Phase III study of bilayer sustained-release tramadol tablets in patients with cancer pain: a double-blind parallel-group, non-inferiority study with immediate-release tramadol capsules as an active comparator.

PURPOSE: We investigated whether twice-daily administration of a bilayer tablet formulation of tramadol (35% immediate-release [IR] and 65% sustained-release) is as effective as four-times-daily IR tramadol capsules for managing cancer pain. METHODS: This randomized, double-blind, double-dummy, active-comparator, non-inferiority study enrolled opioid-naïve patients using non-steroidal anti-inflammatory drugs or acetaminophen (paracetamol) to manage cancer pain and self-reported pain (mean value over 3 days ≥ 25 mm on a 100-mm visual analog scale [VAS]). Patients were randomized to either bilayer tablets or IR capsules for 14 days. The starting dose was 100 mg/day and could be escalated to 300 mg/day. The primary endpoint was the change in VAS (averaged over 3 days) for pain at rest from baseline to end of treatment/discontinuation. RESULTS: Overall, 251 patients were randomized. The baseline mean VAS at rest was 47.67 mm (range: 25.6-82.7 mm). In the full analysis set, the adjusted mean change in VAS was - 22.07 and - 19.08 mm in the bilayer tablet (n = 124) and IR capsule (n = 120) groups, respectively. The adjusted mean difference was - 2.99 mm (95% confidence interval [CI] - 7.96 to 1.99 mm). The upper 95% CI was less than the predefined non-inferiority margin of 7.5 mm. Other efficacy outcomes were similar in both groups. Adverse events were reported for 97/126 (77.0%) and 101/125 (80.8%) patients in the bilayer tablet and IR capsule groups, respectively. CONCLUSION: Twice-daily administration of bilayer tramadol tablets was as effective as four-times-daily administration of IR capsules regarding the improvement in pain VAS, with comparable safety outcomes. CLINICAL TRIAL REGISTRATION: JapicCTI-184143/jRCT2080224082 (October 5, 2018).

Postoperative Adjuvant Anastrozole for 10 or 5 Years in Patients With Hormone Receptor-Positive Breast Cancer: AERAS, a Randomized Multicenter Open-Label Phase III Trial.

PURPOSE: Treatment with an aromatase inhibitor for 5 years is the standard treatment for postmenopausal hormone receptor-positive breast cancer. We investigated the effects of extending this treatment to 10 years on disease-free survival (DFS). PATIENTS AND METHODS: This prospective, randomized, multicenter open-label phase III study assessed the effect of extending anastrozole treatment for an additional 5 years in postmenopausal patients who were disease-free after treatment with either 5 years of anastrozole alone or 2-3 years of tamoxifen followed by 2-3 years of anastrozole. Patients were allocated randomly (1:1) to continue anastrozole for an additional 5 years or stop anastrozole. The primary end point was DFS, including breast cancer recurrence, second primary cancers, and death from any cause. This study is registered with University Hospital Medical Information Network, Japan (UMIN) clinical trials registry (UMIN000000818). RESULTS: We enrolled 1,697 patients from 117 facilities between November 2007 and November 2012. Follow-up information was available for 1,593 patients (n = 787 in the continue group, n = 806 in the stop group), who were defined as the full analysis set, including 144 patients previously treated with tamoxifen and 259 patients who underwent breast-conserving surgery without irradiation. The 5-year DFS rates were 91% (95% CI, 89 to 93) in the continue group and 86% (95% CI, 83 to 88) in the stop group (hazard ratio, 0.61; 95% CI, 0.46 to 0.82; P < .0010). Notably, extended anastrozole treatment reduced the incidence of local recurrence (continue group, n = 10; stop group, n = 27) and second primary cancers (continue group, n = 27; stop group, n = 52). There was no significant difference in overall or distant DFS. Menopausal or bone-related all-grade adverse events were more frequent among patients in the continue group than those in the stop group, but the incidence of grade ≥3 adverse events was <1% in both groups. CONCLUSION: Continuing adjuvant anastrozole for an additional 5 years after 5 years of initial treatment with anastrozole or tamoxifen followed by anastrozole was well tolerated and improved DFS. Although no difference in overall survival was observed as in other trials, extended anastrozole therapy could be one treatment choice in postmenopausal patients with hormone receptor-positive breast cancer.

Evaluation of a novel medical device for pegfilgrastim administration.

