Nipple-areolar complex malposition in breast reconstruction after nipple-sparing mastectomy: a multi-institutional retrospective observational study in Japan.

BACKGROUND: Position of the nipple-areolar complex (NAC) is an important factor in the esthetic impression of the breast, and NAC malposition is often an issue in breast reconstruction after nipple-sparing mastectomy (NSM). The purpose of this study was to evaluate the degree of NAC malposition depending on several factors using data quantified with the Mamma Balance application (Medic Engineering K.K., Kyoto, Japan). METHODS: Patients who underwent unilateral breast reconstruction after NSM at eight hospitals in Japan between 2007 and 2020 were retrospectively investigated. Using Mamma Balance, NAC malposition was quantified separately in horizontal and vertical directions using patient photographs from pre-operatively and 6-24 months post-operatively. The degree of malpositioning was then statistically compared using various factors. RESULTS: The NAC deviated more cranially and medially with implants than that with flaps. Cases with latissimus dorsi flap showed lateral malposition more often than cases with deep inferior epigastric artery perforator flap. With flaps, lateral incisions showed more lateral malposition, and peri-areolar incisions tended to show more medial NAC malposition. In cases with severe post-operative infection of the implant, the NAC tended to deviate cranially. In radiation cases, the NAC deviated cranially. No significant difference was observed according to the degree of breast ptosis or use of the pull-down operation. Only a very weak correlation was observed between a larger amount of mastectomy and more cranial NAC malposition with both flaps and implants. CONCLUSIONS: This study provides insights into the tendencies and characteristics of NAC malposition.

Impact of neoadjuvant chemotherapy on the safety and long-term outcomes of patients undergoing immediate breast reconstruction after mastectomy.

BACKGROUND: In breast cancer patients receiving neoadjuvant chemotherapy (NAC), immediate breast reconstruction (IBR) as a breast cancer treatment option remains controversial. We assessed the impact of NAC on surgical and oncological outcomes of patients undergoing IBR. METHODS: This was a retrospective multicenter study of 4726 breast cancer cases undergoing IBR. The rate of postoperative complications and survival data were compared between IBR patients who received NAC and those who did not receive NAC. Propensity score matching analysis was performed to mitigate selection bias for survival. RESULTS: Of the total 4726 cases, 473 (10.0%) received NAC. Out of the cases with NAC, 96 (20.3%) experienced postoperative complications, while 744 cases (17.5%) without NAC had postoperative complications. NAC did not significant increase the risk of complications after IBR (Odds ratio, 0.96; 95%CI 0.74-1.25). At the median follow-up time of 76.5 months, 36 patients in the NAC group and 147 patients in the control group developed local recurrences. The 5-year local recurrence-free survival rate was 93.1% in the NAC group and 97.1% in the control group. (P < 0.001). After matching, there was no significant difference between the two groups. CONCLUSION: IBR after NAC is a safe procedure with an acceptable postoperative complication profile.

Impact of radiation therapy for breast cancer with involved surgical margin after immediate breast reconstruction: A multi-institutional observational study.

INTRODUCTION: Involved surgical margins are risk factors for local recurrence and re-excision is often difficult, particularly in patients with breast cancer undergoing immediate breast reconstruction (IBR). However, the magnitude of the effect of radiation therapy on preventing local recurrence for breast cancers with involved margins has not been sufficiently assessed. MATERIALS AND METHODS: We retrospectively assessed sites of involved surgical margins and local recurrence after mastectomy with IBR in patients with early breast cancer between 2008 and 2016. The effect of postoperative radiation therapy was evaluated in patients with involved margins, adjusted for nuclear grade, lymphatic invasion, surgical procedures, and primary systemic therapy. RESULTS: A total of 274 (5.8 %) out of 4726 patients who underwent mastectomy with IBR had involved surgical margins: 133, 68, 88, and 26 had involvement of the skin, deep margin, lateral margins, and nipple, respectively (including duplicates). Radiation therapy was administered to 54 patients with involved margins. In patients with involved margins, 7-year cumulative incidences of local recurrence were 1.9 % and 12.6 % with and without radiation therapy, respectively (adjusted hazard ratio, 0.17; 95 % CI, 0.04-0.80). Local recurrence occurred in 28 patients, and the sites were skin, subcutaneous tissue, muscle, and nipple-areola complex in 7, 17, 1, and 3 patients, respectively. Among them, 23 (82.1 %) were associated with involved margin sites. CONCLUSIONS: Radiation therapy meaningfully reduced the incidence of local recurrence in patients with breast cancer with margin involvement after mastectomy with IBR. Most local recurrences occurred at involved margin-related sites.

