Optimization of prediction methods for risk assessment of pathogenic germline variants in the Japanese population.

Predicting pathogenic germline variants (PGVs) in breast cancer patients is important for selecting optimal therapeutics and implementing risk reduction strategies. However, PGV risk factors and the performance of prediction methods in the Japanese population remain unclear. We investigated clinicopathological risk factors using the Tyrer-Cuzick (TC) breast cancer risk evaluation tool to predict BRCA PGVs in unselected Japanese breast cancer patients (n = 1,995). Eleven breast cancer susceptibility genes were analyzed using target-capture sequencing in a previous study; the PGV prevalence in BRCA1, BRCA2, and PALB2 was 0.75%, 3.1%, and 0.45%, respectively. Significant associations were found between the presence of BRCA PGVs and early disease onset, number of familial cancer cases (up to third-degree relatives), triple-negative breast cancer patients under the age of 60, and ovarian cancer history (all P < .0001). In total, 816 patients (40.9%) satisfied the National Comprehensive Cancer Network (NCCN) guidelines for recommending multigene testing. The sensitivity and specificity of the NCCN criteria for discriminating PGV carriers from noncarriers were 71.3% and 60.7%, respectively. The TC model showed good discrimination for predicting BRCA PGVs (area under the curve, 0.75; 95% confidence interval, 0.69-0.81). Furthermore, use of the TC model with an optimized cutoff of TC score ≥0.16% in addition to the NCCN guidelines improved the predictive efficiency for high-risk groups (sensitivity, 77.2%; specificity, 54.8%; about 11 genes). Given the influence of ethnic differences on prediction, we consider that further studies are warranted to elucidate the role of environmental and genetic factors for realizing precise prediction.

Correction to: Multidisciplinary treatment for locally advanced breast cancer with internal mammary lymph node metastasis in an elderly patient.

[This corrects the article DOI: 10.1007/s13691-018-0344-z.].

Pegfilgrastim-induced fatigue and leukocytosis improved following dose reduction in a young patient with breast cancer: A case report.

Dose-dense (DD) chemotherapy is a treatment option for patients with high-risk premenopausal breast cancer. Pegfilgrastim may be administered as prophylaxis against the development of febrile neutropenia and enables the continuation of the DD schedule; however, it is associated with adverse effects, including bone and muscle pain and fatigue. We herein describe our experience with pegfilgrastim administration alongside DD chemotherapy in a patient with breast cancer. A 29-year-old female patient was diagnosed with locally advanced breast cancer during lactation. The patient was diagnosed with cT2N1M0, stage IIB triple-negative breast cancer and underwent four cycles of DD chemotherapy with epirubicin plus cyclophosphamide, followed by four cycles of docetaxel (DTX) every 2 weeks preoperatively, with 3.6 mg pegfilgrastim administered subcutaneously on day 3 of each cycle. The absolute neutrophil count (ANC) was 2,700, 8,400, 11,100, 13,300 and 15,000/mm3 on day 1 of each cycle. The patient experienced fatigue after each pegfilgrastim injection and was considered to be a high responder to pegfilgrastim. Therefore, 1.8 mg pegfilgrastim on day 3 of the first DD-DTX cycle was recommended. On day 1 of the second cycle, the ANC was 13,090/mm3. The patient experienced less fatigue after the administration of 1.8 mg pegfilgrastim, but there was a significant decline in her performance status. As there is currently no evidence of pegfilgrastim dose reduction to below 1.8 mg, pegfilgrastim was omitted on day 3. On day 14, the patient developed viral enteritis, fever (38°C), and an ANC of 297/mm3. Therefore, the third cycle was postponed. After 1 week, the patient's ANC recovered to 2,480/mm3 and she was administered the third cycle with 3.6 mg pegfilgrastim on day 3. Between January 2015 and March 2018, a total of 55 patients with breast cancer received chemotherapy with pegfilgrastim at the Shiga General Hospital. No patients other than the one presented herein experienced leukocytosis during chemotherapy. Although this was a rare complication, a dose of 1.8 mg pegfilgrastim was effective in palliating the patient's symptoms and preventing DD chemotherapy discontinuation.

