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Supplementary Figure 1, Supplementary Tables 1-9 and Supplementary Appendix 1

Preclinical studies suggest that statins contribute to the prevention of pancreatic cancer; however, the results of epidemiologic studies are inconsistent. Furthermore, sufficient data are unavailable for the general population of Asia. Here, we conducted an observational study using a comprehensive patient-linked, longitudinal health insurance database comprising the records of 2,230,848 individuals residing in Shizuoka Prefecture, Japan, from April 2012 to September 2018. We included individuals older than 40 years with data for medical examinations and statin exposure (≥365 statin prescription days). To balance baseline characteristics between the statin exposure and statin nonexposure groups, we used inverse probability of treatment propensity score weighting method. We estimated hazard ratios for associations with pancreatic cancer using the Cox proportional hazards regression model. Among 2,230,848 individuals, we included 100,537 in the statin exposure group (24%) and 326,033 in the statin nonexposure group (76%). Among the statin exposure group (352,485 person-years) and the statin nonexposure group (1,098,463 person-years), 394 (1.12 per 1,000 person-years) and 1176 (1.07 per 1,000 person-years) developed pancreatic cancer, respectively (P = 0.464). After adjustments using inverse probability of treatment weighting, the statin exposure group was associated with a decreased incidence of pancreatic cancer (hazard ratio, 0.84; 95% confidence intervals, 0.72–0.99; P = 0.036). In conclusion, the current Japanese regional population-based cohort study shows that statin exposure was associated with a lower incidence of pancreatic cancer.Prevention Relevance:This study may support the possible role of statins in preventing pancreatic cancer in the general population in Japan.

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Supplementary Figures S1-S9 PDF file - 984K, Representative photomicrographs of tissue sections immunostained for PLS3 (S1); The clinical significance of PLS3 expression in a second independent set of 110 primary colorectal cancer samples (S2); PLS3 expression profiles in various tissues, including peripheral blood-derived cells (S3); EMT induction in CaR-1 cells by TGF-beta1 (S4); PLS3 mRNA expression in LoVo cells expressing stem cell makers (S5); Immunocytochemical staining of PLS3 in rectal cancer cell line CaR-1 and peripheral blood mononuclear cells (S6); Validation of PLS3 expression in PB after recurrence (S7); Survival curves of Dukes stage B CRC patients based on the level of CK19/CK20 mRNA expression in PB (S8); PLS3 expression profiles in several cancer cell lines (S9)

Supplementary Tables S1-S2 PDF file - 41K, CRC Patient characteristics in training set (2000-2004) and validation set (2005-2008) (S1); Gene list of GSEA analysis (S2).

Supplementary Figure Legends PDF file - 49K, Legend for Supplementary Figures S1-S9

Neuroblastoma, one of the most common pediatric solid tumors, is characterized by two extreme disease courses, spontaneous regression and life-threatening progression. Here, we conducted a genome-wide search for differences in DNA methylation that distinguish between neuroblastomas of the two types. Three CpG islands (CGI) and two groups of CGIs were found to be methylated specifically in neuroblastomas with a poor prognosis. By quantitative analysis of 140 independent cases, methylation of all the five CGI (groups) was shown to be closely associated with each other, conforming to the CpG island methylator phenotype (CIMP) concept. The presence of CIMP was sensitively detected by methylation of the PCDHB CGIs and associated with significantly poor survival (hazard ratio, 22.1; 95% confidence interval, 5.3-93.4; P < 0.0001). Almost all cases with N-myc amplification (37 of 38 cases) exhibited CIMP. Even in 102 cases without N-myc amplification, the presence of CIMP (30 cases) strongly predicted poor survival (hazard ratio, 12.4; 95% confidence interval, 2.6-58.9; P = 0.002). Methylation of PCDHB CGIs, located in their gene bodies, did not suppress gene expression or induce histone modifications. However, CIMP was significantly associated with methylation of promoter CGIs of the RASSF1A and BLU tumor suppressor genes. The results showed that neuroblastomas with CIMP have a poor prognosis and suggested induction of silencing of important genes as an underlying mechanism.

