Oral Administration of Glucosylceramide Suppresses Tumor Growth by Affecting the Ceramide/Sphingosine-1-Phosphate Balance in Breast Cancer Tissue.

Background: Ceramide and sphingosine-1-phosphate (S1P) play opposing roles in cell death and survival, and maintain a dynamic balance called the sphingolipid rheostat. Glucosylceramide is a substrate to generate ceramide but its effect on breast cancer by oral administration was never tested. The purpose of this study was to reveal the anticancer activity of glucosylceramide and its potential as a new therapeutic agent in breast cancer. Methods: E0771 cells were inoculated into the breast tissue of female C57BL/6NJcl mice. Glucosylceramide was administered orally to the mice for nine consecutive days. The concentrations of sphingolipid mediators including ceramide, glucosylceramide, and S1P in tumor tissues and serum were determined by mass spectrometry. Results: Oral administration of glucosylceramide significantly suppressed E0771 tumor growth compared with the control group (P = 0.006). There were no significant differences in the serum concentrations of sphingolipid mediators including ceramide and S1P between the mice treated with glucosylceramide and control-treated mice. The ceramide concentration was significantly lower in tumor tissues (P = 0.026), and the S1P concentration was significantly higher than that in paired non-tumor tissues (P = 0.009). The S1P concentration in tumor tissues was significantly lower in mice treated with glucosylceramide than in control-treated mice (P = 0.001). The ceramide-to-S1P concentration ratio in tumor tissues was significantly higher in mice treated with glucosylceramide than in control-treated mice (P = 0.034). Conclusions: Breast tumors could enhance their survival by increasing S1P conversion from ceramide. Oral administration of glucosylceramide suppressed tumor growth by affecting the ceramide/S1P balance. Oral administration of glucosylceramide is a promising basis for a new therapeutic approach.

The Japanese Breast Cancer Society Clinical Practice Guidelines for systemic treatment of breast cancer, 2022 edition.

The Japanese Breast Cancer Society (JBCS) Clinical Practice Guidelines for systemic treatment of breast cancer were updated to the 2022 edition through a process started in 2018. The updated guidelines consist of 12 background questions (BQs), 33 clinical questions (CQs), and 20 future research questions (FRQs). Multiple outcomes including efficacy and safety were selected in each CQ, and then quantitative and qualitative systematic reviews were conducted to determine the strength of evidence and strength of recommendation, which was finally determined through a voting process among designated committee members. Here, we describe eight selected CQs as important updates from the previous guidelines, including novel practice-changing updates, and recommendations based on evidence that has emerged specifically from Japanese clinical trials.

Copy number alteration is an independent prognostic biomarker in triple-negative breast cancer patients.

BACKGROUND: Next-generation sequencing (NGS) has enabled comprehensive genomic profiling to identify gene alterations that play important roles in cancer biology. However, the clinical significance of these genomic alterations in triple-negative breast cancer (TNBC) patients has not yet been fully elucidated. The aim of this study was to clarify the clinical significance of genomic profiling data, including copy number alterations (CNA) and tumor mutation burden (TMB), in TNBC patients. METHODS: A total of 47 patients with Stage I-III TNBC with genomic profiling of 435 known cancer genes by NGS were enrolled in this study. Disease-free survival (DFS) and overall survival (OS) were evaluated for their association to gene profiling data. RESULTS: CNA-high patients showed significantly worse DFS and OS than CNA-low patients (p = 0.0009, p = 0.0041, respectively). TMB was not associated with DFS or OS in TNBC patients. Patients with TP53 alterations showed a tendency of worse DFS (p = 0.0953) and significantly worse OS (p = 0.0338) compared with patients without TP53 alterations. Multivariable analysis including CNA and other clinicopathological parameters revealed that CNA was an independent prognostic factor for DFS (p = 0.0104) and OS (p = 0.0306). Finally, multivariable analysis also revealed the combination of CNA-high and TP53 alterations is an independent prognostic factor for DFS (p = 0.0005) and OS (p = 0.0023). CONCLUSIONS: We revealed that CNA, but not TMB, is significantly associated with DFS and OS in TNBC patients. The combination of CNA-high and TP53 alterations may be a promising biomarker that can inform beyond standard clinicopathologic factors to identify a subgroup of TNBC patients with significantly worse prognosis.

