Publications by authors named "Masaaki Kawai"

56 Publications

Targeting Amino Acid Metabolic Reprogramming via L-Type Amino Acid Transporter 1 (LAT1) for Endocrine-Resistant Breast Cancer.

Cancers (Basel) 2021 Aug 30;13(17). Epub 2021 Aug 30.

Department of Pathology Tohoku University Hospital, 1-1 Seiryo-machi, Aoba-Ku, Sendai 980-8574, Japan.

The PI3K/Akt/mTOR pathway has been well known to interact with the estrogen receptor (ER)-pathway and to be also frequently upregulated in aromatase inhibitor (AI)-resistant breast cancer patients. Intracellular levels of free amino acids, especially leucine, regulate the mammalian target of rapamycin complex 1 (mTORC1) activation. L-type amino acid transporters such as LAT1 and LAT3 are associated with the uptake of essential amino acids. LAT1 expression could mediate leucine uptake, mTORC1 signaling, and cell proliferation. Therefore, in this study, we explored amino acid metabolism, including LAT1, in breast cancer and clarified the potential roles of LAT1 in the development of therapeutic resistance and the eventual clinical outcome of the patients. We evaluated LAT1 and LAT3 expression before and after neoadjuvant hormone therapy (NAH) and examined LAT1 function and expression in estrogen deprivation-resistant (EDR) breast carcinoma cell lines. Tumors tended to be in advanced stages in the cases whose LAT1 expression was high. LAT1 expression in the EDR cell lines was upregulated. JPH203, a selective LAT1 inhibitor, demonstrated inhibitory effects on cell proliferation in EDR cells. Hormone therapy changed the tumor microenvironment and resulted in metabolic reprogramming through inducing LAT1 expression. LAT1 expression then mediated leucine uptake, enhanced mTORC1 signaling, and eventually resulted in AI resistance. Therefore, LAT1 could be the potential therapeutic target in AI-resistant breast cancer patients.
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http://dx.doi.org/10.3390/cancers13174375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8431153PMC
August 2021

Ppp6c deficiency accelerates K-ras -induced tongue carcinogenesis.

Cancer Med 2021 07 18;10(13):4451-4464. Epub 2021 Jun 18.

Division of Cancer Chemotherapy, Miyagi Cancer Center Research Institute, Miyagi, Japan.

Background: Effective treatments for cancer harboring mutant RAS are lacking. In Drosophila, it was reported that PP6 suppresses tumorigenicity of mutant RAS. However, the information how PP6 regulates oncogenic RAS in mammals is limited.

Methods: We examined the effects of PP6 gene (Ppp6c) deficiency on tongue tumor development in K (K-rasG12D)- and KP (K-rasG12D + Trp53-deficient)-inducible mice.

Results: Mice of K and KP genotypes developed squamous cell carcinoma in situ in the tongue approximately 2 weeks after the induction of Ppp6c deficiency and was euthanized due to 20% loss of body weight. Transcriptome analysis revealed significantly different gene expressions between tissues of Ppp6c-deficient tongues and those of Ppp6c wild type, while Trp53 deficiency had a relatively smaller effect. We then analyzed genes commonly altered by Ppp6c deficiency, with or without Trp53 deficiency, and identified a group concentrated in KEGG database pathways defined as 'Pathways in Cancer' and 'Cytokine-cytokine receptor interaction'. We then evaluated signals downstream of oncogenic RAS and those regulated by PP6 substrates and found that in the presence of K-rasG12D, Ppp6c deletion enhanced the activation of the ERK-ELK1-FOS, AKT-4EBP1, and AKT-FOXO-CyclinD1 axes. Ppp6c deletion combined with K-rasG12D also enhanced DNA double-strand break (DSB) accumulation and activated NFκB signaling, upregulating IL-1β, COX2, and TNF.
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http://dx.doi.org/10.1002/cam4.3962DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8267137PMC
July 2021

Guidelines for the management of dermatomycosis (2019).

J Dermatol 2020 Dec 25;47(12):1343-1373. Epub 2020 Sep 25.

Maruyama Dermatology Clinic, Tokyo, Japan.

The "Guidelines for the management of dermatomycosis" of the Japanese Dermatological Association were first published in Japanese in 2009 and the Guidelines Committee of the Japanese Dermatological Association revised it in 2019. The first guidelines was prepared according to the opinions of the Guidelines Committee members and it was of educational value. The revised version is composed of introductory descriptions of the disease concepts, diagnosis, medical mycology and recent advances in treatment, along with clinical questions (CQ), which is intended to help in general practice for dermatologists. The CQ are limited to those involved in therapy but include some of the recently launched antifungal agents. The level of evidence and the degree of recommendation for each item were reviewed by the committee based on clinical studies published by 2018. For rare dermatomycoses, recommendations by the committee are described in the guidelines. In this field, there are still few good quality studies on treatment. Periodic revision in line with new evidence is necessary.
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http://dx.doi.org/10.1111/1346-8138.15618DOI Listing
December 2020

Breast cancer survival among Japanese individuals and US residents of Japanese and other origins: a comparative registry-based study.

Breast Cancer Res Treat 2020 Nov 20;184(2):585-596. Epub 2020 Aug 20.

Department of Surgery, Teikyo University School of Medicine, Tokyo, Japan.

Background: Breast cancer survival outcomes vary across different ethnic groups. We clarified the differences in clinicopathological and survival characteristics of breast cancer among Japanese, US residents with Japanese origin (USJ), and US residents with other origins (USO).

Method: Using Surveillance, Epidemiology, and End Results (SEER) 18 dataset and Japanese Breast Cancer Society (JBCS) registry, we included patients first diagnosed with breast cancer between 2004 and 2015. We categorized the patients into three groups based on the database and the recorded ethnicity: Japanese (all those from the JBCS registry), USJ (those from SEER with ethnicity: Japanese), and USO (those from SEER with ethnicity other than Japanese). Excluding patients diagnosed after 2012, stage 0, and 4 patients, we examined the overall survival (OS) and breast cancer-specific survival (BCSS) using the Kaplan-Meier method and Cox proportional hazards models, adjusting for age, sex, cancer stage, and hormone receptor (HR) status.