Circulating tumor cells (CTC) in blood have attracted attention both as potential seeds for metastasis and as biomarkers. However, most CTC detection systems might miss epithelial–mesenchymal transition (EMT)-induced metastatic cells because detection is based on epithelial markers. First, to discover novel markers capable of detecting CTCs in which EMT has not been repressed, microarray analysis of 132 colorectal cancers (CRC) from Japanese patients was conducted, and 2,969 genes were detected that were overexpressed relative to normal colon mucosa. From the detected genes, we selected those that were overexpressed CRC with distant metastasis. Then, we analyzed the CRC metastasis-specific genes (n = 22) to determine whether they were expressed in normal circulation. As a result, PLS3 was discovered as a CTC marker that was expressed in metastatic CRC cells but not in normal circulation. Using fluorescent immunocytochemistry, we validated that PLS3 was expressed in EMT-induced CTC in peripheral blood from patients with CRC with distant metastasis. PLS3-expressing cells were detected in the peripheral blood of approximately one-third of an independent set of 711 Japanese patients with CRC. Multivariate analysis showed that PLS3-positive CTC was independently associated with prognosis in the training set (n = 381) and the validation set [n = 330; HR = 2.17; 95% confidence interval (CI) = 1.38–3.40 and HR = 3.92; 95% CI = 2.27–6.85]. The association between PLS3-positive CTC and prognosis was particularly strong in patients with Dukes B (HR = 4.07; 95% CI = 1.50–11.57) and Dukes C (HR = 2.57; 95% CI = 1.42–4.63). PLS3 is a novel marker for metastatic CRC cells, and it possesses significant prognostic value. Cancer Res; 73(7); 2059–69. ©2012 AACR.

Supplementary Tables 1-3 from CpG Island Methylator Phenotype Is a Strong Determinant of Poor Prognosis in Neuroblastomas

Supplementary Figure Legends from CpG Island Methylator Phenotype Is a Strong Determinant of Poor Prognosis in Neuroblastomas

Preclinical studies suggest that statins contribute to the prevention of pancreatic cancer; however, the results of epidemiologic studies are inconsistent. Furthermore, sufficient data are unavailable for the general population of Asia. Here, we conducted an observational study using a comprehensive patient-linked, longitudinal health insurance database comprising the records of 2,230,848 individuals residing in Shizuoka Prefecture, Japan, from April 2012 to September 2018. We included individuals older than 40 years with data for medical examinations and statin exposure (≥365 statin prescription days). To balance baseline characteristics between the statin exposure and statin nonexposure groups, we used inverse probability of treatment propensity score weighting method. We estimated hazard ratios for associations with pancreatic cancer using the Cox proportional hazards regression model. Among 2,230,848 individuals, we included 100,537 in the statin exposure group (24%) and 326,033 in the statin nonexposure group (76%). Among the statin exposure group (352,485 person-years) and the statin nonexposure group (1,098,463 person-years), 394 (1.12 per 1,000 person-years) and 1176 (1.07 per 1,000 person-years) developed pancreatic cancer, respectively (P = 0.464). After adjustments using inverse probability of treatment weighting, the statin exposure group was associated with a decreased incidence of pancreatic cancer (hazard ratio, 0.84; 95% confidence intervals, 0.72–0.99; P = 0.036). In conclusion, the current Japanese regional population-based cohort study shows that statin exposure was associated with a lower incidence of pancreatic cancer. Prevention Relevance: This study may support the possible role of statins in preventing pancreatic cancer in the general population in Japan.

[Background] Smoking is an established risk factor for breast cancer incidence. As for breast cancer prognosis, the effect of patient’s smoking on her mortality is also substantial. However, there are very few reports of investigating patient’s smoking and smoking cessation effects on breast cancer recurrence, especially those with controlling for treatment effects. [Methods] We conducted a prospective cohort study (Cohort 05 of the Rainbow of KIBOU study) for the patients enrolled in the N-SAS BC 05 trial (AERAS, UMIN:000000818). The N-SAS BC 05 trial is the randomized multi-center open-label phase III trial to assess the effect of the extended use of anastrozole for an additional 5 years where postmenopausal patients with stage I-III, hormone-receptor-positive breast cancer, disease-free after 5 years of either anastrozole alone or tamoxifen 2-3 years followed by anastrozole 3-2 years were randomized to continual group with anastrozole for an additional 5 years or stop group without an additional anastrozole. Our primary end point was disease-free survival. Since the data came from well controlled randomized trial of treatment comparison, precise recurrence and treatment data were available. [Results] We enrolled 1,510 women from the participants of the NSAS BC 05 trial. After a median follow up of 5.1 years, there were 144 events including breast cancer recurrences, secondary cancers, and deaths. The 5-year disease-free survival rates from the entry of the study (10 year from diagnosis) were 89.4% (95% confidence interval [CI], 87.4 to 91.5) in nonsmokers, 87.7% (95% CI: 82.0 to 93.4) in quitters (both before and after diagnosis), and 76.1% (95% CI, 62.7 to 89.4) in smokers (P=0.02 by a two sided log-rank test). Hazard ratios are 2.13 (95% CI, 1.14 to 3.97) for smokers and 1.35 (95% CI, 0.83 to 2.20) for quitters compared to nonsmokers after controlling treatment and age effects. If the quitters were divided into two groups by the time of cessation, hazard ratios are 1.31 (95% CI, 0.74 to 2.34) for those who quitted before diagnosis and 1.47 (95% CI, 0.64 to 3.34) for those who quitted after diagnosis. The results were not substantially changed if the events were restricted to recurrence. [Conclusion] Ten year disease-free survival for smokers was significantly worse than that of nonsmokers after almost perfectly controlling treatment effects. Compared to that, 10 year disease-free survival for quitters was not different from that of nonsmokers. The risk was decreased if they quit smoking even after diagnosis. Our study shows the importance of smoking cessation for breast cancer patients. Citation Format: Yuri Mizota, Takuji Iwase, Yasuo Ohashi, Hirofumi Mukai, Seiichiro Yamamoto. The effects of smoking and smoking cessation on postmenopausal breast cancer recurrence -Results from the Cohort 05 of the Rainbow of KIBOU (ROK) study: A prospective breast cancer survivor cohort in Japan [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-08-36.

