Koji Ohnuki

Age-specific interval breast cancers in Japan: estimation of the proper sensitivity of screening using a population-based cancer registry.

The age‐specific sensitivity of a screening program was investigated using a population‐based cancer registry as a source of false‐negative cancer cases. A population‐based screening program for breast cancer was run using either clinical breast examinations (CBE) alone or mammography combined with CBE in the Miyagi Prefecture from 1997 to 2002. Interval cancers were newly identified by linking the screening records to the population‐based cancer registry to estimate the number of false‐negative cases of screening program. Among 112 071 women screened by mammography combined with CBE, the number of detected cancers, false‐negative cases and the sensitivity were 289, 22 and 92.9%, respectively, based on the reports from participating municipalities. The number of newly found false‐negative cases and corrected sensitivity when using the registry were 34 and 83.8%, respectively. In detected cancers, the sensitivity of screening by mammography combined with CBE in women ranging from 40 to 49 years of age based on a population‐based cancer registry was much lower than that in women 50–59 and 60–69 years of age (40–49: 18, 71.4%, 50–59: 19, 85.8%, 60–69: 19, 87.2%). These data suggest that the accurate outcome of an evaluation of breast cancer screening must include the use of a population‐based cancer registry for detecting false‐negative cases. Screening by mammography combined with CBE may therefore not be sufficiently sensitive for women ranging from 40 to 49 years of age. (Cancer Sci 2008; 99: 2264–2267)

A Case Control Study on the Effectiveness of Breast Cancer Screening by Clinical Breast Examination in Japan

A case‐control study was conducted in Miyagi and Gunma prefectures, Japan, to evaluate the effectiveness of breast cancer screening by clinical breast examination (CBE) alone in reducing breast cancer mortality. Case subjects, who were female and had died of breast cancer, were collected from residential registry files and medical records. Control subjects matched in sex, age and residence were randomly selected from residential registry files. The screening histories during 5 years prior to the cases having been diagnosed as breast cancer were surveyed using the examinee files of the screening facilities. Finally, the data of 93 cases and 375 controls were analyzed. The odds ratio (OR) of breast cancer death for participating in screening at least once during 5 years was 0.93 (95% confidence interval (95%CI) 0.48‐1.79). The cases were more symptomatic than the controls when screened. If the participants who had had symptoms in their breasts were classified as not screened, the OR decreased to 0.56 (95%CI 0.27‐1.18). The case control study suggests that the current screening modality (CBE) lacks effectiveness (OR=0.93), although it might be effective for an a symptomatic population (OR=0.56). The number of cases was small, and a larger case‐control study is desirable to define whether CBE is effective or not. However, it is necessary to consider the introduction of mammographic screening to reduce breast cancer mortality in Japan.

Increased androgen receptor activity and cell proliferation in aromatase inhibitor-resistant breast carcinoma

Aromatase inhibitors (AI) are commonly used to treat postmenopausal estrogen-receptor (ER)-positive breast carcinoma. However, resistance to AI is sometimes acquired, and the molecular mechanisms underlying such resistance are largely unclear. Recent studies suggest that AI treatment increases androgen activity during estrogen deprivation in breast carcinoma, but the role of the androgen receptor (AR) in breast carcinoma is still a matter of controversy. The purpose of this study is to examine the potential correlation between the AR- and AI-resistant breast carcinoma. To this end, we performed immunohistochemical analysis of 21 pairs of primary breast carcinoma and corresponding AI-resistant recurrent tissue samples and established two stable variant cell lines from ER-positive T-47D breast carcinoma cell line as AI-resistance models and used them in in vitro experiments. Immunohistochemical analysis demonstrated that the expression of prostate-specific antigen (PSA) and Ki-67 were significantly higher and ER and progesterone receptor (PR) were lower in recurrent lesions compared to the corresponding primary lesions. Variant cell lines overexpressed AR and PSA and exhibited neither growth response to estrogen nor expression of ER. Androgen markedly induced the proliferation of these cell lines. In addition, the expression profile of androgen-induced genes was markedly different between variant and parental cell lines as determined by microarray analysis. These results suggest that in some cases of ER-positive breast carcinoma, tumor cells possibly change from ER-dependent to AR-dependent, rendering them resistant to AI. AR inhibitors may thus be effective in a selected group of patients.