Results: We identified 7362 USJ, 701,751 USO, and 503,013 Japanese breast cancer patients. The proportion of HR-positive breast cancer was the highest among USJ (71%). OS was significantly longer among Japanese and USJ than USO (Hazard ratio 0.46; 95% Confidence Interval [CI] 0.45-0.47 for Japanese and 0.66 [95% CI 0.59-0.74] for USJ) after adjusting for baseline covariates. BCSS was also significantly higher in the two groups (HR 0.53 [95% CI 0.51-0.55] for Japanese and 0.53 [95% CI 0.52-0.74] for USJ).

Conclusions: In stage I-III breast cancer, Japanese and US residents with Japanese origin experienced significantly longer survival than US residents with non-Japanese origins.
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http://dx.doi.org/10.1007/s10549-020-05869-yDOI Listing
November 2020

Divergent metabolic responses dictate vulnerability to NAMPT inhibition in ovarian cancer.

FEBS Lett 2020 05 26;594(9):1379-1388. Epub 2020 Jan 26.

Division of Cancer Chemotherapy, Miyagi Cancer Center Research Institute, Natori, Japan.

It is of current interest to target cancer metabolism as treatment for many malignancies, including ovarian cancer (OVC), in which few druggable driver mutations have been identified. Nicotinamide phosphoribosyltransferase (NAMPT), a rate-limiting enzyme in the NAD salvage pathway, is a potential therapeutic target in OVC. However, factors that determine responsiveness to NAMPT inhibition are not fully understood. Here, we report that OVC cell lines can be divided into subgroups exhibiting NAMPT-dependent or NAMPT-independent glycolysis, and these metabolic differences correlate with vulnerability to NAMPT inhibition. Interestingly, cells showing NAMPT-dependent glycolysis were enriched in a group of cells lacking BRCA1/2 gene mutations. Our findings suggest the importance of selecting appropriate patients for NAMPT-targeting therapy in OVC.
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http://dx.doi.org/10.1002/1873-3468.13736DOI Listing
May 2020

Alcohol consumption and survival after breast cancer diagnosis in Japanese women: A prospective patient cohort study.

PLoS One 2019 13;14(11):e0224797. Epub 2019 Nov 13.

Department of Breast Surgery, Miyagi Cancer Center Hospital, Natori, Miyagi, Japan.

Background: It is unclear whether alcohol consumption may impact survival after breast cancer diagnosis. To clarify the association between pretreatment alcohol consumption and survival in breast cancer patients, a prospective patient cohort study was conducted.

Methods: The cohort comprised 1,420 breast cancer patients diagnosed during 1997-2013 at a single institute in Japan. Alcohol drinking and other lifestyle factors were assessed by questionnaire survey at the initial admission. The patients were followed until December 31, 2016. The crude associations of pretreatment alcohol intake with survival were evaluated by Kaplan-Meier analysis. The Cox proportional hazards model was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) controlled by confounders.

Results: During a median follow-up period of 8.6 years, 261 all-cause and 193 breast cancer-specific deaths were documented. Survival curves showed that ever-drinkers tended to have better survival than never-drinkers (breast cancer-specific survival, log-rank p = 0.0381). Better survival was also observed for light drinkers with an intake of <5.0 g per day. In the Cox model, ever-drinking was associated with a decreased risk of all-cause (HR: 0.75; 95% CI: 0.54-1.05) and breast cancer-specific death (HR: 0.68; 95% CI: 0.46-0.99). Light drinkers had a lower risk of breast cancer-specific death (frequency of drinking, HR = 0.57 for occasional or 1-2 times per week and 0.72 for 3-7 times per week; amount of alcohol consumed per day, HR = 0.57 for <5.0 g and 0.68 for ≥5.0 g compared with never-drinking). In terms of hormone receptor status, a significantly decreased risk of death associated with ever-drinking was observed among women with receptor-negative cancer (ER-/PR-, HR = 0.41; 95% CI: 0.20-0.84 for breast cancer-specific death).

Conclusions: Pretreatment, i.e., pre-diagnosis alcohol consumption is unlikely to have an adverse effect on survival after breast cancer diagnosis. Light alcohol consumption may have a beneficial effect on patient survival.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0224797PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6853331PMC
March 2020

Characteristics and Efficacy of Two Topical Therapeutic Agents for Onychomycosis.

Authors:
Masaaki Kawai

Med Mycol J 2019 ;60(3):71-74

Department of Dermatology, Juntendo University Koshigaya Hospital.

Tinea pedis and tinea unguium are the most common dermatophytoses seen in the daily practice of dermatology. According to a report in Japan Foot Week 2006, it is estimated that about 1 in 5 Japanese have tinea pedis and that about 1 in 10 have tinea unguium. Thus far, use of oral antifungal agents has been the first-line therapy for onychomycosis. Many patients with onychomycosis, however, are elderly and have concomitant diseases as well as liver function disorder. Moreover, oral medications are reportedly associated with risks of impaired liver function and interactions. Due to such risks, therefore, treatment with topical agents is the only applicable therapy for most patients with onychomycosis. Recently, two topical agents (efinaconazole in 2014 and luliconazole in 2016) have been approved for the treatment of onychomycosis in Japan. Efinaconazole 10% solution is a triazole antifungal drug developed in Japan. Due to its low keratin affinity, efinaconazole shows high transungual penetration into nails and retains a high antifungal activity in the nail plate and the nail bed. Luliconazole 5% solution is an imidazole antifungal agent that has high keratin affinity. Luliconazole has also been shown in vitro to permeate from the superficial to the deep layers of the nail and to achieve concentrations above the MIC in all layers of the nail. Both efinaconazole 10% solution and luliconazole 5% solution have high antifungal activities for Trichophyton species. These two topical agents, therefore, have certainly increased treatment options for onychomycosis in the daily practice of dermatology.
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http://dx.doi.org/10.3314/mmj.19.006DOI Listing
February 2020

A population-based recurrence risk management study of patients with pT1 node-negative HER2+ breast cancer: a National Clinical Database study.

