Imprint Cytology of Tall Cell Carcinoma with Reversed Polarity of the Breast: A Case Report.

INTRODUCTION: Tall cell carcinoma with reversed polarity (TCCRP) is a rare histologic subtype of breast cancer that was newly categorized in 2020. TCCRP is a relatively novel tumor, and there are no detailed reports about its cellular morphology. We were able to obtain imprint cytological specimens from fresh TCCRP tissue, and we provide our detailed observations. CASE PRESENTATION: The patient was a 73-year-old Japanese female with a 15-mm mass in her right breast. After invasive breast carcinoma was diagnosed based on a core needle biopsy, a lumpectomy was performed. The pathological examination revealed TCCRP, and Sanger sequencing detected IDH2 p.R172M hotspot mutation, which is characteristic of TCCRP. Soon after the surgery, the lumpectomy specimen was sliced before fixation for use in a clinical trial, and imprint cytological materials were obtained from the tumor's cut surface. Cytologically, the tumor showed papillary-like cell clusters and isolated cells with moderate cellularity. Neoplastic cell aggregates and clusters with thick vascular cores as the axis or with delicate fibrovascular stroma were observed. Most of the neoplastic cells were cuboidal-to-columnar in shape, with mildly to moderately irregularly shaped blunt nuclei. Some intranuclear cytoplasmic inclusions and nuclear grooves were present, resembling the nuclear findings of papillary thyroid carcinoma. The most characteristic finding was the columnar cell clusters with apically located nuclei, giving the impression of reversed polarity. CONCLUSION: We described cytological findings in TCCRP, a newly classified rare mammary tumor. Most of the characteristic histologic findings were also observed in imprint cytological specimens. Further studies on practical specimens such as fine-needle aspiration are needed for clinical application.

Eribulin induces micronuclei and enhances the nuclear localization of cGAS in triple-negative breast cancer cells.

Eribulin (ERI), clinically utilized for locally advanced or metastatic breast tumors, has shown potential links to the immune system. Notably, the cGAS-STING pathway, a key component of innate immunity, has gained prominence. Yet, limited reports explore ERI's effects on the cGAS-STING pathway. Additionally, the nuclear presence of cGAS remains poorly understood. This study uniquely delves into ERI's impact on both the cytosolic cGAS-STING pathway and nuclear cGAS. ERI enhances nuclear localization of cGAS, resulting in hyper-activation of the cGAS-STING pathway in triple-negative breast cancer cells. Reduction of cGAS heightened both cell proliferation and ERI sensitivity. In clinical data using ERI in a neo-adjuvant setting, patients with low cGAS cases exhibited reduced likelihood of achieving pathological complete response after ERI treatment. These findings illuminate the potential of cGAS and IFNß as predictive biomarkers for ERI sensitivity, providing valuable insights for personalized breast cancer treatment strategies.

Ex vivo dual gene therapy using human adipocytes secreting anti-HER2 antibody on HER2-positive xenograft tumor models.

BACKGROUND: Although targeted treatments against human epidermal growth factor receptor 2 (HER2) have improved survival in patients with metastatic HER2-positive breast cancer, long and repeated treatment is time-consuming and costly for patients. To reduce these burdens, we developed ex vivo gene-transduced adipocytes that secrete anti-HER2 antibodies and evaluated their anti-tumor effects. METHODS: Ceiling culture-derived proliferative adipocytes (ccdPA) secreting anti-HER2 antibody against domain IV receptors: TRA-ccdPA, and domain II receptors: PER-ccdPA, were constructed using a plasmid lentivirus. Delivery of secreted antibody and its specific binding to HER2 breast cancer were evaluated in vitro and in vivo. To optimize antibody production from ccdPA, different conditions of ccdPA implantation were examined. Anti-tumor efficacy was evaluated in HER2-positive-cancer-inoculated nude mice. RESULTS: Anti-HER2 antibody against domain II was identified in supernatants from PER-ccdPAs. The optimal method to achieve the highest concentration of antibody in mouse sera was injecting differentiated ccdPA cells into the mammary fat pad. Antibody in supernatants from PER-ccdPAs bound to the surface of HER2-positive breast cancer cells similar to pertuzumab. Antibodies in mouse sera were delivered to HER2-positive breast cancer tumors and tumor necrosis was observed microscopically. One-time administration of combined TRA-ccdPAs and PER-ccdPAs produced antibody continuously in mouse sera, and anti-tumor effects were maintained for the duration of this study in xenograft models. Furthermore, combination therapy significantly suppressed tumor growth compared with a single administration. CONCLUSION: Ex vivo gene-transduced adipocytes might be useful for cell-based gene therapy. This system may be a platform for various antibody therapies.

