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Background: Nipple-sparing mastectomy (NSM) is an increasingly popular surgical procedure for treatment of breast cancer. However, NSM is controversial because of its association with locoregional recurrence. We started performing NSM in 1978. Methods: We investigated the surgical safety including nipple necrosis, and nipple–areola recurrence (NAR) and skin flap recurrence (SFR) after NSM for 1071 patients with breast cancer, including 31 with stage 0, 414 with stage 1, 479 with stage 2, 141 with stage 3 and 6 with stage 4, from 1985 to 2017. Our NSM method involved creating a thick skin flap to avoid surgical complications. No patients received radiotherapy. In 1034 patients with stage 1–3 breast cancer treated with NSM who developed NAR or SFR, we evaluated cancer stage, nuclear grade, lymph node metastasis, tumor–nipple–areola distance, and histological classification as tubule forming, solid and scirrhous type. In 748 patients with early stage 1 and 2A breast cancer treated with NSM, NAR and SFR were evaluated for estrogen receptor and HER2 expression. We evaluated disease-free interval and frequency of late NAR and SFR. Results: Median follow-up after NSM was 87 (3–397) months. There was only one case of total nipple necrosis among all 1071 patients. There were 96 patients (9.0%) with local recurrence, including 44 (4.0%) with NAR and 52 (4.8%) with SFR. NAR was seen in 1 (3.1%), 14 (3.4%), 17 (5.1%), 5 (3.4%), 7 (5.0%) and 0 patients with stage 0, 1, 2A, 2B, 3 and 4 cancer, respectively. SFR was seen in 0, 15 (3.6%), 8 (2.7%), 7 (4.8%), 22 (15.6%) and 0 patients with stage 0, 1, 2A, 2B, 3 and 4 cancer, respectively. Median disease-free interval of NAR and SFR was 3.4 (0.96–22.3) and 2.5 (0.21–21.2) years, respectively. Twenty-three (53%), 12 (27.9%) and 6 (14%) patients had NAR at more than 3, 5 and 10 years after NSM, respectively. Twenty (38%), 13 (25%) and 6 (11.5%) patients had SFR at more than 3, 5 and 10 years after NSM, respectively. Therefore, late NAR and SFR were observed. Patients with stage 1–3 cancer treated with NSM who had significantly more frequent NAR, were characterized by high nuclear grade and tubule-forming type cancer. Patients with significantly more frequent SFR were characterized by stage 3 cancer, positive lymph node metastasis and age ≤40 years. Patients with early stage breast cancer treated with NSM with significantly more frequent NAR had negative estrogen receptor expression, positive HER2 expression and shorter tumor–nipple–areola distance (≤2 cm). Overall survival was significantly better in patients with NAR (97% at 5 years and 80% at 10 years) than SFR (71% at 5 years and 50% at 10 years). Regarding SFR, overall survival was significantly worse for multiple (≥2) and diffuse (clinical inflammatory syndrome) recurrence than for single-nodule recurrence. There was no significant difference in prognosis between NAR and single-nodule SFR. Conclusions: Our data showed that clinicopathological features and prognosis differed between patients with NAR and SFR. There was no significant difference in prognosis between NAR and single-nodule SFR. Late NAR and SFR were seen, and careful long-term follow-up observation is necessary after NSM. Citation Format: Sakurai T, Suzuma T, Yoshimura G, Sasaki E, Umemura T, Sakurai T. Clinicopathological features and prognosis of nipple–areola and skin flap recurrence after nipple-sparing mastectomy for breast cancer over 20 years [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-14-08.