[Background] Past studies revealed that a moderate to high level of physical activity after diagnosis of breast cancer reduces both the risk of breast cancer-related death and death from all causes. Furthermore, some randomized studies suggested that exercise programs improve the percentage of patients who complete the chemotherapy and quality of life, and decrease fatigue, and adverse events. The issues to be determined include defining an established uniform exercise program and the efficacy of a long-term exercise program after breast cancer surgery. [Object] To elucidate the efficacy of a long-term exercise program and to verify the safety and feasibility of a uniform exercise program using an ‘existing social resource’ after primary therapy of breast cancer. [Design] A multi-center, randomized trial. [Method] Subjects: The subjects included patients who had completed treatment for primary breast cancer, including surgery and/or adjuvant chemotherapy. Patients with metastatic breast cancer were excluded. Randomization & intervention: The patients were randomly assigned to three groups. The first group followed an exercise program at Curves® that involved 30 minutes of exercise, including aerobics, weight training, and stretching 3 times a week for 4 months. The second group was given life-style guidance at least once that patients participate in a lecture program about recommended exercise at this point and the importance of weight control after diagnosis of breast cancer using a brochure. The third group served as controls that the patients receive a brochure used same one in the second group. The variables included age and weight. Outcome: The primary endpoint is level of physical activity at 1 year after randomization, and the secondary endpoints are the percentage of those completing the exercise program, patient reported outcomes (QOL, cancer or treatment associated symptoms, fatigue, depression, and anxiety), body mass index, bone density, and level of lymphedema. Period of research: The study will last 2 years beginning March 2016. Sample size: We plan to enroll 400 patients to detect 20% difference with 90% power. Additional study: Some biochemical markers in the blood will be evaluated to determine the mechanism of the effect of exercise on the human body. Citation Format: Kawada K, Taira N, Hatono M, Takahashi Y, Miyoshi Y, Nogami T, Iwamoto T, Motoki T, Sien T, Matsuoka J, Doihara H, Ikeda M, Ogasawara Y, Takabatake D, Yoshitomi S, Kiyoto S, Yamamoto S, Mizota Y, Oka K. Influence of exercise or educational programs on long-term physical activity by patients after surgery for primary breast cancer: A randomized trial [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT3-07-02.