Breast Cancer Res Treat 2019 Dec 26;178(3):647-656. Epub 2019 Aug 26.

Department of Surgery, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo, 173-8606, Japan.

Purpose: Recurrence risk management of patients with small (≤ 2 cm), node-negative, human epidermal growth factor receptor 2 (HER2)-positive breast cancer remains challenging. We studied the effects of adjuvant chemotherapy and/or trastuzumab and survival outcomes among these patients, using data from the population-based Japanese National Clinical Database (NCD).

Methods: We identified a cohort of 2736 breast cancer patients with HER2+ pT1N0 disease: 489 pT1a, 642 pT1b, and 1623 pT1c. The median observation period was 76 months, and the 5-year follow-up rate was 48.2%. The number of events was 212 for disease-free survival (DFS), 40 for breast cancer-specific survival, and 84 for overall survival (OS).

Results: There were 24.5% of pT1a, 51.9% of pT1b, and 63.3% of pT1c patients who were treated systemically after surgery. OS in pT1b (logrank test; p = 0.03) and DFS in pT1c (logrank test; p < 0.001) were significantly improved in treated compared with untreated patients. In the Cox proportional hazards model, treated patients had significantly longer OS than untreated patients in pT1b (hazard ratio (HR) 0.20) and pT1c (HR 0.54) groups. Estrogen receptor-negative tumors was also a significant predictor of survival in pT1c (HR 2.01) but not pT1ab patients. Furthermore, HR was greater in patients aged ≤ 35 years (3.18) compared to that in patients aged 50-69 years in the pT1b group.

Conclusions: NCD data revealed that systemic treatment improved OS in pT1bc but not in pT1a node-negative HER2+ breast cancer patients. Future observational research using big-sized data is expected to play an important role in optimizing treatment for patients with early-stage breast cancer.
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http://dx.doi.org/10.1007/s10549-019-05413-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6817748PMC
December 2019

Role of Postmastectomy Radiotherapy After Neoadjuvant Chemotherapy in Breast Cancer Patients: A Study from the Japanese Breast Cancer Registry.

Ann Surg Oncol 2019 Aug 17;26(8):2475-2485. Epub 2019 May 17.

Department of Breast and Endocrine Surgery, Tokai University School of Medicine, Isehara, Japan.

Background: The role of postmastectomy radiotherapy (PMRT) in breast cancer patients receiving neoadjuvant chemotherapy (NAC) is controversial. We aimed to evaluate the effectiveness of radiotherapy in patients treated with NAC and mastectomy in the Japanese Breast Cancer Registry.

Methods: We enrolled patients who received NAC and mastectomy for cT1-4 cN0-2 M0 breast cancer. We evaluated the association between radiotherapy and outcomes, locoregional recurrence (LRR), distant disease-free survival (DDFS), and overall survival (OS) based on ypN status by multivariable analysis.

Results: Of the 145,530 patients, we identified 3226 who met the inclusion criteria. Among ypN1 patients, no differences were found in LRR, DDFS, or OS between groups with and without radiotherapy (p = 0.72, p = 0.29, and p = 0.36, respectively). Radiotherapy was associated with improved LRR-free survival (p < 0.001), DDFS (p = 0.01), and OS (p < 0.001) in patients with ypN2-3. Multivariable analysis demonstrated that use of radiotherapy was independently associated with improved LRR [hazard ratio (HR) 0.61, 95% confidence interval (CI) 0.45-0.82, p = 0.001] and OS [HR 0.69, 95% CI 0.53-0.89, p = 0.004) for ypN2-3 patients only. The association between radiotherapy and OS was not statistically significant among ypN0 (p = 0.22) and ypN1 patients (p = 0.51).

Conclusions: The results from this nationwide database study did not show significant associations between PMRT and improved survival among ypN0 and ypN1 patients. Radiotherapy may be beneficial only for ypN2-3 breast cancer patients who receive NAC and mastectomy in the modern era.
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http://dx.doi.org/10.1245/s10434-019-07453-1DOI Listing
August 2019

Reproductive history and breast cancer survival: a prospective patient cohort study in Japan.

Breast Cancer 2019 Nov 15;26(6):687-702. Epub 2019 Apr 15.

Department of Breast Surgery, Miyagi Cancer Center Hospital, 47-1 Nodayama, Medeshima-Shiode, Natori, Miyagi, 981-1239, Japan.

Background: Reproductive factors may influence breast cancer progression and patient survival; however, evidence has been limited.

Methods: The associations of reproductive factors with tumor characteristics and patient survival were analyzed among 1468 breast cancer patients diagnosed during 1997-2013 at a single institute in Japan. The patients were followed until 2016. During a median follow-up period of 8.6 years, 272 all-cause and 199 breast cancer deaths were documented.

Results: In case-case comparisons, later age at menarche was inversely associated with advanced tumors. Nulliparous patients tended to have receptor-positive [estrogen receptor (ER)+ or progesterone receptor (PR)+] tumors. Conversely, the Cox proportional-hazards model including adjustment for tumor characteristics revealed U-shaped relationship between parity number and the risk of all-cause death among the patients overall [hazard ratio (HR) = 2.10 for nulliparous, 1.28 for 2, and 1.50 for ≥ 3 vs. one child]. According to hormone receptor, later age at menarche and later age at last birth were positively associated with the risk of all-cause death among patients with ER- and PR- cancer (menarche, HR = 2.18 for ≥ 15 vs. ≤ 12 years, p = 0.03; last birth, HR = 3.10 for ≥ 35 vs. ≤ 29 years, p = 0.01). A shorter time since last birth was associated with the risk of death among receptor-positive patients (HR = 5.72 for ≤ 4 vs. ≥ 10 years, p = 0.004).

Conclusion: The results indicate that the timing of menarche and parity have significant effects on patient survival, providing clues for understanding the association between women's life course and breast cancer outcome.
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http://dx.doi.org/10.1007/s12282-019-00972-5DOI Listing
November 2019

PKM1 Confers Metabolic Advantages and Promotes Cell-Autonomous Tumor Cell Growth.