Long-Term Outcomes of Breast Cancer Patients with Local Recurrence After Mastectomy Undergoing Immediate Breast Reconstruction: A Retrospective Multi-institutional Study of 4153 Cases.

BACKGROUND: The number of breast cancer patients in Japan undergoing immediate breast reconstruction (IBR) has increased and the postoperative follow-up period has been extended. This study was conducted to clarify the clinical aspects of, and factors associated with, local recurrence (LR) after IBR. METHODS: This was a multicenter study which included 4153 early breast cancer patients who underwent IBR. Clinicopathological characteristics were examined and factors potentially contributing to LR were analyzed. Risk factors for LR were examined separately for non-invasive and invasive breast cancers. RESULTS: The median follow-up period was 75 months. The 7-year LR rates were 2.1% and 4.3% for non-invasive and invasive cancers, respectively (p < 0.001). The proportions of LR detected by palpation, subjective symptoms, and ultrasonography were 40.0%, 27.3%, and 25.9%, respectively. Overall, 75.7% of LR were solitary, and 92.7% of these cases had no further recurrences during the observational period. Multivariate analysis of LR for invasive cancer showed that skin-sparing mastectomy (SSM) or nipple-sparing mastectomy (NSM), the presence of lymphovascular invasion, cancer at the surgical margin, and not receiving radiation therapy were factors related to LR. The 7-year overall survival rates of the patients with LR and non-LR of invasive cancers were 92.5% and 97.3%, respectively, (p = 0.002). CONCLUSIONS: The rate of LR after IBR was acceptably low and IBR can thus be performed safely for early breast cancer patients. Invasive cancer, SSM/NSM, lymphovascular invasion, and/or cancer at the surgical margin should prompt awareness of the possibility of LR.

Physicians' perception about the impact of breast reconstruction on patient prognosis: a survey in Japan.

BACKGROUND: One barrier to the widespread use of breast reconstruction (BR) is physicians' perception that BR adversely affects breast cancer prognosis. However, there is limited information regarding physicians' understanding of the impact of BR on patient prognosis and which physicians have misunderstandings about BR. METHODS: We conducted an e-mail survey regarding the impact of BR on the prognosis of patients with breast cancer among members of the Japanese Breast Cancer Society. RESULTS: Of 369 respondents, 99 (27%) said that they believe BR affects patient prognosis. Female respondents and those who treat fewer new breast cancer patients per year were more likely to state that they believe BR affects patient prognosis (P = 0.006 and 0.007). Respondents who believed that BR affects patient prognosis underestimated 5-year overall survival rates in patients who receive BR and subsequently have local or regional recurrence in different sites. CONCLUSION: Our survey demonstrated that a quarter of respondents believe that BR affects patient prognosis and underestimate survival rates in patients who receive BR and have subsequent local or regional recurrence. Because of the lack of evidence regarding the impact of BR on patient prognosis, educating physicians by providing accurate knowledge regarding BR and patient prognosis is highly recommended.

Classification of Local Recurrence After Nipple-Sparing Mastectomy Based on Location: The Features of Nipple-Areolar Recurrence Differ from Those of Other Local Recurrences.

BACKGROUND: Little information is available about the clinical and pathologic characteristics of local recurrence (LR) after nipple-sparing mastectomy according to the locations of LR. METHODS: This study classified 99 patients into the following two groups according to the location of LR after nipple-sparing mastectomy: nipple-areolar recurrence (NAR) group and other locations of LR (oLR) group. The study evaluated whether the location of LR was associated with disease-free survival (DFS) after LR resection. RESULTS: For about half of the patients (44.4 %) with NAR, the primary cancer was estrogen receptor (ER)-negative and human epidermal growth factor receptor 2 (HER2)-positive. Conversely, in most of the patients with oLR (79.2 %), the primary cancer was ER-positive and HER2-negative. Among the LR tumors, the frequency of noninvasive carcinoma in the NAR tumors was significantly higher than in the oLR tumors (51.9 % vs 4.2 %, respectively). During a median follow-up period of 46 months, the location of LR was not associated with DFS after LR. In the NAR group, the presence or absence of LR tumor invasiveness was the only factor associated with DFS. In the oLR group, age at primary surgery was the only factor associated with DFS. CONCLUSION: This multi-institutional retrospective study demonstrated that the features of NAR, such as the characteristics of the primary and recurrent tumors and the prognostic factors after LR resection, were quite different from those of oLR.