Cost‐effectiveness analysis of screening modalities for breast cancer in Japan with special reference to women aged 40–49 years

Although the introduction of screening mammography in Japan would be expected to reduce mortality from breast cancer, the optimal screening modality in terms of cost‐effectiveness remains unclear. We compared the cost‐effectiveness ratio, defined as the cost required for a life‐year saved, among the following three strategies: (1) annual clinical breast examination; (2) annual clinical breast examination combined with mammography; and (3) biennial clinical breast examination combined with mammography for women aged 30–79 years using a hypothetical cohort of 100 000. The sensitivity, specificity and early breast cancer rates were derived from studies conducted from 1995 to 2000 in Miyagi Prefecture. The treatment costs were based on a questionnaire survey conducted at 13 institutions in Japan. We used updated parameters that were needed in the analysis. Although the effectiveness of treatment in terms of the number of expected survival years was highest for annual combined modality, biennial combined modality had a higher cost‐effectiveness ratio, followed by annual combined modality and annual clinical breast examination in all age groups. In women aged 40–49 years, annual combined modality saved 852.9 lives and the cost/survival duration was 3 394 300 yen/year, whereas for biennial combined modality the corresponding figures were 833.8 and 2 025 100 yen/year, respectively. Annual clinical breast examination did not confer any advantages in terms of effectiveness (815.5 lives saved) or cost‐effectiveness (3 669 900 yen/year). While the annual combined modality was the most effective with respect to life‐years saved among women aged 40–49 years, biennial combined modality was found to provide the highest cost‐effectiveness. (Cancer Sci 2006; 97: 1242–1247)

Effect of screening mammography on breast cancer survival in comparison to other detection methods: a retrospective cohort study.

The effectiveness of screening mammography (SMG) on mortality has been established in randomized controlled trials in Western countries, but not in Japan. This study evaluated the effectiveness by comparing the survival based on detection methods. The survivals were estimated by the Kaplan–Meier method. Breast cancer patients diagnosed from 1 January 1989 to 31 December 2000 were determined using the Miyagi Prefectural Cancer Registry and follow‐up was performed from the date of the diagnosis until the date of death or the end of follow‐up, 31 December 2005. The hazard ratios (HR) and 95% confidence interval (CI) of breast cancer death based on the detection methods were estimated by the Cox proportional‐hazard regression model. The mean age of the 7513 patients was 55.7 years (range, 15.0–99.3). The 5‐year survival associated with the SMG group, the clinical breast examination (CBE) group, and the self‐detection group was 98.3%, 94.3%, and 84.8%, respectively. The HR (95% CI) of deaths from breast cancer was 2.50 (1.10–5.69) for patients in the CBE group and 6.57 (2.94–14.64) for the self‐detection group in comparison to the SMG group. In women aged 50–59, the HRs were 1.64 (0.58–4.62) among the CBE group and 3.74 (1.39–10.03) among the self‐detection group, and the HRs for the CBE and self‐detection groups in women aged 60–69 were 2.96 (0.68–12.83) and 9.51 (2.36–38.26), respectively. After adjusting for stage, the HRs dropped remarkably. Screening mammography may be more effective in the elderly group and be able to reduce the mortality of breast cancer in Japan. (Cancer Sci 2009)

A meta-analysis of mammographic screening with and without clinical breast examination

Mammographic screening with clinical breast examination has been recommended in Japan since 2000. Although mammographic screening without clinical breast examination has not been recommended, its introduction is anticipated. The efficacies of mammographic screening with and without clinical breast examination were evaluated based on the results of randomized controlled trials. PubMed and other databases for studies published between 1985 and 2014 were searched. The study design was limited to randomized controlled trials to evaluate mortality reduction from breast cancer. Five studies were eligible for meta‐analysis of mammographic screening without clinical breast examination. The relative risk for women aged 40–74 years was 0.75 (95% confidence interval, 0.67–0.83). Three studies evaluated the efficacy of mammographic screening with clinical breast examination. The relative risk for women aged 40–64 years was 0.87 (95% confidence interval, 0.77–0.98). The number needed to invite was always lower in mammographic screening without clinical breast examination than in mammographic screening with clinical breast examination. In both screening methods, the number needed to invite was higher in women aged 40–49 years than in women aged 50–70 years. These results suggest that mammographic screening without clinical breast examination can afford higher benefits to women aged 50 years and over. Although evidence of the efficacy of mammographic screening without clinical breast examination was confirmed based on the results of the randomized controlled trials, a Japanese study is needed to resolve local problems.

The Japanese Guidelines for Breast Cancer Screening

OBJECTIVE The incidence of breast cancer has progressively increased, making it the leading cause of cancer deaths in Japan. Breast cancer accounts for 20.4% of all new cancers with a reported age-standardized rate of 63.6 per 100 000 women. METHODS The Japanese guidelines for breast cancer screening were developed based on a previously established method. The efficacies of mammography with and without clinical breast examination, clinical breast examination and ultrasonography with and without mammography were evaluated. Based on the balance of the benefits and harms, recommendations for population-based and opportunistic screenings were formulated. RESULTS Five randomized controlled trials of mammographic screening without clinical breast examination were identified for mortality reduction from breast cancer. The overall relative risk for women aged 40-74 years was 0.75 (95% CI: 0.67-0.83). Three randomized controlled trials of mammographic screening with clinical breast examination served as eligible evidence for mortality reduction from breast cancer. The overall relative risk for women aged 40-64 years was 0.87 (95% confidence interval: 0.77-0.98). The major harms of mammographic screening were radiation exposure, false-positive cases and overdiagnosis. Although two case-control studies evaluating mortality reduction from breast cancer were found for clinical breast examination, there was no study assessing the effectiveness of ultrasonography for breast cancer screening. CONCLUSIONS Mammographic screening without clinical breast examination for women aged 40-74 years and with clinical breast examination for women aged 40-64 years is recommended for population-based and opportunistic screenings. Clinical breast examination and ultrasonography are not recommended for population-based screening because of insufficient evidence regarding their effectiveness.

