Masaya Hattori

Phase I and pharmacokinetic study of trastuzumab emtansine in Japanese patients with HER2-positive metastatic breast cancer

OBJECTIVE Trastuzumab emtansine (T-DM1), an antibody-drug conjugate composed of the cytotoxic agent DM1 conjugated to trastuzumab via a stable thioether linker, has shown clinical activity in human epidermal growth factor receptor 2-positive metastatic breast cancer patients. This study evaluated the maximum tolerated dose, toxicity and pharmacokinetics of trastuzumab emtansine in Japanese breast cancer patients. METHODS Inoperable advanced or recurrent human epidermal growth factor receptor 2-positive breast cancer patients were administered trastuzumab emtansine intravenously at a dose of 1.8, 2.4 or 3.6 mg/kg every 3 weeks. The maximum tolerated dose was estimated using the continual reassessment method. RESULTS This study enrolled 10 patients who were administered trastuzumab emtansine for a median of seven cycles. The dose-limiting toxicity was Grade 3 elevation of aspartate aminotransferase/alanine aminotransferase at the 2.4 mg/kg dose level. The maximum tolerated dose was estimated to be 3.6 mg/kg because at the point when dose-limiting toxicity was evaluable in 10 patients, the probability of dose-limiting toxicity estimated using the continual reassessment method was closest to 25% at a dose of 3.6 mg/kg and this was unchanged by the results for patients enrolled after that. The most frequent adverse events were nausea, arthralgia, fever, fatigue and decreased appetite. Adverse events were generally tolerable. The maximum concentration and area under the concentration-time curve increased linearly with the dose. CONCLUSIONS Trastuzumab emtansine up to 3.6 mg/kg was well tolerated by Japanese breast cancer patients. Although thrombocytopenia and hepatotoxicity tended to be more severe than was seen in Western patients in previous trastuzumab emtansine trials, those adverse events recovered without special supportive treatment.

Impact of intrinsic subtype on predicting axillary lymph node metastasis in breast cancer

Axillary lymph node (LN) metastasis is one of the most important prognostic factors for the survival of breast cancer. The correlation between LN metastasis and the tumor (T) category has previously been investigated in certain case series. At present, the initial treatment approach is to define the intrinsic subtype, as it is significant in determining medical treatments, as well as being a prognostic factor. However, the intrinsic subtype is not known to predict the frequency of LN metastasis. The aim of the present study was to evaluate the frequency of LN metastasis with regard to tumor size according to the intrinsic subtype. In total, 654 patients with primary breast cancer were evaluated who underwent surgical resection between 2010 and 2011 at the Aichi Cancer Center Hospital (Nagoya, Aichi). The clinical and pathological data were analyzed for patients who underwent an axillary LN dissection or a sentinel LN biopsy for primary breast cancer. The intrinsic subtype of the primary tumors was classified using immunohistochemical staining of thin, paraffin-embedded sections. In total, 157 (24.0%) of the 654 patients exhibited LN metastasis, and according to the primary tumor category, a larger tumor size was found to correlate with a higher proportion of LN positivity, as well as with the luminal A subtypes (n=364). In luminal B subtypes (n=110), T1a (n=2), T1b (n=12), T1c (n=55), T2 (n=34), and T3 (n=2) exhibited 50, 8.3, 38.2, 55.9 and 50% LN positivity, respectively. In luminal-human epidermal growth factor receptor 2 (HER2) subtypes (n=46), T1c (n=17), T2 (n=10), and T3 (n=1) exhibited 40.1, 60 and 100% LN positivity, respectively. In HER2 subtypes (n=53), T1a (n=6), T1b (n=4), T1c (n=15), and T2 (n=10) exhibited 16.7, 25, 46.7 and 60% LN positivity, respectively. In triple-negative subtypes (n=81), T1b (n=15), T1c (n=29), T2 (n=20), and T3 (n=2) exhibited 26.7, 24.1, 50 and 50% LN positivity, respectively. In conclusion, the intrinsic subtype is significant in predicting the frequency of LN metastasis with regard to tumor size.