Pegfilgrastim, a pegylated form of granulocyte colony-stimulating factor, has reduced the risk of developing febrile neutropenia, which is associated with an increase in severe infection and prolonged hospitalization. However, pegfilgrastim administration requires that patients visit hospital following cancer chemotherapy, thus imposing a burden on patients and those around them. An on-body injector (OBI), which automatically administers pegfilgrastim about 27 hours after chemotherapy, was used in this study. The OBI, which consists of a main pump unit and infusion set, is a drug delivery device designed to be attached to the patient's body, with a timer-controlled dosing function. This study was conducted in breast cancer patients to evaluate the safety of pegfilgrastim administered subcutaneously via the OBI. The study period consisted of screening and treatment observation periods involving four cycles of neoadjuvant or adjuvant chemotherapy with docetaxel plus cyclophosphamide. One 3.6-mg pegfilgrastim dose was administered subcutaneously via OBI during each cycle of chemotherapy. The study enrolled 35 patients, and no serious adverse events or febrile neutropenia occurred. Administration of pegfilgrastim was successfully completed at all times when the OBI was attached to the patient, and no safety concerns associated with OBI function arose. For outpatients requiring pegfilgrastim following cancer chemotherapy, the use of an OBI was considered to be a safe option to reduce the need for outpatient visits that restrict their activities of daily living.

Overnight fasting before lapatinib administration to breast cancer patients leads to reduced toxicity compared with nighttime dosing: a retrospective cohort study from a randomized clinical trial.

BACKGROUND: The bioavailability of lapatinib is affected by food, even following the 1 hour fast recommended by the package insert. We hypothesized that overnight fasting would minimize food-drug interactions. Here, we investigated if lapatinib administration timing is associated with its tolerability, efficacy, and pharmacokinetics. METHODS: This is a retrospective cohort study utilizing the medical records of patients enrolled in the JBCRG-16/Neo-LaTH randomized phase 2 trial for breast cancer patients treated with lapatinib. Lapatinib administration timing was divided into three groups: before breakfast (BB), between meals (BM), and at bedtime (AB). Side effects (SE), treatment discontinuation rate (TDR), relative dose intensity (RDI), pathological complete response (pCR) rate, and lapatinib serum trough concentration were compared between groups. RESULTS: About 140 patients were included in this study: BB 15, BM 51, and AB 74. A reduced risk of diarrhea {adjusted hazard ratio (HR), 0.51, 95% confidence interval (CI), 0.27-0.89, p = 0.018}, and rash {adjusted HR, 0.37; 95% CI, 0.17-0.70, p = 0.002} was seen in BB versus AB. Fewer patients with low RDI (< 0.85/<0.6) were in the BB group (BB 13% / 0%, BM 22% / 3.9%, AB 24% / 14%, p = 0.70 / 0.11). pCR was not diminished (p = 0.75). BB group had the lowest serum lapatinib concentration and variability (mean ±SD were 0.35 ± 0.15, 0.65 ± 0.32, 0.96 ± 0.43 µg/ml). CONCLUSIONS: Compared to bedtime administration, lapatinib administration after overnight fasting reduces its toxicity without diminishing its therapeutic efficacy.

Metachronous bilateral breast metastases of a lung neuroendocrine tumor: A case report.

Breast metastases of primary lung neuroendocrine tumors are rarely reported. The current report presents the case of a 41-year old female with no history of smoking who initially underwent surgery for a breast fibroadenoma, during which a neuroendocrine tumor of the right lung was detected via chest X-ray. The patient underwent surgery for the tumor and developed right breast nodules after adjuvant chemotherapy. Histological and immunohistochemical examinations of biopsies from these nodules indicated breast metastasis of the primary lung neuroendocrine tumor. The patient underwent mastectomy of the right breast but subsequently developed metastases in the left breast, for which local radiotherapy was administered. The observed metachronous bilateral breast metastases indicated that the contralateral breast should be considered during an investigation of metastasis.

A randomized study comparing docetaxel/cyclophosphamide (TC), 5-fluorouracil/epirubicin/cyclophosphamide (FEC) followed by TC, and TC followed by FEC for patients with hormone receptor-positive HER2-negative primary breast cancer.