Intramedullary spinal cord metastasis to the cauda equina in a patient with HER2-positive metastatic breast cancer: A case report.

The rate of metastasis to the central nervous system is high in human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer patients. Metastatic cauda equina tumors are characterized by rapid progression of symptoms, thus signifying the requirement of their early treatment. However, these tumors are rarely reported, and their optimal treatment options have not been established yet. Here, we report a case study of a patient with HER2-positive breast cancer that metastasized to the cauda equina. The patient underwent urgent surgery to relieve the spinal cord compression. The pain in her back and lower limbs was greatly reduced. Unfortunately, her ability to walk did not improve sufficiently. Overall, surgical treatment may be a favorable option to improve a patient's quality of life.

Subsequent-abemaciclib Treatment After Disease Progression on Palbociclib in Patients With ER-positive HER2-negative Metastatic Breast Cancer.

BACKGROUND/AIM: This study investigated the efficacy of continuing cyclin-dependent kinase (CDK) 4 and 6 inhibitors in patients with estrogen receptor-positive (ER+) human epidermal growth factor receptor 2-negative (HER2- ) metastatic breast cancer (MBC) after disease progression on prior-palbociclib combined with endocrine therapy (ET). PATIENTS AND METHODS: This retrospective study based on 25 ER+/HER2- MBC patients reported the efficacy and predictive factors of subsequent-abemaciclib after disease progression on prior-palbociclib. RESULTS: The overall response rate and clinical benefit rate were 16.0% and 44.0%, respectively. The median progression-free survival (PFS) was 5.3 months. In multivariate analysis, the best overall response (BOR) to prior-palbociclib was the only independent predictive factor for PFS (p=0.015). The median time to chemotherapy was 33.9 months. The median PFS in patients treated with next-line chemotherapy after progression on subsequent-abemaciclib was 6.2 months. CONCLUSION: BOR to prior-palbociclib was the only independent predictive factor for PFS in ER+/HER2- MBC patients undergoing subsequent-abemaciclib after disease progression on prior-palbociclib.

Feasibility Study of Nanoparticle Albumin-Bound-Paclitaxel and S-1 Followed by Epirubicin/Cyclophosphamide as Neoadjuvant Chemotherapy in Patients With Operable Breast Cancer: A Prospective Study.

BACKGROUND: The efficacy and safety of nanoparticle albumin-bound (nab)-paclitaxel combined with S-1 in patients with operable breast cancer is uncertain. We evaluated the feasibility of this combination followed by epirubicin/cyclophosphamide (EC) as neoadjuvant chemotherapy in such patients. PATIENTS AND METHODS: This was an open-label, single-arm, phase II, single-institution prospective study of 4 cycles of nab-paclitaxel (260 mg/m2) administered intravenously on day 1 in combination with S-1 (65 mg/m2 orally twice daily) on days 1 to 14 every 21 days followed by EC as neoadjuvant chemotherapy. RESULTS: Of 30 patients, 1 required a dose interruption for nab-paclitaxel combined with S-1; 4 required a dose reduction for nab-paclitaxel, 1 for S-1, and 4 for EC. Mean relative dose intensities of nab-paclitaxel, S-1, and EC were 98.0%, 99.3%, and 98.2%, respectively. Overall clinical response rate was 96.7%. In histological response, grade 3, pathological complete response (pCR; ypT0/is and ypN0) rate was 63.3% and grade 2b (near pCR) was 3.3%. pCR was observed in 57.1% of luminal B human epidermal growth factor receptor type 2 (HER2)-negative patients, 55.6% of luminal B HER2-positive patients, 100% of HER2-positive patients, and 57.1% of triple-negative breast cancer patients. Grade 3/4 neutropenia was observed in 1 patient during nab-paclitaxel combined with S-1 and in 7 during EC treatments. The most frequent nonhematological severe adverse events were grade 3 peripheral neuropathy in 2 patients and grade 3 arthralgia in 2 patients during nab-paclitaxel combined with S-1. CONCLUSION: Tri-weekly nab-paclitaxel with S-1 followed by EC is effective and well tolerated as neoadjuvant chemotherapy in patients with operable breast cancer.

