The impact of PIK3CA mutations and PTEN expression on the effect of neoadjuvant therapy for postmenopausal luminal breast cancer patients.

BACKGROUND: There is pressing needs to find the biomarker in the selection of neoadjuvant therapy in postmenopausal luminal breast cancer patients. We examined the hypothesis that PIK3CA mutations and low phosphatase and tensin homolog (PTEN) expression affect the response to neoadjuvant therapy and prognosis in postmenopausal luminal breast cancer patients. METHODS: Postmenopausal patients with estrogen receptor-positive, human epidermal growth factor receptor 2-negative breast cancer, up to stage II, who underwent neoadjuvant chemotherapy (NAC; n = 60) or neoadjuvant endocrine therapy (NAE; n = 55) were selected. PIK3CA exon 9 and exon 20 mutations were screened by high resolution melting analysis and confirmed by Sanger sequence. PTEN expression was evaluated by immunohistochemistry. The relationships among PIK3CA mutations, PTEN expression, clinicopathological features, the pathological effect of neoadjuvant therapy, recurrence-free survival (RFS) and overall survival were analyzed. RESULTS: Among 115 patients, PIK3CA mutations and low PTEN expression before treatment were detected in 35 patients (30.4%) and in 28 patients (24.3%), respectively. In the NAC group, tumor with PIK3CA mutations showed significantly poorer response than tumor with PIK3CA wild-type (p = 0.03). On the other hand, in the NAE group, there was no significant difference in pathological therapeutic effect between tumor with PIK3CA mutations and tumor with PIK3CA wild-type (p = 0.54). In the NAC group, the log-rank test showed no difference in RFS between patients with PIK3CA mutations and PIK3CA wild-type (p = 0.43), but patients with low PTEN expression showed significantly worse RFS compared to patients with high PTEN expression (5 year RFS 0.64 vs. 0.87, p = 0.01). In the Cox proportional hazards model for RFS, PTEN expression, progesterone receptor, and pathological therapeutic effect were predictive factors for time to recurrence (All p < 0.05). CONCLUSIONS: PIK3CA mutations are associated with resistance to NAC but do not affect the response to NAE. Low PTEN expression does not affect response to either NAC or NAE but correlates with shorter RFS in patients who received NAC. These biomarkers will be further evaluated for clinical use to treat postmenopausal luminal breast cancer patients.

[Improved QOL in a Case of Breast Cancer with Meningeal Carcinomatosis Treated with Radiation Therapy and Intrathecal Chemotherapy].

A 50's woman was diagnosed with left local-advanced breast cancer(pT4bN2aM0, stage ⅢB, estrogen-receptor positive and human epidermal growth factor-2 negative)in 2016. Neoadjuvant therapy consisting of 4 courses of epirubicin plus cyclophosphamide and 4 courses of docetaxel were administered. After neoadjuvant therapy, a mastectomy with axillary node dissection was performed. And after surgery, she was received radiation and endocrine therapy. In May 2019, multiple bone metastases were detected. We administered endocrine therapy. In February 2020, she developed leg paralysis and malignant cells were collected from the cerebrospinal fluid. She was diagnosed with meningeal carcinomatosis without brain metastasis from breast cancer. To improve quality of life, we started radiation therapy, intrathecal chemotherapy and systemic chemotherapy. After 3 months of these therapies, leg paralysis was improved and quality of life was maintained for 9 months. Herein, we report a case of meningeal carcinomatosis without brain metastasis from breast cancer which is improved by radiation therapy, intrathecal chemotherapy and systemic chemotherapy.

[Breast-Conserving Surgery Using Real-Time Virtual Sonography in a Breast Cancer Patient Who Received Neoadjuvant Chemotherapy - ACase Report].