Background: Obesity is reported to be associated with worse prognosis in early breast cancer. However, there is little data regarding the impact of low BMI on survival in patients with breast cancer. As obesity is rare and low BMI is relatively common in Japanese population compared to Caucasians, Japanese cohort is suitable to assess the impact of low BMI on survival in patients with early breast cancer. Recently an exploratory analysis of a small Japanese randomized phase II trial (JFMC 34-0601) suggested that low BMI was associated with a decreased overall response rate to neoadjuvant endocrine therapy with exemestane. We further explored the impact of low BMI on survival in patients with early breast cancer using a dataset of randomized phase III trials in Japan. Methods: Patients included in prospective randomized phase III trial N-SAS BC02 and BC03 were retrospectively analyzed. N-SAS BC02 investigated four arms of adjuvant chemotherapy consisted of taxane alone or in combination with anthracycline-containing regimen (median follow up of 6.1 years). NSAS BC03 compared anastorozole with tamoxifen as adjuvant endocrine therapy (median follow up of 6.4 years). The correlation of BMI and overall survival was exploratory analyzed. This study was supported by the Public Health Research Center Foundation CSPOR. Results: A total of 1726 patients were included in our study. Median age was 56 (24 – 82) years, 71.2% of tumors were ER positive, and 9.7% were HER2 overexpressed. Lymph node metastases were observed in 76% of patients. Mean value of BMI was 23.3 and only 4.6% of patients had BMI over 30. 33.1% of patients had BMI under 22 and 4.8% had BMI under 18.5. In the univariate Cox proportional hazard model, lower BMI was significantly associated with worse prognosis (BMI27, HR 0.55, 95% CI 0.32 – 0.93, p = 0.025). The same trend was observed in multivariate analysis (HR 0.61, p = 0.064). Conclusion: We confirmed that obese patients were relatively rare in Japanese patients with early breast cancer. In this non-obese population, lower BMI was correlated with worse prognosis. However these results should be cautiously interpreted. Our findings suggest that there may be an optimal BMI in patients with early breast cancer and it should be confirmed by another cohort. Citation Format: Yoichi Naito, Yasuo Ohashi, Isao Yokota, Toru Watanabe, Hiroji Iwata, Shozo Ohsumi, Shinji Ohno, Yasuo Hozumi, Seiichiro Yamamoto, Masato Takahashi, Tomohiko Aihara, Hirofumi Mukai. Low body mass index (BMI) is associated with poor survival in Japanese patients with early breast cancer; an exploratory analysis of prospective randomized phase III trials N-SAS BC02 and 03 [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-08-21.

Background: The potential for infertility caused by treatment is one of the important quality-of-life issues in young breast cancer (YBC) patients. Insufficient communication and partnership between oncologists and reproductive specialists has been identified as a major barrier to meeting their needs. However, the perception of reproductive specialists towards fertility preservation (FP) of YBC has not been evaluated. Objective: To investigate the perception and needs of reproductive specialists towards FP of YBC patients. Methods: A cross-sectional survey was developed and sent to 423 certified reproductive specialists registered to the Japan Society for Reproductive Medicine to self-evaluate their perceptions and practices regarding FP in YBC patients. Results: Two hundred reproductive specialists (47%) responded to the survey. 99% responded that reproductive specialists should be engaged in FP of YBC patients. 46% responded that cancer treatment is more important than childbirth even if the patient was recurrence-free five years after primary treatment. 83% responded that they would like to treat YBC patients. Respondents affiliated with private clinics were more likely to accept both fertilized egg and unfertilized egg preservation than those affiliated with academic or general hospitals (p < 0.01). 58% responded that ovulation induction methods should be modified in YBC patients. The choice of ovulation induction methods varied both in non-cancer women and YBC patients, however, the frequency of the use of letrozole was significantly higher (p < 0.01) and that of LHRH-agonist short protocol was significantly less (p < 0.05) in the management of breast cancer patients than in the practice of non-cancer women. 70% of the reproductive specialists responded that they were anxious in treating YBC patients. Concerns for greater or unknown risk of disease recurrence (66%), insufficient knowledge about breast cancer (47%), and lack of patient's spouse/partner (24%) were identified as major barriers in supporting FP for YBC patients. Conclusion Reproductive specialists recognize the needs of FP in YBC patients and are willing to participate and support care for YBC. Affiliation of reproductive specialists was related to positive attitude towards to egg preservation. Various concerns regarding FP among reproductive specialists indicate the need for evidence that supports the safety of FP for YBC patients and guidelines that facilitate the practice and communication of oncologists and reproductive specialists. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-11-02.

Activation of the EGFR, KRAS, and ALK oncogenes defines 3 different pathways of molecular pathogenesis in lung adenocarcinoma. However, many tumors lack activation of any pathway (triple-negative lung adenocarcinomas) posing a challenge for prognosis and treatment. Here, we report an extensive genome-wide expression profiling of 226 primary human stage I–II lung adenocarcinomas that elucidates molecular characteristics of tumors that harbor ALK mutations or that lack EGFR, KRAS, and ALK mutations, that is, triple-negative adenocarcinomas. One hundred and seventy-four genes were selected as being upregulated specifically in 79 lung adenocarcinomas without EGFR and KRAS mutations. Unsupervised clustering using a 174-gene signature, including ALK itself, classified these 2 groups of tumors into ALK-positive cases and 2 distinct groups of triple-negative cases (groups A and B). Notably, group A triple-negative cases had a worse prognosis for relapse and death, compared with cases with EGFR, KRAS, or ALK mutations or group B triple-negative cases. In ALK-positive tumors, 30 genes, including ALK and GRIN2A, were commonly overexpressed, whereas in group A triple-negative cases, 9 genes were commonly overexpressed, including a candidate diagnostic/therapeutic target DEPDC1, that were determined to be critical for predicting a worse prognosis. Our findings are important because they provide a molecular basis of ALK-positive lung adenocarcinomas and triple-negative lung adenocarcinomas and further stratify more or less aggressive subgroups of triple-negative lung ADC, possibly helping identify patients who may gain the most benefit from adjuvant chemotherapy after surgical resection. Cancer Res; 72(1); 100–11. ©2011 AACR.