A novel MRI-based predictive index can identify patients suitable for preservation of the nipple-areola complex in breast reconstructive surgery.

INTRODUCTION: Accurately predicting nipple-areola complex (NAC) involvement in breast cancer is necessary for identifying patients who may be candidates for a nipple-sparing mastectomy. Although multiple risk factors are indicated in the guidelines, it is difficult to predict NAC involvement (NAC-i) preoperatively even if these factors are evaluated individually. This study aimed to develop a more accurate and practical preoperative NAC-i prediction model using magnetic resonance imaging (MRI). MATERIALS AND METHODS: All tumors in 252 patients were evaluated using postcontrast T1-weighted subtraction on MRI. RESULTS: The receiver operating characteristic curves identified cut-off values for tumor size and tumor-to-nipple distance (TND) as 4 cm and 1.2 cm, respectively. Multivariate analysis demonstrated that TND (p < 0.001), ductal enhancement extending to the nipple (DEEN) (p < 0.001), and nipple enhancement (NE) (p = 0.005) were independent clinical risk factors for pathological NAC-i. A formula was constructed using odds ratios for these three independent preoperative risk factors in multivariate analysis: the MRI-based NAC-i predictive index (mNACPI) = TND × 4 + DEEN × 3 + NE × 1. A total score of ≤4 points was defined as low risk and ≥5 points as high risk. NAC-i rates were 2.4% in the low-risk group and 89.4% in the high-risk group; a significant correlation was observed between the risk group and permanent pathological NAC-i (p < 0.001). Assuming that the NAC was preserved in low-risk patients and resected in high-risk patients, NAC-i was verified using the mNACPI. CONCLUSION: mNACPI may contribute greatly to the improvement of selecting suitable patients for NAC preservation in breast reconstructive surgery while maintaining oncological safety.

Utility of the periareolar incision technique for breast reconstructive surgery in patients with breast cancer.

PURPOSE: Periareolar incisions for nipple-sparing mastectomy offer the advantages of smaller inconspicuous wounds and easier resection below the nipple-areolar complex. However, they provide a narrow surgical field, which complicates the procedure and carries a risk of nipple necrosis. This study evaluated the clinical outcomes and safety of periareolar incisions for breast reconstructive surgery in patients with breast cancer. METHODS: The study included 181 patients with primary operable breast cancer who underwent nipple-sparing mastectomy for reconstructive breast procedures without intraoperative nipple-areolar complex resection. The clinical outcomes and complications were retrospectively evaluated. The recurrence-free survival was compared using Kaplan-Meier curves. RESULTS: Nipple-sparing mastectomy was performed via inframammary fold and periareolar incisions in 31 and 150 patients, respectively. There were no significant differences in clinical outcomes related to surgery, frequency of complications, nipple necrosis (inframammary fold incision vs. periareolar incision: 0% vs. 3.3%, P = 0.590), or the recurrence-free survival (P = 0.860) between the 2 groups. CONCLUSION: Our results showed that the clinical outcomes and complication rates of periareolar incisions for breast reconstruction were equivalent to those of inframammary fold incisions, suggesting that the periareolar incision technique for breast reconstructive surgery may safely improve cosmetic outcomes if done with adequate care.

Efficacy and Safety of Palbociclib and Fulvestrant in Japanese Patients With ER+/HER2- Advanced/Metastatic Breast Cancer.

