Proton Pump Inhibitors and Cyclin-Dependent Kinase 4/6 Inhibitors in Patients With Breast Cancer.

BACKGROUND: Proton pump inhibitors (PPIs) reduce the bioavailability of several anticancer drugs. The impact of PPIs co-administered with cyclin-dependent kinase 4 and 6 inhibitors is controversial. We aimed to clarify whether the concomitant use of PPIs impacts palbociclib and abemaciclib effectiveness in breast cancer treatment. PATIENTS AND METHODS: This multicenter, retrospective, observational study, conducted across 4 medical institutions in Japan, consecutively included patients with endocrine-resistant metastatic breast cancer, receiving palbociclib or abemaciclib between December 2017 and August 2022. Propensity score-matched analyses were performed. Treatment efficacy and safety with and without PPIs were compared. Progression-free survival and overall survival were estimated using the Kaplan-Meier method and compared using a log-rank test. A Cox proportional hazards model was used to estimate the hazard ratio. RESULTS: The study included 240 patients. After 1:1 matching, 112 patients were treated with and without PPIs. The median progression-free survival period was 1.2 years in the PPI group and 1.3 years in the non-PPI group (hazard ratio, 1.19; 95% CI, 0.70-2.02). The median overall survival period was 3.6 years in the PPI group, whereas it was not reached in the non-PPI group (hazard ratio, 1.23; 95% CI, 0.61-2.47). Consistent results were obtained for subgroups receiving palbociclib (n = 177) and abemaciclib (n = 63) without propensity score matching. Adverse event incidence and severity were similar in both groups. CONCLUSION: The effectiveness of cyclin-dependent kinase 4/6 inhibitors is unlikely to be affected by concomitant PPI use. Future prospective pharmacokinetic studies are warranted.

The effects of breast density on the benefits of mammograms with adjunctive ultrasonography in breast screening.

OBJECTIVE: Various efforts have been made to improve the accuracy of breast cancer screening. This study aimed to report differences in the contribution of ultrasonography to cancer screening assessments of dense and non-dense breasts. METHODS: The participants in this study were 29,640 Japanese women in their 40 s who underwent breast cancer screening at the Iwate Cancer Society between 2018 and 2021. This included women who chose mammography alone or mammography with adjunctive ultrasonography (overall assessment). They were classified into two groups according to the breast density in mammography: dense breasts and non-dense breasts. Recall rate, breast cancer detection rate, and positive predictive value of the two screening-type groups were evaluated for each breast density group. RESULTS: Of the 29,640 women analyzed, 18,861 (63.6%) underwent mammography alone and 10,779 (36.3%) were by overall assessments. The number of women recalled was higher in the overall assessment group than in the mammography-alone group (2.9% vs. 1.9%, p < 0.01). The proportion of women in whom breast cancer was detected was higher in the overall assessment group than in the mammography-alone group (0.31% [n = 33] vs. 0.15% [n = 28], p < 0.01). For non-dense breasts, there were no significant differences in either the recall rate or the breast cancer detection rate between those who underwent mammography alone and those who underwent overall assessment. Conversely, for dense breasts, the recall rate after mammography alone was lower than that after overall assessment (1.8% vs. 3.8%, p < 0.01), and the breast cancer detection rate was higher after overall assessment than after mammography alone (0.40% vs. 0.18%, p < 0.01). CONCLUSION: We found the benefits of adjunctive ultrasonography with mammography to differ depending on breast density. This could be used to tailor the selection of screening modalities to individuals.

Overall assessment system of combined mammography and ultrasound for breast cancer screening in Japan.