Reoperative sentinel lymph node biopsy for ipsilateral breast tumor recurrence after previous axillary lymph node dissection: Report of a case

Sentinel lymph node biopsy has become a standard component of the evaluation of early-stage breast cancer, with a gradually increasing number of indications in this patient population. This report presents the case of a patient who underwent reoperative sentinel lymph node biopsy as part of an evaluation of ipsilateral breast tumor recurrence; she had previously undergone axillary lymph node dissection. Preoperative lymphoscintigraphy showed aberrant lymphatic drainage, and all three sentinel lymph nodes were positive for cancer. Although the optimal management of regional lymph nodes in patients with ipsilateral breast tumor recurrence who have already undergone axillary lymph node dissection has not been established, reoperative sentinel lymph node biopsy in this setting may therefore potentially enable the identification of subclinical, aberrantly located nodal metastasis.

Occult breast cancer may originate from ectopic breast tissue present in axillary lymph nodes

PurposeOccult breast cancer (OBC) is classified as a carcinoma of unknown primary, and involves axillary lymphadenopathy and is histologically consistent with metastatic breast cancer. OBC has been conventionally considered as a metastatic lymph node lesion, the origin of which is an undetectable breast tumor. Therefore, OBC patients would usually have undergone axillary lymph node dissection, and mastectomy or whole breast radiotherapy (WBRT). However, majority of OBC reports have been based on cases that were diagnosed during a period when diagnostics was still relatively primitive, and when magnetic resonance imaging was not yet a standard preoperative assessment. Therefore, there have been many false negatives in the breast based on preoperative assessment.MethodsWe herein hypothesize that the origin of OBC is ectopic breast tissue present in axillary lymph nodes (ALNs). If our hypothesis is true, mastectomy and WBRT may be unnecessary for OBC patients.ResultsOur hypothesis is supported by several findings. First, advances in radiological imaging have suggested that a primary breast tumor is absent in OBC patients. Second, proliferative breast lesions arising from ectopic breast present in ALNs have been reported. Lastly, cellular subtypes in OBC based on immunohistochemistry are of various types including ordinary breast cancer and the prognosis is not worse than stage II breast cancer.ConclusionIt is important to distinguish between “primary” OBC in ALNs and “metastatic” OBC from micro-primary breast tumor. Further studies are required to determine if omission of mastectomy and WBRT is acceptable.

The investigation study using a questionnaire about the employment of Japanese breast cancer patients

Background Breast cancer is the most common cancer among women, and its survival rate has improved. As the number of cancer survivors increases, it is important to support their social comeback during and after treatment. Methods Questionnaires were distributed to breast cancer patients treated in Aichi Cancer Center Hospital between June and November 2014. Responders were categorized according to adjuvant therapy (Group A: none, Group B: endocrine therapy, Group C: chemotherapy), or if they had advanced or recurrent breast cancer (Group D). Results A total of 279 patients returned questionnaires (62, 79, 92 and 46 patients in Groups A, B, C and D, respectively). In adjuvant treatment groups, 43 patients (18.5%) quit their job during or after treatment. Most patients had quit their jobs at the time of diagnosis (7.5%), followed by those undergoing chemotherapy (5.6%) and those at the time of operation (4.9%). Quit rate from the workplace in which patients worked at the time of diagnosis was highest in Group C (30%), followed by Group B (20%) and Group A (13%). At the time of operation, 127 patients (57%) were absent from work. In Group D, 16 patients (35%) quit their job during treatment. Rates for patients currently working who had anxiety were 62, 30, 26 and 9% in Groups D, C, B and A, respectively. Conclusions In adjuvant treatment groups, in which quit rate was highest at the time of diagnosis, consultation about working is necessary immediately after diagnosis. Patients treated most heavily had higher quit rates and experienced more anxiety about working.

Factors associated with prolonged time to treatment failure with fulvestrant 500 mg in patients with post-menopausal estrogen receptor-positive advanced breast cancer: a sub-group analysis of the JBCRG-C06 Safari study

Abstract Objective: The JBCRG-C06 Safari study showed that earlier fulvestrant 500 mg (F500) use, a longer time from diagnosis to F500 use, and no prior palliative chemotherapy were associated with significantly longer time to treatment failure (TTF) among Japanese patients with estrogen receptor-positive (ER+) advanced breast cancer (ABC). The objective of this sub-group analysis was to further examine data from the Safari study, focusing on ER + and human epidermal growth factor receptor-negative (HER2−) cases. Methods: The Safari study (UMIN000015168) was a retrospective, multi-center cohort study, conducted in 1,072 patients in Japan taking F500 for ER + ABC. The sub-analysis included only patients administered F500 as second-line or later therapy (n = 960). Of these, 828 patients were HER2−. Results Multivariate analysis showed that advanced age (≥65 years; p = .035), longer time (≥3 years) from ABC diagnosis to F500 use (p < .001), no prior chemotherapy (p < .001), and F500 treatment line (p < .001) were correlated with prolonged TTF (median = 5.39 months). Conclusions: In ER+/HER2− patients receiving F500 as a second-line or later therapy, treatment line, advanced age, no prior palliative chemotherapy use, and a longer period from ABC diagnosis to F500 use were associated with longer TTF.