BACKGROUND/AIM: Published data have shown that palbociclib-fulvestrant can significantly improve the progression-free survival (PFS) of estrogen receptor-positive/human epidermal growth factor receptor 2-negative (ER+/HER2-) metastatic breast cancer patients, but not of Japanese patients. We conducted this retrospective study to verify the efficacy and safety of palbociclib-fulvestrant in Japanese patients. PATIENTS AND METHODS: ER+/HER2- metastatic breast cancer patients treated with fulvestrant (n=39) or palbociclib-fulvestrant (n=31) at the Saitama Medical Center from July 2012 to November 2018 were evaluated. RESULTS: Overall response rates (ORRs) were 2.6% (fulvestrant) and 41.9% (palbociclib-fulvestrant) (p<0.001), and clinical benefit rates (CBRs) were 23.1% and 61.3% (p=0.002), respectively. The palbociclib-fulvestrant group had significantly higher CBR and PFS (hazard ratio(HR):0.272, 95% confidence interval(95CI):0.128-0.574 for PFS). Grade 3/4 neutropenia occurred in 80.6% of the palbociclib-fulvestrant group, while febrile neutropenia was not detected. CONCLUSION: Japanese ER+/HER2- metastatic breast cancer patients tolerated palbociclib-fulvestrant, with significantly improved clinical outcomes.

A novel nipple-areola complex involvement predictive index for indicating nipple-sparing mastectomy in breast cancer patients.

BACKGROUND: Nipple-sparing mastectomy (NSM) is increasingly used in breast cancer patients, as it offers better cosmetic outcomes and improves quality of life. Nipple-areola complex (NAC) involvement must be accurately determined to identify which patients may be candidates for NSM. We aimed to identify the predictors of NAC involvement and develop a clinical predictive model to determine the patients for whom NAC preservation may be considered. PATIENTS AND METHODS: Patients (n = 168) with primary operable breast cancer who underwent subcutaneous mastectomy for breast reconstruction at Saitama Medical Center from July 2013 to December 2017 were selected from the hospital's surgical database. RESULTS: The clinicopathological factors of tumor size ≧ 4 cm (p < 0.001), nipple-to-tumor distance (NTD) < 1 cm by mammography (p = 0.002), NTD < 1 cm by magnetic-resonance imaging (MRI) (p < 0.001), nipple contrast findings by MRI (p < 0.001), tumor in central portion (p < 0.001), multicentric/focal lesion (p < 0.001), and clinical node involvement (p = 0.014) were significantly associated with the presence of NAC involvement. Each predictor was scored 0 or 1. A score of 0-3 points was defined as low risk, 4 points as intermediate risk, and 5-7 points as high risk. Using these classification criteria, NAC involvement rate was determined to be 3.5% in low-risk, 68.7% in intermediate-risk, and 90.0% in high-risk specimens. A significant correlation was observed between the risk group and NAC involvement (p < 0.001). CONCLUSION: This nipple-areola complex involvement predictive index can be used to determine the appropriate indication for NSM in breast cancer patients who request NAC preservation with more oncological safety.

Phase II trial of eribulin mesylate as a first- or second-line treatment for locally advanced or metastatic breast cancer: a multicenter, single-arm trial.

BACKGROUND: Eribulin mesylate is currently indicated as a sequential monotherapy to be administered after two chemotherapeutic regimens, including anthracycline and taxane treatments, for treatment of metastatic breast cancer. This open-label, multicenter phase II study was designed to evaluate the efficacy and safety of eribulin as a first- or second-line treatment for patients with metastatic breast cancer. METHODS: The primary objective was to determine the overall response rate. Secondary objectives were to evaluate progression-free survival and the safety profile. Patients were scheduled to receive eribulin mesylate 1.4 mg/m2 intravenously on days 1 and 8 of a 21-day cycle. Patients received the study treatment unless disease progression, unacceptable toxicity, or a request to discontinue from the patient and/or investigator eventuated. RESULTS: Between December 2012 and September 2015, 32 patients with metastatic breast cancer were enrolled at 10 participating clinical institutions in Japan, and toxicity and response rates were evaluated. The overall response rate was 43.8% (95% confidence interval [CI] 26.5-61.0). The clinical benefit and tumor control rates were 56.3% (95% CI 39.0-73.5) and 78.1% (95% CI 63.8-92.5), respectively. Median progression-free survival was 8.3 months (95% CI 7.1-9.4). A subgroup analysis did not identify any factors affecting the efficacy of eribulin. The most common adverse events were neutropenia (71.9%), alopecia (68.7%), and peripheral neuropathy (46.9%). As a first- or second-line therapy, eribulin showed sufficient efficacy for metastatic breast cancer compared with taxane and capecitabine treatment in previous clinical trials. The safety profile of eribulin was acceptable. CONCLUSIONS: Eribulin may be another option for first-line chemotherapeutic regimens for metastatic breast cancer. TRIAL REGISTRATIONS: This trial was retrospectively registered at the University Hospital Medical Information Network (UMIN) Clinical Trial Registry (ID number: UMIN000010334 ). Date of trial registration: April 1st, 2013.

