Efficacy of radiation therapy in Japanese patients with positive margins after breast-conserving surgery.

BACKGROUND: Additional surgical resection is recommended after breast-conserving surgery if the surgical margin is pathologically positive. However, in clinical practice, radiation therapy is sometimes used instead for several reasons. Irradiation may be appropriate for some patients, but real-world data is still insufficient to establish it as standard treatment. We retrospectively investigated the status of local control in patients who received irradiation for positive margins. METHODS: We investigated 85 patients with positive margins after curative partial mastectomy who were treated with irradiation instead of additional excision during the period 2006-2013. The patients received whole-breast irradiation (43.2-50 Gy) using photon beams and additional tumour-bed boost (8.1-16 Gy) using electron beams. Intrabreast tumour recurrence was defined as secondary cancer within the ipsilateral conserved breast. Surgical margin was defined as positive if tumour cell exposure was pathologically confirmed on the margin. RESULTS: Seven patients (8.2%) developed intrabreast tumour recurrence during a mean observation period of 119 months. As to components of positive margin, 76 cases were positive for an intraductal component, of which seven (9.2%) developed intrabreast tumour recurrence. Meanwhile, all nine cases positive for an invasive component were free from intrabreast tumour recurrence. Two of the intrabreast tumour recurrence cases seemed to develop new lesions rather than recurrence, considering tumour location. The cumulative incidence of intrabreast tumour recurrence over 10 years was 6.1%. Limited to true recurrence, intrabreast tumour recurrence incidence was 4.9%. CONCLUSION: Our real-world data supports irradiation as an alternative to additional surgical intervention for positive margins after breast-conserving surgery and offers a basis for further research.

Acute myocarditis during adjuvant therapies for breast cancer: a case report.

BACKGROUND: With the improvement of optimal perioperative drug therapy for breast cancer patients, physicians now have to treat the adverse effects and comorbidities associated with long-term treatments. We report a case who suffered cardiac arrest due to acute myocarditis developed after initiation of adjuvant treatment. CASE PRESENTATION: After completing preoperative chemotherapy and undergoing curative surgery for right breast cancer, a 46-year-old female patient started adjuvant tamoxifen and resumed trastuzumab. Two months later, she complained fever and dyspnea. Blood tests showed a marked increase in hepatic enzymes, and the patient was rushed to our emergency room on suspicion of drug-induced liver injury. In the emergency room, the patient went into cardiac arrest shortly after tachycardia with ST-segment elevation appeared on the monitored electrocardiogram. Resuscitation was started immediately and tracheal intubation, intra-aortic balloon pumping, and extracorporeal membrane oxygenation were started. Coronary angiography results were negative for ischemic heart disease. A diagnosis of fulminant myocarditis was made and steroid pulse therapy and immunoglobulin therapy were started. After the start of treatment, the symptoms of heart failure improved steadily and the patient was discharged on the 28th day. Histological findings of the myocardial biopsy revealed degeneration and necrosis of myocardial cells with marked lymphocytic infiltration, consistent with the histology of lymphocytic myocarditis. Serum cytomegalovirus, coxsackie B virus and adenovirus antibodies were all elevated and these findings were consistent with acute viral myocarditis. CONCLUSIONS: We report a case with strong indications for therapy-induced liver damage, who was ultimately diagnosed with acute viral myocarditis and successfully treated with multidisciplinary therapy. We believe that our findings would be useful for other clinicians in managing similar patients.

Clinicopathological Features Related to the Efficacy of CDK4/6 Inhibitor-Based Treatments in Metastatic Breast Cancer.

BACKGROUND: Resistance to endocrine therapy has been a major obstacle in the management of hormone receptor (HR)-positive metastatic breast cancer (MBC). Meanwhile, a number of treatments are available to such patients, and physicians often encounter difficulties in choosing the most appropriate treatments for individual patients. The combination of CDK 4/6 inhibitors (CDKi) and endocrine therapy has now become a standard treatment for HR-positive and human epidermal growth factor receptor 2 (HER2)-negative MBC. However, no predictive markers for CDKi-based treatments have been established. Considering their side effects and the financial burden on patients, identifying such markers is crucial. METHODS: Clinicopathological features of 107 patients with HR-positive HER2-negative MBC, who received CDKi-based treatments at our institution were retrospectively investigated. HR status in distant metastatic lesions and immunocompetent cells in peripheral blood were also studied. RESULTS: Progression-free survival (PFS) was significantly shorter in patients whose primary tumour was high grade (P = 0.016) or high neutrophil-to-lymphocyte ratio (NLR) at baseline (P = 0.017). Meanwhile, there were no differences in other factors, such as expression levels of hormone receptors. Patients whose metastatic lesions were of low tumour grade or high Ki67 labelling index had longer PFS, and such trends were more obvious than primary lesions. CONCLUSION: Our data indicate that tumour grade in primary lesion and NLR are potential predictive factors for CDKi-based treatments. Moreover, pathological assessment of metastatic lesions might also be useful.

