6/n-3 ratio

R2

Beta

P value

0.14 0.16 0.14 0.14 0.14 0.14 0.14 0.14

0.053 –0.169 0.010 0.120 0.082 0.094 0.069 –0.003

0.53 0.046 0.90 0.13 0.33 0.27 0.44 0.97

0.21 0.24 0.21 0.22 0.21 0.21 0.21 0.21

0.053 –0.176 0.023 0.120 0.043 0.061 0.035 –0.017

0.52 0.03 0.78 0.14 0.61 0.46 0.68 0.84

0.25 0.27 0.25 0.26 0.25 0.25 0.25 0.25

0.037 −0.165 0.001 0.108 0.056 0.071 0.033 0.001

0.64 0.04 0.94 0.17 0.49 0.38 0.69 0.90

Each row was calculated using the following models. Model 1: adjusted for age, sex, living alone, history of family cancer, duration from diagnosis, cancer stage, and history of chemotherapy. Model 2: adjusted for the variables of Model 1 and the total score on the Hospital Anxiety and Depression Scale (HADS). Model 3: adjusted for the variables of Model 2 and the total Impact of Event Scale-Revised (IES-R) score. Abbreviations: ALA, alpha-linolenic acid; EPA, eicosapentaenoic acid; DHA, docosapentaenoic acid; LA, linoleic acid; AA, arachidonic acid.

beneficial effect of ALA on FCR and the possibility of a novel nutritional intervention using ALA for reducing FCR. Our results showed that the relationship between ALA and FCR was independent of depressive symptoms. Because cumulative evidence indicates a significant association between n-3 PUFAs and depressive 1116

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Supplementary materials

underlying the relationship between PUFAs including ALA and FCR, our recent review (Okubo et al., 2018) suggested reduced inflammation (Su et al., 2015), modulated signal transduction through changes in the CB1 receptor (Yamada et al., 2014), upregulating adult neurogenesis (Beltz et al., 2007), and normalizing microbiota-gut-brain axis (Hoban et al., 2017; Kaliannan et al., 2015). Dietary modification to increase the consumption of ALA-rich plant-based oils such as flaxseed oil, perilla oil, and chia seed might help to prevent or ameliorate FCR in cancer survivors. Survivors’ diet could play an important role in cancer survivorship. This study has some limitations. First, it was conducted in a single institute and with survivors of breast cancer only. Studies including other cancers are necessary. Second, our findings were obtained from a cross-sectional study. The impact of PUFAs on FCR should be examined prospectively. Lastly, we did not use correction for multiple comparisons to compare our findings directly with previous studies examined the relationship between PUFA levels and anxiety disorders (Matsuoka et al., 2013; Ross, 2009; Yamashita et al., 2017). These previous studies and other studies using blood PUFAs (Albert et al., 2002; Brasky et al., 2013) also did not use correction for multiple comparisons. Considering exploratory purpose of this study, we did not consider lack of correction for multiple comparisons to be fatal impairment. Nonetheless, our findings provide the first evidence of a beneficial effect of ALA on FCR. Further studies should assess the beneficial effects of PUFAs on FCR using a prospective design, such as a randomized control study. Our recent meta-analysis of 19 randomized controlled trials indicated that n-3 PUFAs could attenuate anxiety symptoms (Su et al., 2018). FCR among breast cancer survivors might be controllable by prudent selection of an ALA-containing cooking oil.

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Conflicts of interest Dr. Matsuoka has received speaking honoraria from Morinaga Milk, Eli Lilly, and NTT Data and is conducting collaborative research with Morinaga Milk. Ms. Katsumata and Dr. Xiao are employees of Morinaga Milk Industry Co., Ltd. The other authors have no conflicts of interest to declare. Role of funding source A donation from Morinaga Milk Industry Co. Ltd. was used for analyses of the blood polyunsaturated fatty acids. A Grant-in-Aid for Scientific Research B from the Japan Society for the Promotion of Science (No. 17H04253) and a research grant for cancer survivorship from Foundation for Promotion of Cancer Research were used for manuscript writing and editing. Author statement ▓ Contributors Dr. Okubo, Noguchi, Hamazaki, Sekiguchi, Kinoshita, Katsumata, Uezono, Xiao, and Matsuoka significantly contributed to making the protocol of this study. Dr. Okubo, Noguchi, Narisawa, and Kinoshita, significantly contributed to the data collection. Dr Okubo, Noguchi, Hamazaki, Sekiguchi, and Matsuoka significantly contributed to the interpretation of our data and writing the manuscript. Acknowledgments We thank Kaori Hayashi, Shin Takayama, Souta Asaga, Kenjiro Jinbo, and Syo Shiino for data collection. 1117

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