Yayoi Adachi

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.

RASEF expression correlates with hormone receptor status in breast cancer

Breast cancer (BC) is the most frequently diagnosed malignant tumor in women worldwide, and the development of new molecules associated with BC is essential for the management of this disease. RAS and EF-hand domain-containing (RASEF) encodes the GTPase enzyme that belongs to the Rab family. Although the effects of this gene have been reported in several malignant tumor types, the role of RASEF in BC has not been completely elucidated. The aim of the present study was to investigate the importance of RASEF expression in BC. RASEF mRNA expression levels were evaluated in BC and non-cancerous mammary cell lines. The association between RASEF mRNA expression levels and clinicopathological factors in 167 patients with BC were then determined. Among the 13 examined BC cell lines, ER-negative/HER2-negative cell lines expressed lower RASEF mRNA levels, when compared with the other examined cell lines (P=0.014). Of the 167 patients examined, patients with negative hormone receptor status exhibited significantly lower RASEF mRNA expression levels (P<0.001). In addition low RASEF expression in BC tissues was associated with negative estrogen receptor status (P<0.001), negative progesterone receptor status (P<0.001), and triple-negative status (P<0.001). Additionally, although the differences were not statistically significant, patients with low RASEF expression levels exhibited poorer disease-free survival (P=0.123) and overall survival (P=0.086) than other patients. The results of the present study indicate that RASEF mRNA expression levels are associated with hormone receptor status in BC.

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.

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.

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.

Synchronous bilateral pheochromocytomas and paraganglioma with novel germline mutation in MAX: a case report

BackgroundRecent advance of genetic testing has contributed to the diagnosis of hereditary pheochromocytoma and paraganglioma (PPGL). The clinical characteristics of hereditary PPGL are varying among the types of mutational genes. It is still difficult to specify the pathognomonic symptoms in the case of rare genetic mutations. Here, we report the case of synchronous bilateral pheochromocytomas and paraganglioma with novel MYC associated factor X (MAX) gene mutation.Case presentationA 24-year-old female had hyperhidrosis and hypertension. Her urine test showed high normetanephrine and vanillylmandelic acid. Enhanced computed tomography revealed three enhanced masses in right adrenal gland, left adrenal gland, and left renal hilus. She was diagnosed with PPGL. Because 123I-metaiodobenzylguanidine scintigraphy indicated the accumulations in the left adrenal gland mass and the left renal hilus mass and not in the right adrenal gland mass, we performed laparoscopic left adrenalectomy and extirpation of the left renal hilus mass to preserve the right adrenocortical function. However, her symptoms recurred shortly after the operation presumably due to unveiling of the activity of the right pheochromocytoma. Following right adrenalectomy as the second operation, the catecholamine levels declined to normal range. Her genetic testing indicated the novel germline mutation in MAX gene (c.70_73 del AAAC/p.Lys24fs*40).ConclusionsMAX germline mutation is recently identified as a rare cause of hereditary PPGL. The deletion mutation in MAX gene in this patient has never reported before. In the case of bilateral pheochromocytomas, the surgical indication should be decided considering each patient’s genetic background. Due to the possibility for other types of malignant tumors, close follow-up is essential for MAX mutation carriers.

Expression of regulatory factor X1 can predict the prognosis of breast cancer

Breast cancer (BC) is the most common malignancy among women. Identifying novel biomarkers to predict prognosis accurately is important in managing this disease. The regulatory factor X1 (RFX1) gene is a member of the regulatory factor X gene family. Its protein reportedly downregulates the proto-oncogene c-myc, but its role in BC has been unclear. In this study, expression and methylation status of RFX1 were determined in BC cell lines. We then evaluated RFX1 mRNA expression levels with regard to clinicopathological factors including postoperative prognosis in 167 patients with BC. Expression of RFX1 was heterogeneous among cell lines, and we found no DNA methylation at the RFX1 promoter region. Patients were categorized into groups with high or low RFX1 expression, based on ratio of RFX1 mRNA expression in BC and adjacent non-cancerous tissues. The high RFX1 group was significantly associated with low T factor (P=0.028), earlier disease stage (P=0.015), positive expression of estrogen receptor (P=0.005) and progesterone receptor (P=0.011), negative expression of human epidermal growth factor receptor 2 (P=0.001). The high RFX1 group experienced more favorable disease-free survival (P=0.007) and overall survival (P=0.013). In multivariate analysis, RFX1 expression was an independent prognostic factor for disease-free survival. Our findings indicate that RFX1 may serve as a prognostic marker for BC.

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.

Abstract P2-01-18: Preoperative axillary imaging with ultrasonography: Among the breast cancer patients with lymph node metastases, can we identify the patients who may omit axillary dissection?