Cancer Cell 2018 03;33(3):355-367.e7

Division of Cancer Chemotherapy, Miyagi Cancer Center Research Institute, Natori 981-1293, Japan; Division of Cancer Molecular Biology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.

Expression of PKM2, which diverts glucose-derived carbon from catabolic to biosynthetic pathways, is a hallmark of cancer. However, PKM2 function in tumorigenesis remains controversial. Here, we show that, when expressed rather than PKM2, the PKM isoform PKM1 exhibits a tumor-promoting function in KRAS-induced or carcinogen-initiated mouse models or in some human cancers. Analysis of Pkm mutant mouse lines expressing specific PKM isoforms established that PKM1 boosts tumor growth cell intrinsically. PKM1 activated glucose catabolism and stimulated autophagy/mitophagy, favoring malignancy. Importantly, we observed that pulmonary neuroendocrine tumors (NETs), including small-cell lung cancer (SCLC), express PKM1, and that PKM1 expression is required for SCLC cell proliferation. Our findings provide a rationale for targeting PKM1 therapeutically in certain cancer subtypes, including pulmonary NETs.
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http://dx.doi.org/10.1016/j.ccell.2018.02.004DOI Listing
March 2018

Alcohol Consumption and Breast Cancer Risk According to Hormone Receptor Status in Japanese Women: A Case-Control Study.

Tohoku J Exp Med 2018 01;244(1):63-73

Division of Community Health, Tohoku University Graduate School of Medicine.

Alcohol consumption is a risk factor for breast cancer in Western countries, but few studies have evaluated the risk for Japanese women, who have a relatively low alcohol intake. This case-control study investigated the association of alcohol consumption with breast cancer risk according to estrogen-receptor and progesterone-receptor (ER/PgR) status in Japanese women. From female patients aged 30 years and over admitted to a single hospital in Japan between 1997 and 2011, 1,256 breast cancer cases (669 ER+/PgR+, 162 ER+/PgR-, 21 ER-/PgR+, 305 ER-/PgR-, and 99 missing) and 2,933 controls were selected. Alcohol-related measures were assessed using a self-administered questionnaire. Unconditional logistic regression analysis was performed. Alcohol-related measures were not associated with breast cancer risk among the women overall. Moreover, no association was observed between ever drinking and the risk of a concordant receptor subtype (ER+/PgR+ or ER-/PgR-). Conversely, ever drinking was inversely associated with the risk of discordant subtype (ER+/PgR-, odds ratio (OR) = 0.63, 95% confidence interval (CI): 0.41-0.95; ER-/PgR+, OR = 0.44, 95% CI: 0.14-1.42). For ER+/PgR-, an inverse association with the amount of alcohol consumed per day was observed (P for trend = 0.04), and this inverse association was limited to premenopausal women. Alcohol consumption may have differential effects on concordant and discordant receptor subtypes of breast cancer. In view of the low frequency of discordant subtype in Japanese women and their relatively low alcohol intake, our findings may provide a clue for elucidating the etiology of breast cancer rather than for preventing discordant subtype.
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http://dx.doi.org/10.1620/tjem.244.63DOI Listing
January 2018

model of non-small cell lung cancer using mouse lung epithelial cells.

Oncol Lett 2017 Dec 28;14(6):6863-6868. Epub 2017 Sep 28.

Division of Cancer Chemotherapy, Miyagi Cancer Center Research Institute, Natori, Miyagi 981-1293, Japan.

Lung cancer is the most common cause of cancer mortality, however, efficient methods to culture, expand and transform lung epithelial (LE) cells have not been established. In the present study, an efficient method was applied to recapitulate lung carcinogenesis using mouse LE cells. A Matrigel-assisted three-dimensional culture was used to isolate and selectively expand LE cells from mouse lungs. Purified LE cells were passaged and expanded for at least 2 to 3 months while maintaining epidermal growth factor-dependence. LE cells were also easily transformed by genetic manipulations using retroviral vectors. A SV40 large-T antigen, suppressing p53 and pRB, plus an activated oncogene, such as Kras or EGFR, were required to transform LE cells. Transformed cells formed tumors resembling non-small cell lung cancer (NSCLC) in allograft models and exhibited strong oncogene addiction. This experimental system provided a unique model system to study lung tumorigenesis and develop novel therapeutics against NSCLC.
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http://dx.doi.org/10.3892/ol.2017.7098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5754888PMC
December 2017

Minimal impact of postmastectomy radiation therapy on locoregional recurrence for breast cancer patients with 1 to 3 positive lymph nodes in the modern treatment era.

Surg Oncol 2017 Jun 16;26(2):163-170. Epub 2017 Mar 16.

Department of Surgical Oncology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan.

Introduction: Given modern treatment strategies, controversy remains regarding whether postmastectomy radiation therapy (PMRT) is necessary for breast cancer patients with 1-3 positive axillary lymph nodes (ALN). Our aim was to assess the significance of PMRT in the modern treatment era for these patients.

Material And Methods: We have conducted the retrospective multicenter study and identified 658 patients with 1-3 positive ALN who were treated with mastectomy and ALN dissection between 1999 and 2012. Propensity score weighting was used to minimize the influence of confounding factors between the PMRT and no-PMRT groups. The variables including tumor size, lymph nodes status, skin and/or muscle invasion, histological grade, lymphovascular invasion and ER positivity which were statistically unbalanced between the groups were used to define the propensity scores.

Results: The median follow-up time was 7.3 years. In the modern era (2006-2012), no significant difference in locoregional recurrence (LRR)-free survival was noted between the PMRT and no-PMRT groups (P = 0.3625). The 8-year LRR-free survival rates of the PMRT and no-PMRT groups were 98.2% and 95.3%, respectively. After matching patients by propensity scores, the PMRT group, compared to the no-PMRT group, exhibited significantly better locoregional control (P = 0.0366) in the entire cohort. The 10-year LRR-free survival rates were 97.8% and 88.4% in the PMRT and no-PMRT groups, respectively. In contrast, no significant difference in LRR-free survival was noted between the PMRT and no-PMRT groups in the modern era (P = 0.5298). The 8-year LRR-free survival rates of patients treated in the modern era were approximately the same between the groups (98.0% and 95.7% in the PMRT and no-PMRT groups, respectively). Particularly, LRR-free survival of HER2 positive breast cancer significantly improved in the modern treatment era, compared with that of the old treatment era (P = 0.0349).

