Tomoyuki Aruga

Clinicopathological analysis of ten patients with metaplastic squamous cell carcinoma of the breast

PurposePrimary squamous cell carcinoma (SCC) and metaplastic squamous cell carcinoma (MSCC) are rare types of breast cancer with specific histological features. They are characterized by rapid progression, a tendency toward cyst formation, and negativity for hormone receptors. Many studies have concluded that SCC of the breast carries a poor prognosis, based on the fact that conventional chemotherapy for ductal carcinoma of the breast is ineffective against SCC. This is a retrospective study of patients in a single center with SCC or MSCC.MethodsWe searched the records of the Tokyo Metropolitan Komagome Hospital for patients diagnosed with breast SCC or MSCC between 1979 and 2006. Squamous cell carcinoma was diagnosed when 100% of the malignant cells showed a squamous component (pure SCC) and MSCC was diagnosed when more than 50% of the malignant cells showed a squamous component. We analyzed the clinicopathological features, treatment methods, and outcomes of these patients.ResultsWe identified 10 (0.28%) patients with SCC or MSCC from among 3565 patients with malignant breast tumors treated at our hospital during this period. Nine patients had adenocarcinoma with squamous metaplasia, and one had pure SCC. Ultrasound showed a central cystic-necrotic component in seven tumors, and all of the tumors were negative for hormone receptors and HER2. Recurrence developed in two patients with lymph node metastasis, but not in the other eight patients. The 5-year survival rate and median survival time were 85.7% and 97 months, respectively.ConclusionsSquamous cell carcinoma or MSCC of the breast with features of the triple-negative subtype seems to be associated with a poor prognosis; however, nodenegative patients are likely to have a favorable prognosis.

Flare hypercalcemia after letrozole in a patient with liver metastasis from breast cancer: a case report

IntroductionTamoxifen may occasionally precipitate serious and potentially life-threatening hypercalcemia. However, to date, this has not been documented with aromatase inhibitors.Case presentationA 65-year-old Japanese woman with liver metastasis from breast cancer was admitted to our hospital with vomiting, anorexia, fatigue, arthralgia, muscle pain and dehydration. She had started a course of letrozole five weeks earlier. Our patients calcium level was 11.6 mg/dL. She was rehydrated and elcatonin was administered. Our patients parathyroid hormone and parathyroid hormone-related protein levels were not increased and a bone scintigram revealed no evidence of skeletal metastasis. After our patients serum calcium level returned to within the normal range, letrozole was restarted at one-half of the previous dose (1.25 mg). There were no episodes of hypercalcemia. However, 84 days after restarting letrozole, our patient again complained of arthralgia and treatment was changed to toremifene. During these periods, repeated ultrasonograms revealed no progression of liver metastasis.ConclusionTo the best of our knowledge, this is the first case report of flare hypercalcemia after treatment with letrozole in a patient with metastatic breast cancer.

Phase I study of weekly nab‐paclitaxel combined with S‐1 in patients with human epidermal growth factor receptor type 2‐negative metastatic breast cancer

We conducted a phase I study of a weekly nab‐paclitaxel and S‐1 combination therapy in patients with human epidermal growth factor receptor type 2‐negative metastatic breast cancer. The primary objective was to estimate the maximum tolerated and recommended doses. Each treatment was repeated every 21 days. Levels 1, 2a, 2b, and 3 were set depending on the S‐1 dose (65 or 80 mg/m2) and nab‐paclitaxel infusion schedule (days 1 and 8 or days 1, 8, and 15). Fifteen patients were enrolled. Dose‐limiting toxicity was observed in one patient at Level 3 (100 mg/m2 nab‐paclitaxel on days 1, 8, and 15 with 80 mg/m2 S‐1 daily for 14 days, followed by 7 days of rest). Although the maximum tolerated dose was not reached, the recommended dose was determined to be Level 3. Neutropenia was the most frequent grade 3–4 treatment‐related adverse event. For patients with measurable lesions, the response rate was 50.0% and the median time to treatment failure and median progression‐free survival was 13.2 and 21.0 months, respectively. The present results show the feasibility and potential for long‐term administration of this combination therapy.