[A Case of Esophageal Carcinoma with Tracheal Invasion after Preoperative Treatment with Docetaxel, Cisplatin, and 5-Fluorouracil in Which Definitive Chemoradiotherapy and Salvage Esophagectomy Prolonged Survival].

A 57-year-old man was diagnosed as having resectable advanced esophageal carcinoma adjacent to the trachea(Ut, cT3N0M0)and received preoperative docetaxel, cisplatin, and 5-fluorouracil therapy. Due to tracheal tumor invasion and upstaging to cT4bN0M0 after 1 course of chemotherapy, the treatment was converted to definitive chemoradiotherapy (CRT). A remarkable response with no evidence of tracheal invasion was observed on computed tomography following definitive CRT. He underwent successful curative resection with salvage esophagectomy, and the resected tumor was staged as pT1bN0M0. No adjuvant therapy was administered, and the patient was alive with no evidence of disease at the 5-year postoperative follow-up. The response to preoperative treatment should be meticulously assessed and appropriate treatment modalities used to avoid overlooking the potential for cure, even if the response to preoperative treatment with docetaxel, cisplatin, and 5-fluorouracil is poor.

[Cancer of the Ascending Colon and Left Breast in an Older Adult Complicated by Thoracic Aortic Aneurysm].

An 87-year-old woman with a gradually enlarging mass in her left breast, diagnosed as having left-sided breast cancer with skin invasion by a local practitioner, was referred to our hospital. Computed tomography revealed ascending colon cancer with abdominal wall invasion and a thoracic aortic aneurysm(Stanford type B), in addition to breast cancer with skin invasion. A thoracic endovascular aortic repair and bypass surgery between the subclavian arteries were both performed for the thoracic aortic aneurysm. After 6 days, a right hemicolectomy and D2 lymphadenectomy were performed for the ascending colon cancer. A postoperative pathological diagnosis of pT3N0M0, pStage Ⅱa, was made. A total left mastectomy with a full-thickness skin graft for left breast cancer was performed after 2 months following the ascending colon cancer surgery. The postoperative pathological diagnosis was pT3N0M0, pStage ⅡB. No evidence of local recurrence or distant metastasis of the ascending colon cancer has been observed at 20 months postoperatively, or of the breast cancer after 18 months following surgery.

Advanced Stage Is a Risk for Severe Neutropenia in Breast Cancer Patients Undergoing Neoadjuvant Adriamycin/Cyclophosphamide/Docetaxel Chemotherapy.

Background: Severe neutropenia, including febrile neutropenia, is a major toxicity of systemic chemotherapy that leads to delays in treatment, higher costs, and mortality. Severe neutropenia may occur during neoadjuvant chemotherapy even when the patients are free from known risk factors. Pegfilgrastim, a covalent conjugant of filgrastim that stimulate the production of neutrophils, is used for prevention. The current study aimed to reveal the characteristics of patients who need pegfilgrastim for primary prophylaxis to prevent severe neutropenia, including febrile neutropenia and grade 3 neutropenia, during neoadjuvant chemotherapy. Methods: A retrospective analysis of 83 patients treated with neoadjuvant adriamycin/cyclophosphamide followed by docetaxel chemotherapy was performed. The factors which associated with severe neutropenia were examined by univariate and multivariate analyses. Results: Severe neutropenia developed in one of 22 patients (5%) with pegfilgrastim for primary prophylaxis and in 17 of 61 patients (28%) without it. In 83 patients, the incidence of severe neutropenia was significantly decreased in the patients with pegfilgrastim for primary prophylaxis shown by the univariate analysis (P = 0.023) and multivariate analysis (P = 0.030). In 61 patients without pegfilgrastim for primary prophylaxis, the univariate analysis showed that severe neutropenia was associated with tumor size (P = 0.004), clinical stage (P = 0.009), and cancer antigen 15-3 (CA15-3) (P = 0.026). The multivariate analysis showed that clinical stage was associated with severe neutropenia (P = 0.021). Conclusions: The current study demonstrated that advanced stage is a risk for severe neutropenia in patients treated with neoadjuvant adriamycin/cyclophosphamide followed by docetaxel chemotherapy. Given that prophylaxis with pegfilgrastim was associated with significantly lower incidence of severe neutropenia, patient with advance stage breast cancer may benefit from pegfilgrastim during neoadjuvant chemotherapy.

Plasma Sphingosine-1-Phosphate Levels Are Associated with Progression of Estrogen Receptor-Positive Breast Cancer.