We report a case of breast-conserving surgeryusing real-time virtual sonography(RVS)in a breast cancer patient who received neoadjuvant chemotherapy(NAC). The patient was a 63-year-old woman. Ultrasound(US)showed a lobulated 45 ×40×40mm diameter mass in the C area of the right breast. Histological examination found invasive ductal carcinoma that was negative for estrogen and progesterone receptors and for human epidermal growth factor receptor type 2/neu protein expression, and the Ki-67 index was 50%. The patient was diagnosed with breast cancer clinical stage II A(T2N0M0). The basal-like subtype is more sensitive to anthracycline-based NAC than luminal breast cancers. The patient wanted breastconserving surgery. Therefore, we treated the patient with NAC. First, we obtained US volume data of the tumor as a Digital Imaging and Communication in Medicine(DICOM)file, simplyscanning the skin over the lesion gentlywith the probe. We administered tri-weeklynanoparticle albumin-bound paclitaxel(nab PTX)followed bya fluorouracil, epirubicin, and cyclophosphamide( FEC)regimen. Follow-up computed tomography(CT)and US showed good tumor concentric shrinkage without anysurrounding lesion after NAC. Finally, right breast-conserving surgerywas performed, using RVS to detect the area where the tumor was before NAC in the US image after NAC. Histopathologically, the effect of the chemotherapy was Grade 2a and the surgical margins were negative.

Cancer-mediated adipose reversion promotes cancer cell migration via IL-6 and MCP-1.

The objective of this study is to investigate interactions between adipocytes and breast cancer cells, and identify the responsible factors for the observed effects. In 27 breast cancer patients undergoing mastectomy, mammary adipose tissue was obtained from the breast quadrant bearing the tumor and corresponding non-tumoral quadrant. Isolated normal breast adipocytes (NBAs) and cancer-associated adipocytes (CAAs) were cultured in collagen gels to mimic the in vivo environment. Immunohistochemistry, qRT-PCR, and cell proliferation assays were performed to analyze adipocyte phenotypes. MCF7 and MDA-MB-231 breast cancer cell lines were co-cultured with adipocytes to detect phenotypic changes. Migration of MCF7 and MDA-MB-231 cells was assessed in NBA- and CAA-conditioned media. Cytokine levels in conditioned media were measured by cytokine array. Migration assays were repeated using conditioned media containing neutralizing antibodies. NBAs and CAAs lost their morphological phenotype in culture, acquiring a spindle-like shape, and CAAs showed higher cell proliferation, suggesting reversion to an immature phenotype. In co-cultures with MCF7 or MDA-MB-231 cells, NBAs exhibited increased cell proliferation, indicating acquisition of the immature phenotype of CAAs. MCF7 and MDA-MB-231 showed higher migration in a CAA-conditioned medium than in an NBA-conditioned medium. Cytokine array analysis of conditioned media revealed higher levels of interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1) in the CAA-conditioned medium. Neutralization experiments using antibodies against IL-6 or MCP-1 showed abrogation of migration-enhancing effects of the CAA-conditioned medium. Adipocytes revert to an immature and proliferative phenotype in the presence of breast cancer cells, and promote cancer cell migration via adipokines including IL-6 and MCP-1.

Low-rise scar deep inferior epigastric artery perforator flap for breast reconstruction.

BACKGROUND: To achieve an unnoticeable postoperative scar in patients with little abdominal skin laxity for breast reconstruction by deep inferior epigastric artery perforator (DIEP) flap, we devised a new design called the low-rise scar DIEP flap; the skin paddle of this flap is located lower with a smaller vertical width, and more adipose tissue is elevated to obtain enough volume. The purpose of this report is to evaluate the utility of the low-rise scar DIEP flap compared with that of the conventionally designed flap. METHODS: Twelve patients who underwent low-rise scar DIEP flaps (study group) and 11 patients who underwent conventionally-designed DIEP flaps (control group) were included in the present study. The distance from the umbilicus to horizontal scar was divided by the patient's height. The length of the scar was divided by the abdominal circumference. These ratios were compared between groups. RESULTS: All flaps survived completely and no recipient site complication was observed, except for one case in the control group with small-range fat necrosis. No donor site complication was observed in either group. The distance ratio was significantly larger in study group (<0.01, 0.049 ± 0.004, and 0.028 ± 0.005, respectively). The length ratio was significantly smaller in the study group <0.01, 0.42 ± 0.02 and 0.36 ± 0.02, respectively). The weight of the flap used for reconstruction was 338.8 ± 127.7 g in the study group and 320.5 ± 63.0 g in the control group CONCLUSIONS: A low-rise scar DIEP flap leaves a lower and shorter postoperative scar.