PURPOSE: Our primary objective was to determine the benefit/risk of anthracycline-free regimens by comparing docetaxel + cyclophosphamide (TC) alone, fluorouracil + epirubicin + cyclophosphamide (FEC) followed by TC, or TC followed by FEC as a primary treatment for patients with HR-positive, HER2-negative BC. METHODS: We randomized patients with stage I-III HR-positive HER2-negative, operable BC to receive either six cycles of TC (TC6), three cycles of FEC followed by three cycles of TC (FEC-TC), or three cycles of TC followed by three cycles of FEC (TC-FEC). The primary endpoint was the pathological response. Secondary endpoints included clinical response, type of surgical procedure, recurrence, death, and adverse events (by NCI-Common Terminology Criteria for Adverse Events v.3.0). We conducted all statistical analyses using SAS Version 9.2. RESULTS: We enrolled 195 patients and analyzed data from 193 as the intention-to-treat population. Pathological complete response rates were numerically higher in the TC6 group than in the other groups (p = 0.321). The breast conservation rate was significantly higher in the TC6 group (73%) than in the other groups (FEC-TC 51%, TC-FEC 45%, p = 0.007). Adverse events with grade > 3 were not common in the treatment groups (p = 0.569). The overall and distant disease-free survivals were similar among the groups with median follow-up of 5.80 years. CONCLUSIONS: Despite similar long-term efficacy and safety profile, the higher breast conservation rate in the TC6 group suggests that preoperative chemotherapy without an anthracycline may benefit patients with HR-positive HER2-negative BC. TRIAL REGISTRATION: UMIN000003283 https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000003873.

Intrapericardial carboplatin in the management of malignant pericardial effusion in breast cancer: a pilot study.

PURPOSE: Malignant pericarditis is observed in 5.1-7.0% of all cases of acute pericarditis, and malignant pericardial effusion (MPE) can lead to cardiac tamponade in the later stages of cancer. Breast cancer is the second most common primary cancer associated with MPE, but the efficacy and safety of intrapericardial carboplatin (CBDCA) have never been evaluated in breast cancer. In this study, we assessed the clinical significance of intrapericardial CBDCA following catheter drainage in patients with breast cancer-related MPE. METHODS: A catheter was inserted percutaneously into the pericardial space under echocardiographic guidance. After complete drainage, 150 mg of CBDCA was instilled into the pericardial space through the catheter. RESULTS: Eight patients with symptomatic breast cancer-related MPE were treated at the Gunma Prefectural Cancer Center, between July 2010 and March 2016. One month after treatment, 100% of MPE was controlled. The median survival time from the recurrence of breast cancer until death or study follow-up was 2336 days (range 293-3937 days), while that from intrapericardial CBDCA administration until death or study follow-up was 552 days (range 35-1673 days). Grade 1 fever, nausea, hypotension, fatigue, and chest discomfort were observed in one patient (12.5%) after intrapericardial CBDCA administration. CONCLUSIONS: We found that intrapericardial administration of CBDCA after catheter drainage appears to be safe and effective in managing breast cancer-associated MPE. As the number of patients in this study was small, further studies are warranted to determine the safety and efficacy of intrapericardial CBDCA in the management of breast cancer-related MPE.

Multicenter Phase II Study of Intraoperative Radiotherapy of Early Breast Cancer: Ipsilateral Tumor Recurrence.

BACKGROUND: We performed a multicenter phase II study on the efficacy and safety of intraoperative radiotherapy (IORT) as partial breast irradiation using multiple devices. METHODS: The primary endpoint was ipsilateral breast tumor recurrence (IBTR). Key inclusion criteria were T < 2.5 cm, age > 50 years, surgical margin > 1 cm, intraoperative pathologically free margins, and sentinel node negative. After resection of the tumor, radiation at 21 Gy was delivered directly to the mammary gland employing an electron linear accelerator in the operating room, otherwise the patient was transported from the surgical suite to the radiation room. RESULTS: Overall, 142 patients were enrolled in this study and 129 underwent IORT. Stage 0: n = 4 (3.1%); stage I: n = 98 (76.0%); and stage IIA: n = 27 (20.9%). Luminal type: n = 116 (89.9%); triple-negative: n = 9 (7.0%); and human epidermal growth factor receptor 2: n = 4 (3.1%). Median follow-up time was 59.5 months (range 27.5-99.0), and the rate of IBTR was 3.1% (95% confidence interval 0.9-7.8). The toxicities included fibrosis in deep-connective tissue: grade 1, 78.1%; wound infection: grade 3, 1.6% and grade 2, 1.6%; and soft tissue necrosis: grade 3, 0.8% and grade 2, 0.8%. Recurrence in the breast occurred in four cases; the site of recurrence was just under the skin near the primary tumor site, with similar histology and subtype. CONCLUSIONS: In this multicenter phase II study, the rate of IBTR was low and IORT at 21 Gy was feasible in properly selected patients. It is important to use a careful surgical technique to reduce local recurrence because the skin is not included in the radiation field of IORT.