Although numerous experiments revealed an essential role of a lipid mediator, sphingosine-1-phosphate (S1P), in breast cancer (BC) progression, the clinical significance of S1P remains unclear due to the difficulty of measuring lipids in patients. The aim of this study was to determine the plasma concentration of S1P in estrogen receptor (ER)-positive BC patients, as well as to investigate its clinical significance. We further explored the possibility of a treatment strategy targeting S1P in ER-positive BC patients by examining the effect of FTY720, a functional antagonist of S1P receptors, on hormone therapy-resistant cells. Plasma S1P levels were significantly higher in patients negative for progesterone receptor (PgR) expression than in those positive for expression (p = 0.003). Plasma S1P levels were also significantly higher in patients with larger tumor size (p = 0.012), lymph node metastasis (p = 0.014), and advanced cancer stage (p = 0.003), suggesting that higher levels of plasma S1P are associated with cancer progression. FTY720 suppressed the viability of not only wildtype MCF-7 cells, but also hormone therapy-resistant MCF-7 cells. Targeting S1P signaling in ER-positive BC appears to be a possible new treatment strategy, even for hormone therapy-resistant patients.

[A Case of HER2-Positive Recurrent Breast Cancer and Liver Metastases of GIST Treated with Combined Anti-HER2 Therapy and Imatinib].

A 70-year-old female with liver metastases from gastrointestinal stromal tumor(GIST)that were found 3 months after partial gastrectomy for the primary GIST underwent Auchincloss operation for left breast cancer with ipsilateral axillary lymph node metastases. The diagnosis was microinvasive ductal cancer that was pT1miN1M0, pStage ⅡA, hormone receptor negative, and HER2 positive. Given the impact of this cancer on the prognosis of liver metastases of GIST, imatinib therapy, but not adjuvant chemotherapy, was started promptly for breast cancer after surgery. Four months after the surgery, left subclavian lymph node recurrence of breast cancer was found. Since the liver metastases of GIST had been stable, imatinib was discontinued, and paclitaxel and anti-HER2 therapy were administered. After confirming tolerability, imatinib was carefully added in combination. Because the lymph nodes shrank and liver metastases of GIST were stable, both anti-HER2 therapy and imatinib were continued. There are few reports of combined chemotherapy for synchronous double cancer, and we report our experience in which careful treatment was required.

Sphingosine Kinase 1 is Associated With Immune Cell-Related Gene Expressions in Human Breast Cancer.

BACKGROUND: Although previous experiments have implicated sphingosine-1-phosphate (S1P) as a links between immune reactions and cancer progression, the exact mechanism of this interaction has not comprehensively studied in clinical human samples. This study sought to evaluate the S1P regulation by sphingosine kinase 1 (SPHK1), an S1P-producing enzyme, in the immunity/immuno-reactivity of clinical human breast cancer surgical specimens. METHODS: S1P levels were examined in tumor, peritumoral, and normal human breast samples using mass spectrometry. Genomics Data Commons data portal of The Cancer Genome Atlas cohort was used to assess the expression of S1P-related and immune-related genes. RESULTS: S1P levels were significantly higher in tumor samples compared to peritumoral (P < 0.05) or normal human breast samples (P < 0.001). SPHK1 gene expression was elevated in tumoral samples compared to normal breast samples (P < 0.01). Furthermore, the elevated expression of SPHK1 in breast cancer tissue was associated with an increased expression of the different kinds of immune-related genes, such as CD68, CD163, CD4, and FOXP3 (forkhead box P3), in HER2-negative breast cancer. Network analysis showed the central role of SPHK1 in the interaction of S1P signaling and expression of immune cell-related proteins. CONCLUSIONS: We demonstrated that S1P is mainly produced by tumor tissue, rather than peritumoral tissue, in breast cancer patients. Our data revealed the involvement of S1P signaling in the regulation of immune-related genes, suggesting the links between S1P and complicated immune-cancer interactions in breast cancer patients.

[A Case of High-Frequency Microsatellite Instability in Colorectal Cancer with MSH2 Mutation Detected Using Gene Panel Testing with a Next-Generation Sequencer].