Mammography is the only screening method with evidence in support of reduced breast cancer mortality, but yields poor accuracy outcomes in women with dense breast tissue. The Japan Strategic Anti-cancer Randomized Trial (J-START) was conducted as part of the measures implemented to deal with women with dense breast tissue. Although the sensitivity was increased, the specificity was significantly lower in the intervention group because further examination was required in all positive cases classified by either mammography or ultrasound in the J-START. To address the issue, an overall assessment system of combined mammography and adjunctive ultrasound for breast cancer screening has been developed in Japan. The basic concept is based on a comprehensive assessment that includes a mammography assessment followed by an adjunctive assessment for ultrasound similar to the clinical setting. Currently, mammography alone is recommended for population-based breast cancer screening in Japan, but additional ultrasonography is extensively available for women, especially for women with dense breasts with shared decision-making for personalized breast cancer screening. The overall assessment system is recommended for use in Japan when breast cancer screening is conducted using both mammography and ultrasonography. In this article, we summarize the advantages of the overall assessment and the simultaneous mammography/ultrasound method, the basic approach used in Japan to assign the overall assessment category for breast cancer screening, and we outline the future directions of adjunctive screening ultrasound.

A survey on the current status of clinical resources for diagnosis and treatment of breast cancer in rural hospitals of the Tohoku region in Japan.

BACKGROUND: We administered a questionnaire survey to assess the available clinical resources for the diagnosis and treatment of breast cancer and identify the issues faced by rural hospitals in the Tohoku region in Japan. METHODS: The term rural hospital was defined by the following three criteria: the facility is a certified regional cancer center and hospital, no breast specialist is on staff, and ≥ 10 breast surgeries per year have been performed. Thirty-eight rural hospitals were eligible, and each was sent a self-administered questionnaire consisting of 26 questions by mail. RESULTS: Responses were received from 29 of the 38 hospitals. Most of the hospitals had adequate facilities for diagnosis and treatment, but they needed specialists' support for ≥ 2 days per month. Approximately half of the hospitals indicated that applying resources for diagnosis and treatment of breast cancer, especially during planning of treatment and management of advanced breast cancer patients, was a burden. Interestingly, the hospitals felt that being able to provide treatment to their patients was more ideal rather than referring them to urban hospital like the prefectural cancer center and hospital providing specialized cancer treatment. CONCLUSIONS: The surveyed rural hospitals needed practical and knowledge-based support from specialists. Unfortunately, the number of specialists is currently insufficient in Tohoku. Increased number of certified physicians, clinical pathways for sharing patient's information and updated knowledge, and information and communication technology for treatment with specialists' intervention in rural hospitals may solve issues in Tohoku.

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.

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.

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.

Effect of screening mammography on cumulative survival of Japanese women aged 40-69 years with breast cancer.

BACKGROUND: The effectiveness of screening mammography (MMG) has mainly been demonstrated by studies in western countries. This study was conducted to evaluate cumulative survival and the risk of breast cancer death among Japanese women aged 40-69 years with screening-detected and interval breast cancer divided into three groups: MMG with clinical breast examination (CBE), CBE alone, and self-detection. METHODS: By matching a list of 126,537 women (358,242 person-screenings) who participated in the Miyagi Cancer Society Screening program between 1 April 1995 and 31 December 2002 with the Miyagi Prefectural Cancer Registry, 429 MMG with CBE, 522 CBE, and 3,047 self-detected cases were included in this study. Follow-up was performed until the date of death or 31 December 2007. Survival was estimated by the Kaplan-Meier method. The Cox proportional hazards model was used to estimate hazard ratios (HR) and 95 % confidence intervals (CI) for breast cancer death. RESULTS: Five-year survival for women in the MMG with CBE, CBE, and self-detection groups was 96.8, 92.7, and 86.6 %, respectively. The HR (95 % CI) for breast cancer death was 2.38 (0.72-7.94) among CBE-screened and 4.44 (1.42-13.89) among self-detected cases for women aged 40-49 years, but was 3.00 (1.63-5.50) among CBE-screened and 4.51 (2.69-7.56) among self-detected cases for women aged 50-69 years relative to cases screened by use of MMG with CBE. CONCLUSIONS: In terms of the survival and risk of breast cancer death, MMG with CBE may be more effective than MMG alone or self-detection for Japanese women aged 40-69 years.

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.

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.

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.

Mammographic screening for non-palpable breast cancer in Japan.