[A Case of Glycogen-Rich Clear Cell Carcinoma of the Breast with Extensive Intraductal Components and Micrometastases to the Axillary Lymph Node].

A 48-year-old woman had a left breast mass identified during routine breast cancer screening. The mammogram showed pleomorphic-segmental microcalcifications in the mediolateral-oblique view of the left breast. Ultrasonography showed a hypoechoic mass approximately 3.7 cm in diameter with multiple calcifications. Contrast-enhanced magnetic resonance imaging of the breast showed non-mass like enhancement of approximately 4 cm in diameter in the C area of the left breast. She was diagnosed with glycogen-rich clear cell carcinoma (GRCC) by ultrasound-guided vacuum-assisted biopsy. Nipplesparing mastectomy was performed along with sentinel lymph node biopsy. The intraoperative consultation suggested sentinel lymph node metastasis and we therefore performed axillary lymph node dissection. Pathological examination reported microinvasive carcinomas, 0.4 cm in maximum diameter, and extensive intraductal components, 5 cm in size. The tumor cells were stained on PAS staining, but the stains were digested with diastase. The cells were negative for adipophilin. GRCC was first reported by Hull et al. This is a rare type of breast carcinoma. There is no standard therapy for this disease or any data on the prognosis of breast cancer patients with GRCC.

HOXB9 expression promoting tumor cell proliferation and angiogenesis is associated with clinical outcomes in breast cancer patients.

BACKGROUND: Studies have suggested that HOXB9 expression in breast cancer cells promotes cellular invasiveness, metastatic ability, and tumor neovascularization in the surrounding tissue in in vitro and in vivo assays. These findings imply that HOXB9 overexpression may alter tumor-specific cell fates and the tumor stromal microenvironment, contributing to breast cancer progression. The objective of this study was to analyze whether these results could be applied to clinical practice. METHODS: A total of 141 consecutive, invasive ductal carcinoma patients who underwent surgical treatment were examined. Immunohistochemical staining was performed to evaluate the expression of HOXB9, Ki-67, CD31, and CD34, and the association of tumor proliferation and angiogenesis with HOXB9 expression was analyzed. RESULTS: Of the 141 tumor specimens immunostained for HOXB9, 69 (48.9%) stained positive. Larger primary tumor size, hormone receptor negativity, HER2 positivity, higher nuclear grade, and number of pathologic nodal metastases were significant variables associated with HOXB9 expression. Notably, 12 (92.3%) of 13 triple-negative breast cancer cases showed HOXB9 expression. Disease-free survival and overall survival were significantly different between the HOXB9-positive and HOXB9-negative groups (hazard ratio 20.714, P = 0.001; and hazard ratio 9.206, P = 0.003, respectively). Multivariate analysis indicated that HOXB9 expression was the only independent prognostic factor for disease-free survival (hazard ratio 15.532, P = 0.009). HOXB9-positive tumors showed a significant increase in the number of vasculature and the Ki-67 ratio compared with HOXB9-negative tumors. CONCLUSIONS: HOXB9 expression, which promotes tumor proliferation and angiogenesis, is a significant prognostic factor in breast cancer.

Primary systemic chemotherapy of breast cancer: indication and predictive factors.

Primary systemic chemotherapy has become a standard of care for operable breast cancer patients who are candidates for adjuvant chemotherapy. Induction of pathological complete response (pCR) is one of the main goals of primary systemic chemotherapy because patients with pCR have shown a better prognosis. The definition of pCR has varied across clinical trials. It would be ideal for all researchers to use the same terminology in describing pathologic response. Identification of accurate predictive factors of pCR to primary systemic chemotherapy is urgent, because patients with a low chance of pCR and clinical response should be spared unnecessary toxicity. Early response to primary systemic chemotherapy might be correlated with a high probability of a pCR. Therefore, evaluation of early response is useful to avoid unnecessary toxicity without potential benefit from chemotherapy.