Cerebral hemorrhage due to amyloid angiopathy that was difficult to differentiate from breast cancer metastasis: a case report.

BACKGROUND: Breast cancer patients are known to develop brain metastasis at a relatively high frequency. However, imaging findings of brain metastases vary, and it is sometimes very difficult to distinguish these from other tumorous lesions and non-neoplastic lesions, such as cerebral hemorrhage. Meanwhile, there are various causes of cerebral hemorrhage; a major one is cerebral amyloid angiopathy (CAA). With the advancement of imaging technology, CAA-related cerebral hemorrhage can be more precisely diagnosed with magnetic resonance imaging (MRI), but definitive diagnosis of CAA can only be made based on pathological assessment. Herein, we report a case of consciousness disorder appearing during adjuvant therapy for breast cancer. We initially considered that the patient's cerebral hemorrhage was due to a metastatic tumor, but based on excisional biopsy, she was diagnosed with CAA. CASE PRESENTATION: A 73-year-old Japanese woman underwent curative surgery for left breast cancer. Her disease was hormone receptor-positive and human epidermal growth factor receptor 2 (HER2)-positive invasive ductal carcinoma (pStage IIB). While receiving adjuvant treatment, she developed disorientation, and emergent imaging revealed multiple cerebral hemorrhages. There was no apparent enhancement in the cerebral parenchyma on MRI, and differential diagnosis included hemorrhage due to a metastatic tumor, intravascular large B-cell lymphoma, CAA and thrombotic intracranial bleeding. After hospitalization, the bleeding lesion enlarged, resulting in cerebral hernia, and she needed emergency drainage surgery. The tissue surrounding the hemorrhage was pathologically assessed, and she was diagnosed with CAA. Although we initially suspected the lesion to be a metastatic tumor from breast cancer, there were no tumorous cells. CONCLUSION: Atypical MRI findings made diagnosis difficult in this case, but it should be considered for differential diagnosis when multiple cerebral hemorrhages in elderly patients are observed, especially in cases with symptoms such as transient multifocal neurological deficits and dementia.

Neutrophil-to-lymphocyte ratio and histological type might predict clinical responses to eriburin-based treatment in patients with metastatic breast cancer.

BACKGROUND: Metastatic breast cancer (MBC) is generally considered to be incurable. Although many options are available for treating MBC, physicians often encounter difficulties in choosing the most appropriate treatment because the MBCs of individual patients respond differently even to the same treatments. Thus, predictive markers for therapeutic efficacy are urgently needed. Neutrophil- and platelet-to-lymphocyte ratios (NLR and PLR, respectively), have been studied and established as prognostic markers for breast cancer patients but whether either or both of these markers are predictive of treatment responses is still unclear. Herein, we investigated predictive markers for eribulin-based treatment responsiveness in patients with MBC, by examining clinicopathological features, including several markers of immunocompetent cells in peripheral blood. METHODS: Clinicopathological features of the 104 patients with metastatic/Stage IV breast cancer given eribulin-based regimens were investigated in relation to clinical responses to eribulin-based treatments and progression-free-survival (PFS). RESULTS: Special histological types and high NLR at baseline were independently related to poor clinical responses to the treatments (p = 0.023 and 0.039, respectively). The Cox hazard model revealed that patients with oestrogen receptor (ER)-negative tumours and high NLR, monocyte-to-lymphocyte ratio (MLR) and PLR showed significantly shorter PFS (p = 0.021, 0.005, 0.008 and 0.030, respectively). On multivariate analysis, only ER status and NLR remained independent factors related to PFS (p = 0.011 and 0.003, respectively). CONCLUSIONS: Our data revealed that special histological types and high NLR might be factors related to low responsiveness to eribulin-based regimens in patients with MBC.