Conclusion: PMRT had minimal impact on LRR for breast cancer patients with 1-3 positive ALN in the modern treatment era.
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http://dx.doi.org/10.1016/j.suronc.2017.03.003DOI Listing
June 2017

Drug delivery of oral anti-cancer fluoropyrimidine agents.

Expert Opin Drug Deliv 2017 12 11;14(12):1355-1366. Epub 2017 Apr 11.

h Department of Neurosurgery , Miyagi Cancer Center , Natori , Japan.

Introduction: Sixty years since its introduction, 5-FU still forms the core of chemotherapy regimens for many types of malignancies. 5-FU is a time-dependent drug but is rapidly degraded in plasma by dihydropyrimidine dehydrogenase (DPD). Although originally developed in an intravenous form, 5-FU oral prodrugs were developed with the goal of improving efficacy and minimizing toxicity as well as to capitalize on the advantages of oral drug administration. The inactive 5-FU prodrug is gradually converted into the active form in the systemic circulation. UFT, S-1, and capecitabine are oral 5-FU prodrugs currently in clinical use. However, the efficacy of 5-FU can be further improved by its combination with DPD inhibitors and biochemical modulators, such as uracil and leucovorin, in addition to modifying administration schedules. Areas covered: We focused on the drug delivery of oral 5-FU prodrugs, their pharmacokinetics, and the development of DPD inhibitors. Since oral 5-FU prodrugs have been formulated into combination drugs, we also discussed the regulatory approval of combination drugs. Expert opinion: Many regimens that include intravenously administered 5-FU can be replaced by oral 5-FU prodrugs. Patients would benefit from development of combination 5-FU oral prodrug formulations and its associated path through the combination drug regulatory approval process.
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http://dx.doi.org/10.1080/17425247.2017.1316260DOI Listing
December 2017

Associations of obesity and physical activity with serum and intratumoral sex steroid hormone levels among postmenopausal women with breast cancer: analysis of paired serum and tumor tissue samples.

Breast Cancer Res Treat 2017 02 2;162(1):115-125. Epub 2017 Jan 2.

Division of Community Health, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan.

Purpose: It has been hypothesized that intratumoral estrogens may play important roles in the growth of breast cancer. However, few studies have investigated such intratumoral hormones, or their association with risk factors of breast cancer.

Methods: In this cross-sectional study, hormone levels in paired serum and tumor tissue samples from 146 postmenopausal women with breast cancer were measured by liquid chromatography-tandem mass spectrometry and compared between estrogen/progesterone (ER/PgR) subtypes. The associations of risk factors including body mass index (BMI) and other lifestyle factors with these hormone levels were investigated using analysis of covariance.

Results: The level of estradiol (E2) in tumor tissue was extremely high in women with ER+ (geometric mean 95.6 pg/g) relative to women with ER-/PgR- (8.9 pg/g), whereas serum E2 level did not differ much between the two groups (3.1 and 2.8 pg/ml, respectively). Serum levels of precursors for E2, including testosterone (T) and androstenedione (Adione), and tissue Adione level, were high among women with ER+. After adjustment for confounding variables, BMI was found to be positively associated with tissue levels of E2, estrone (E1), T, and Adione among women with ER+ (P  < 0.0001 for E2; 0.0016 for E1; 0.0002 for T; and 0.03 for Adione).

Conclusion: The data suggest that tissue E2 is related to the growth of receptor-positive breast cancer and that risk factors such as BMI affect tissue levels of E2 and its precursors. Understanding of hormonal environments within tumor tissue may be important for elucidating hormonal etiology of breast cancer and improving the prognosis of patients.
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http://dx.doi.org/10.1007/s10549-016-4094-3DOI Listing
February 2017

Postoperative hormonal therapy prevents recovery of neurological damage after surgery in patients with breast cancer.

Sci Rep 2016 10 6;6:34671. Epub 2016 Oct 6.

Department of Functional Brain Imaging, Institute of Development, Aging and Cancer (IDAC), Tohoku University, Sendai, Japan.

Cancer survivors are exposed to several risk factors for cognitive dysfunction, such as general anesthesia, surgical trauma, and adjuvant therapies. In our recent study we showed that thalamic volume reduction and attentional dysfunction occurred shortly after surgery. Here, we examined the 6-month prognosis of the 20 patients with breast cancer who underwent surgery. Seven patients did not receive any adjuvant therapy after the surgery and 13 patients received a hormonal therapy after the surgery. We assessed their attentional functions, and thalamic volumes shortly after and 6 months after surgery. We found a significant group x time interaction in the attentional functions (p = 0.033) and the right thalamus (p <  0.05, small volume correction), suggesting the thalamic volume reduction and attentional dysfunction recovered in patients without adjuvant therapy. Our findings provide a better understanding of the potential role of hormonal therapy in relation to the cognitive dysfunction of cancer survivors.
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http://dx.doi.org/10.1038/srep34671DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5052558PMC
October 2016

Young adult breast cancer patients have a poor prognosis independent of prognostic clinicopathological factors: a study from the Japanese Breast Cancer Registry.

Breast Cancer Res Treat 2016 11 19;160(1):163-172. Epub 2016 Sep 19.

Department of Breast and Endocrine Surgery, Tokai University School of Medicine, Kanagawa, Japan.

Purpose: The aim of this study was to investigate whether young age at onset of breast cancer is an independent prognostic factor in patients from the Japanese Breast Cancer Registry, after adjustment of known clinicopathological prognostic factors.

Methods: Of the 53,670 patients registered between 2004 and 2006 and surveyed after a 5-year follow-up prognosis, 25,898 breast cancer patients (48.3 %), who were obtained prognostic data, were examined. Clinicopathological factors were compared between young adult (YA; <35 years), middle-aged adult (MA; 35-50 years), and older adult (OA; >50 years) patients. Five-year disease-free survival (DFS) and overall survival (OS) rates were studied.