In Japan, mammography was endorsed for breast cancer screening in women aged 40 and over by the Ministry of Health, Labor and Welfare in 2004. The spread of mammographic screening has caused an increase in the incidence of non-palpable breast cancer. Precision reading for mammography is necessary to detect non-palpable breast cancer. When mass and focal asymmetric density is noted, it is important to analyze the density, density gradient, internal structure, margin and associated findings. Calcifications are classified by morphology and distribution mainly. It is necessary to distinguish secretor-type calcifications from necrotic-type calcifications. The Iwate Cancer Association performed a population-based screening program for breast cancer using mammography combined with clinical breast examination of 42,065 women in Iwate Prefecture from 1999 to 2003. A total of 2,329(5.7%)women were recalled and the 112 cases(0.27%) of cancer were detected in 114 breasts. Of 114 breast cancers, 40 (35%) were non-palpable and 74(65%) were palpable. The early breast cancer (stage 0 and I) rate of the non-palpable group was significantly higher than that of the palpable group (90% and 47%, p = 0.0003). The node-negative rate of the non-palpable group was significantly higher than that of the palpable group (92% and 68%, p = 0.011). It is expected that mammographic screening will be expanded and that the mortality rate from breast cancer in Japan will decrease, as in Europe and the United States.

[Treatment strategy for liver metastasis from breast cancer].

Distant metastases, including supraclavicular and parasternal lymph node metastases, were observed in about 23% of primary breast cancers in our institute. The liver was the primary site of metastasis in about 8% of cases. This rate was low compared with metastases to the bone, lung, and pleura. As treatment for metastatic lesions to other organs fails, metastatic frequency to the liver increases. As treatment, whole-body control with chemoendocrine therapy is fundamental. In chemotherapy, anthracyclines are the first choice and taxanes are the second, but the use of herceptin for herceptest-positive patients should be considered. Endocrine therapy should be adopted for patients with hormone receptor-positive tumors. Achieving a temporary partial response is possible, although cure is almost impossible. The prognosis of patients with metastasis to the liver is poor; the 3- and 5-year survival rates are 22% and 11%, respectively. We must emphasize the prevention of liver metastases by early detection using mass screening with mammography and neoadjuvant/adjuvant chemoendocrine therapy.

Loss of heterozygosity analyses of asynchronous lesions of ductal carcinoma in situ and invasive ductal carcinoma of the human breast.

BACKGROUND: Ductal carcinoma in situ (DCIS) of the breast is known to possess characteristics of the pre-invasive stage of breast cancer and is the precursor to invasive ductal carcinoma (IDC). However, the natural history of the progression from DCIS to IDC remains unknown at the molecular level. METHODS: We investigated the loss of heterozygosities (LOHs) in tumors of seven patients with a history of breast biopsy. The seven specimens were diagnosed as DCIS on histopathological re-examination. These patients were diagnosed with ipsilateral breast cancer a few years after biopsy. We used thirteen selected microsatellite markers that were mapped to and/or very close to the tumor suppressor genes or regions with frequent LOHs in breast cancer. DNA isolated from microdissected formalin-fixed, paraffin-embedded tissues was subjected to a PCR-LOH analysis for these chromosome loci, and the pattern of LOHs was compared between the two asynchronous lesions for the seven cases. RESULTS: In all patients except one, the LOHs were concordant at 91% as the informative chromosome loci in cases 1 to 6 were 56, and the concordance in LOH pattern between DCIS and IDC was detected at 50 loci. The LOHs had accumulated in accordance with the tumor progression from DCIS to IDC. The recurrent lesion occurred at or near the site of the primary biopsy and had similar or identical histopathologic features. CONCLUSIONS: These recurrences observed were probably residual disease rather than true recurrences. Our results suggest the following: (i) genetic alternations accumulate during cancer progression from DCIS to IDC, (ii) DCIS is a lesion that has a high risk of developing invasive transformation and (iii) after approximately 5 years without treatment, DCIS may develop into IDC.