[Follicle-Stimulating Hormone and Estradiol Levels in Japanese Women Treated with Toremifene and Anastrozole for Two Years - A Retrospective Analysis of Data from a Prospective Randomized Trial].

The criteria for biological postmenopause have not been clearly defined, although determining the menopausal status is crucial for selecting agents for adjuvant endocrine therapy for patients with breast cancer. The long-term effects of adjuvant toremifene(TOR)and anastrozole(ANA)on serum follicle-stimulating hormone(FSH)and estradiol(E2)levels in Japanese women were examined using data from a prospective randomized study that mainly studied serum lipids and bone metabolism for 2 years. The study medications were administered orally daily at 40 mg and 1 mg for TOR and ANA, respectively. Sixty-nine patients were randomly assigned to the TOR group(n=36)or ANA group(n=33). FSH and E2 levels were measured using chemiluminescent immunoassay. The mean ages of the patients in the TOR and ANA groups were 62.5 and 60.0 years, respectively. None of the patients experienced menstruation during the course of the study. The baseline serum FSH level in the TOR group(69.6mIU/mL)decreased to 59.2%, 54.6%, and 50.0% at 6, 12, and 24 months, respectively, after therapy commencement. The FSH levels ranged from 8.6 to 68.1mIU/mL and were<20mIU/mL in 2 patients(9.5%; 8.6 and 14.4mIU/mL). The serum FSH levels in the ANA group did not change markedly over 24months. The baseline serum E2 level in the ANA group(11.6 pg/mL)decreased to 72.4%, 70.7%, and 61.2%at 6, 12, and 24months, respectively, after therapy commencement. The serum E2 level in the TOR group did not change markedly over 24 months. When switching to other endocrine agents as adjuvant therapy for patients with breast cancer treated with TOR, the serum FSH level decreased to half of the preinitiation level, and one-tenth of the FSH levels was<20mIU/mL, while the postmenopausal serum E2 level was maintained.

Phase II Study of S-1 plus Trastuzumab for HER2-positive Metastatic Breast Cancer (GBCCSG-01).

AIM: Treatment strategies for patients with human epidermal growth factor 2 (HER2)-positive metastatic breast cancer (MBC) have significantly progressed. The use of trastuzumab, a monoclonal antibody targeting the HER2 (human epidermal growth factor 2) protein, in combination with chemotherapy improves survival in patients with HER2-positive breast cancer. S-1, an oral combination of fluorouracil derivatives, is widely used in Japan and is more convenient than intravenous drugs. However, little is known about the combination of S-1 and trastuzumab in patients with HER2-positive MBC. PATIENTS AND METHODS: We conducted a single-arm, open-label, multicenter prospective phase II study to evaluate the efficacy of an S-1 plus trastuzumab regimen for HER2-positive MBC. S-1 was administered orally [80-120 mg, based on body surface area (BSA)] twice a day for 14 consecutive days in a 3-week cycle. Patients with BSA of <1.25 m2 received a total of 80 mg of S-1, those with BSA ≥1.5 m2 received 120 mg, and the remaining received 100 mg daily in two divided doses. Trastuzumab was administered intravenously at 8 mg/kg on day 1 of the first cycle and at 6 mg/kg on day 1 of subsequent cycles, i.e., every 3 weeks. RESULTS: Between December 2008 and March 2013, 10 patients were enrolled and received a median of 17 (range=3-76) cycles of treatment. Overall response and clinical benefit rates were 60.0% and 90.0%, respectively. Progression-free survival was 15.8 (95% confidence interval=9.4-29.6) months and overall survival was 45.5 (95% confidence interval=37.1-62.2) months. Grade 3/4 adverse events included were neutropenia and hyperglycemia in one patient each (10.0%). There was no clinically significant cardiotoxicity. CONCLUSION: The combination of S-1 and trastuzumab was tolerable and had excellent efficacy with good response and disease control in this study. S-1 plus anti-HER2 therapy is a feasible treatment option for HER2-positive MBC.