[The Case of a Patient with Invasive Lobular Carcinoma with Solitary Metastasis in Pectoralis Major Muscle].

A 44 -year-old woman presented at the outpatient department with a chief complaint of swelling in the right breast. MRI showed a huge breast tumor accompanied by solitary enhanced masses in the pectoralis major muscle. After receiving neoadjuvant chemotherapy, she underwent mastectomy (Halsted operation) and axillary dissection. Pathological examination revealed an E-cadherin-positive infiltrating lobular carcinoma (ILC), and the absence of residual tumor in the muscle was confirmed. In cases of solitary metastasis in the muscle, treatment selection is sometimes difficult. Further research is needed to determine whether surgery contributes to local control in cases of advanced ILC with muscle metastasis.

[Long-Term Outcome of Radiofrequency Ablation Therapy for Breast Cancer].

Although radiofrequency ablation (RFA) is promising for the local treatment of breast cancer, data concerning the longterm results are limited. The present study attempted to evaluate the safety and efficacy of RFA and to clarify patient outcomes after treatment. The study included 26 breast cancer patients treated with RFA between 2006 and 2010. There were no acute complications such as burns. All subjects were followed-up after breast radiation and systemic therapies. At the median follow-up period of 88 months, no local recurrence or distant metastases had occurred. After treatment, a hard lump was formed around the ablated area, which gradually decreased in size in all cases (p<0.001). The lumps were calcified in 9 cases. Nipple retraction persisted in 2 cases. However, it is necessary to recognize that a cosmetic result of RFA was not excellent in all cases, RFA appears to be a safe local treatment technique for breast cancer patients.

Evaluation of a near-infrared-type contrast medium extravasation detection system using a swine model.

PURPOSE: To refine the development and evaluate the near-infrared (NIR) extravasation detection system and its ability to detect extravasation during a contrast-enhanced computed tomography (CT) examination. MATERIALS AND METHODS: The NIR extravasation detection system projects the NIR light through the surface of the human skin then, using its sensory system, will monitor the changes in the amount of NIR that reflected, which varies based on absorption properties.Seven female pigs were used to evaluate the contrast media extravasation detection system, using a 20-gauge intravenous catheter, when injected at a rate of 1 mL/s into 4 different locations just under the skin in the thigh section. Using 3-dimensional CT images, we evaluated the extravasations between time and volume, depth and volume, and finally depth and time to detect. RESULTS: We confirmed that the NIR light, 950-nm wavelength, used by the extravasation detection system is well absorbed by contrast media, making changes easy to detect. The average time to detect an extravasation was 2.05 seconds at a depth of 2.0 mm below the skin with a volume of 1.3 mL, 2.57 seconds at a depth between 2.1 and 5 mm below the skin and a volume of 3.47 mL, 10.5 seconds for depths greater than 5.1 mm and a volume of 11.1 mL. The detection accuracy was significantly deteriorated when the depth exceeded 5.0 mm (Tukey-Kramer, P < 0.05) CONCLUSIONS: The extravasation system detection system that is using NIR has a high level of detection sensitivity. The sensitivity enables the system to detect extravasation at depths less than 2 mm with a volume of 1.5 mL and at depths less than 5 mm with a volume of 3.5 mL. The extravasation detection system could be suitable for use during examinations.

Aldehyde dehydrogenase 1-positive cells in axillary lymph node metastases after chemotherapy as a prognostic factor in patients with lymph node-positive breast cancer.

BACKGROUND: Aldehyde dehydrogenase 1 (ALDH1)-positive cells exhibit stem-like or progenitor ability and have been considered a clinically important diagnostic and therapeutic target in patients with breast cancer. In this study, the authors evaluated responsiveness to chemotherapy of ALDH1-positive cells in primary and metastatic lesions and its relation to prognosis for patients with lymph node-positive breast cancer. METHODS: In total, 115 patients who had breast cancer with cytologically confirmed lymph node metastases and who underwent surgery after neoadjuvant chemotherapy (NAC) were evaluated. By using ALDH1 immunohistochemistry in core-needle biopsy specimens of the primary tumor, cytology samples of axillary lymph nodes before NAC, and pathologic samples of each after NAC, the clinical significance of ALDH1-positive cell status was evaluated in primary and metastatic lesions before and after NAC. RESULTS: The presence of ALDH1-positive cancer cells, but not ALDH1-negative cancer cells, in primary and metastatic lesions after NAC was associated with a worse prognosis. In multivariate analysis, only ALDH1-positive cells in metastatic lesions after NAC correlated with overall survival. The responsiveness of ALDH1-positive cells to chemotherapy differed between primary and metastatic lesions, and the findings indicated that ALDH1-positive cells in metastatic lesions after NAC may clinically precede those in the primary lesion. CONCLUSIONS: The responsiveness of ALDH1-positive cells to chemotherapy in primary and metastatic lesions and its prognostic significance were clarified in patients with breast cancer. The authors concluded that ALDH1-positive status may represent a surrogate marker as a new concept in patients with lymph node-positive breast cancer.