Introduction: Achievement of a good cosmetic outcome is one of the most important goals of surgical treatment of breast cancer. However, most patients must undergo a mastectomy if the outcome of breast-conserving surgery is discordant. All potential techniques that maintain oncological safety should be considered to maximize the cosmetic outcome for patients who require a mastectomy. We began performing nipple-sparing mastectomy (NSM) in 1978. Recent reports have suggested that NSM is oncologically as safe as mastectomy and affords a better cosmetic outcome. Conversely, the surgical complications and recurrence associated with NSM remain controversial. Objective: In the present study, we review the safety of the NSM surgical technique, discuss nipple–areola recurrence and skin flap recurrence after NSM, and compare recurrence and prognosis between NSM and mastectomy based on our long-term follow-up data. Patients and Methods: We retrospectively analyzed 723 patients with early-stage breast cancer who underwent NSM from 1985 to 2007. The patients' median age, tumor size, and tumor–areola distance were 50 y, 2.1 cm, and 1.5 cm, respectively. We used a thick skin flap method to avoid surgical complications including nipple and skin flap necrosis. We analyzed nipple–areola recurrence and skin flap recurrence after NSM. We also analyzed 100 patients who underwent mastectomy for early-stage breast cancer during the same period as those who underwent NSM. We compared the local recurrence rate (LRR), disease-free survival (DFS) rate, and overall survival (OS) rate among all 723 patients who underwent NSM and 100 patients who underwent mastectomy. No patients in either group received radiotherapy. Results: Among all patients who underwent NSM, stage 0, 1, 2A, and 2B disease was present in 21, 320, 253, and 129 patients, respectively. Notably, no nipple necrosis occurred during the average 114-month follow-up period. Local recurrence developed in 49 patients (6.7%), including recurrence at the nipple–areola complex in 24 (3.3%) and recurrence at the skin flap in 25 (3.4%). The average disease-free interval in patients with nipple–areola recurrence was 50 months, and that in patients with skin flap recurrence was 68 months. The clinical features of nipple–areola recurrence were a low rate of ER positivity (27%), high rate of Her2/neu positivity (60%), Paget type recurrence rate of 52%, and small tumor–areola distance (0.5 cm). The clinical features of skin flap recurrence were a relatively high rate of ER positivity (55%), solitary type recurrence rate of 88%, and diffuse type recurrence rate of 12%. The prognosis of diffuse type skin flap recurrence was significantly worse than that of solitary type recurrence (p = 0.01). There were no significant differences between the NSM and mastectomy groups in the LLR (6.7% vs. 4.0%, respectively), 10-y DFS rate (88% vs. 90%, respectively), or 10-y OS rate (92% vs. 91%, respectively). Conclusion: Our long-term follow-up data show that NSM should be considered as an alternative option for mastectomy when the outcome of breast-conserving surgery is discordant in patients with early-stage breast cancer. Citation Format: Sakurai T, Suzuma T, Yoshimura G, Jinta E, Umemura T, Sakurai T. Long-term follow-up of nipple-sparing mastectomy for early-stage breast cancer without radiotherapy: A single-center study at a Japanese institution. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-12-09.

Introduction: Cosmetic outcome is one of the most important goals of surgical treatment for breast cancer. Therefore, to maximize the cosmetic outcome for patients who require a mastectomy, the actions that can be taken from an oncologically safe perspective must be considered. Recent reports have suggested that nipple-sparing mastectomy (NSM) is oncologically as safe as a standard mastectomy and provides a better cosmetic outcome. However, little is known about the outcome of NSM for patients with multifocal breast cancer. Aim: To determine the oncological and technical outcomes of NSM for patients with multifocal breast cancer compared with NSM for patients with unifocal breast cancer using retrospective long-term follow-up data. Patients and Methods: We retrospectively analyzed 799 patients with primary breast cancer who underwent NSM, including 45 patients with multifocal breast cancer and 754 patients with unifocal breast cancer. The indications for NSM in this study were defined as any stage, any tumor size and any tumor–areola distance. Briefly, NSM was performed when no involvement of the nipple areola complex was revealed by radiographic and clinical examinations. Our surgical notes for NSM comprised a thick skin flap method for conserving the breast volume using subcutaneous fat and avoiding surgical complications including nipple necrosis. No patients received radiotherapy. We compared the local recurrence rate (LRR), disease-free survival (DFS), breast cancer-specific survival (BCSS) and overall survival (OS) between the 45 multifocal breast cancer and 754 unifocal breast cancer cases. Results: The numbers of multifocal breast cancer cases in stages 0, 1, 2A, 2B, 3 and 4 were 1, 17, 12, 8, 7 and 0, respectively. The corresponding numbers of unifocal breast cancer cases were 18, 288, 223, 117, 102 and 6, respectively. The median follow-up periods of the multifocal and unifocal breast cancer cases were 108 and 98 months, respectively. No nipple necrosis was recorded in either group (0/45, 0/754). Regarding NSM for patients with multifocal breast cancer, there were 8 patients (17.7%) with local recurrence, including 4 (8.9%) at the nipple and 4 (8.9%) at the skin flap. In NSM for patients with unifocal breast cancer, there were 63 patients (8.3%) with local recurrence, including 26 (3.4%) at the nipple and 37 (4.9%) at the skin flap. There were significant differences between NSM for patients with multifocal and unifocal breast cancer in the LRR (17.7% vs. 8.3%, p = 0.03) and DFS (10 yr, 72.4% vs. 83.8%, p = 0.04), but no significant differences in the BCSS (10 yr, 83.6% vs. 90.9%, p = 0.18) and OS (10 yr, 83.6% vs. 89.5%, p = 0.32). Conclusions: The present results suggest that NSM for patients with multifocal breast cancer can be technically performed as safely as NSM for patients with unifocal breast cancer. Our long-term follow-up data show that survival after NSM for multifocal breast cancer is equal to that after NSM for unifocal breast cancer. However, careful local observation after NSM is required. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-18-08.