The Japanese Breast Cancer Society Clinical Practice Guideline for screening and imaging diagnosis of breast cancer

The Breast Imaging Reporting and Data System (BIRADS) developed by the American College of Radiology (ACR) as a standardized quality assessment tool for drawing up imaging findings and reports is universally recognized. In Japan, the ‘‘Guidelines for Mammography’’ complied on the basis of the 2nd edition of BI-RADS were published in 1999. According to those guidelines, mammogram findings are finally assessed for malignancy using 5 grading categories, i.e., category 1 or 2 requiring no additional detailed examination and categories 3–5 warranting further detailed examinations. The 4th edition of BI-RADS [1], on the other hand, is designed to provide a general flow of the breast cancer screening process as follows: lesions presenting screening mammographic findings based on which malignancy cannot be negated are classified into category 0 and subjected to detailed examination performed later, i.e., additional mammography and ultrasonography at the initial screening site; if no malignant findings are noted in the detailed examination, the lesion is classified into category 1 or 2; if findings are probably benign (malignancy level: B2 %) requiring a follow-up at 6 months later, the lesion is classified into category 3; or if a higher malignancy level is suspected, the lesion is classified into category 4 or 5, warranting histopathological examination. It is often the case in Japan at present that screening and the subsequent medical workup are conducted at different facilities, so that radiologists and other physicians at the latter sites may experience some difficulty in referring to screening mammograms. Eventually, it is considered necessary for precise control of accurate screening in Japan to classify lesions presenting findings that correspond to BIThis article is an English digested edition of the Nyugan Shinryo guideline 2013 nen ban, published by Kanehara & Co., LTD.

Asynchronous LOH analysis of ductal carcinoma in situ from patients who subsequently developed invasive ductal carcinoma

Management of women with ductal carcinoma in situ (DCIS) is currently a major concern. Biological characteristics in the light of progression from DCIS to invasive ductal carcinoma (IDC) remain unknown. Our previous study [1] investigating synchronous lesions demonstrated higher LOH frequencies in parallel with the tumor progression from atypical ductal hyperplasia (ADH) to DCIS and IDC [1]. We report here an asynchronous LOH analysis of DCIS from patients who subsequently developed IDC. We collected 88 biopsy specimens, originally diagnosed benign, from the patients who subsequently developed IDC in the ipsilateral breast. Seven asynchronous lesions of initial biopsy (re-evaluation was DCIS) and the respective IDC were subjected to LOH analysis in this study. Thirteen microsatellite markers, which were mapped to and/or very close to the tumor suppressor genes or regions with frequent LOH in breast cancer, were used. LOHs were observed in parallel with the tumor progression from DCIS to IDC in all cases except for one that developed IDC in another quadrant. The six patients developed IDC near the initial biopsy, and presented similar or identical histopathologic features. LOH analysis of biopsy specimens from patients who subsequently developed IDC demonstrated acquisition of genetic change at an earlier stage, as the same allele at the same genomic locus was lost in DCIS. Our results suggest that genetic alternations accumulate during cancer progression from DCIS to IDC, and DCIS presents a high risk of developing invasive transformation.

Review of Mammographic Screening Trials in Western Countries: Mortality Reduction in Women Younger than 49.

欧米ではマンモグラフィを用いた乳癌検診が一般的であり, RCTと症例対照研究により50歳以上では有効であると言えるが, 49歳以下についての有効性評価は定まっていない。今回, 欧米で実施された主なRCTと症例対照研究を, とくに49歳以下に絞ってレビューし, マンモグラフィ検診による死亡リスク減少効果について検討を加えた。40-49歳における死亡リスク減少効果は7つのRCTの平均で18%とある程度の有効性は期待されるが, 50歳以上に比して限界があるといわざるを得ない。ただし, スウェーデンの最近の研究報告では23%の死亡リスク減少効果が認められており, 有効性が強く示唆される。わが国では現在, マンモグラフィの導入について検討が重ねられているが, 49歳以下への導入については, 50歳以上に比較して, 乳腺実質による乳癌発見感度の低下, 累積検診による被曝リスクの上昇を考慮しなければならない。しかし, 40歳代の乳癌罹患率ならびに死亡率は高いことから, 今後, 49歳以下女性に対するマンモグラフィ検診の有効性評価が欠かせない。