Serum lipid and bone metabolism effects of Toremifene vs. Letrozole as adjuvant therapy for postmenopausal early breast cancer patients: results of a multicenter open randomized study.

A prospective randomized phase II trial was conducted to evaluate the time course effects of toremifene (TOR) and letrozole (LET), as adjuvant hormone therapy, on serum lipid profiles and bone metabolism in estrogen receptor (ER)-positive, postmenopausal breast cancer patients.Fifty-four postmenopausal breast cancer patients [ER positive, HER2 negative, T1-2, node metastases (n = 0-3), M0] who had undergone curative resection were enrolled. They were randomized to receive either TOR 40 mg/day or LET 2.5 mg/day as adjuvant hormone therapy. Serum lipids and bone markers were measured prior to, and again at 6, 12, and 24 months after initiation of treatment. Changes in serum lipids and bone markers were compared. Serum levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) were decreased compared with the baseline values at 6 months in 6.5 and 14.0% of patients, respectively, receiving TOR. Lipid levels did not change in patients administered LET. Significant differences were observed in TC and LDL-C between the two groups at 12 and 24 months. In the TOR group, serum bone-specific alkaline phosphatase (BAP) was decreased by 25.0% at 12 months, and serum cross-linked N-telopeptide of type-I collagen (NTx) was decreased by 13.6% at 6 months, and these reductions were maintained for at least 24 months. In contrast, in the LET group, serum BAP did not change and NTx was increased by 16.0% at 6 months and by 18.6% at 24 months, as compared with the baseline.TOR and LET exert different effects on serum lipid profiles and bone metabolism markers. The effects of TOR, as adjuvant hormone therapy, on both lipids and bone metabolism in postmenopausal breast cancer patients are superior to those of LET.

Adjuvant Capecitabine for Breast Cancer after Preoperative Chemotherapy.

BACKGROUND: Patients who have residual invasive carcinoma after the receipt of neoadjuvant chemotherapy for human epidermal growth factor receptor 2 (HER2)-negative breast cancer have poor prognoses. The benefit of adjuvant chemotherapy in these patients remains unclear. METHODS: We randomly assigned 910 patients with HER2-negative residual invasive breast cancer after neoadjuvant chemotherapy (containing anthracycline, taxane, or both) to receive standard postsurgical treatment either with capecitabine or without (control). The primary end point was disease-free survival. Secondary end points included overall survival. RESULTS: The result of the prespecified interim analysis met the primary end point, so this trial was terminated early. The final analysis showed that disease-free survival was longer in the capecitabine group than in the control group (74.1% vs. 67.6% of the patients were alive and free from recurrence or second cancer at 5 years; hazard ratio for recurrence, second cancer, or death, 0.70; 95% confidence interval [CI], 0.53 to 0.92; P=0.01). Overall survival was longer in the capecitabine group than in the control group (89.2% vs. 83.6% of the patients were alive at 5 years; hazard ratio for death, 0.59; 95% CI, 0.39 to 0.90; P=0.01). Among patients with triple-negative disease, the rate of disease-free survival was 69.8% in the capecitabine group versus 56.1% in the control group (hazard ratio for recurrence, second cancer, or death, 0.58; 95% CI, 0.39 to 0.87), and the overall survival rate was 78.8% versus 70.3% (hazard ratio for death, 0.52; 95% CI, 0.30 to 0.90). The hand-foot syndrome, the most common adverse reaction to capecitabine, occurred in 73.4% of the patients in the capecitabine group. CONCLUSIONS: After standard neoadjuvant chemotherapy containing anthracycline, taxane, or both, the addition of adjuvant capecitabine therapy was safe and effective in prolonging disease-free survival and overall survival among patients with HER2-negative breast cancer who had residual invasive disease on pathological testing. (Funded by the Advanced Clinical Research Organization and the Japan Breast Cancer Research Group; CREATE-X UMIN Clinical Trials Registry number, UMIN000000843 .).

Control of nausea with palonosetron versus granisetron, both combined with dexamethasone, in patients receiving cisplatin- or anthracycline plus cyclophosphamide-based regimens.