Multidisciplinary treatment for locally advanced breast cancer with internal mammary lymph node metastasis in an elderly patient.

Internal mammary lymph node (IMLN) metastasis is one of the important prognostic indicators in breast cancer. However, the management for IMLN metastasis is not established. The dissection for IMLN metastasis is not recommended in the National Comprehensive Cancer Network guidelines version3. 2015. Furthermore, radiotherapy including IMLN region and biopsy have attendant risks and hence should be performed with caution. Here, we describe our experience of multidisciplinary treatment for locally advanced breast cancer with IMLN metastasis in an elderly patient. Core-needle biopsy of the breast tumor histologically diagnosed the tumor as estrogen receptor positive, progesterone receptor positive, human epidermal growth factor receptor-2 negative, and high Ki-67 labeling index. IMLN swelling was detected by ultrasonography and breast cancer metastasis was diagnosed by fine-needle aspiration cytology. The patient underwent mastectomy and axillary lymph node dissection, followed by postmastectomy radiation therapy. Systemic therapy using tegafur plus uracil (UFT®; Taiho Pharmaceutical Co., Ltd, Tokyo, Japan) and letrozole was beneficial treatment for disease control.

Prevention of locoregional recurrence and distant metastasis in Japanese breast cancer patients using Japanese standard postoperative radiation fields: Experience at a single institution.

BACKGROUND: Radiotherapy is an effective local control therapy for breast cancer. Locoregional control is associated with distant metastasis risk and survival after surgery. AIM: We aimed to evaluate whether Japanese standard postoperative radiotherapy after surgery correlates with disease-free survival (DFS) and overall survival and clarify the characteristics of patients who benefit from it. METHOD AND RESULTS: This retrospective study included 626 operable breast cancer patients. Tumor characteristics and survival outcomes were compared between patients who received radiotherapy and those who did not. Cox proportional hazard analysis was used to analyze prognostic factors for DFS and perform subgroup analysis. Propensity score matching was used to evaluate the efficacy of radiotherapy using a logistic regression model in patients who received radiotherapy or did not. The median follow-up duration after diagnosis of breast cancer was 63 months. DFS and overall survival were better in the irradiated group (P= .002 and P = .001, respectively). Radiotherapy was more effective for estrogen receptor (ER)-positive disease and for early breast cancer without lymph node metastasis. Multivariate analysis revealed that radiotherapy was a dependent risk factor for recurrence or metastasis. CONCLUSION: Radiotherapy prevents distant metastasis and recurrence in early breast cancer patients. In particular, ER-positive, node-negative patients benefit from Japanese standard tangent field radiation.

Hormone signaling via androgen receptor affects breast cancer and prostate cancer in a male patient: A case report.

BACKGROUND: Male breast cancer (MBC) is rare, accounting for only around 1% of all breast cancers. Most MBCs are hormone-driven. Not only the estrogen receptor (ER), but also other steroid hormone receptors, including the androgen receptor (AR) and progesterone receptor (PgR) are expressed in MBC. AR activation in breast cancer cells facilitates downstream gene expression that drives tumorigenesis in a similar manner to ER. AR-mediated signalling works paradoxically in breast cancer and prostate cancer, and cancer cells expressing the AR are endocrine-sensitive. CASE PRESENTATION: We describe a case of double cancer of MBC and prostate cancer. A 69-year-old man was referred to our hospital with a lump in his left breast in the 1990s. The patient had cT3N3M0, stage IIIC breast cancer, and underwent a mastectomy and axillary lymph node dissection. Though adjuvant chemotherapy was administered, he experienced pleural metastasis 2 months after the surgery. Two years after the recurrence during endocrine therapy with oral 5-fluorouracil, he complained of frequent urination. Radiological and histological examinations revealed that the patient had cT3N0M0, stage III primary prostate cancer with a prostate-specific antigen (PSA) level of 40.5 ng/mL. Germline mutations in the BRCA1 and BRCA2 genes were not tested. He received multidisciplinary, continuous therapy for both breast and prostate cancer; however, 5 and 3 years after each diagnosis, respectively, he experienced a deep vein thrombosis in his right leg related to the endocrine therapy. Liver metastasis progressed after he stopped breast cancer therapy. However, long-term disease control had been achieved with anti-estrogen therapy for breast cancer and estrogen replacement therapy for prostate cancer. CONCLUSIONS: Several studies have shown that estrogen exposure after estrogen depletion likely causes apoptosis of ER-positive breast cancer cells. Our findings indicate that this also applies to the environment in male body. AR dominant signaling prevents breast cancer recurrence and metastasis, especially in MBC patients.