Impact of circulating tumour cells on survival of eribulin-treated patients with metastatic breast cancer.

Several clinical studies have examined circulating tumour cells (CTCs). However, the application of CTCs as a predictive/prognostic marker for breast cancer patients has yet to be established, particularly the selection of suitable markers for detecting CTCs. We recently investigated CTCs, including mesenchymal status, from metastatic breast cancer patients who had received eribulin-based treatment. We found that assessment of both mesenchymal and epithelial CTCs might be important for predicting eribulin responsiveness. In the current study, we followed up the outcomes of these patients after eribulin treatment and investigated the possibility of CTC analysis results serving as prognostic markers for this patient population. Twenty-one patients were enrolled and peripheral blood samples were collected before eribulin-based treatments. CTCs were then examined using a Microfluidic Chip device. CTCs positive for vimentin and pan-cytokeratin were defined as mesenchymal and epithelial CTCs, respectively. Overall survival (OS) was assessed in relation to the number of CTCs and clinicopathological factors. During the observation period, 13 patients (62%) died due to breast cancer and the median OS was 18 months. Patients with high-grade tumours and a high total number of CTCs showed significantly shorter OS than those with low-grade tumours and smaller CTC burdens (p = 0.026 and 0.037, respectively). Patients who received eribulin as the first chemotherapy for metastatic disease showed longer OS (p = 0.006). Our data suggest that determining numbers of both mesenchymal and epithelial CTCs might predict survival for patients receiving eribulin.

Breast Cancer in Lean Postmenopausal Women Might Have Specific Pathological Features.

BACKGROUND/AIM: The rate of obesity, an independent risk factor for breast cancer in post-menopausal women, is quite low in Japan, indicating breast cancer in lean women to be more common in the Japanese than in Westerners. However, biological characteristics of such breast cancers have not been adequately investigated. PATIENTS AND METHODS: We retrospectively investigated clinicopathological breast cancer features of 566 postmenopausal Japanese women, who underwent curative surgery, in relation to patient physique based on the body mass index. RESULTS: There were no differences in several factors examined such as tumour size according to patient physique. On the other hand, mean values of the Ki67 labelling index were significantly higher in lean compared to obese patients (p=0.027). Likewise, HER2-positive tumours were more often observed in lean patients (p=0.051). CONCLUSION: Lean postmenopausal women had more aggressive tumours, apparently contradicting the widely held view for breast cancer in obese women.

Analysis of circulating tumour cell and the epithelial mesenchymal transition (EMT) status during eribulin-based treatment in 22 patients with metastatic breast cancer: a pilot study.

BACKGROUND: Liquid biopsy approaches, such as measuring circulating tumour cells (CTCs), have recently been introduced in several clinical studies. However, the development of CTCs as a predictive marker for treatment effects on breast cancer remains an enormous task. We investigated CTCs, including epithelial mesenchymal transition (EMT) status, from metastatic breast cancer patients who had received eribulin-based treatment, which reportedly suppresses EMT as a means of tumour suppression. Our aim was to test the possibility of this method serving as a tool predicting eribulin efficacy. METHODS: Twenty-two patients were enrolled and peripheral blood samples were collected before eribulin treatment. CTCs were then examined using a Microfluidic Chip device. CTCs positive for vimentin and pan-cytokeratin were defined as mesenchymal and epithelial CTCs, respectively. Progression-free survival (PFS) and clinical response were assessable in 20 and 18 patients, respectively, in relation to the number of CTCs. RESULTS: Numbers of total CTCs were significantly increased in patients with progressive disease during treatment (p = 0.006). Median PFS was 14.6 weeks and patients with more total and mesenchymal CTCs at baseline had significantly shorter PFS (p = 0.0013 and 0.013, respectively). Multivariate logistic regression analysis revealed small number of total baseline CTCs and long disease-free survival to be related to long PFS (p = 0.0004 and 0.020, respectively). CONCLUSIONS: Our data suggest that determining both mesenchymal and epithelial CTCs at baseline might be a good tool for predicting eribulin responsiveness. Evaluation of mesenchymal CTC can be considered as a parameter in larger studies, while most clinical trials are currently employing only the detection of the epithelial cellular adhesion molecule (EpCAM).

Relationship between alcohol metabolism and chemotherapy-induced emetic events in breast cancer patients.