Here, we report about a woman in her 30s who had peritoneal dissemination and multiple colon cancer with high-frequency microsatellite instability(MSI-H). Her father, paternal grandfather, and maternal grandmother had a history of colorectal cancer treatment. Thus, Lynch syndrome was suspected. We performed R0 resection for peritoneal dissemination and subsequent peritoneal dissemination. A 435-gene panel testing using a next-generation sequencer identified MSH2 and other mutations in the tumor. Hence, we speculated that she could have a germline mutation of MSH2, which causes Lynch syndrome. In the future, if she wishes to receive genetic counseling and undergo germline testing for variants to confirm the diagnosis of Lynch syndrome, we will perform them after receiving informed consent.

[A Case of Invasive Lobular Carcinoma of Accessory Mammary Gland That Was Difficult for Evaluate for Lesion Spread].

A 48-year-old female discovered a mass in her left axilla. A thorough examination resulted in a diagnosis of left invasive lobular carcinoma(ILC)of the accessory mammary gland with wide ductal spread. Considering the wide ductal spread, massive resection of the left axilla mass, left lymph node dissection, and a latissimus dorsi musculocutaneous flap procedure were performed. However, histological analysis revealed ILC measuring 80×50 mm with lymph node metastases(5/23)and extensive cancer spread, resulting in a positive surgical margin. It is important to recognize the characteristics of ILC, axillary accessory breast cancer, and the axilla in a treatment strategy.

[Case of Ductal Carcinoma In Situ of the Nipple in a 93-Year-Old Man].

We report the case of an elderly male patient with ductal carcinoma in situ(DCIS) of the nipple. A 93-year-old man visited the hospital because of pain and bleeding in and swelling of the right nipple. A benign tumor was suspected, but a definite diagnosis could not be made before surgery based on echo and cytology findings; thus, a malignant tumor could not be ruled out. He underwent partial mastectomy combined with the areola and nipple for diagnosis and treatment. Histologic examination confirmed the diagnosis of DCIS of the nipple. The surgical margin was negative. At 6 months after the surgery, he was doing well with no evidence of disease in the absence of postoperative adjuvant therapy. Thus, clinicians should consider breast carcinoma of the nipple as a differential diagnosis when an elderly man presents with swelling of the nipple.

Left colic artery aneurysm rupture after stent placement for abdominal aortic aneurysm associated with neurofibromatosis type 1.

BACKGROUND: Neurofibromatosis type 1 (NF1) is an autosomal dominant disease of the skin and soft tissue. Aneurysms associated with NF1 can occur, but a secondary aneurysm rupture is very rare, with very few cases reported in literature. CASE PRESENTATION: We describe the case of a 67-year-old female with NF1 who underwent endovascular aneurysm repair (EVAR) for an abdominal aortic aneurysm (AAA) rupture. She developed a type Ib endoleak requiring a redo-EVAR. Eighteen days after her primary operation, she was found to have two new left colic artery aneurysms. She required emergency surgery consisting of a left hemicolectomy and transverse colon colostomy. Pathology showed neurofibromatous changes to the peri-vasculature tissue, consistent with her underlying disease. CONCLUSIONS: Although rare, secondary aneurysms can occur following AAA repair. Patients with soft tissue connective tissue disorders, like NF1, may be at an increased risk for development of these secondary aneurysms. Endovascular repair appears to be a safe approach for NF1 patients with AAA, but endovascular management can be challenging in the setting of NF1. Surgeons should be ready to convert to open surgery if the patient displays persistent signs of bleeding or structural changes related to connective tissue disorders like NF1.

Clinical target sequencing for precision medicine of breast cancer.

Precision medicine can be defined as the customization of medical treatment based on the individual genetic profile, which enables one to identify patients who respond to therapies while sparing side effects for those who do not. Breast cancer patients have been treated based on subtyping, which is considered a prototype of precision medicine. Furthermore, the development of multigene panel testing has resulted in a paradigm shift in the treatment of breast cancer. The knowledge generated from the Human Genome Project, and subsequently The Cancer Genome Atlas, has provided the concept of precision medicine, in which cancer patients can be sub-classified based on actionable driver mutations that can be selectively targeted by molecular targeted drugs and treated by appropriate molecular targeted therapies. Development of next-generation sequencing has both dramatically advanced genomic sequencing technology and revealed actionable driver mutations for individual cancer patients when applied to a clinical setting. Clinical target sequencing by next-generation sequencing enables one to formulate treatment strategies, not only by selecting a subgroup of patients who are expected to experience more effectiveness of each drug, but also by revealing patients with drug resistance based on their actionable driver mutations.

Different Roles of Sphingosine Kinase 1 and 2 in Pancreatic Cancer Progression.

