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.

Clinical impact of the biology of synchronous axillary lymph node metastases in primary breast cancer on preoperative treatment strategy.

BACKGROUND AND OBJECTIVES: The purpose of this study was to assess the utility of determining the biological features of synchronous axillary lymph node (syLN) metastasis of breast cancer in evaluating the efficacy of preoperative systemic chemotherapy (PST). MATERIALS AND METHODS: The retrospective subjects initially comprised 59 patients (T1c-4 N1-3 M0) diagnosed with syLN metastasis via core needle biopsy who received PST. The hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) status in each patient was assessed in primary breast tumor (pBT) and syLNs using immunohistochemistry, and the patients were classified into HR(+), HER2(+), and triple negative breast cancer (TN) subtypes. RESULTS: Subtype shift (SS) of pBT in syLNs was observed in 28% cases for HR(+), in 6% cases for the HER2(+), and in 16% cases for the TN. The pCR rate of the pBT and syLNs types were 45% and 36% in the HR(+), 45% and 39% in the TN, and 94% and 100% in the HER2(+), respectively. In SS cases, the pCR rate was significantly higher in 75% cases compared with 33% of the no-SS cases. CONCLUSION: A SS in syLNs was more frequent in HR(+) than in other types.

[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.

Open-Y technique for the internal mammary vein in the free abdominal flap of unilateral breast reconstruction.

BACKGROUND: In microvascular breast reconstruction, the internal mammary vein (IMV) has emerged as the most common recipient vein. The open-Y technique can increase the vessel diameter via the bifurcation site. This study aimed to investigate the open-Y technique for IMV. METHODS: The characteristics and details of the operative procedure in patients who had undergone unilateral breast reconstruction with and without the open-Y approach for the free abdominal flap were compared. Differences in IMV anastomosis site (the bifurcation of the main duct or that of the perforator branch) were also compared in patients with the open-Y technique. The open-Y technique was performed on the IMV side. RESULTS: The open-Y and conventional groups included 127 and 62 patients, respectively. The main duct diameter of IMV was significantly smaller (median 2.5 vs. 3.0 mm, P < 0.001), and the rate of right-sided anastomosis (47.2 vs. 82.3%, P < 0.001) was significantly lower in the open-Y group. When comparing the main duct and perforator groups, the branch diameter (1.8 vs. 1.0 mm, P < 0.001) and the diameter after the open-Y technique (5.0 vs. 3.9 mm, P < 0.001) were significantly higher, and the angle of bifurcation (45° vs. 60°, P = 0.007) was significantly lower in the main duct group. CONCLUSIONS: Given a small venous diameter, the open-Y technique is superior, especially for left-sided breast reconstruction. Owing to the lower angle of bifurcation and large diameter, the open-Y technique at the main duct bifurcation of IMV causes less turbulence in the blood flow. TAKE HOME MESSAGE: The open-Y technique is especially effective for left-sided breast reconstruction. Considering the lower angle of bifurcation and large diameter, the open-Y technique at the main duct bifurcation of the internal mammary vein causes less turbulence in the blood flow.

Clinical Impact of Fine Needle Aspiration Cytology on Sentinel Node Biopsy after Preoperative Chemotherapy for Core Needle Biopsy-Proven Metastatic Lymph Nodes.