(Introduction) ACOSOG Z11 and EORTC AMAROS showing little benefit to axillary dissection(ALND) for early stage breast cancers with limited nodal disease have led us to questioning the value of preoperative axillary imaging. It may not result in a benefit to the patients to perform ALND by diagnosing a few or small axillary lymph node(ALN) metastases preoperatively. (Aim) A purpose of this study is to determining the association between diagnostic method and metastatic number of ALN metastases, and to find the patients who can omit ALND safely even if with ALN metastases. (Methods)A database of consecutive primary breast cancer patients who underwent comlete ALND at our institution in 2008-2011 was analyzed. After we excluded patients treated with neoadjuvant systemic therapy, a total of 390 patients were included. By diagnostic methods of ALN metastases, we classified them in four groups as follows. Group A (n=41) : suspicious ALNs on axillary ultrasound(AUS) and ultrasound-guided fine needle aspiration cytology (FNAC) positive, Group B (n=47) : only one abnormal ALN on AUS +/- FNAC, Group C(n=53) : multiple abnormanl ALNs +/- FNAC, Group D (n=249) : negative ALNs on AUS but SLNB positive . (Results) The median number (range) of ALN metastases were 3(1-22) in GropuA, 2(0-12) in Group B, 7(1-37) in Group C, 1(1-17) in Group D. There were significant differences in number of metastases between Group A/B/C and Group D (p=.02, p=.01, p=.002). Paitents with 3 or less positive ALNs were 24.5% (13/53) in Group C, whereas 61.0% (25/41) in Group A and 68.1% (32/47) in Group B (p=.04, p=.02). We next evaluated the influence of patient- and tumour-related variables on the number of positive ALNs in Group A/B. Factors such as age, tumour size ( 20mm), ER status(positive vs negative), HER2 status (positive vs negative), nuclear grade (1/2 vs 3), menstruation status (pre vs post menopausal) were examined. However there were no significant differences in all factors between the patients with 4 or more ALN metastases and patients with 3 or less ALN metastases. As a result of multivariable analysis, relative risk (95%CI, p-value) of age was 0.92 (0.546-1.347, 0.84), tumour size : 0.82 (0.511-1.418, 0.76), ER status : 1.06 (0.873-1.821, 0.76), HER2 status : 1.17 (0.853-2.390, 0.28), nuclear grade : 0.43 (0.420-1.22, 0.34), menstruation status : 0.85 (0.538-1.693, 0.89). (Conclusion) In our contemporary series, patients diagnosed as ALN metastases preoperatively have significantly more involved nodes compared to SLNB positive patients regardless of the diagnostic method, suggesting that such patients should proceed to ALND. Preoperative axillary imaging are useful to identify node-positive breast cancer patients requiring ALND . Citation Format: Naoto Kondo, Takashi Fujita, Masataka Sawaki, Masaya Hattori, Akiyo Yoshimura, Mari Ichikawa, Junko Ishiguro, Yayoi Adachi, Haruru Kotani, Tomoka Hisada, Hiroji Iwata. Preoperative axillary imaging with ultrasonography: Among the breast cancer patients with lymph node metastases, can we identify the patients who may omit axillary dissection? [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 P2-01-18.

Abstract P5-14-02: Postmastectomy radiation improves loco-regional control for patients with advanced breast cancer treated with neoadjuvant chemotherapy

Purpose The value of postmastectomy radiation (PMRT) with adjuvant chemotherapy has been established, but the role of PMRT after neoadjuvant chemotherapy remains unclear. The aim of this study was to evaluate the efficacy of radiation in patients treated with neoadjuvant chemotherapy and mastectomy, and to determine which subsets of patients benefit from PMRT. Patients and Methods From 2003 to 2008, 94 patients were treated with neoadjuvant chemotherapy and mastectomy. The median number of lymph nodes removed was 20. 90 patients received anthracycline-based (anthracycline alone: 5, anthracycline followed by taxane: 85) chemotherapy and 4 patients received taxane alone. 82.6 percent (19/23) of the patients with HER2 positive cancer received trastuzumab and 91.3 percent (63/69) of the patients with hormone receptor positive cancer received hormone therapy. In this study, pathological complete response (pCR) was defined as absence of invasive tumor in the breast. We compared the outcomes of 55 patients who received radiation (PMRT group) from 39 patinets who did not receive radiation (non-PMRT group). The 5 years rate of loco-regional recurrence (LRR) was calculated according to the Kaplan-Meier method, and comparisons between the two groups were made using the log-rank test. Results Median follow-up time was 61.8 months. The breast pCR rate was 17.0% (16/94). 14 patients developed LRR as first events (local: 8, regional: 4, local and regional: 2). There were no differences between the two groups with respect to age, use of trastzumab, use of hormone therapy, pathological tumor size, number of dissected axillary nodes, percentage of hormone receptor positive tumors, or HER2 positive tumors. The 5-years rate of LRR for the PMRT group and the non-PMRT group were 12.8% and 27.0% respectively. (p = 0.144) In the patients with positive lymph nodes after neoadjuvant chemotherapy, the PMRT group had significantly lower LRR risk than the non-PMRT group (5-yaers rate: 11.9% vs 37.5%, p = 0.039). But in the patients with negative lymph node, there were no significant difference between the PMRT group and the non-PMRT group. For hormone receptor positive and HER2 negative subtype, a significantly improved LRR risk found after PMRT (5-yaers rate: 5.9% vs 26.1%, p = 0.048). No significant difference in HER2 positive subtype and triple negative subtype were observed between two groups. In the patients who did not achieve breast pCR, the PMRT group had significantly lower LRR risk than the non-PMRT group (5-yaers rate: 9.0% vs 30.6%, p = 0.037). The 5-years rate of lymphedema was no significant difference between the two groups (p = 0.787). Conclusion After neoadjuvant chemotherapy and mastectomy, PMRT was found to benefit local control for the patients with positive lymph nodes, the patients with hormone receptor positive and HER2 negative cancer, and the patients who did not achieve breast pCR. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-14-02.