Patients who achieved long-term clinical complete response and subsequently terminated multidisciplinary and anti-HER2 therapy for metastatic breast cancer: A case series.

BACKGROUND: Human epidermal growth factor receptor 2 (HER2) -positive breast cancers tend to be more aggressive and more likely to recur than HER2-negative breast cancers. However, novel anti-HER2 therapies have dramatically improved the prognosis of patients with HER2-positive breast cancer. CASE REPORT: We review the cases of 4 women with metastatic breast cancer who achieved clinical complete response (cCR) and terminated their systemic therapy. Two patients had de novo metastatic disease and two patients experienced relapse after adjuvant therapy. All patients achieved cCR using multidisciplinary therapy, experienced prolonged complete remission, and subsequently terminated their systemic therapy without experiencing secondary recurrence. CONCLUSION: There is no evidence that systemic therapy can be safely terminated after a specific time period, although adverse events (e.g., cardiotoxicity) and unnecessary treatment should be avoided. Thus, it is possible that select patients may be suitable for termination of systemic therapy after they have achieved a prolonged period of cCR.

Low neutrophil-lymphocyte ratio correlates with extended survival in patients with metastatic breast cancer who achieved clinically complete response following multidisciplinary therapy: A retrospective study.

The prognosis of patients with metastatic or recurrent breast cancer (MBC) is improving as novel treatments are developed. The present study compared the clinical characteristics of patients with MBC with or without a complete clinical response (cCR) and identified the survival-associated factors. This was a retrospective study, which included 171 patients treated for MBC between 2011 and 2017 at the Shiga Medical Center for Adults. Neutrophil to lymphocytes ratios (NLRs) were determined in blood samples. The median follow-up period following diagnosis of MBC was 44 months (range, 0-217 months). A total of 32 patients (18.7%) achieved a cCR. Compared with the non-cCR group, the cCR group had significantly fewer metastases or recurrences (P<0.001), significantly fewer visceral metastases (P<0.001), a significantly lower NLR (P<0.001) and were diagnosed with primary breast cancer at a significantly earlier stage (P=0.003). Prognosis was significantly improved in the cCR group compared with the non-cCR group (P<0.001) and a high NLR (≥19) independently predicted worse survival in a multivariate analysis (P=0.0218; hazard ratio, 1.75; 95% confidence interval, 1.09-2.85). In conclusion, the present study determined that achieving a cCR and having a low NLR are important for the long-term survival of patients with MBC.

Overall survival of elderly patients with breast cancer is not related to breast-cancer specific survival: A single institution experience in Japan.

BACKGROUND: As the aging population grows, the number of elderly breast cancer patients has rapidly increased especially in Japan; a suitable treatment for elderly patients, considering chronic comorbidities and treatment tolerance, is urgently needed. METHODS: In this retrospective study, 286 elderly breast cancer patients were investigated. Tumor characteristics and survival outcome were compared between 70-79-year-old and ≥ 80-year-old groups. Disease-free survival, overall survival, and breast cancer-specific survival were compared, and the effect of variables was analyzed statistically. For resectable cases, prognoses were compared based on treatment (standard therapy or undertreated). RESULTS: Tumor characteristics were similar between groups, but the Ki-67 labeling index tended to be higher in older patients. Elderly patients with resectable cancer tended to be undertreated. During the median 59-month follow-up period, overall survival was significantly worse in the ≥80-year-old than in the 70-79-year-old group (p < 0.001), but disease-free and breast cancer-specific survivals were equivalent. Recurrence or death event hazard rates tended to be lower in patients receiving standard treatment. CONCLUSIONS: Standard multidisciplinary treatment for breast cancer prevents recurrence and metastasis and tends to extend breast cancer-specific survival even in elderly patients.