Diffusion-weighted MRI as an adjunct to mammography in women under 50 years of age: an initial study.

PURPOSE: To evaluate diffusion-weighted magnetic resonance (DW) imaging as an adjunct to mammography for the detection of small invasive breast cancer. MATERIALS AND METHODS: Institutional review board standards were followed for this retrospective study. We performed both breast DW imaging and mammography on 25 women under 50 years of age with pathologically proven T1 breast cancer and on 21 healthy women under 50 years of age. Four offsite radiologists blind to the clinical information independently interpreted the mammograms and DW images and then classified their confidence level regarding the presence of breast cancer. The composite area under receiver operating characteristic curve (AUC), of mammography alone, DW imaging alone, and the combination of DW imaging and mammography (DWI/Cal) were calculated. RESULTS: The AUC of composite ROC curves of mammography, DW imaging, DWI/Cal combination, was 0.79 (95% CI, 0.72-0.87), 0.86 (95% CI, 0.84-0.87), and 0.96 (95% CI, 0.92-1.00), respectively. CONCLUSION: DW imaging may be a useful adjunct to mammography in the detection of small invasive breast cancer in women under 50 years of age.

Response rate to neoadjuvant chemotherapy measured on imaging predicts early recurrence and death in breast cancer patients with lymph node involvements.

BACKGROUND: The use of neoadjuvant chemotherapy for breast cancer is effective as postoperative adjuvant therapy, permits more lumpectomies, and can be used to study breast cancer biology. Although pathological response is the strongest prognostic factor, response rates vary according to various parameters, such as dissociation between breast and axillary node responses. PURPOSE: To clarify the correlation of response rates between breast tumors and metastasized lymph nodes and to identify the clinical significance; response rates measured on imaging were evaluated among breast cancer patients with axillary lymph node involvement. MATERIAL AND METHODS: Subjects consisted of 98 patients diagnosed with node-positive breast cancer who received chemotherapy before surgery. The response to the therapy was evaluated by changes in the largest dimensions of the breast mass and of regional lymph nodes measured on a multidetector row helical CT before and after chemotherapy. The percent reduction was calculated as a response rate. The correlation between response rate and patient outcome was analyzed retrospectively. RESULTS: Breast tumor response rates correlated statistically well with those of lymph nodes (p < 0.001). Disease-free cases had a greater tumor and/or nodal response rates than recurrence cases (p = 0.021, p < 0.001, respectively), regardless of tumor size, histological grade and HER2 amplification. Cancer-associated death was observed more frequently in cases with lower response rates compared to surviving cases (p = 0.007, p = 0.021, respectively). The prognostic difference was found most strongly in nodal response rates (p = 0.001). CONCLUSION: The present series evaluated the therapeutic effect of NAC on breast tumors and metastasized lymph nodes, and a significant correlation with patient outcome was observed. Evaluating the response rate measured by imaging could be used as a surrogate marker for prognosis before assessment of the pathological response which is ordinarily obtained after surgery.

Clinical significance of axillary microresiduals after neoadjuvant chemotherapy in breast cancer patients with cytologically proven metastases.