BACKGROUND: Pancreatic cancer is a disease with poor prognosis, and development of new treatments is necessary. Sphingosine-1-phosphate (S1P), a bioactive lipid mediator produced by sphingosine kinases (SphK1 and SphK2), plays a critical role in progression of many types of cancer. However, little is known about the role of sphingosine kinases in pancreatic cancer. This study investigated the roles of sphingosine kinases in pancreatic cancer progression. MATERIALS AND METHODS: S1P levels in pancreatic cancer and noncancerous pancreatic tissue were measured in 10 patients. We generated PAN02 murine pancreatic cancer cell lines with a clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated system genes 9 (Cas9)-mediated deletion of SphK1 or SphK2 and assessed cell growth and migration. In an animal model, we assessed the survival of mice injected with PAN02 cells intraperitoneally. RESULTS: S1P levels in the pancreatic cancer tissue were significantly higher than those in noncancerous tissue. SphK1 knockout (KO) cells showed greater proliferation and migration than wild type (WT) cells, and SphK2 KO cells showed less proliferation and migration than WT cells. Animal experiments showed that the survival of mice injected with SphK1 KO cells was significantly shorter than those injected with WT cells, and the survival of mice injected with SphK2 KO cells was longer than those injected with WT cells. Surprisingly, cytotoxic assay using gemcitabine showed that SphK1 KO cells survived less than WT cells, and SphK2 KO cells survived more than WT cells. CONCLUSIONS: S1P produced by SphK1 and SphK2 may have different functions in pancreatic cancer cells. Targeting both SphK1 and SphK2 may be a potential strategy for pancreatic cancer treatment.

Ceramide species are elevated in human breast cancer and are associated with less aggressiveness.

Sphingolipids have emerged as key regulatory molecules in cancer cell survival and death. Although important roles of sphingolipids in breast cancer progression have been reported in experimental models, their roles in human patients are yet to be revealed. The aim of this study was to investigate the ceramide levels and its biosynthesis pathways in human breast cancer patients. Breast cancer, peri-tumor and normal breast tissue samples were collected from surgical specimens from a series of 44 patients with breast cancer. The amount of sphingolipid metabolites in the tissue were determined by mass spectrometry. The Cancer Genome Atlas was used to analyze gene expression related to the sphingolipid metabolism. Ceramide levels were higher in breast cancer tissue compared to both normal and peri-tumor breast tissue. Substrates and enzymes that generate ceramide were significantly increased in all three ceramide biosynthesis pathways in cancer. Further, higher levels of ceramide in breast cancer were associated with less aggressive cancer biology presented by Ki-67 index and nuclear grade of the cancer. Interestingly, patients with higher gene expressions of enzymes in the three major ceramide synthesis pathways showed significantly worse prognosis. This is the first study to reveal the clinical relevance of ceramide metabolism in breast cancer patients. We demonstrated that ceramide levels in breast cancer tissue were significantly higher than those in normal tissue, with activation of the three ceramide biosynthesis pathways. We also identified that ceramide levels have a significant association with aggressive phenotype and its enzymes have prognostic impact on breast cancer patients.

Targeting the SphK1/S1P/S1PR1 Axis That Links Obesity, Chronic Inflammation, and Breast Cancer Metastasis.

Although obesity with associated inflammation is now recognized as a risk factor for breast cancer and distant metastases, the functional basis for these connections remain poorly understood. Here, we show that in breast cancer patients and in animal breast cancer models, obesity is a sufficient cause for increased expression of the bioactive sphingolipid mediator sphingosine-1-phosphate (S1P), which mediates cancer pathogenesis. A high-fat diet was sufficient to upregulate expression of sphingosine kinase 1 (SphK1), the enzyme that produces S1P, along with its receptor S1PR1 in syngeneic and spontaneous breast tumors. Targeting the SphK1/S1P/S1PR1 axis with FTY720/fingolimod attenuated key proinflammatory cytokines, macrophage infiltration, and tumor progression induced by obesity. S1P produced in the lung premetastatic niche by tumor-induced SphK1 increased macrophage recruitment into the lung and induced IL6 and signaling pathways important for lung metastatic colonization. Conversely, FTY720 suppressed IL6, macrophage infiltration, and S1P-mediated signaling pathways in the lung induced by a high-fat diet, and it dramatically reduced formation of metastatic foci. In tumor-bearing mice, FTY720 similarly reduced obesity-related inflammation, S1P signaling, and pulmonary metastasis, thereby prolonging survival. Taken together, our results establish a critical role for circulating S1P produced by tumors and the SphK1/S1P/S1PR1 axis in obesity-related inflammation, formation of lung metastatic niches, and breast cancer metastasis, with potential implications for prevention and treatment.Significance: These findings offer a preclinical proof of concept that signaling by a sphingolipid may be an effective target to prevent obesity-related breast cancer metastasis. Cancer Res; 78(7); 1713-25. ©2018 AACR.