Results: YA patients were associated with an advanced TNM stage and aggressive characteristics (e.g. human epidermal growth factor receptor 2 (HER2)-positive or oestrogen receptor (ER)-negative breast cancers) compared to MA and OA patients (P < 0.001). The 5-year DFS and OS rates were 79.4 % and 90.8, 88.5 and 95.0 %, and 87.8 % and 91.6 % for YA, MA, and OA patients, respectively. From the multivariable regression analysis, young age at onset was confirmed as an independent prognostic factor for both DFS (hazard ratio 1.73, 95 % confidence interval 1.42-2.10; P < 0.001) and OS (hazard ratio 1.58, 95 % confidence interval 1.16-2.15; P = 0.004).

Conclusions: Young age at onset is an independent negative prognostic factor in breast cancer. Further studies are required to develop new therapeutic strategies for YA breast cancer patients.
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http://dx.doi.org/10.1007/s10549-016-3984-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5050233PMC
November 2016

Distinct breast cancer characteristics between screen- and self-detected breast cancers recorded in the Japanese Breast Cancer Registry.

Breast Cancer Res Treat 2016 Apr 5;156(3):485-494. Epub 2016 Apr 5.

Department of Breast and Endocrine Surgery, Tokai University School of Medicine, Kanagawa, Japan.

The rate of breast cancer screening for women of all ages in Japan is increasing. However, little is known about the biological differences between screen- and self-detected tumors. We used data from the Japanese Breast Cancer Registry (JBCR), a nationwide registry of newly diagnosed breast cancer cases in Japan, to investigate patients diagnosed between January 1, 2004 and December 31, 2011. We compared the clinicopathological features of tumors and assessed yearly trends regarding the proportion of screen-detected cases during the study period. We found that 31.8 % (65,358/205,544) of cancers were detected by screening. Asymptomatic tumors detected by screening (asymptomatic) were more likely to have favorable prognostic features than those that were self-detected (ductal carcinoma in situ [DCIS]: 19.8 versus 4.1 %, node-negative: 77.0 versus 61.6 %, and estrogen receptor-positive [ER+]: 82.0 versus 72.9 %, respectively). All these findings were statistically significant (p < .001). The proportion of breast cancers detected by screening among all cases increased from 21.7 % in 2004 to 37.1 % in 2011. During the same time period, the proportion of screen-detected DCIS increased from 41.5 to 66.0 % and that of ER+ cancers increased from 23.2 to 39.7 %. This study demonstrated that low-risk tumors, including DCIS, ER+, and lower TNM stage, account for a substantial proportion of clinical screening-detected cancers. The differences in biological characteristics between screen- and self-detected cancers may account in part for the limited efficacy of breast cancer screening programs aimed at improving breast cancer mortality.
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http://dx.doi.org/10.1007/s10549-016-3770-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4837218PMC
April 2016

Body mass index and survival after diagnosis of invasive breast cancer: a study based on the Japanese National Clinical Database-Breast Cancer Registry.

Cancer Med 2016 06 29;5(6):1328-40. Epub 2016 Feb 29.

Departments of Breast and Endocrine Surgery, Tokai University School of Medicine, Isehara, Japan.

Few studies have reported the association between body mass index (BMI) and outcome among Asian breast cancer patients. We analyzed data for 20,090 female invasive breast cancer patients who had been followed-up for a median period of 6.7 years entered in the National Clinical Database-Breast Cancer Registry between 2004 and 2006. We used mainly the WHO criteria for BMI (kg/m(2) ) categories; <18.5 (underweight), ≥18.5-<21.8 (reference), ≥21.8-<25, ≥25-<30 (overweight), and ≥30 (obese). We divided normal weight patients into two subgroups because this category includes many patients compared to others. The timing of BMI measurement was not specified. The Cox proportional hazards model and cubic spline regression were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Smoking, alcohol, and physical activity were not controlled. A total of 1418 all-cause, 937 breast cancer-specific deaths, and 2433 recurrences were observed. Obesity was associated with an increased risk of all-cause (HR: 1.46; 95% CI: 1.16-1.83) and breast cancer-specific death (HR: 1.47; 95% CI: 1.11-1.93) for all patients, and with all-cause (HR: 1.47; 95% CI: 1.13-1.92) and breast cancer-specific death (HR: 1.58; 95% CI: 1.13-2.20) for postmenopausal patients. Being underweight was associated with an increased risk of all-cause death for all (HR: 1.41; 95% CI: 1.16-1.71) and for postmenopausal patients (HR: 1.45; 95% CI: 1.15-1.84). With regard to subtype and menopausal status, obesity was associated with an increased risk of breast cancer-specific death for all cases of luminal B tumor (HR: 2.59; 95% CI: 1.51-4.43; Pheterogeneity of Luminal B vs. Triple negative = 0.016) and for postmenopausal patients with luminal B tumor (HR: 3.24; 95% CI: 1.71-6.17). Being obese or underweight is associated with a higher risk of death among female breast cancer patients in Japan.
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http://dx.doi.org/10.1002/cam4.678DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4924391PMC
June 2016

Sensitivity and specificity of mammography and adjunctive ultrasonography to screen for breast cancer in the Japan Strategic Anti-cancer Randomized Trial (J-START): a randomised controlled trial.

Lancet 2016 Jan 5;387(10016):341-348. Epub 2015 Nov 5.

Department of Surgical Oncology, Graduate School of Medicine, Tohoku University, Sendai, Japan.

Background: Mammography is the only proven method for breast cancer screening that reduces mortality, although it is inaccurate in young women or women with dense breasts. We investigated the efficacy of adjunctive ultrasonography.

