[A Case of De Novo Stage â £ Breast Cancer with Umbilical Metastasis and Peritoneal Dissemination].

The patient was a 48-year-old woman. At the time of consultation, a hard mass of 30 mm in size was palpated in area A of the right breast, and a firm mass of about 10 mm was seen in the umbilical region. Histological diagnosis of the breast mass was invasive ductal carcinoma. PET-CT scan showed accumulation in the right breast, as well as suspicion of umbilical metastasis and peritoneal dissemination, uterine mass, and left ovarian cancer. Since this is an atypical metastatic site for invasive ductal carcinoma of the breast, and the possibility of peritoneal dissemination due to gynecological cancer complications cannot be ruled out, resection of the umbilical mass and laparoscopy was performed. The review laparoscopy revealed no evidence of primary cancer in the uterine body or left ovary, and a white nodular lesion of suspected seeding in the peritoneum around the left ovary. The histology and immunostaining results of the umbilical mass and left peri-ovarian nodule both showed glandular luminal structures similar to those of the primary breast cancer, and the left peri-ovarian nodule was ER positive, GATA3 positive, and PAX8 negative, leading to the diagnosis of umbilical metastasis and peritoneal seeding derived from breast cancer. Umbilical metastasis is often referred to as Sister Mary Joseph's nodule in the case of visceral malignancies and is often associated with peritoneal dissemination and is often caused by invasive metastasis of peritoneal dissemination lesions on the dorsal side of the umbilical region. In this case, histological examination of the umbilical specimen showed no disseminated lesion on the peritoneal side, so it was not considered to be an invasive metastasis due to peritoneal dissemination.

[A Case of Breast Nodular Fasciitis Needed to Differentiate from Borderline Phyllodes Tumor].

A 28-year-old woman realized a left breast tumor. Mammography and ultrasonography revealed focal asymmetric density on the MI area(category 3)and a low-echoic 10 mm tumor with unclear boundaries. We performed an US-guided breast biopsy to confirm the diagnosis. The histopathological examination result suspected nodular fasciitis; however, borderline phyllodes tumor cannot be denied. Tumorectomy was performed under general anesthesia. The final histopathological examination revealed nodular fasciitis due to amplifying fibroblasts with irregular directions. Nodular fasciitis is a benign lesion and sometimes disappears spontaneously. Tumorectomy is often needed to confirm the diagnosis that cannot be identified by needle biopsy. We report a case of breast nodular fasciitis needed to differentiate from borderline phyllodes tumor.

[A Case of De Novo Stage â £ Her2-Positive Breast Cancer with Cardiac Tamponade Caused by Cancerous Pericarditis].

The patient was a 58-year-old woman. She was diagnosed with cT4b, cN3c, cM1, cStage Ⅳ, Her2 positive breast cancer with liver, lung and bone metastases. Seven days after the first visit, she came to our hospital for dyspnea. Chest X-ray, chest CT, and echocardiography showed a decrease in EF to 50.6% due to a large amount of pericardial effusion, and she was diagnosed with cardiac tamponade. On the same day, pericardial drainage was performed urgently. The cytopathology of pericardial fluid was malignant, that is to say, she was diagnosed with cancerous pericarditis. Pericardial drainage relieved respiratory distress, and echocardiography showed disappearance of pericardial fluid and improvement of EF up to 80.4%. Docetaxel plus trastuzumab plus pertuzumab therapy was started 10 days after pericardial drainage as first-line treatment. After starting chemotherapy, the response has continued for 6 months without re-accumulation of pericardial fluid.

[A Case of Drug-Induced Interstitial Pneumonia after Dose-Dense AC Therapy].