Pros and cons of immediate Vicryl mesh insertion after lumpectomy.

BACKGROUND: Lumpectomy is a standard surgery for breast cancer; however, it results in breast deformity, especially after radiation therapy. Wider surgical margin correlates lower local recurrence rate. However, bigger defect brings worse cosmetic outcome. The use of a simple filler for the defect is expected. We aimed to improve the cosmetic outcome by using an absorbable Vicryl mesh for breast reconstruction immediately post-lumpectomy. METHODS: One sheet of Vicryl woven mesh was prepared for insertion, washed the cavity with natural saline, and placed into the space. The cosmetic outcome was scored for the size, shape, scar, and softness of the breast. The size, shape, color, and position of the nipple-areola complex were also scored. Adverse events were collected retrospectively. RESULTS: From April 2008 to October 2014, 24 female patients received immediate Vicryl mesh insertion. A lumpectomy only group was recruited for cosmetic analysis. All patients received postsurgical radiotherapy. The mean cosmetic assessment score was 8.0 and 9.1 of 12 for the Vicryl mesh group and lumpectomy only group, respectively (P = 0.17). Sixteen patients had adverse events such as erythema at approximately 2 weeks post-surgery. No significant differences were shown except adverse events between two groups. No patient has had local recurrence thus far. CONCLUSION: Immediate Vicryl mesh insertion leads to significantly increased incidence of postoperative complications and delay in commencement of adjuvant radiotherapy. Furthermore, the cosmetic outcomes are not superior to that of no reconstruction. The development of superior biomaterials is anticipated for breast reconstruction after lumpectomy.

Palliative surgery for giant mucinous carcinoma of the breast in an elderly patient: A rare case report.

Mucinous breast carcinoma (MBC) is relatively rare, accounting for <10% of all breast cancers in women. These tumors are usually slow-growing and exhibit less aggressive characteristics compared with other types of breast cancer. Between 1989 and 2016, 55 patients underwent surgery for MBC at the Shiga Medical Center for Adults (Moriyama, Japan). The 10-year disease-free survival (DFS) and overall survival rates were 94.5 and 100.0%, respectively. Specifically, the 10-year DFS rates of pure MBC (PMBC) and mixed MBC were 97.7 and 83.3%, respectively. We herein report the case of a sizeable mucinous carcinoma causing rupture of the skin and bleeding due to tumor pressure. Palliative surgery was performed in order to remove the bleeding source after a total of 5 months of preoperative endocrine-based therapy. In conclusion, palliative surgery improved the patient's quality of life and may be a viable option for PMBC patients. The aim of the present study was to review the characteristics and management of these tumors, particularly in elderly patients.

Chondrolipoma of the breast as a rare variant of myofibroblastoma: an immunohistochemical study of two cases.

Chondrolipoma of the breast is a very rare tumor whose histogenesis remains obscure. We report two cases (56-year-old and 43-year-old women) and present the results of an immunohistochemical study which strongly suggests that this tumor is a variant of myofibroblastoma. The tumors predominantly consisted of lipoma-like, mature adipose tissue, and many islands of hyaline cartilage. A proliferation of spindle cells associated with the deposition of collagen fibers was also seen. On immunohistochemical examination, spindle cells showed cytoplasmic reactivity for vimentin, desmin, bcl-2, and α-smooth muscle actin, as well as nuclear reactivity for estrogen receptor (ER) and progesterone receptor (PgR). Chondrocytes were immunoreactive for ER, PgR, S-100 protein, and Sox9. The nuclei of adipocytes, chondrocytes, and spindle cells were not immunoreactive for Rb (retinoblastoma) protein. The immunoreactivity of spindle cells for muscle markers indicates myofibroblastic differentiation, and the lack of the nuclear expression of Rb protein suggests the close relationship of this tumor with myofibroblastoma and spindle cell lipoma. The immunoreactivity of chondrocytes for ER and PgR suggests that they are derived from metaplasia of hormone-sensitive spindle cells. These findings support the concept that chondrolipoma of the breast could be a lipomatous variant of myofibroblastoma associated with cartilaginous metaplasia and that it should be added to members of the "13q/Rb family of tumors."