BACKGROUND: Chemotherapy-induced nausea and vomiting (CINV) can negatively affect quality of life and treatment compliance in breast cancer patients. Habitual alcohol consumption reportedly shows an inverse correlation with CINV, though the underlying mechanism is unknown. Acetaldehyde dehydrogenase 2 (ALDH2), one of the two ALDH isozymes, is reportedly the major factor among several genetic polymorphisms possibly affecting alcohol metabolism. More than 40% of Japanese have ALDH2 mutations, while almost all Westerners have the wild type. We hypothesized that ALDH2 polymorphism status might relate to the metabolism of emetic chemotherapeutic drugs. Relationships among habitual alcohol consumption, ALDH2 polymorphisms, and CINV in Japanese breast cancer patients given adjuvant chemotherapy containing high-emetic drugs were, thus, investigated. METHODS: We enrolled 81 women, between 20 and 55 years of age, who had been diagnosed with primary breast cancer and received (neo-) adjuvant chemotherapy at our institution. ALDH2 genotypes were analyzed employing the smart amplification process in peripheral blood samples. RESULTS: The wild type (ALDH2*1/*1), heterozygote (ALDH2*1/*2), and mutant homozygote (ALDH2*2/*2) genotypes were found in 53, 44, and 3% of patients, respectively. Complete response, i.e., no vomiting without rescue anti-emetics, was more frequent in patients who habitually consumed alcohol than in those who did not (p = 0.036). This trend remained only in ALDH2 heterozygotes when patients were categorized according to ALDH2 genotype. Logistic regression analysis revealed alcohol intake to be an independent predictive factor for complete response (p = 0.013). CONCLUSIONS: Our results revealed habitual alcohol intake to be related to a lower CINV incidence. The impact of alcohol intake on CINV in patients with ALDH2 polymorphisms merits further investigation.

The efficacy of intraoperative ultrasonography during laparoscopic cholecystectomy.

BACKGROUND/AIMS: Intraoperative ultrasonography (IOUS) has been used to delineate anatomy during laparoscopic cholecystectomy (LapC) and screen for common bile duct stones (CBDS), however no consensus about its efficacy has been reached in Japan. In this study, we compared and evaluated the performance of intraoperative cholangiography(IOC) and IOUS during LapC. METHODOLOGY: We evaluated 295 cases of cholecystolithiasis that underwent surgery from 2005- 2009 at our hospital. Frequency of CBDS and duration of surgery was examined in cases with IOC alone or IOC and IOUS in combination. RESULTS: There were 5 cases (1.7%) in which IOUS or IOC detected CBDS that had not been detected by preoperative evaluation using abdominal CT, abdominal ultrasonography or MRCP. Out of 62 LapC cases involving both IOC and IOUS, 60 cases showed the same findings, i.e. no false-negative results, indicating that IOUS is a trustworthy examination method. The mean duration of surgery involving IOUS alone was 135 minutes while a longer mean time of 163 minutes was found for that involving IOC alone or IOC and IOUS in combination. CONCLUSIONS: This study shows that IOC can be considered useful as it did not produce any false-negative results in screening CBDS and it also shortened the operation time. We also found some problems associated with IOC, such as small calculi falling within the gallbladder during examination procedures and the irradiation of patients and staff.

[A case of recurrent breast cancer responding to vinorelbine/trastuzumab combination therapy].

A 60-year-old woman with Stage II, ER-positive, PgR-positive, HER2 (2+) cancer in the right breast underwent right mastectomy with right axillary dissection after chemotherapy with EC followed by docetaxel (DOC) alone. Exemestane was used for postoperative adjuvant treatment. She underwent a right chest wall tumor resection for local recurrence. Hormone therapy was continued with toremifene in place of exemestane. In December 2007, two years after the second surgery, CEA was elevated and PET showed a local recurrence in the right chest wall and metastases to the right axillary nodes and liver. The tumor was ER-positive, PgR-negative and HER2 (3+) at recurrence, and vinorelbine/trastuzumab combination was initiated as first-line chemotherapy for the recurrent lesion and liver metastasis. All lesions in the right chest wall, right axillary nodes and liver disappeared from PET and CT images after five courses of the regimen, resulting in clinical CR. Vinorelbine combined with trastuzumab appears to be a useful therapy for HER2-positive recurrent breast cancer.