BACKGROUND: Neoadjuvant chemotherapy (NAC) has been widely accepted for advanced breast cancer patients, and pathological complete remission (pCR) was revealed to be an important prognostic factor. The pCR status of cytologically proven axillary metastases (ALN-pCR) offers a more powerful prognostic predictor than pCR of the main tumor. This study evaluated the clinical significance of residual micrometastases and discusses screening methods after NAC in patients with cytologically proven axillary metastases. METHODS: Eighty patients with a diagnosis of cytologically proven axillary metastases received NAC. All dissected lymph nodes were evaluated using multislice sectioning and cytokeratin immunohistochemistry, and categorized into four groups: no metastases (ALN-pCR), and with metastases 0.2 mm but 2 mm (ALN-mac). Disease-free survival (DFS) and overall survival (OS) were calculated by Kaplan-Meier method based on the status of residual metastases. RESULTS: DFS in patients with ALN-pCR and ALN-itc was significantly longer than that with ALN-mic (P = 0.007, P = 0.045, respectively). OS with ALN-pCR was significantly longer than that with ALN-mic (P = 0.004). There was no significant difference in DFS or OS between ALN-mac and ALN-mic. These data showed the clinical significance of microresidual metastases >0.2 mm after NAC in patients with cytologically proven axillary metastases. CONCLUSIONS: Using multislice sectioning, screening for ALN-mic after NAC was clinically important, and that for ALN-itc was not clinically essential.

Coexistence of regulatory B cells and regulatory T cells in tumor-infiltrating lymphocyte aggregates is a prognostic factor in patients with breast cancer.

BACKGROUND: Tumors can acquire tolerance to tumor immunity and develop enhanced proliferation. Regulatory B cells (Bregs), whose role in immune tolerance is similar to that of regulatory T cells (Tregs), appear to be involved in tumor immunity. Recently, Bregs were found to induce Tregs against tumor immunity. However, the platform for the coexistence of Bregs and Tregs in cancer patients and its clinical significance remain unclear; thus, they were evaluated in breast cancer patients. METHODS: In 489 breast cancer patients, CD25- and IL10-positive Bregs and Foxp3-positive Tregs were immunohistochemically evaluated in tumor-infiltrating lymphocyte aggregates (TIL aggregates) that consisted of CD19-positive B-cell follicles and CD3-positive T-cell parafollicles. Then the correlations of the localization and existence of these cells with metastasis-free survival (MFS) were evaluated in breast cancer patients. RESULTS: TIL aggregates were observed in marginal regions of tumors in breast cancer patients. In the TIL aggregates, the existence of Bregs was closely related to that of Tregs (p < 0.0001). On multivariate analysis, the coexistence of Bregs and Tregs in TIL aggregates was correlated with MFS in breast cancer patients (p = 0.007). Furthermore, MFS was significantly shorter for patients with the coexistence of Tregs and Bregs in TIL aggregates than in those with Tregs alone without Bregs (p = 0.0475). CONCLUSIONS: The present results suggest that Bregs are related to the induction of Tregs in TIL aggregates and the development of metastasis of breast cancer cells. Bregs are expected to be a new diagnostic and therapeutic target in breast cancer patients.

Breast-conserving surgery using supine magnetic resonance imaging in breast cancer patients receiving neoadjuvant chemotherapy.

BACKGROUND: Success of breast-conserving surgery (BCS) following neoadjuvant chemotherapy (NAC) depends on accurate assessment of the initial lesion. We developed a new procedure (NIPR) in which initial naked magnetic resonance images are projected onto the skin before BCS. METHODS: Thirty-five breast cancer patients underwent supine oblique MRI of the operative area. In 20 DCIS patients, the metallic clips were reproduced by projection on the skin using NIPR, and discrepancies between the projection site and clip were measured on X-rays. Fifteen patients (T1;3,T2;8,T3;4 cases) treated with NIPR were compared to 20 (T1;5 , T2;15 cases) treated using the conventional method with regard to excision area and additional excision rate of BCS after NAC. RESULTS: The median discrepancy (linear distance) was 2.6 mm. NIPR significantly reduced the excision area and additional excision rate in T1 and T2 compared to the conventional method (P<0.05). CONCLUSIONS: NIPR is a reliable technique for BCS following NAC with significant reductions in excision area and additional excision rate and superior cosmetic results.

Angiosarcoma arising in the breast following breast-conserving surgery with radiation for breast carcinoma.