Less necessity of adjuvant S-1 treatment in non-monarchE-eligible patients.

BACKGROUND: In monarchE and Postoperative Therapy with Endocrine and TS-1 (POTENT) trials, abemaciclib and S-1 have, respectively, shown to be effective as adjuvant therapies for luminal breast cancer (BC), although whether patients who meet the criteria are at high risk of recurrence compared to non-eligible patients is still unknown. Here, we investigated recurrence risk according to the criteria of each trial in Japanese patients. METHODS: We reviewed the records of 992 patients who received surgery at Chiba University Hospital for stage I-III BC from January 2017 to May 2022 and selected 553 analytic cohort patients and retrospectively analyzed the relapse-free survival of the patients as the primary endpoint. High-recurrence risk was defined according to monarchE trial and POTENT trial. RESULTS: The 5-year RFS for monarchE cohort 1 and cohort 2 eligible patients were 77.78% and 89.33%, respectively, which were significantly lower than monarchE non-eligible patients (98.31%; p < 0.0001). However, the 5-year RFS rate for POTENT eligible patients (90.51%) was lower than for POTENT non-eligible patients (98.75%; p = 0.0001); excluding those who met the monarchE criteria, the prognosis of POTENT eligible patients had no significant differences from the prognosis of patients with POTENT non-eligible BC (p = 0.3100). CONCLUSION: MonarchE criteria accurately identify patients who are prone to relapse. Moreover, although POTENT criteria also suggested a reasonable capacity for recurrence prediction, there was no significant difference in recurrence between POTENT non-eligible patients and the patients who were POTENT but not monarchE eligible. This might offer justification for reconsidering the use of S-1 in monarchE non-eligible patients.

A review of MRI (CT)/US fusion imaging in treatment of breast cancer.

The ultrasound fusion imaging system is a diagnostic device developed in Japan that utilizes ultrasound and magnetic positioning/navigation. A position sensor with a probe reads spatial location information from a magnetic field generator and by synchronously displaying ultrasound images and magnetic resonance (MR)/computed tomography (CT) images in real time. Lesions that are difficult to observe via ultrasonography alone, such as non-mass enhancement, can be identified. Furthermore, lesions that are difficult to identify with ultrasound alone indicated for MRI-guided biopsy under the National Health Insurance Scheme can be identified using ultrasound fusion technology, thereby enabling tissue biopsy to be performed under ultrasound guidance. Using this ultrasound fusion technology, not only non-mass enhancement but also small lesions that are difficult to identify using ultrasound alone can be detected, thus ensuring that a more accurate preoperative imaging diagnosis is established, and leading to safer, more reassuring examinations and surgical procedures. In this paper, we outline the use of this ultrasound fusion technology and fusion techniques in the treatment of breast cancer.

Oncoplastic breast-conserving surgery using chest wall perforator flaps: Three-dimensional quantitative analysis of the percentage of breast volume excised and changes over time in flap volume.

BACKGROUND AND OBJECTIVES: We investigated the effects of oncoplastic breast-conserving surgery (BCS) using chest wall perforator flaps (CWPFs) on the subsequent expected deformity and evaluated the longevity of flap volume. METHODS: We retrospectively reviewed oncological and cosmetic outcomes of 33 women who had undergone the above procedure. We calculated the percentage of breast volume excised (PBVE) from computed tomography volumetry and compared it between a historical BCS alone and the study (flap) group. We also sequentially evaluated flap volumes by magnetic resonance imaging volumetry. RESULTS: Oncoplastic BCS using 25 lateral flaps and eight inferior flaps, depending on the site of the defect, was performed; mean PBVEs were 31.1% and 19.0%, respectively. No local and two distant recurrences occurred in a median follow-up of 61 months. PBVE was 2.6 times larger in the flap than in the BCS alone group. Over half the patients in the BCS alone group had poor cosmetic results when PBVE exceeded 15%, whereas patients in the flap group achieved good cosmetic results with PBVE >25%. In most patients, 80% of flap volume was maintained 5 years after surgery. CONCLUSIONS: CWPF improves cosmetic outcomes in patients with predicted deformity after BCS alone and maintains its volume for at least 5 years.