A low number of tumor infiltrating FOXP3-positive cells after primary systemic chemotherapy is correlated with favorable relapse-free survival in breast cancer patients.

CTRC-AACR San Antonio Breast Cancer Symposium: 2008 Abstracts Abstract #5043 Background: Cancer cells induce proliferation and local accumulation of immunosuppressive cells such as FOXP3-positive cells which known as regulatory T cells (Tregs). Tregs prevent the maturation of dendritic cells and their capacity to present tumor antigens to cytotoxic T lymphocytes (CTLs) and leads to tumor-induced tolerance. Although cancer chemotherapy was usually considered as immunosuppressive, some chemotherapeutic agents have recently been shown to activate an anticancer immune response, which is involved in the curative effect of these treatments. Therefore, we hypothesized that number of tumor infiltrating FOXP3-positive cells during primary systemic chemotherapy is correlated with therapeutic results in breast cancer patients. Methods: To test the hypothesis, between September 2000 and January 2005, breast cancer patients treated with primary systemic chemotherapy (PSC) (n=93) were included in the study. Three cases were excluded because main tumors were resected before PSC and three cases of pathological complete reaction were excluded because they were hard to define “tumor infiltrating” Tregs. To compare the number of FOXP3 positive cells in the tumors before and after PST, both core-needle biopsy (CNB) and surgical resected specimens were stained with FOXP3 monoclonal antibody. Numbers of tumor infiltrating FOXP3-positive cells were counted in 3 and 5 randomly chosen high power fields (CNB and surgical specimens, respectively). A median cutoff of >16.3 and > 6.6 defined patients with high numbers of Tregs (CNB and surgical specimens, respectively). We also divided the patients into four groups (high numbers of FOXP3 positive cells in both CNB and surgical specimens; HH, low numbers in the both specimens; LL, high numbers in CNB and low in the surgical specimens; HL, and low in CNB and high in surgical specimens; LH). All patients were treated with anthracyclin containing therapy and 79.3 %( n=69) of them were added taxanes sequentially. Results: In the tumors after PST, numbers of Tregs were significantly higher in lymphvessel invasion positive tumors (P=0.01) and ER negative tumors (P=0.02) but there was no correlation between lymph node involvement and numbers of Tregs (P=0.8). As for the comparison of four groups, LL group shows the longest relapse-free (P=0.04) and overall survival (P=0.09) and HH group shows the shortest relapse-free and overall survival among four groups. Interestingly, HL group shows better outcome than HH group and LH group shows worse one than LL. Conclusions: These findings suggest that the control of Tregs in the tumor is important for the control of the disease and Tregs might be an important therapeutic target for breast cancer. Furthermore, it is suggested that some chemotherapeutic agents could be a potential inhibitor of the Tregs in tumor and show antitumor effects addition to their direct cytotoxicity against cancer cells. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5043.

Tumor development in Japanese patients with Lynch syndrome

Background Lynch syndrome (LS) patients have a high risk of developing various tumors. This study aimed to clarify the characteristics of tumors developing in LS patients. Methods This is a retrospective review of 55 LS patients treated at Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital. Results The median age at the diagnosis of the first malignant tumor and first LS-related tumor was 44 (range, 19−65) and 44 (range, 24−66) years, respectively. Of the 55 LS patients with developing malignant tumors, 45 (93.8%) developed an LS-related tumor as the first malignant tumor. Colorectal cancer (CRC) developed in 47 patients (85.4%), followed by endometrial cancer (n = 13, 56.5%) in females and gastric cancer (n = 10, 18.1%). In 6 gastric cancer patients, Helicobacter pylori was detected in resected specimens. Twenty-nine patients (52.7%) developed CRC and extra-colonic tumors; of these, 15 patients (48.3%) had mutations in MLH1, 10 (58.8%) in MSH2, and 4 (57.1%) in MSH6. At the age of 50, the cumulative incidence was 50.9% [95% confidence interval (CI), 36.9−63.3%] for CRC, 17.4% (95% CI, 5.2−35.6%) for endometrial cancer, and 5.5% (95% CI, 1.4−13.8%) for gastric cancer. Eight gastric cancer, one breast cancer patient, five bladder cancer patients, and one prostate cancer patient demonstrated loss of expression of the mismatch repair (MMR) protein; patients with thyroid cancer, spindle cell sarcoma, and giant cell tumors did not demonstrate this. Conclusion Gastric cancer incidence was high in Japanese patients with LS and associated with H. pylori infection. MMR protein deficiency caused the development of malignant tumors in LS patients.

