Kazutaka Narui

Observational study of blue dye-assisted four-node sampling for axillary staging in early breast cancer

BACKGROUND The use of radioisotopes (RIs) is regulated and not all institutions have nuclear medicine facilities for sentinel node biopsy (SNB). We previously reported blue dye-assisted four-node axillary sampling (4NAS/dye) to be a suitable method for detecting sentinel nodes (SNs) without RIs. Here, we present an interim report on an observational study of this technique. METHODS From May 2003 to June 2008, 234 early breast cancer patients underwent SNB with 4NAS/dye. Lymphatic mapping was performed by injection of patent blue, and axillary sampling was performed until 4 SNs were detected. Patients with metastatic SNs underwent axillary lymph node dissection (ALND) at levels I and II, while SN-negative patients did not undergo further axillary procedures. RESULTS The SN identification rate was 99%. In total, 44 patients were diagnosed with metastatic disease by using the 4NAS/dye technique and underwent ALND; the remaining 189 patients did not undergo ALND (the SNB group). After a median follow-up period of 54 months, only 1 patient (0.5%) in the SNB group developed axillary recurrence. For the 4NAS/dye procedure, blue SNs were harvested in 220 patients (94%) and only unstained SNs were harvested in 13 patients (6%). Among the 44 patients with SN metastases, foci were found in blue SNs in 37 patients (84%), while they were found in only unstained SNs in 7 patients (16%). CONCLUSIONS SNB with 4NAS/dye is a safe and reliable technique for treatment of early breast cancer patients. This technique may be particularly useful for surgeons who do not have access to radioisotope facilities.

Donor site selection and clinical outcomes of nipple-areola skin-sparing mastectomy with immediate autologous free flap reconstruction: A single-institution experience.

BACKGROUND The objective of this study was to examine the clinical outcomes of immediate breast reconstruction using perforator flaps from different donor sites, and to characterize the trends among these flaps. METHODS We retrospectively reviewed 136 consecutive patients who underwent immediate breast reconstruction using free flaps after skin-sparing mastectomy (SSM) or nipple-sparing mastectomy (NSM). The whole breast was pathologically analyzed in 5-mm sections. Breast reconstruction was performed using the deep inferior epigastric perforator (DIEP) flap, gluteal artery perforator (GAP) flap, and posterior medial thigh perforator (PMTP) flap. Patient characteristics were compared among donor sites. RESULTS NSM was converted to SSM because of intraoperative subareolar tumor positivity in 7 of 107 patients. Eleven patients had positive margins in permanent sections. All but one patient had a positive horizontal margin in the peripheral direction. The 5-year recurrence-free survival rate was 91.9%. The locoregional recurrence rate was 5.1% with a mean follow-up observation period of 75 months. DEIP, GAP, and PMTP flaps were used in 64 (47.1%), 38 (27.9%), and 34 (25.0%) patients, retrospectively. DIEP flaps were used in older patients and those with a higher body mass index. GAP flaps were used in younger patients. DIEP and GAP flaps were used for larger breasts, and PMTP flaps for smaller breasts. CONCLUSION NSM or SSM with immediate perforator flap breast reconstruction is an oncologically acceptable surgical option. We believe that age, desire to have children, body mass index, and excised breast volume are valuable factors for selecting the optimal donor site.

Evaluation of the Response to Breast Cancer Neoadjuvant Chemotherapy Using 18F-FDG Positron Emission Mammography Compared With Whole-Body 18F-FDG PET: A Prospective Observational Study.