Background: Although accumulating evidence suggests that Helicobacter pylori plays a role in gastric carcinogenesis, the magnitude of the risk remains uncertain. Aim: We aimed to estimate the magnitude of the risk of gastric cancer associated with H. pylori infection by a large case-control study nested within a prospective cohort. Possible effect modification by CagA status, and serum pepsinogen status, as a marker of atrophic gastritis, was also considered to see its effect on developing gastric cancer. Subjects and Methods: Subjects (n = 123,576) were followed up from 1990 to 2004; 511 gastric cancer cases matched to 511 controls were used in the analysis. Plasma immunoglobulin G antibody to H. pylori, CagA, and pepsinogen I and II were measured. Results: The adjusted odds ratio (95% confidence interval) of gastric cancer associated with H. pylori infection was 5.1 (3.2-8.0). Assuming all CagA-positive subjects are true H. pylori positives doubled this risk. Atrophic gastritis was also associated with an elevated risk of gastric cancer and the risk increased further with pepsinogen levels. Conclusions: Subjects with pepsinogen levels indicative of severe atrophic gastritis may need careful examination regularly regardless of H. pylori infection. Those who have other pepsinogen levels but who are H. pylori seropositive are likely to benefit from H. pylori eradication therapy. Considering both the cost and the potential for misclassification that may occur using multiple serologic tests, caution is needed in interpreting or extrapolating these findings into a screening strategy. (Cancer Epidemiol Biomarkers Prev 2006;15(7):1341–7)

Neuroblastoma, one of the most common pediatric solid tumors, is characterized by two extreme disease courses, spontaneous regression and life-threatening progression. Here, we conducted a genome-wide search for differences in DNA methylation that distinguish between neuroblastomas of the two types. Three CpG islands (CGI) and two groups of CGIs were found to be methylated specifically in neuroblastomas with a poor prognosis. By quantitative analysis of 140 independent cases, methylation of all the five CGI (groups) was shown to be closely associated with each other, conforming to the CpG island methylator phenotype (CIMP) concept. The presence of CIMP was sensitively detected by methylation of the PCDHB CGIs and associated with significantly poor survival (hazard ratio, 22.1; 95% confidence interval, 5.3-93.4; P < 0.0001). Almost all cases with N-myc amplification (37 of 38 cases) exhibited CIMP. Even in 102 cases without N-myc amplification, the presence of CIMP (30 cases) strongly predicted poor survival (hazard ratio, 12.4; 95% confidence interval, 2.6-58.9; P = 0.002). Methylation of PCDHB CGIs, located in their gene bodies, did not suppress gene expression or induce histone modifications. However, CIMP was significantly associated with methylation of promoter CGIs of the RASSF1A and BLU tumor suppressor genes. The results showed that neuroblastomas with CIMP have a poor prognosis and suggested induction of silencing of important genes as an underlying mechanism.

Here we show that TP53 SNP is involved in chemotherapeutic responses in non-small cell lung cancer (NSCLC) patients. To identify polymorphisms in DNA repair genes that affect responses to platinum-based doublet chemotherapy, 640 NSCLC patients, who received platinum-based doublet chemotherapy and whose responses were evaluated by the Response Evaluation Criteria in Solid Tumors, were subjected to an association study between the response and genotypes for 30 SNPs in 27 DNA repair genes. Candidate SNPs were selected by screening of a discovery set of 201 cases and their associations were validated in an independent set of 439. Homozygotes for the TP53–72Pro allele of the TP53-Arg72Pro SNPs showed a better response rate (54.3%) than those for the TP53–72Arg allele (29.1%), and TP53–72Pro allele homozygotes had significantly longer progression-free and overall survivals than TP53–72Arg allele homozygotes. Minor allele carriers for a SNP, Lys940Arg, in the PARP1 (poly ADP-ribose polymerase 1) gene showed a better response rate to the regimen using paclitaxel (45.8%) than to the regimen using gemcitabine (10.5%). These results indicate that polymorphisms in the TP53 and PARP1 genes are involved in inter-individual differences in the response to platinum-based doublet chemotherapy in NSCLC patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C109.