Abstract P6-09-09: Body mass index and prognosis after breast cancer diagnosis in Japanese women

Background: Studies conducted mainly in Western countries have reported a relationship between body mass index (BMI) and prognosis among women with breast cancer. Only a few studies have been conducted in Japan so far because the percentage of high BMI is low. In the present retrospective study, we investigated the associations between BMI and the clinical characteristics and prognosis among breast cancer patients. Methods: We analyzed 1,744 breast cancer patients who started treatment between 2004 and 2012 at a single hospital in Japan. All patients with ductal carcinoma in situ, male breast cancer as well as metachronous and synchronous bilateral breast cancer were excluded. Median age was 57 years (range 23–91). The number of patients less than 50 years old was 496. World Health Organization BMI classifications were used: Underweight, less than18.5 kg/m 2 , n=157; Normal, 18.5–24.9 kg/m 2 , n=1181; Overweight, 25–29.9 kg/m 2 , n=316; and Obese, more than or equal to 30kg/m 2 , n=90. The Cox proportional hazards model was used to estimate hazard ratios for recurrence free survival (RFS) in relation to BMI classifications. Results: Median follow up interval was 4.2 years. During the follow-up period, 126 breast cancer recurrences were observed. BMI classification correlated with clinical tumor size (cT) significantly and BMI classification tended to correlate with lymph node metastases and estrogen receptor (ER) status. Among patients less than 50 years old, the RFS of those with BMI ≥25.0 kg/m 2 was compared to that of patients with BMI 2 . In multivariate analyses, BMI classification was one of the significant factors (p=0.02) along with lymph node metastases (p=0.0001) and ER status (p=0.04). However in patients aged 50 years or over BMI category was not a significant factor (p=0.12). Conclusions: It has been reported that higher BMI is a risk factor for breast cancer recurrence among postmenopausal patients. Our results suggest that higher BMI is also associated with an increased risk of breast cancer recurrence among premenopausal patients. It raises the possibility that maintaining an appropriate body weight improves the prognosis in premenopausal patients after they have been diagnosed. Citation Format: Toshinari Yamashita, Tomoyuki Aruga, Hiromi Miyamoto, Kazumi Horiguchi, Yayoi Honda, Nami Idera, Risa Goto, Katsumasa Kuroi. Body mass index and prognosis after breast cancer diagnosis in Japanese women [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 P6-09-09.

Sunitinib monotherapy in a patient with primary breast cancer

Sunitinib is an oral multi-targeted tyrosine kinase inhibitor approved for use in patients with advanced renal cell carcinoma (RCC). However, despite its preclinical biological effect on breast cancer, it is yet to be proven effective for clinical use in patients with breast cancer. The present report describes a case of a 69-year-old woman with advanced clear-cell RCC and a luminal B subtype invasive ductal carcinoma of the right breast that showed a partial response to monotherapy with sunitinib. This is the first report of the effect of sunitinib monotherapy in a patient with early-stage breast cancer.

Abstract P3-13-08: A phase I study of weekly nab-paclitaxel in combination with S-1 in patients with metastatic breast cancer