Abstract P2-01-09: Circulating tumor cells (CTCs) in the venous drainage of the breast in patients with primary breast cancer

Background: CTCs are shed from tumors and circulate in the peripheral blood after passing through the drainage vein. Axillary lymph node dissection (ALND) provides access to the lateral thoracic vein which flows directly into the axillary vein. In this preliminary study, we evaluated the feasibility of detecting CTCs in the peripheral blood and in the lateral thoracic venous blood for breast cancer patients who underwent ALND. Methods: From June 2016 to March 2017, breast cancer patients who underwent ALND in our institute were eligible for this study. A peripheral blood sample,10ml, was drawn just before the surgery or one day before the surgery. A lateral thoracic venous blood sample was taken from the resected breast just after resection. A blood sample of 0.2ml or more was necessary for CTC isolation. The CTCs in the peripheral blood before surgery (periCTC) and in the blood from the lateral thoracic vein of the resected breast (ltvCTC) were quantitatively examined by using a size-selective CTC isolation platform. Results: A total of 21 patients with median age 51 years (37-75) were enrolled to the study. Of the 21 patients, 38% were premenopausal, 52% had neoadjuvant chemotherapy. Fifty-seven percent were ER and/or PgR positive, 24% were HER2 positive. Fifty-seven percent were stage II disease and 43% were stage III. In 3 patients, we couldn9t obtain sufficient blood samples from the lateral thoracic vein. Of the remaining 18 patients, we were able to obtain the median 0.5ml (0.2-2.0) blood samples from the lateral thoracic vein. CTCs were detected in peripheral blood in 15 patients (71%) and median periCTC count was 1 CTC/10ml (0-39). In lateral thoracic venous blood, CTCs were detected in all patients who had sufficient blood samples and the median ltv CTC count was 35.5 CTC/ml (2.5-370). In 5 of 6 patients whom CTCs in peripheral blood samples were not detected, CTCs could be detected in the blood samples from lateral thoracic vein. Conclusion: CTCs can be detected in the peripheral blood and in the blood from lateral thoracic vein in patients with localized breast cancer, and can be detected at a higher rate and at a higher concentration in the blood from lateral thoracic vein than in peripheral blood. Citation Format: Hattori M, Nakanishi H, Yoshimura A, Adachi Y, Iwase M, Gondo N, Kotani H, Sawaki M, Yatabe Y, Iwata H. Circulating tumor cells (CTCs) in the venous drainage of the breast in patients with primary breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-01-09.

Correction to: Phase I dose-finding study of eribulin and capecitabine for metastatic breast cancer: JBCRG-18 cape study

The article “Phase I dose-finding study of eribulin and capecitabine for metastatic breast cancer: JBCRG-18 cape study”, written by Masaya Hattori, Hiroshi Ishiguro, Norikazu Masuda, Akiyo Yoshimura, Shoichiro Ohtani, Hiroyuki Yasojima, Satoshi Morita, Shinji Ohno, and Hiroji Iwata, was originally published electronically on the publisher’s Internet portal (currently SpringerLink) on 31 August 2017 without open access. With the author(s)’ decision to opt for Open Choice the copyright of the article changed on [9 November 2017] to ©.