Methods: Between July, 2007, and March, 2011, we enrolled asymptomatic women aged 40-49 years at 42 study sites in 23 prefectures into the Japan Strategic Anti-cancer Randomized Trial (J-START). Eligible women had no history of any cancer in the previous 5 years and were expected to live for more than 5 years. Randomisation was done centrally by the Japan Clinical Research Support Unit. Participants were randomly assigned in 1:1 ratio to undergo mammography and ultrasonography (intervention group) or mammography alone (control group) twice in 2 years. The primary outcome was sensitivity, specificity, cancer detection rate, and stage distribution at the first round of screening. Analysis was by intention to treat. This study is registered, number UMIN000000757.

Findings: Of 72,998 women enrolled, 36,859 were assigned to the intervention group and 36,139 to the control group. Sensitivity was significantly higher in the intervention group than in the control group (91·1%, 95% CI 87·2-95·0 vs 77·0%, 70·3-83·7; p=0·0004), whereas specificity was significantly lower (87·7%, 87·3-88·0 vs 91·4%, 91·1-91·7; p<0·0001). More cancers were detected in the intervention group than in the control group (184 [0·50%] vs 117 [0·32%], p=0·0003) and were more frequently stage 0 and I (144 [71·3%] vs 79 [52·0%], p=0·0194). 18 (0·05%) interval cancers were detected in the intervention group compared with 35 (0·10%) in the control group (p=0·034).

Interpretation: Adjunctive ultrasonography increases sensitivity and detection rate of early cancers.

Funding: Ministry of Health, Labour and Welfare of Japan.
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http://dx.doi.org/10.1016/S0140-6736(15)00774-6DOI Listing
January 2016

Postoperative Structural Brain Changes and Cognitive Dysfunction in Patients with Breast Cancer.

PLoS One 2015 4;10(11):e0140655. Epub 2015 Nov 4.

Division of Surgical Oncology, Graduate School of Medicine, Tohoku University, Sendai, Japan.

Objective: The primary purpose of this study was to clarify the influence of the early response to surgery on brain structure and cognitive function in patients with breast cancer. It was hypothesized that the structure of the thalamus would change during the early response after surgery due to the effects of anesthesia and would represent one aspect of an intermediate phenotype of postoperative cognitive dysfunction (POCD).

Methods: We examined 32 postmenopausal females with breast cancer and 20 age-matched controls. We assessed their cognitive function (attention, memory, and executive function), and performed brain structural MRI 1.5 ± 0.5 days before and 5.6 ± 1.2 days after surgery.

Results: We found a significant interaction between regional grey matter volume (rGMV) in the thalamus (P < 0.05, familywise error (FWE), small volume correction (SVC)) and one attention domain subtest (P = 0.001, Bonferroni correction) after surgery in the patient group compared with the control group. Furthermore, the changes in attention were significantly associated with sevoflurane anesthetic dose (r2 = 0.247, β = ‒0.471, P = 0.032) and marginally associated with rGMV changes in the thalamus (P = 0.07, FWE, SVC) in the Pt group.

Conclusion: Our findings suggest that alterations in brain structure, particularly in the thalamus, may occur shortly after surgery and may be associated with attentional dysfunction. This early postoperative response to anesthesia may represent an intermediate phenotype of POCD. It was assumed that patients experiencing other risk factors of POCD, such as the severity of surgery, the occurrence of complications, and pre-existing cognitive impairments, would develop clinical POCD with broad and multiple types of cognitive dysfunction.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0140655PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4633203PMC
June 2016

Midostaurin preferentially attenuates proliferation of triple-negative breast cancer cell lines through inhibition of Aurora kinase family.

J Biomed Sci 2015 Jul 4;22:48. Epub 2015 Jul 4.

Biosignal Research Center, Kobe University, Kobe, 657-8501, Japan.

Background: Breast cancer is classified into three subtypes by the expression of biomarker receptors such as hormone receptors and human epidermal growth factor receptor 2. Triple-negative breast cancer (TNBC) expresses none of these receptors and has an aggressive phenotype with a poor prognosis, which is insensitive to the drugs that target the hormone receptors and human epidermal growth factor receptor 2. It is, thus, required to develop an effective therapeutic reagent to treat TNBC.

Results: The study using a panel of 19 breast cancer cell lines revealed that midostaurin, a multi-target protein kinase inhibitor, suppresses preferentially the growth of TNBC cells comparing with non-TNBC cells. Clustering analysis of the drug activity data for the panel of cancer cell lines predicted that midostaurin shares the target with Aurora kinase inhibitors. Following studies indicated that midostaurin attenuates the phosphorylation reaction mediated by Aurora kinase in the cells and directly inhibits this protein kinase in vitro, and that this reagent induces apoptosis accompanying accumulation of 4N and 8N DNA cells in TNBC cells.

Conclusion: Midostaurin suppresses the proliferation of TNBC cells among the breast cancer cell lines presumably through the inhibition of the Aurora kinase family. The precise study of midostaurin on cell growth will contribute to the development of the drug for the treatment of TNBC.
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http://dx.doi.org/10.1186/s12929-015-0150-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4491224PMC
July 2015

Smoking and survival after breast cancer diagnosis in Japanese women: A prospective cohort study.

Cancer Sci 2015 Aug 14;106(8):1066-74. Epub 2015 Jul 14.

Division of Community Health, Tohoku University Graduate School of Medicine, Miyagi, Japan.

The results of previous studies investigating whether there is an association between active smoking and risk of death among breast cancer patients have been inconsistent. We investigated the association between active and passive smoking and risk of all-cause and breast cancer-specific death among female breast cancer patients in relation to menopausal and tumor estrogen/progesterone receptor (ER/PR) status. The present study included 848 patients admitted to a single hospital in Japan from 1997 to 2007. Active or passive smoking status was assessed using a self-administered questionnaire. The patients were followed until 31 December 2010. We used a Cox proportional-hazard model to estimate hazard ratios (HR). During a median follow-up period of 6.7 years, 170 all-cause and 132 breast cancer-specific deaths were observed. Among premenopausal patients, current smokers showed a non-significant higher risk of all-cause and breast cancer-specific death. A duration of smoking >21.5 years was positively associated with all-cause (HR = 3.09, 95% confidence interval [CI], 1.17-8.20) and breast cancer-specific death (HR = 3.35, 95% CI: 1.22-9.23, Ptrend  = 0.035) among premenopausal patients. In premenopausal patients with ER+ or PR+ tumors, there was some suggestion that a longer duration of smoking was associated with higher risk of all-cause and breast cancer-specific death. Passive smoking demonstrated no significant risk. Our results suggest that a longer duration of active smoking is associated with an increased risk of all-cause and breast cancer-specific death among premenopausal patients, possibly with hormonal receptor-positive tumors. Breast cancer patients should be informed about the importance of smoking cessation.
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http://dx.doi.org/10.1111/cas.12716DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4556397PMC
August 2015

The use of natural products in colorectal cancer drug discovery.