Background: S-1 is an oral, fixed dose combination product comprised of tegafur, a fluoropyrimidine prodrug of 5-fluorouracil (5-FU), and modulators of 5-FU metabolism, 5-chloro-2.4-dihydrooxypyridine and oteracil potassium. S-1 is designed to provide oral delivery of 5-FU, a pyrimidine analog antimetabolite antineoplastic agent, while reducing the rate of degradation of 5-FU and its conversion in the gastrointestinal tract to its toxic phosphorylated metabolite. S-1 is active in breast cancer and a variety of solid tumors. nab™-Paclitaxel (nab-P) is a treatment option in metastatic breast cancer (MBC) (approved 260 mg/m2 q3w dosing schedule), and high activity of nab-P with single-agent weekly administration at 100 mg/m2 has been investigated in MBC as well as other disease states. Since these two agents differed in their mechanisms of action and toxicity profiles, we sought to test their combined activity in a phase I study of nab-P/S-1 for HER2-negative MBC. The primary objectives of this study was to determine the maximum tolerated dose (MTD) and recommended dose (RD) of nab-P/S-1 in patients with HER-2 negative MBC. The secondary objective of this study was to evaluate pharmacokinetic (PK) parameters of both agents. Methods: Patients received treatment on 3 week cycles. S-1 was administered orally at a twice-daily dose of 65 mg/m2 (dose level 1 and 2b) or 80 mg/m2 (dose level 2a and 3) for 14 days and nab-P was administered as a 30-minute IV infusion at a dose of 100 mg/m2 on days 1 and 8 (dose level 1 and 2b) or 100 mg/m2 on days 1, 8 and 15 (dose level 2a and 3). Results: Fifteen patients were enrolled in this study; nab-P/S-1 was given as first-line chemotherapy for MBC in 9 patients, and as second-line therapy subsequent to an anthracycline-containing therapy in 6 patients. At dose level 3, one patient experienced a DLT. The observed DLT was delay of initiation of next cycle, G4 neutropenia had not recovered to G1/G0 in a period defined on the protocol. No cases of febrile neutropenia were observed. Judged from the status of dose reduction and the extension of drug holidays (cycle start delay), and the occurrence of non-severe adverse events after 2 cycles, the dose level was not increased above level 3. Seven patients were able to be treated 10 cycles or more. Additionally, three patients were able to be treated 20 cycles or more. Among of the 12 patients who had a measurable lesion which was evaluable by RECISTv1.1, the overall response rate was 50%, with 1 CR, 5 PR, 4 SD, and 1 PD. Pharmacokinetics of Paclitaxel and 5-FU in the combination therapy were comparable to those after single-agent administration of nab-P and S-1, respectively. Conclusion: Based on the results of this study, the RD was determined to be dose level 3 (S-1 80 mg/m2 twice daily plus nab-P 100 mg/m2 on days 1, 8, and 15). Since this combination therapy was generally well tolerated even with prolonged treatment, it is suggested that this combination therapy may be a promising treatment regimen in HER-2 negative MBC and merits further evaluation. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-13-08.

Abstract P2-10-04: The clinicopathological features of androgen receptor expression in primary HER2-positive breast carcinomas

Background: Human epidermal growth factor receptor 2 (HER2)-positive breast carcinomas are aggressive subtypes associated with a variable response to systemic therapies. HER2-positive breast carcinomas are not homogeneous, and it has been reported that androgen receptor (AR) signaling is an important determinant of cell growth and relation with HER3 expression. The aim of this study was to investigate the clinicopathological significance of AR expression in primary HER2-positive breast carcinomas. Patients and Methods: 102 primary HER2-positive breast tumor samples were obtained from patients operated on at the Cancer and Infectious Disease Center, Tokyo Metropolitan Komagome Hospital from 2001 to 2010. 92 tumors were IHC (HercepTest) score 3, whereas 10 were IHC score 2 and FISH- positive. We evaluated AR using immunohistochemistry. Tumors with equal or more than 10% nuclear-stained cells were determined to be positive for AR and the relationship between AR and clinicopathological parameters was analyzed. The expression of HER3 was evaluated by immunohistochemistry using the following scoring system: 0 (no staining), 1 (less than 20% of cells stained or weak staining), 2 (more than or equal to 20% of cells stained, or strong staining) and the relation with AR expression was examined. The differences among variables were calculated by chi-square test. Results : The median age of all patients was 56 years old (from 31 to 84). AR-positive carcinomas corresponded to 37(36.2%) of 102 HER2-positive breast carcinomas. The median age of AR-positive patients was 54 years old while that of AR-negative patients was 57 years old. There was no significant difference between the two groups. AR-positive carcinomas were not associated with ER and progesterone receptor (PgR) co-expression and nuclear grade. The stage distribution of AR-positive patients was: stage I(n = 23), stage IIA(n = 11), stage IIB (n = 3), and averaged 18.5mm in tumor size, while AR-negative patients distributed as stage I(n = 16), stage IIA(n = 27), stage IIB (n = 15), stage IIIA(n = 5), stage IIIB(n = 2), and averaged 23.7mm in size. AR-positive carcinomas were associated with larger pathological tumor size and more advanced clinical stages, though lymph node involvement did not differ between the two groups. The HER3 expression score distribution was: scrore 0 (n = 14), score 1 (n = 54), score 2 (n = 34). The expression of HER3 was not associated with clinicopathological parameters. Furthermore, there was no significant relation between AR expression and HER3 expression. Median follow-up interval was 63 months. 20 patients (19.6%) suffered recurrence. Four patients suffered recurrence in the AR-positive group while there were 16 patients in the AR-negative group. AR-positive patients had significant better prognosis in recurrence than AR-negative patients. Conclusion: Among HER2-positive breast carcinomas, AR-positive carcinomas have the tendency to be smaller in tumor size and of early clinical stage compared with those that are AR-negative. The expression of AR might be a better prognostic factor in HER2-positive breast carcinomas. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-10-04.