Localized primary amyloidosis of the breast: a case report and review of the literature.

BACKGROUND: Primary amyloidosis of the breast is an unusual benign disease that mostly occurs in postmenopausal elderly women. Amyloidosis is the deposition of amorphous protein within tissues. Breast biopsy is necessary to make a definite diagnosis in order to avoid unnecessary surgical methods. Localized primary amyloidosis of the breast has a good prognosis. However, secondary amyloidosis is a systemic disease and has a poor prognosis. CASE PRESENTATION: We report the case of a 77-year-old female with primary amyloidosis of the breast. She noticed a lump in her left breast. Mammographic and ultrasonographic examinations indicated breast cancer. However, core needle biopsy showed amyloidosis, not cancer of the breast. For further examinations, the patient visited the outpatient clinics of the hematology, dermatology, and gastroenterology departments. She underwent bone marrow aspiration, computed tomography, cardiac ultrasonography, random skin biopsy, gastrofiberscopy, and colonofiberscopy. Plasma cell myeloma and systemic amyloidosis were ruled out, and localized breast amyloidosis was highly suspected. Lumpectomy was performed to make a definite diagnosis, and histological evaluations revealed that this patient had localized amyloidosis of the breast, and the deposited amyloid protein was of the amyloid light chain kappa type. CONCLUSIONS: Breast biopsy is necessary in order to avoid unnecessary surgical technique. A diagnosis should be achieved only through a histological evaluation. The main treatment of localized primary amyloidosis of the breast is surgical removal.

A case of ductal carcinoma with squamous differentiation in malignant phyllodes tumor.

Carcinoma derived from the lining epithelial cells in malignant phyllodes tumor is a rare neoplasm of the breast and belongs to the category of carcinosarcoma. We report a case of ductal carcinoma with squamous differentiation arising in malignant phyllodes tumor. A 54-year-old woman was admitted with a rapidly enlarging left breast mass. A breast tumor with a diameter of 6 cm was located mainly in the left outer area of the breast. Mammography revealed a high-density mass with an irregular margin and ultrasound showed a cystic tumor. A pathological diagnosis of ductal carcinoma with squamous differentiation was made by fine needle aspiration and a core needle biopsy. She underwent neoadjuvant chemotherapy followed by a modified radical mastectomy with a skin flap. Histopathological examination revealed that the invasive ductal carcinoma with squamous differentiation originated from the lining epithelial cells in malignant phyllodes tumor and that there was no transition area between the carcinomatous and the sarcomatous component. She experienced lung and facial bone metastases, microscopic features of which were consistent with the sarcomatous component of the original breast carcinosarcoma. This is an extremely rare case of carcinosarcoma and the histopathological findings and review of the literature are discussed.

Combination of alpha-fetoprotein mRNA-based detection of hematogenously disseminating hepatocellular carcinoma cells and analysis of cancer cell membrane fluidity is more accurate in screening patients at risk of postoperative recurrence.

We developed an mRNA-based, highly specific and sensitive method to detect hepatocellular carcinoma cells present in blood. However, the reason for some patients being positive for blood analysis and negative for recurrence has yet to be found. We recently established a method to measure membrane fluidity of hepatocellular carcinoma cells, and used it to analyze the actual membrane fluidity of human hepatocellular carcinoma cells. We found that patients with carcinoma cells with lower membrane fluidity less frequently developed recurrence. The analysis of both membrane fluidity and alpha-fetoprotein mRNA thus greatly increased the accuracy of the prediction of postoperative recurrence.

Successive cultures of mature hepatocytes for hepatocyte autotransplantation to assist liver function after liver resection for cancer.

We developed a method for the rapid successive cultures of adult rat mature hepatocytes on plastic dishes while avoiding viral transformation or co-culture with other cell lines. This method also allows for culturing adult human mature hepatocytes up to the secondary culture. These can be expected to provide a good source for hepatocyte autotransplantation, and, combined with the previously reported methods for the transplantation of hepatocytes into the spleen, a promising option for the support of liver function after liver resection for cancer without the need for immunosuppressive agents.