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.

[Differences in Treatment Effect between Local and Distant Lesions in Breast Cancer Patients Administered Neoadjuvant Endocrine TherapyGuided byOncoty pe DX-A Case Report].

We report different treatment effects between local and distant lesions based on oncotype DX in a patient with breast cancer administered neoadjuvant endocrine therapy. The patient was a 50-year-old woman. Ultrasound(US)showed a mass 16×11×11mm in diameter in the C area of her right breast. Histological examination revealed invasive ductal carcinoma positive for estrogen and progesterone receptor and negative for human epidermal growth factor receptor type 2(HER2), and a Ki-67 index of 38%. The recurrence score(RS)calculated from the core needle biopsy was 4(low-risk group)with a predicted 10-year risk of distant recurrence of 4% after 5 years of endocrine therapy. Oncotype DX showed that this patient would not benefit from chemotherapy. We administered neoadjuvant endocrine therapy. However, the tumor size increased to 26×18×15mm 1 month after treatment initiation. Therefore, right breast-conserving surgery and sentinel lymph node biopsy were performed. Histopathologically, the effect of the endocrine therapy was grade 0 and the surgical margins were negative. Even though RS was low in the breast, the effect of endocrine therapy differed between local and distant lesions such as circulating tumor cells.

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.

An increased neutrophil-to-lymphocyte ratio predicts poorer survival following recurrence for patients with breast cancer.

The aim of the present study was to evaluate the association between changes in the neutrophil-to-lymphocyte ratio and the survival rate, as well as tumor subtype, in recurrent breast cancer. Patients with recurrent breast cancer following surgery were included in this study. NLR was calculated and compared between two time points: Pre-treatment and recurrence. The associations between the longitudinal NLR change, the NLR at the time of recurrence and overall survival following recurrence (OSrec) were evaluated. A total of 89 patients were evaluated. NLR increased by 0.59 at recurrence, as compared with the initial treatment (P<0.05). The triple negative (TN) type demonstrated 4.59 in NLR, which was the highest among the four subtypes at the time of recurrence (P<0.05). The highest change (an increase of 2.0) was observed in TN type cancer (P<0.05). Patients with high NLR upon recurrence demonstrated significantly shorter OSrec rates (P<0.05). On the other hand, patients with an NLR increased by more than a third quartile demonstrated a shorter OSrec rate (P=0.06). When adjusted by covariates, the NLR and tumor subtype were determined to be associated with OSrec (P<0.05). Therefore, an increased NLR predicts survival, even in patients with recurrent breast cancer, and the NLR is potentially useful as an inflammation marker for TN breast cancer.

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.

[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.

Impact of body fat distribution on neoadjuvant chemotherapy outcomes in advanced breast cancer patients.

Obesity is known to decrease the efficacy of neoadjuvant chemotherapy (NAC) against breast cancer; however, the relationship between actual body composition and NAC outcomes remains unknown. Therefore, we determined the effect of body composition on NAC outcomes. A total of 172 advanced breast cancer patients who underwent surgery after NAC were retrospectively analyzed. Body composition parameters including abdominal circumference (AC), subcutaneous fat area (SFA), visceral fat area (VFA), and skeletal muscle area (SMA) were calculated using computed tomography volume-analyzing software. VFA/SFA ratio was used to evaluate visceral obesity. The associations of body composition parameters with pathological complete remission (pCR) and survival were analyzed. AC, SFA, and VFA were significantly correlated with body mass index (BMI) (all P < 0.05; r = 0.82, r = 0.71, and r = 0.78, respectively). AC, SFA, and VFA increased significantly and SMA decreased significantly after menopause (all P < 0.05). VFA/SFA ratio increased significantly after menopause, even though BMI remained unchanged. Body composition parameters were not associated with pCR. Distant disease-free survival (DDFS) was significantly worse in the high VFA group than in the low VFA group (P < 0.05). Furthermore, in the high VFA group, postmenopausal patients had significantly shorter DDFS than premenopausal patients (P < 0.05). VFA was independently associated with DDFS in the multivariate analysis (P < 0.05). High visceral fat is associated with worse NAC outcomes in breast cancer patients, especially postmenopausal patients. Interventions targeting visceral fat accumulation will likely improve NAC outcomes.

[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.

[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.