Abstract P6-11-11: Characteristics of long-term survivors after brain metastases in breast cancer patients

Background: Brain metastases (BM) occur in 10%-15% patients of breast cancer patients. It is associated with poor prognosis, requiring great effort to manage local and systemic treatment for BM. The purpose of this study was to analyze the clinico-pathological characteristics of long-term survivors with BM in breast cancer patients. Method: 63 patients with breast cancer BM diagnosed from 2002 to 2010 at the Tokyo Metropolitan Komagome hospital were included. Long–term survival group (Long) was defined as to be consisted of the patients with survival duration more than 36 months after diagnosed with BM and the patients with less than 36 month was into Short-term survival group (Short) in this study. The clinico-pathological characteristics were compared between these two groups. Survival rate and prognostic factors of BM were analyzed by the Kaplan–Meier method and employed by Log–Rank test. Multivariate analysis was performed by the Cox proportional hazard model. Results: Median age of the 63 patients was 53 years (range, 35–78). Median survival time after BM was 12 months (range, 1–168), with about 90 percent of cause of death related to BM (e.g. failure of PS due to BM). As for ER and HER2 status, the number of ER+/HER2- (Luminal:Lum), ER+or-/HER2+ (HER2-enrich:Her2-E), ER-/HER2- (Basal:Bas) were 18, 27, 18, respectively. Among those 63 patients, 11 survived 36 months or more after BM. However, there was no difference in the rate of ER status between Long (55%) and Short (38%), there were significantly high rate of Her2-E case in Long (73%) as compared with Short (29%). Median survival duration after diagnosed with BM of Lum, Her2-E and Bas were 11, 37, 3 months, respectively. Prognosis of Bas was significantly poor (Bas vs. Her2-E p p = 0.188), survival time after BM of Her2-E was the tendency to be long. In univariate analysis, Karnofsky performance status (KPS≥70 or p = 0.0458, 0.0398, 0.0385, respectively). Meningitis status was a borderline. ( p = 0.052) In multivariate analysis, KPS, HER2 status and DFI were significant prognostic factors. (KPS: RR 2.08, 95% CI 1.08-4.07; HER2: RR 2.911, 95% CI 1.396- 6.484; DFI: RR 1.933, 95% CI 0.83-4.102) Conclusions: Although, it was believed that the prognosis after BM was poor, Her2-E BM had a comparatively good prognosis. An existing report supports extension of the survival time after BM by HER2–targeted treatment in BM cases with Her2 positive breast cancer. This newest study reviles the median survival after BM as 37 months in Her2-E BM group, but that of Bas group was only 3 months and this is not improved at all compared with historically reported survival duration (2.4-4.9months). Our reports suggested that the innovation of Her2–targeted treatment leads this surprising improvement of life extension in HER2 positive BM patients but innovation of cytotoxic agents could not contribute toward improvement of clinical outcome in triple negative BM patients. So the necessity of examining the medical treatment of breast cancer BM according to subtype from now on is also considered. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-11-11.