We report a case of angiosarcoma arising in the breast following breast-conserving surgery with radiation therapy for breast carcinoma. The patient, a 49-year-old postmenopausal woman, had undergone breast-conserving surgery for invasive ductal carcinoma of the left breast (pT2 pN0 M0 Stage IIA). Adjuvant radiotherapy (50 Gy with a booster dose to the tumor bed of 10 Gy) was then performed for the residual breast tissue and the patient was treated with hormone therapy (tamoxifen, 20 mg daily) for 5 years. She presented with skin erosion with bleeding 10 years after the initial operation. Incisional biopsy revealed angiosarcoma of the breast, and total mastectomy was subsequently performed. The patient was the treated with chemotherapy (weekly paclitaxel, 80 mg/m2 x cycles) and has remained well without evidence of local or distant recurrence.

Phase II study of neoadjuvant anthracycline combined with nanoparticle albumin-bound paclitaxel for human epidermal growth factor receptor 2-negative breast cancer.

Neoadjuvant chemotherapy (NAC) with anthracyclines followed by taxane chemotherapy has become the standard treatment for patients with locally advanced, operable breast cancer. Recently, the efficacy of nanoparticle albumin-bound paclitaxel (nab-PTX) for metastatic breast cancer was reported. However, there are still few studies of a neoadjuvant regimen including nab-PTX. Thus, the present phase II study evaluated the efficacy and safety of 5-fluorouracil, epirubicin and cyclophosphamide (FEC regimen) followed by nab-PTX as neoadjuvant treatment for operable human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Women with operable HER2-negative breast cancer (clinical stage T1a-4N1-3) received 4 cycles of FEC (5-fluorouracil 500 mg/m2, epirubicin 100 mg/m2 and cyclophosphamide 500 mg/m2 every 21 days), followed by 4 cycles of nab-PTX at 260 mg/m2 every 21 days. The patients then underwent mastectomy or breast-conserving surgery (BCS). The primary endpoint was pathological complete response (pCR) rate. The secondary endpoints included clinical response rate, pathological response rate, BCS rate and safety. A total of 16 patients were evaluated and 3 patients (18%) achieved pCR (1 patient with estrogen receptor-positive cancer and 2 with estrogen receptor-negative cancer). The pCR rate was 12 and 25% in patients with estrogen receptor-positive and -negative cancers, respectively. The clinical response rate was 100% (clinical complete and partial response in 6 and 10 patients, respectively). The BCS rate was 31.25%. Three patients experienced grade 3 neutropenia during FEC therapy, and no grade 3/4 events occurred during nab-PTX therapy. Thus, neoadjuvant therapy with FEC followed by nab-PTX for operable HER2-negative breast cancer was found to be a safe and effective option.

Expression of cell polarity protein scribble differently affects prognosis in primary tumor and lymph node metastasis of breast cancer patients.

BACKGROUND: We evaluated the relationship between the immunohistochemically determined expression of the cell polarity protein scribble to prognosis in different environments of estrogen receptor (ER) expression and epithelial-to-mesenchymal transition (EMT). METHODS: We immunohistochemically evaluated the expression level of scribble in primary tumors and lymph node metastases of 225 node-positive breast cancer patients who had received chemotherapy. We then evaluated metastasis-free survival (MFS) in the absence or presence of ER and the EMT-related protein vimentin. RESULTS: Among patients with ER-positive tumors, patients with low scribble expression in the primary tumor had a significantly shorter MFS than patients with high scribble expression (p = 0.0225). Furthermore, among patients with vimentin-negative tumors, patients with low expression of scribble in the primary tumor had significantly shorter MFS than patients with high expression of scribble (p = 0.0463). In contrast, among patients with vimentin-positive tumors, patients with high expression of scribble in the primary tumor had significantly shorter MFS than patients with low expression of scribble (p = 0.0343). Moreover, among patients with ER-negative tumors, patients with high expression of scribble in lymph node metastases showed significantly higher expression of E-cadherin in metastases (p = 0.0407) and had significantly shorter MFS than patients with low expression of scribble (p = 0.0064). CONCLUSIONS: The prognostic significance of cell polarity depended on the ER expression and EMT. Furthermore, the preservation of cell polarity in metastases was associated with mesenchymal-to-epithelial transition and worse prognosis. Cell polarity promotes the diversity of metastasis in combination with malignancy grade in breast cancer patients.