PURPOSE: In a comparative phase 3 study involving 1114 Japanese patients receiving highly emetogenic chemotherapy (HEC), palonosetron (PALO) was found to be superior to granisetron (GRA) for the prophylaxis of chemotherapy-induced nausea and vomiting (CINV) in the delayed phase. This post hoc analysis of the phase 3 study evaluated the efficacy of PALO for the control of nausea. METHODS: The proportion of patients without nausea was assessed at 24-h intervals during the acute phase (0-24 h), delayed phase (24-120 h), and overall (0-120 h). No nausea rates were also evaluated by sex, type of chemotherapy (cisplatin or doxorubicin/epirubicin plus cyclophosphamide [AC/EC]), and age (<55 vs. ≥55 years). Nausea severity was categorized using a 4-point Likert scale (0 = no nausea to 3 = severe nausea). RESULTS: The proportion of patients without nausea was significantly higher in the PALO arm than in the GRA arm in the delayed phase (37.8 % vs. 27.2 %; p = 0.002) and overall (31.9 % vs. 25.0 %; p = 0.0117). When analyzed by stratification factors, the proportion of patients without nausea was significantly higher in the PALO arm in the delayed phase and overall in patients who were female, younger, or treated with cisplatin and in the delayed phase in patients who were older or treated with doxorubicin or epirubicin plus cyclophosphamide (all p < 0.05). CONCLUSIONS: PALO was more effective than GRA in prophylaxis of HEC-induced nausea in the delayed phase and overall. In addition, PALO was more effective than GRA in young and female patients, who are at high risk of CINV, both in the delayed phase and overall.

Tumor-infiltrating CD45RO(+) memory cells are associated with a favorable prognosis breast cancer.

BACKGROUND: CD45RO is a marker for memory lymphocytes. Whether CD45RO(+) tumor-infiltrating lymphocytes (TILs) prevent breast cancer recurrence is unclear. METHODS: In the present study, we evaluated CD45RO expression in TILs as a predictor of prognosis in 98 patients with breast cancer who underwent radical surgery without neoadjuvant chemotherapy. Patients were classified as CD45RO(+)/TILs(High) or CD45RO(+)/TILs(Low) based on median immunohistochemistry levels. RESULTS: CD45RO(+)/TILs(High) were associated with smaller tumor size. The CD45RO(+)/TILs(High) group also had significantly fewer metastatic lymph nodes (P = 0.0082) and fewer peritumoral lymphatic invasions (P = 0.0284). The CD45RO(+)/TILs(High) group enjoyed longer recurrence-free survival (P = 0.0453) but not cancer-specific survival (P = 0.0640) in univariate analysis. CONCLUSIONS: These results suggested that CD45RO(+) effector cells may both help eradicate local tumors and prevent metastases to the lymphatic systems in breast cancer patients. High ratio of CD45RO expressing TILs was associated with recurrence-free survival improvement and a trend toward cancer-specific survival improvement in breast cancer patients.

Prognostic value of extracapsular invasion of axillary lymph nodes combined with peritumoral vascular invasion in patients with breast cancer.

BACKGROUND: Extracapsular invasion (ECI) of metastatic axillary lymph nodes has been associated with aggressive nodal disease but its prognostic role in breast cancer is unclear. The present study evaluated nodal ECI as a predictor of breast cancer recurrence. METHODS: We evaluated 154 women with histologically proven node-positive breast cancer who were diagnosed with invasive ductal carcinoma, and investigated the relationships between ECI and recurrences and other clinicopathological factors, particularly vascular invasion and the number of lymph node metastases. RESULTS: The presence of ECI at positive nodes was significantly associated with the number of positive nodes, and with disease recurrence and survival in univariate (but not multivariate) analysis. Interestingly, all ECI(+) patients with distant metastases in our series had peritumoral vascular invasion (PVI), which may have reflected systemic disease; ECI with PVI of the primary tumor strongly predicted recurrent disease and shorter survival. CONCLUSION: ECI of axillary metastases combined with PVI indicates high tumor aggressiveness. Patients with ECI and PVI may be considered for stronger adjuvant therapies because of their high risk for distant recurrences.

Extracapsular invasion of sentinel lymph nodes is not associated with disease recurrence in breast cancer.