The patient is a 67-year-old female. She was diagnosed with left breast cancer cT2N1M0, Stage ⅡB, Luminal B-like, and was desided dose-dense AC therapy(ddAC)plus dose-dense paclitaxel therapy(ddPTX)as preoperative chemotherapy. After completing 4 courses of ddAC and visiting to start the first course of ddPTX, she presented with symptoms of fatigue and shortness of breath on exertion. Chest X-ray showed no abnormality and echocardiography showed decreased left ventricular wall motion, leading to a diagnosis of doxorubicin-induced cardiac dysfunction. Preoperative chemotherapy was discontinued and surgery was decided. Two weeks later, CT imaging was performed for preoperative evaluation, which showed the appearance of diffuse pale ground-glass opacity in the bilateral lung fields, and a diagnosis of drug-induced interstitial pneumonia was made. After 3 weeks of steroid treatment, the symptoms improved and the ground-glass opacity disappeared on CT imaging. We were keenly aware that interstitial pneumonia can develop with pale ground-glass opacity that is difficult to diagnose without CT imaging, and that the need for CT should always be considered.

[A Case of Locally Advanced Breast Cancer That Responded to Paclitaxel plus Bevacizumab and Underwent Radical Surgery].

The patient is a 69-year-old female. She was aware of a right breast mass about a year ago, but left it alone. In March 2021, she visited our hospital with a 11 cm mass occupying the right breast and self-destruction due to skin invasion. The diagnosis of invasive ductal carcinoma of the breast(ER-positive, PgR-positive, HER2-negative), cT4bN1M0, Stage ⅢB was made, and preoperative chemotherapy was decided. We expected a high response rate for bevacizumab(Bv)because it was predicted that the skin defect would increase at surgical resection if a response to chemotherapy was not achieved, and in April 2021, paclitaxel(PTX)plus Bv therapy was initiated. After 4 courses, the mass had shrunk to 5 cm and a marked response had been achieved. However, she was unable to continue the treatment due to peripheral neuropathy. Therefore, considering the period of delayed wound healing due to Bv, we decided on AC therapy followed by surgery. In December 2021, Bt plus Ax was performed and the wound could be closed without skin grafting. Since PTX plus Bv therapy is expected to have a high response rate, we considered it to be one of the effective treatment options for locally advanced breast cancer.

Vasculogenic mimicry is associated with trastuzumab resistance of HER2-positive breast cancer.

BACKGROUND: Trastuzumab is a drug that targets the receptor tyrosine kinase HER2 and is essential for the treatment of HER2-positive breast cancer. Resistance to the drug leads to severe consequences, including disease recurrence, tumor enlargement, and metastasis. We hypothesized that trastuzumab treatment might be associated with phenotypic switching in HER2-positive breast cancer cells (BCCs), enabling them to escape and survive the effect of trastuzumab. METHODS: We conducted comprehensive immunophenotyping to detect phenotypic changes in HER2-positive BCCs treated with trastuzumab, based on criteria determined a priori. Based on immunophenotyping results, we characterized the vascular phenotypes of HER2-positive BCCs by western blotting, real-time RT-PCR, and tube formation assay. The vascular phenotype of tumor cells from clinical samples was evaluated by staining with periodic acid-Schiff and an anti-CD31 antibody. We explored small molecule inhibitors that suppress tube formation and determined the inhibitory mechanism. RESULTS: Out of 242 cell surface antigens, 9 antigens were significantly upregulated and 3 were significantly downregulated by trastuzumab treatment. All upregulated antigens were related to endothelial and stem cell phenotypes, suggesting that trastuzumab treatment might be correlated to switching to a vascular phenotype, namely, vasculogenic mimicry (VM). Several VM markers were upregulated in trastuzumab-treated cells, but these cells did not form tubes on Matrigel, a functional hallmark of VM. Upon analysis of three trastuzumab-resistant HER2-positive cell lines, we found that all three cell lines showed tube formation on Matrigel in the presence of angiogenic growth factors including EGF, FGF2, IGF1, or VEGF. Clinically, VM channels significantly increased in surviving cancer cell clusters of surgically removed tumors pretreated with trastuzumab and chemotherapy compared to both surgically removed tumors without prior systemic treatment and tumors biopsied before presurgical treatment with trastuzumab. Finally, we found that salinomycin completely suppressed VM in all three trastuzumab-resistant cell lines through disruption of actin cytoskeletal integrity. CONCLUSIONS: VM promotes metastasis and worsens patient outcomes. The present study indicates that HER2-positive BCCs can exhibit VM in an angiogenic microenvironment after eventually acquiring trastuzumab resistance. The clinical finding supports this in vitro observation. Thus, targeting VM might provide a therapeutic benefit to patients with HER2-positive breast cancer.