[Introduction] Mastectomy has been conducted in general for cases in which breast conservation is inapplicable. Since Nipple-sparing Mastectomy (NSM) conserves nipple-areola, it is not only more advantageous in an aspect that nipple-areola reconstruction isn't required in case of breast reconstruction compared with mastectomy but also significantly meaningful because the sensation of nipple-areola is preserved in about 70% cases by skin flap preparation based on thick flap method we have adopted. On the other hand, NSM is controversial relating to complication of surgery and recurrence as well. [Objective] We've made (1) review of safety in NSM surgical technique, (2) discussion over recurrence and prognosis comparing with those in mastectomy, and (3) consideration of performance in immediate reconstructions. [Result] (1) Of all cases of NSM, the number of cases in stage 0, 1, 2A, 2B, 3 and 4 was 21, 305, 239, 123, 112 and 6 respectively. During 104 months of follow-up period in average, total of seven complication cases (0.9%) were observed, including two flap necrosis cases and five postoperative bleeding cases, but no nipple necrosis case was recorded. Although nipple-areola recurrence rate (%) in stage 0, 1, 2A, 2B and 3A was 0, 2.9, 4.6, 2.4 and 5.3 respectively, prognosis of nipple-areola recurrence cases was good showing no difference between stages (OS: 60M; 93%, 100M; 84%). Skin flap recurrence rate (%) in stage 0, 1, 2A, 2B and 3 was 0, 3.2, 3.3, 4.0 and 14.2 respectively, and prognosis of skin flap recurrence cases was significantly worse in stage 2B and 3 compared with that in stage 1 and 2A (p < 0.001). (2) We analyzed local recurrence rate, recurrent free survival and overall survival between 806 of NSM cases and 200 of mastectomy cases which had been performed during the same period, and the result showed no significant difference in those rates between NSM and mastectomy cases. (3) Infectious complication was observed in one out of 18 immediate reconstruction cases using free dermal fat graft. Among 124 immediate reconstruction cases using implant, complications were observed in five postoperative bleeding. [Conclusion] NSM was excellent in cosmetic aspect showing equivalent results in local recurrence rate and prognosis compared with those in mastectomy cases. Besides, patient's satisfaction was also higher in those who had had NSM alone without reconstruction. Our long term follow-up data shows that NSM may be considered as an alternative option for mastectomy in cases in which breast-conserving surgery is inapplicable in breast cancer patients. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-15-03.