Expert Opin Drug Discov 2015 Apr 27;10(4):411-26. Epub 2015 Feb 27.

Miyagi Cancer Center, Department of Surgery , 47-1 Nodayama, Natori 981-1293 , Japan +81 22 384 3151 ; +81 22 381 1168 ;

Introduction: Natural products (NPs) are evolutionarily designed and contain more complex and challenging structures than synthetic compounds. Since the 1980s, the pharmaceutical industry has gradually shifted to a strategy of developing targeted agents by screening libraries of synthetic compounds. However, NPs have recently received renewed focus as a rich repository for drug discovery. Irinotecan was developed as a derivative of camptothecin and was applied in standard regimens for metastatic colorectal cancer (CRC) worldwide. Additionally, polysaccharide K is approved for CRC in Japan and Taiwan in combination with cytotoxic agents. However, after the approval of irinotecan in 1996, no anti-cancer agents derived from NPs have been approved for CRC.

Areas Covered: This review discusses NPs that are currently under investigation for the treatment of CRC. In addition, other NPs derived as purified ingredients and crude extracts are listed and also discussed.

Expert Opinion: The use of NPs for the discovery of anti-cancer agents has not been fully investigated. New technologies that are currently applied for synthetic compounds may be utilized for anti-cancer drug discovery including NPs for CRC.
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http://dx.doi.org/10.1517/17460441.2015.1018174DOI Listing
April 2015

Participants' understanding of a randomized controlled trial (RCT) through informed consent procedures in the RCT for breast cancer screening, J-START.

Trials 2014 Sep 25;15:375. Epub 2014 Sep 25.

Division of Molecular Epidemiology, Tohoku University Graduate School of Medicine, 2-1, Seiryo-machi, Aoba-ku, Sendai, Japan.

Background: It is often difficult to enrol healthy volunteers into a randomized controlled trial (RCT) as there are barriers to participants' proper understanding of a trial. This study aimed to evaluate degrees of understanding of the informed consent (IC) process among healthy volunteers who participated in an RCT. Additionally, factors associated with degree of understanding were investigated.

Methods: The J-START (the Japan STrategic Anti-cancer Randomized controlled Trial) is an RCT investigating the effectiveness of ultrasonography screening for breast cancer in women aged 40 to 49 years. To evaluate participants' understanding of the J-START, we administered questionnaires to 376 Japanese women on the day of enrolment at five study sites across Japan. The respondents were asked to complete the anonymous questionnaire within 2 weeks. We assessed objective understanding and perceived subjective understanding of IC using a Japanese version of the Quality of Informed Consent scale (QuIC). Then we analyzed the characteristics of women whose understanding was poor, and clarified the association between providing information and their understanding of the study protocol.

Results: The average QuIC scores were 78.2 and 82.2 (out of 100 each) for objective and subjective understanding, respectively. These are generally acceptable scores for participants' understanding of an RCT. However, there were four domains with low scores, indicating poor understanding: (1) experimental nature of the study, (2) potential risks or discomfort, (3) benefit to self, and (4) compensation.

Conclusions: Healthy volunteers generally well understood the J-START. Nevertheless, there were some domains in need of improvement. In order to facilitate participants' understanding, it is necessary to provide training to reduce differences in information-providing procedures between medical centres and to endeavour to provide consistent information and conditions.

Trial Registration: The J-START was registered with the University Hospital Medical Information Network Clinical Trial Registration (UMIN-CTR), Japan (registration number: UMIN000000757), on July 1, 2007.
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http://dx.doi.org/10.1186/1745-6215-15-375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4181002PMC
September 2014

International variation in management of screen-detected ductal carcinoma in situ of the breast.

Eur J Cancer 2014 Oct 19;50(15):2695-704. Epub 2014 Aug 19.

Behavioral Research Program, Division of Cancer Control and Population Sciences, National Cancer Institute, Bethesda, MD, USA.

Background: Ductal carcinoma in situ (DCIS) incidence has grown with the implementation of screening and its detection varies across International Cancer Screening Network (ICSN) countries. The aim of this survey is to describe the management of screen-detected DCIS in ICSN countries and to evaluate the potential for treatment related morbidity.

Methods: We sought screen-detected DCIS data from the ICSN countries identified during 2004-2008. We adopted standardised data collection forms and analysis and explored DCIS diagnosis and treatment processes ranging from pre-operative diagnosis to type of surgery and radiotherapy.

Results: Twelve countries contributed data from a total of 15 screening programmes, all from Europe except the United States of America and Japan. Among women aged 50-69 years, 7,176,050 screening tests and 5324 screen-detected DCIS were reported. From 21% to 93% of DCIS had a pre-operative diagnosis (PO); 67-90% of DCIS received breast conservation surgery (BCS), and in 41-100% of the cases this was followed by radiotherapy; 6.4-59% received sentinel lymph node biopsy (SLNB) only and 0.8-49% axillary dissection (ALND) with 0.6% (range by programmes 0-8.1%) being node positive. Among BCS patients 35% received SLNB only and 4.8% received ALND. Starting in 2006, PO and SLNB use increased while ALND remained stable. SLNB and ALND were associated with larger size and higher grade DCIS lesions.

Conclusions: Variation in DCIS management among screened women is wide and includes lymph node surgery beyond what is currently recommended. This indicates the presence of varying levels of overtreatment and the potential for its reduction.
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http://dx.doi.org/10.1016/j.ejca.2014.07.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4275301PMC
October 2014
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