Endocrine sensitivity of estrogen receptor-positive breast cancer is negatively correlated with aspartate-ß-hydroxylase expression.

Although prognostic markers for early estrogen receptor (ER)-positive breast cancer have been extensively developed, predictive markers for adjuvant endocrine therapy are still lacking. Focusing on the mechanisms underlying endocrine resistance, we investigated whether the endocrine sensitivity of ER-positive breast cancer cells was correlated with the expression of aspartate-ß-hydroxylase (ASPH), which is involved in the development of hepatocellular carcinoma. ASPH expression in ER-positive and tamoxifen-resistant breast cancer cells was upregulated by the MAPK and phosphoinositide-3 kinase (PI3K) pathways, which both play pivotal roles in endocrine resistance. In the clinical setting, ASPH expression was negatively correlated with recurrence-free survival of luminal B breast cancer patients that received adjuvant endocrine therapy, but not in patients that did not receive adjuvant endocrine therapy. Luminal B breast cancer is one of the intrinsic molecular subtypes identified by the Prediction Analysis of Microarray 50 (PAM50) multiple gene classifier, and because of its poor response to endocrine therapy, chemotherapy in addition to endocrine therapy is generally required after surgical resection. Our results suggest that the endocrine sensitivity of luminal B breast cancer can be assessed by examining ASPH expression, which promotes the consideration of a prospective study on the association between ASPH expression at the mRNA and protein levels in luminal B breast cancer and subsequent response to endocrine therapy.

A small-molecule inhibitor of SMAD3 attenuates resistance to anti-HER2 drugs in HER2-positive breast cancer cells.

PURPOSE: Resistance against anti-HER2 drugs in HER2-positive breast cancer is a major obstacle to the improving prognosis. Transforming growth factor ß (TGFß) is a cytokine involved in the acquisition of more malignant phenotypes through epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC) properties. The aim of this study was to investigate the effects of TGFß and its downstream SMAD pathway on resistance to anti-HER2 drugs. METHODS: HER2-positive breast cancer cell lines were stimulated with TGFß for 14 days. Then, the sensitivity to trastuzumab and lapatinib and the expression levels of various EMT and CSC markers were examined. The correlation of nuclear SMAD3 expression in untreated breast tumor tissues with trastuzumab efficacy in neoadjuvant settings was examined. The effect of a small-molecule inhibitor of SMAD3 (SIS3) on resistance to anti-HER2 drugs was explored. RESULTS: We found that continuous activation of the TGFß-SMAD3 pathway induced resistance to anti-HER2 drugs and CSC traits in HER2-positive breast cancer cells. The induction of drug resistance by TGFß required strong activation of SMAD3. In fact, activated SMAD3 regulated multiple genes that harbor SMAD-binding elements and are involved in trastuzumab resistance. Nuclear SMAD3 expression in tumor tissue was inversely correlated with sensitivity to neoadjuvant treatment with trastuzumab. SIS3 not only prevented the acquisition of resistance to anti-HER2 drugs but also restored trastuzumab sensitivity in trastuzumab-resistant cells. CONCLUSIONS: This study indicates that the TGFß-SMAD3 pathway plays an important role in the induction and maintenance of resistance to anti-HER2 drugs. Thus, SMAD3 is a potential therapeutic target that can inhibit resistance and restore sensitivity to anti-HER2 drugs.