Purpose The aim of this study was to assess therapeutic response to breast cancer neoadjuvant chemotherapy (NAC) by 18F-FDG positron emission mammography (PEM) compared with that to whole-body 18F-FDG PET (WBPET). Methods Twenty patients underwent WBPET and PEM 3 times: the first time was before NAC, the second time was after 2 courses of NAC, and the third time was after all courses of NAC. A pathological complete response (pCR) was defined as no evidence of residual invasive cancer with or without ductal carcinoma in situ. The relationships between each modality’s SUVmax and pathological response were evaluated. Results Nine patients achieved a pCR, whereas the other 11 patients had a non-pCR. The SUVmax of WBPET after 2 courses of NAC was significantly lower in the pCR group than in the non-pCR group (1.4 ± 0.4 vs 2.7 ± 2.1, P = 0.0334). There were no significant differences in the SUVmax of PEM (ie, PEM uptake value [PUV]) between the groups. The SUVmax of WBPET (area under the ROC curve [AUC] = 0.761) was superior to the PUVmax (AUC, 0.648) for predicting non-pCR at the interim time point. After all courses of chemotherapy, there were no significant differences between the groups in the SUVmax of WBPET; however, PUVmax was significantly lower in the pCR group than in the non-pCR group (1.0 ± 0.2 vs 2.5 ± 2.7, P = 0.0351). After NAC, the PUVmax (AUC, 0.796) was superior to the SUVmax of WBPET (AUC, 0.671). Conclusions There proved to be no apparent superiority of PEM in predicting pCR at the interim time point. Positron emission mammography had greater diagnostic capability for detecting residual cancer after all courses of NAC.

Objection to postoperative radiation therapy in breast cancer with one to three lymph nodes involvements

My arguments regarding postmastectomy radiotherapy (PMRT) for this case are based on the following 4 reasons: (1) high rate of local recurrence in the no PMRT group in the Early Breast Cancer Trialists’ Collaborative Group meta-analysis on which the present guideline is based, (2) stage migration by sentinel node biopsy, (3) possible adverse events of radiotherapy, and (4) problems on extrapolation of data from western countries.

Acquired resistance to everolimus in aromatase inhibitor-resistant breast cancer

We previously reported the establishment of several types of long-term estrogen-depleted-resistant (EDR) cell lines from MCF-7 breast cancer cells. Type 1 EDR cells exhibited the best-studied mechanism of aromatase inhibitor (AI) resistance, in which estrogen receptor (ER) expression remained positive and PI3K signaling was upregulated. Type 2 EDR cells showed reduced ER activity and upregulated JNK-related signaling. The mTOR inhibitor everolimus reduced growth in cells similar to Type 1 EDR cells. The present study generated everolimus-resistant (EvR) cells from Types 1 and 2 EDR cells following long-term exposure to everolimus in vitro. These EvR cells modeled resistance to AI and everolimus combination therapies following first-line AI treatment failure. In Type 1 EvR cells, everolimus resistance was dependent on MAPK signaling; single agents were not effective, but hormonal therapy combined with a kinase inhibitor effectively reduced cell growth. In Type 2 EvR cells, ER expression remained negative and a JNK inhibitor was ineffective, but a Src inhibitor reduced cell growth. The mechanism of acquired everolimus resistance appears to vary depending on the mechanism of AI resistance. Strategies targeting resistant tumors should be tailored based on the resistance mechanisms, as these mechanisms impact therapeutic efficacy.

Placebo-Controlled, Double-Blinded Phase III Study Comparing Dexamethasone on Day 1 With Dexamethasone on Days 1 to 3 With Combined Neurokinin-1 Receptor Antagonist and Palonosetron in High-Emetogenic Chemotherapy