Comparison of sentinel lymph node biopsy between invasive lobular carcinoma and invasive ductal carcinoma

BackgroundRecent studies suggested that ALND (axillary lymph node dissection) can be avoided in breast cancer patients with limited SLN (sentinel lymph node) metastasis. However, these trials included only several invasive lobular carcinoma (ILC) cases, and the validity of omitting ALND for ILC remains controversial. Here, we examined whether omitting ALND is feasible in ILC treatment.MethodsA total of 3771 breast cancer patients underwent surgery for breast cancer at the Aichi Cancer Center Hospital between January 2006 and December 2015. We excluded patients with neoadjuvant therapy or without axillary management, and identified 184 ILC patients and 2402 invasive ductal carcinoma (IDC) patients. We compared SLN and non-SLN metastasis rates and the number of total ALN metastases between the ILC and IDC cohorts, and we examined the factors that influenced non-SLN metastasis in the SLN micrometastasis group.ResultsSLN biopsies were performed in 171 (93%) ILC and 2168 (90%) IDC cases, and 31 (18%) ILC and 457 (21%) IDC cases were SLN micrometastasis and macrometastasis (p = 0.36). Among SLN macrometastasis patients, 17 (68%) ILC cases and 163 (46%) IDC cases showed non-SLN metastasis (p = 0.03). The number of non-SLN metastases was greater in ILC cases compared with IDC cases. Multivariate analysis showed that ILC was the influential factor predicting non-SLN metastasis in patients with SLN macrometastasis.ConclusionILC cases had more non-SLN metastasis than IDC cases among SLN-positive cases, and ILC was an important factor for the prediction of non-SLN positivity in SLN macrometastasis cases. Omitting ALND for ILC with positive SLNs requires more consideration.

Abstract P6-01-04: Changes in Ki67 expression in breast cancer during the menstrual cycle and menopause

Background Previous studies have shown that the menstrual cycle phase can influence PgR status of breast cancer. But data on whether the menstrual cycle phase affects Ki67 expression is inconsistent. This study aims to compare the Ki67 expression on ultrasonography guided vacuum-assisted breast biopsy (US-guided VABB) with matched breast cancer surgical specimens. Materials and Methods In 120 breast cancer patients without neoadjuvant chemotherapy who underwent US-guided VABB and surgical resection from April 2008 and March 2012 at Aichi Cancer Center Hospital, we examined the concordance of Ki67 level between US-guided VABB and surgical specimen. All the US-guided VABB were performed using 11-gauge Mammotome. In this study, the Ki67 cut-off level for positivity was defined at 20%. Two phases of the menstrual cycle were pre-defined as indicated; phase 1 (low estrogen) days 27–35 or 1–6; phase 2 (high and intermediate estrogen) days 7–26 (Hayes BP, et al. Breast Cancer Res Treat 2013). We defined the three groups as follows: the non-matching menstrual phase group (different menstrual cycle phase at the time of biopsy and surgery: n=18), the matching menstrual phase group (same menstrual cycle phase at the time of biopsy and surgery: n=25), and the post-menstrual group (n=77). We evaluated the discordance of Ki67 expression between US-guided VABB and surgical specimens in the three groups. Results A differential expression of Ki67 was found in 13 patients and the concordance rate of Ki67 expression between US-guided VABB and surgical specimens was 89.2% with a Kappa statistic value of 0.78. (The concordance rate of ER, PgR, and HER2 status were 96.4%, 90.2%, and 97.0%, respectively.) There were no major differences in tumor and patient characteristics (age, pathological tumor size, and number of biopsy specimens) between the non-matching menstrual phase group and the matching menstrual phase group. The discordance rate of Ki67 expression for the non-matching menstrual phase group, the matching menstrual phase group, and the post-menstrual group were 22.2%, 4.0%, and 10.4%, respectively. In the patients with ER positive tumors, the discordance rate of Ki67 expression for the non-matching menstrual phase group, the matching menstrual phase group, and the post-menstrual group were 23.5%, 4.8%, and 10.9%, respectively. The discordance rate of Ki67 expression tended to be higher in the non-matching menstrual phase group than in the matching menstrual phase group. (p=0.11) Conclusions Though limited by the low number of patients, our study suggested that the menstrual cycle could affect Ki67 expression as patients with different menstrual cycle phase at the time of biopsy and surgery show discordant results. Prospective evaluation of Ki67 expression in premenopausal patients with ER positive tumor is needed. Citation Format: Takashi Fujita, Masataka Sawaki, Masaya Hattori, Naoto Kondo, Akiyo Yoshimura, Mari Ichikawa, Yayoi Adachi, Tomoka Hisada, Haruru Kotani, Junko Ishigro, Hiroji Iwata. Changes in Ki67 expression in breast cancer during the menstrual cycle and menopause [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 P6-01-04.