INTRODUCTION: Sentinel node biopsy (SNB) has been increasingly performed for patients with lymph node (LN)-positive (cN1) breast cancer that converted to LN-negative (ycN0) status after neoadjuvant chemotherapy (NAC). This study aimed to clarify the SNB avoidance rates using fine needle aspiration cytology (FNAC) for metastatic LNs after NAC. METHODS: This study included 68 patients with cN1 breast cancer undergoing NAC from April 2019 to August 2021. Patients with biopsy-proven metastatic clip-marked LNs (clipped LNs) underwent eight cycles of NAC. Ultrasonography (US) was performed to evaluate the effect of the treatment on the clipped LNs, and FNAC was performed after NAC. Patients with ycN0 status determined using FNAC underwent SNB. Those with positive results for FNAC or SNB underwent axillary LN dissection. Histopathology results and FNA were compared for clipped LNs after NAC. RESULTS: Of the 68 cases, 53 were ycN0 and 15 were clinically positive LNs after NAC (ycN1) on US. Further, 13% (7/53) of all ycN0 and 60% (9/15) of all ycN1 cases showed residual metastasis in the LNs on FNAC. CONCLUSION: FNAC was diagnostically useful for patients with ycN0 status on US imaging. Using FNAC for LNs after NAC helped avoid unnecessary SNB in 13% of the cases.

Treatment Strategy for Patients with HR-Positive HER2-Negative Metastatic Breast Cancer That Progressed on CDK4/6 Inhibitors.

Background/Aims: The study aim was to evaluate if mTOR inhibitors can be considered as a treatment option for HR+ HER2- metastatic breast cancer (MBC) after progression on CDK4/6 inhibitors in clinical practice. Methods: We retrospectively collected the clinicopathological data of patients with HR+ HER2- MBC treated with CDK4/6 inhibitors and subsequent therapies at our institution between 2014 and 2020. The patients were divided into 3 groups according to the type of subsequent treatment: (A) exemestane plus everolimus, (B) endocrine monotherapy, and (C) chemotherapy. Overall survival (OS) was estimated by using the Kaplan-Meier method and compared by using the log-rank test. The efficacy and adverse events (AEs) of each subsequent treatment were assessed by using Fisher's exact tests. Results: Eighty-six patients (34 in group A, 20 in group B, 32 in group C) were included. The most common endocrine therapy in group B was fulvestrant (40%). The major chemotherapy regimen in group C was eribulin (25%). The median OS times after stopping CDK4/6 inhibitors were 34.5 months (95% confidence interval, 17.2 to NA), 13.6 months (3.9 to NA), and 19.5 months (18.8 to NA) in group A, group B, and group C, respectively. The only significant difference in OS was observed between group A and group B (20.9 months; p = 0.003). There was no difference in the incidence of grade 3 AEs between groups A and C or in the frequency of treatment discontinuation because of AEs among the 3 groups. Conclusion: Our study shows that mTOR inhibitors might be an effective treatment option for patients with HR+ HER2- MBC previously treated with CDK4/6 inhibitors.

Does Routine Follow-Up after Patients Have Completed Adjuvant Therapy for Early-Stage Breast Cancer at a Cancer Center Improve Prognosis?

Introduction: This study aimed to assess whether follow-up of patients with operative breast cancer at cancer centres (CCs) improved prognosis compared with follow-up by family physicians (FPs). Methods: The study included 254 patients who relapsed within 7 years from the first postoperative period. The patients were divided into two groups according to the follow-up facility: the CC and FP groups (the follow-up of patients was structured in the same way between FPs and CCs). There are 146 and 108 cases of recurrence in the CC and FP groups, respectively. The analysis targets of the two groups were determined using the propensity matching method based on the following 7 factors: oestrogen receptor status, progesterone receptor status, human epidermal growth factor receptor 2 status, St. Gallen category, menopausal status, surgical procedure, and receipt of postoperative chemotherapy at the time of surgery. Overall survival (OS) in both groups was analysed using the Kaplan-Meier method and compared using the log-rank test. Results: Overall, 97 patients each in the CC and FP groups who relapsed were analysed using the propensity matching method. The median recurrence-free survival periods were 1,676 and 994 days in the FP and CC groups, respectively, and were significantly longer in the FP group. However, the median OS starting from the day of surgery was 3,424 and 2,794 days in the FP and CC groups, respectively, with no significant difference. Conclusion: This study revealed that regular follow-up at CCs did not improve survival compared with regular follow-up by FPs.

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.

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.

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.