Bone pain caused by bone metastases is one of the most common complications in patients with breast cancer. However, the precise molecular mechanism of bone pain is unknown. We have shown that the acid released upon bone resorption by osteoclasts and the transient receptor potential vanilloid receptor (TRPV1), an acid-sensing receptor on the algetic nerves terminating at the bone, are involved in the mechanism underlying this bone pain. In this study, we investigated the relationships among TRPV1, bone-derived insulin-like growth factor-1 (IGF-1) which is released from bone due to increased bone resorption during the progression of bone metastases, and neuropeptide calcitonin gene-related peptide (CGRP) and examined whether cancer-induced bone pain can be decreased by the inhibition of IGF-1 and CGRP. To study this in vitro, we established organ cultures of mouse dorsal root ganglions (DRGs), which are the primary sensory neurons innervating bone. Culture supernatants harvested from the mouse neonatal calvariae, which had abundant growth factor in bone, showed elevated TRPV1 and CGRP mRNA expressions in mouse DRGs. These up-regulated mRNA expressions were inhibited by the administration of a TRPV1 inhibitor (I-RTX); AG1024, a specific inhibitor of IGF receptor tyrosine kinase; or zoledronate. Taken together, these results suggest that CGRP and bone-derived IGF-1 may play a role in the induction of bone pain. To approach the role of CGRP and bone-derived IGF-1 in vivo, we established a mouse model of cancer-induced bone pain by inoculating the 4T1 mouse breast cancer cells into the marrow cavity of tibiae. Tumor-inoculated tibiae showed significantly increased pain behaviors compared with the non-tumor-bearing tibiae, indicating 4T1 cells induced bone pain. RT-PCR showed elevated mRNA expression of TRPV1 and CGRP in the ipsi-lateral tumor-bearing DRGs. The administration of a CGRP inhibitor (CGRP 8-37) in a continuous manner using an ALZET osmotic pump implanted under the mouse skin; the intraperitoneal administration of AG1024; and the administration of alendronate significantly reduced pain behaviors in tumor-bearing tibiae. In addition, mRNA expression of CGRP was decreased by CGRP 8-37, and mRNA expression of TRVP1 and CGRP was also decreased by AG1024 in the ipsi-lateral DRGs. Neither of these drugs showed a direct effect on the growth of the tumor in this study. In conclusion, our results suggest that TRPV1, CGRP, and the bone-derived IGF-1 are strongly related and might play a role in breast cancer-induced bone pain. The inhibition of the CGRP and bone-derived IGF-1 could be a potential therapeutic strategy to reduce bone pain; although further investigations are required in this direction. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1110.

Abstract #22 Introduction: Cosmetic outcome is one of the most important aspects of surgical treatment of breast cancer. Therefore, to maximize the cosmetic outcome for patients who require a mastectomy, what can be done from an oncologically safe perspective must be considered. Recent reports have suggested that nipple-areola-sparing mastectomy (NSM) is oncologically as safe as a classical mastectomy (MT) and provides a better cosmetic outcome than MT. However, little is known about the long-term outcome of NSM. Aim: To determine the oncological and technical outcomes of NSM compared with MT using long term follow-up data. Patients and Methods: We retrospectively analyzed 788 patients, median age 51 years, with primary breast cancer who underwent NSM from 1985 to 2004. The indication of NSM in this study was defined as being for any stage, any tumor size and any tumor-areola distance. Briefly, NAC was preserved when palpation and the outlook of the nipple was normal. Median tumor size and tumor-areola distance were 2.5cm (0-10.0) and 1.8cm (0-9.0), respectively. Our surgical notes for NSM were; (1) a thin flap (approximately 5 mm thick subcutaneous adipose tissue) was placed close to the tumor, and a thick flap (more than 1cm thick subcutaneous adipose tissue) was created more than 2cm away from the tumor to conserve breast volume using subcutaneous fat, and (2) tissue under the NAC was left at 5 mm in thickness, but the major ducts were removed from within its lumen. Eighty-one patients (10%) underwent immediate breast reconstruction (IBR) using implants. We also analyzed 144 patients with breast cancer who underwent MT in the same period as those who underwent NSM. No patient received radiotherapy. We compared the local recurrence rate (LRR), disease-free survival (DFS) and overall survival (OS) between 788 NSM and 144 MT cases. Results: Median follow-up of NSM and MT was 92 (10-252) and 87 (0-231) months, respectively. To our surprise, no complications of NSM including nipple and areola necrosis were recorded (0/788). For NSM, there were 70 patients (8.9%) with local recurrence, including 23 (2.9%) at the nipple, 4 (0.5%) at the areola, 4 (0.5%) at both nipple and areola, and 39 at the skin flap (4.9%). This suggested that the rate of NAC relapse was quite low. There were no significant differences in LLR between NSM and MT, (10y, 8.9% vs. 7.6%, p=0.62), DFS (10y, 83% vs. 83%, p=0.34) and OS (10y, 88% vs. 86%, p=0.34), respectively. Cosmetic outcome of NSM was better than that of MT in the majority of patients. Conclusion: These results suggested that NSM provides a good cosmetic outcome and is as safe oncologically as MT. Our long term follow-up data shows that NSM is a possible alternative to mastectomy. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 22.