Purpose We evaluated the noninferiority of dexamethasone (DEX) on day 1, with sparing on days 2 and 3, combined with neurokinin-1 receptor antagonist (NK1-RA) and palonosetron (Palo) compared with the 3-day use of DEX in highly-emetogenic chemotherapy (HEC). Patients and Methods Patients who were scheduled to receive HEC (cisplatin ≥ 50 mg/m2 or anthracycline plus cyclophosphamide) were randomly assigned to receive either DEX on days 1 to 3 (Arm D3) or DEX on day 1 and placebo on days 2 and 3 (Arm D1) combined with NK1-RA and Palo. The primary end point was complete response (CR), defined as no emesis and no rescue medications during the overall (0 to 120 h) phase. The noninferiority margin was set at -15.0% (Arm D1 - Arm D3). Results A total of 396 patients-196 and 200 patients in Arms D3 and D1, respectively-were evaluated. CR rates during the overall period were 46.9% for Arm D3 and 44.0% for Arm D1 (95% CI, -12.6% to 6.8%; P = .007). CR rates during the acute (0 to 24 h) phase were 63.3% and 64.5% for Arms D3 and D1, respectively (95% CI, -8.1% to 10.6%; P < .001), and they were 56.6% and 51.5%, respectively, during the delayed (24 to 120 h) phase (95% CI, -14.8% to 4.6%; P = .023). Hot flushes and tremors were observed more frequently as DEX-related adverse events on days 4 and 5 in Arm D3, whereas anorexia, depression, and fatigue were observed more frequently on days 2 and 3 in Arm D1. As an indication of quality of life, global health status was similar in both arms. Conclusion Antiemetic DEX administration on days 2 and 3 can be spared when combined with NK1-RA and Palo in HEC.

Bilateral breast reconstruction and pectus excavatum correction: a case and review of the literature

Pectus excavatum is a chest wall malformation characterized by anterior chest wall depression. It is often associated with hypoplastic breasts, sternal rotation, and consequent breast asymmetry. We present here the case of a 52-year-old female with pectus excavatum, a bilateral nipple-sparing mastectomy for breast cancer, and immediate autologous breast reconstruction using bilateral deep inferior epigastric perforator flaps. To correct reconstructed breast deformities and pectus excavatum depression and to enhance breast volume to treat hypoplastic breasts, three sessions of Brava-assisted fat grafting were performed. These postoperative courses were uneventful and without any complications. The patient was satisfied with the final esthetic results. There are only two case reports to perform bilateral breast reconstruction and surgical correction of pectus excavatum, which were used with both pedicle musculocutaneous flap and breast implant, with or without a sternal implant. In this study, we discuss indications and surgical options for bilateral breast reconstruction, pectus excavatum, and breast augmentation.Level of Evidence: Level V, therapeutic study.

Salvage mastectomy for local recurrence and second ipsilateral autologous breast reconstruction using a perforator flap from a different donor site

Abstract Only one case of second ipsilateral autologous reconstruction for the same breast that had previously undergone reconstruction has been reported. Here we present a patient who underwent breast reconstruction twice using free flap from different donor sites, using a buttock after a local recurrence following the previous reconstruction with a lower abdomen.

Abstract 1767: Analysis of biomarkers and anthracycline benefit for hormone receptor-negative breast cancer: results from a randomized phase 2 neoadjuvant study (KBOG 1101 Study)

AIM: We compared 6 cycles of docetaxel and cyclophosphamide (TC6) with 3 cycles of 5-fluorouracil and epirubicin and cyclophosphamide followed by 3 cycles of docetaxel (FEC-D) as neoadjuvant chemotherapy for patients with hormone receptor (HR)-negative breast cancer (BC) to identify biomarkers requiring anthracycline treatment. Methods: In total, 103 patients with operable HR-negative BC were administered TC6 or FEC-D. Triple-negative BC was subdivided by CK5/6 and EGFR into basal- and non-basal BCs. The primary endpoint was pathological complete response (pCR). Secondary endpoints were safety, breast-conserving surgery ratio, disease-free survival, overall survival, and predictive factors (Ki-67, P-53, ALDH1 and TOP2A by IHC and TOP2A by FISH) for each regimen. Results: Of the 103 patients, 97 completed the study. Overall pCR was higher for patients treated with FEC-D (36%) than for those treated with TC6 (25.5%) (P=0.265). FEC-D was significantly superior to TC6 in basal BC (42.9% vs 13.6%; P=0.033), while no differences in HER2 and non-basal BCs. Aldehyde dehydrogenase 1 (ALDH1) positivity was inversely associated with pCR for both regimens, significantly for FEC-D (FEC-D: p=0.047, TC6: p=0.085). Patients who achieved pCR tended to have longer DFS (P = 0.287) and OS (P = 0.069). Patients with basal and non-basal BC treated with FEC-D had significantly better DFS (P = 0.016) and OS (P = 0.034) than those with TC6. Conclusion: We found TC6 was less effective than FEC-D for HR-negative BC because it was not sufficient to treat basal-BC. This suggests that DNA damaging agents like anthracyclines are required for treating basal-BC. Additionally, ALDH1 could be a marker for resistance to conventional chemotherapy. Citation Format: Takashi Ishikawa, Kazutaka Narui, Mari S. Oba, Akimitsu Yamada, Kumiko Kida, Mikiko Tanabe, Yasushi Ichikawa. Analysis of biomarkers and anthracycline benefit for hormone receptor-negative breast cancer: results from a randomized phase 2 neoadjuvant study (KBOG 1101 Study) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1767. doi:10.1158/1538-7445.AM2017-1767