Actionable gene alterations in an Asian population with triple-negative breast cancer.

PURPOSE: It has been suggested that the biological characteristics of breast cancer may differ among different geographic or ethnic populations. Indeed, triple-negative breast cancer (TNBC), the most lethal breast cancer subgroup, has been reported to show a higher incidence in Japan than in the US. However, most genomic studies of these tumors are from Western countries and the genomic landscape of TNBC in an Asian population has not been thoroughly investigated. Here, we sought to elucidate the geographic and ethnic diversity of breast cancer by examining actionable driver alterations in TNBC tumors from Japanese patients and comparing them with The Cancer Genome Atlas (TCGA) database, which gather data primarily from non-Asian patients. MATERIALS AND METHODS: We performed comprehensive genomic profiling, including an analysis of 435 known cancer genes on Japanese TNBC patients (N=53) and compared the results to independent data obtained from TCGA (N=123). RESULTS: Driver alterations were identified in 51 out of 53 Japanese patients (96%). Although the overall alteration spectrum of Japanese patients was similar to that of the TCGA, we found significant differences in the frequencies of alterations in MYC and PTK2. We identified three patients (5.7%) with a high tumor mutation burden, although no microsatellite instability was observed in any of the Japanese patients. Importantly, pathway analysis revealed that 66.0% (35/53) of Japanese patients, as well as 66.7% (82/123) of the TCGA cohort, had alterations in at least one actionable gene targetable by an FDA-approved drug. CONCLUSION: Our study identified actionable driver alterations in Japanese patients with TNBC, revealing new opportunities for targeted therapies in Asian patients.

[A Case of Metachronal Phyllodes Tumors That Presented Bilaterally in the Breast].

A 33-year-old woman underwent resection of a right breast mass, which was diagnosed as a fibroadenoma 15 years ago. Ten years later, a right breast mass appeared again, and it was diagnosed as a fibroadenoma based on core needle biopsy. After observation for a while, the mass increased in size, and she underwent resection of the tumor, which was diagnosed as a borderline-malignant phyllodes tumor. A mass appeared again in the right breast and rapidly expanded. A malignant phyllodes tumor was suspected, and right mastectomy was performed. The pathological diagnosis revealed a benign phyllodes tumor. Four years ago, a left breast mass was also detected. Because the mass was suspected to be a fibroadenoma, it has been observed for a few years. The mass has increased in size since 1 year ago, and another mass emerged 2 months ago. Core needle biopsy of the 2 masses revealed that both were phyllodes tumors. She underwent left mastectomy, and the pathological examination revealed that both masses were benign phyllodes tumors. We report this rare case of metachronal phyllodes tumors that presented bilaterally.

[A Case of Breast Cancer with Metastatic Nodules in Additionally Resected Specimens].

A 68-year-old woman who had leftbreastcancer (cT2N0M0, cStage ⅡA)underwentbreast -conserving therapy and sentinel lymph node biopsy. Pathological diagnosis of the resected specimen revealed a 60mm cancer lesion including a 50 mm invasive ductal carcinoma with surrounding ductal carcinoma in situ, although the pre-operative MRI suggested a 30mm invasive cancer. The surgical margin was positive with the exposure of ductal carcinoma in situ. Additional resection was performed with a resection margin of 20mm from the head-side stump of the previous surgery. Pathological diagnosis of the additionally resected specimen revealed a 6mm invasive carcinoma with its exposure on the surface of the specimen around the new surgical stump distant from the initial surgical margin, where no remnant cancer was noted. She underwent left mastectomy. Pathological diagnosis further revealed 7mm and 2mm invasive carcinomas in the remnant breast. The preoperative imaging was reviewed retrospectively, and it was found that identifying the nodules in the remnant breast was quite difficult based on the images, including MRI. We report a case of breast cancer with metastatic nodules in additionally resected specimens.