Abstract P2-06-16: The impact of ALDH1 on chemo-resistance and prognosis according to intrinsic subtype in breast cancers

[Background]Aldehyde dehydrogenase 1 (ALDH1) has been identified as a breast cancer stem cell marker. The clinical significance of ALDH1 as a chemo-resistant and prognostic indicator has been reported recently. However, the analysis according to each intrinsic subtype was not reported. [Aims] To investigate the impact of ALDH1 on chemo-resistance and prognosis according to intrinsic subtypes in invasive breast cancers. [Methods] 1) Patients and tumor specimens; A total of 653 primary breast cancer patients were enrolled in this study from 2004 to 2013 at the Yokohama City University Medical Center in Japan. We performed immunohistochemical analyses using paraffin-embedded core needle biopsy sections prior to the treatment. 2) Correlation of ALDH1 with clinicopathological factors; Analyses were performed to investigate association of ALDH1 expression with other biomarkers and clinicopathological factors in breast cancers. Age, histologic type, tumor size, nodal status, ER/PgR/HER2 status, nuclear grade, Ki67, Topo2, p53, CK5/6 and EGFR were observed. 3) Neoadjuvant patient cohort study 234 breast cancer patients receiving neoadjuvant chemotherapy were enrolled. The correlation between ALDH1 and pathological complete response (pCR) rate was investigated in each intrinsic subtype. 4) Prognostic cohort study We performed a Cox analysis of disease free survival and overall survival of all 653 cases according to each subtype, taking account of clinicopathological factors. [Results] ALDH1 expression in tumor cells was seen in 139 of 653 cases (21.3%). The ALDH1 expression correlated significantly with tumor size, clinical node metastasis, clinical staging, nuclear grade and HER2 status positively, ER and PgR status negatively. ALDH1 expression was significantly seen in HER2-positive cancers and triple negative type. In neoadjuvant study, we analyzed 234 patients treated with neoadjuvant chemotherapy including 63 luminal type, 20 luminal-HER2 type, 45 HER2-enriched type and 106 triple negative type. The pCR rate was significantly lower in patients with ALDH1-positive cases (13.5%vs.30.3%,p=0.003). In multivariate analysis, ALDH1 and ER are correlated with pCR rate significantly. According to the intrinsic subtypes, the correlation between pCR and ALDH1 expression was extremely significant in triple negative type (p=0.003). In HER2 positive type, ALDH1 expression had tendency with low pCR, but with no significance. In luminal type, two patients achieved pCR and both had no ALDH1 expression. In prognostic analysis, patients with ALDH1 expression had significantly poor disease free survival (DFS; p [Conclusions] Breast cancers with ALDH1 expression posse biologically aggressive phenotypes that tend to have a poor prognosis. Chemoresistance was significantly seen in ALDH1-positive triple negative type, on the other hand, impact on prognosis was seen in luminal type more highly than triple negative type. Citation Format: Kumiko Kida, Takashi Ishikawa, Akimitsu Yamada, Kazutaka Narui, Sadataka Sugae, Mikiko Tanabe, Yasushi Ichikawa, Itaru Endo. The impact of ALDH1 on chemo-resistance and prognosis according to intrinsic subtype in breast cancers [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P2-06-16.