The purpose of this study was to evaluate the presence of extracapsular invasion (ECI) in positive sentinel lymph nodes (SLNs) as a predictor of disease recurrence in breast cancer. SLN biopsy was performed on 318 breasts of 316 breast cancer patients, of which 50 (15.7%) had positive SLNs. Six (12.0%) of these 50 cases had disease recurrence. The clinicopathologic features of these cases were reviewed. The ECI at SLNs was not significantly associated with disease recurrence. The recurrence-free interval by Kaplan-Meier curves did not differ significantly among patients with and without ECI at SLNs. On the other hand, metastasis at non-SLNs was observed in 12 cases (24.0%) among the 50 cases with positive SLNs, and in the non-SLN metastasis group there were 7 patients with ECI at non-SLNs. Three of 7 cases with ECI at non-SLNs had disease recurrence and none of those 5 without ECI at non-SLNs had disease recurrence. Our current study suggests that the presence of ECI at metastatic SLNs is not associated with recurrent disease in breast cancer. Our results also imply that patients with ECI at positive non-SLNs have a high risk of disease recurrence.

Early predictive value of non-response to docetaxel in neoadjuvant chemotherapy in breast cancer using 18F-FDG-PET.

BACKGROUND: The aim of this prospective study of patients with breast cancer was to identify non-responders to docetaxel in neoadjuvant chemotherapy (NCT) using fluorine-18-fluorodeoxyglucose positron-emission tomography ((18)F-FDG-PET). PATIENTS AND METHODS: We analyzed the maximum standardized uptake value (SUVmax) of (18)F-FDG-PET before and after the first course and the reduction rate in tumor size shown by magnetic resonance imaging (MRI) before the first and after the fourth course of docetaxel. RESULTS: None of the eight patients (0%) whose SUVmax decrease was less than 18% revealed a clinical partial response or clinical complete response; Seven out of the sixteen patients (44%) with an SUVmax decrease over 45% achieved a complete response. CONCLUSION: An SUVmax reduction rate less than 18% is observed in patients with breast cancer after the first course of docetaxel in NCT and may be indicator of non-response to docetaxel.

Clinicopathological significance of decreased galectin-3 expression and the long-term prognosis in patients with breast cancer.

PURPOSE: Galectin-3 expression is modulated in cancer cells, and that finding has led to the recognition of galectin-3 as a diagnostic or prognostic marker for various cancers, including breast cancer. This study investigated the correlation between galectin-3 expression and the clinicopathological features in patients with breast cancer, in order to determine the relevance and role of galectin-3 in breast cancer progression. METHODS: Galectin-3 expression was investigated immunohistochemically in 116 patients with breast cancer, and a statistical analysis was performed. RESULTS: Galectin-3 expression in breast cancer was significantly associated with tumor vascular invasion. However, galectin-3 expression was not associated with Ki-67 expression, which reflects tumor proliferation. Disease-free survival and long-term overall survival were significantly shorter for patients with reduced galectin-3 expression. CONCLUSIONS: This study demonstrated that the galectin-3 expression was associated with tumor vascular invasion and metastasis, suggesting that galectin-3 plays a critical role in tumor progression via an invasive mechanism but not via proliferation in breast cancer. Furthermore, reduced expression of galectin-3 is useful for predicting a long-term poor prognosis in patients with breast cancer.

Analysis of Ki-67 expression with neoadjuvant anastrozole or tamoxifen in patients receiving goserelin for premenopausal breast cancer.

BACKGROUND: The increasing costs associated with large-scale adjuvant trials mean that the prognostic value of biologic markers is increasingly important. The expression of nuclear antigen Ki-67, a marker of cell proliferation, has been correlated with treatment efficacy and is being investigated for its value as a predictive marker of therapeutic response. In the current study, the authors explored correlations between Ki-67 expression and tumor response, estrogen receptor (ER) status, progesterone receptor (PgR) status, and histopathologic response from the STAGE study (S_tudy of T_amoxifen or A_rimidex, combined with G_oserelin acetate to compare E_fficacy and safety). METHODS: In a phase 3, double-blind, randomized trial (National Clinical Trials identifier NCT00605267), premenopausal women with ER-positive, early stage breast cancer received either anastrozole plus goserelin or tamoxifen plus goserelin for 24 weeks before surgery. The Ki-67 index, hormone receptor (ER and PgR) status, and histopathologic responses were determined from histopathologic samples that were obtained from core-needle biopsies at baseline and at surgery. Tumor response was determined by using magnetic resonance imaging or computed tomography. RESULTS: In total, 197 patients were randomized to receive either anastrozole plus goserelin (n = 98) or tamoxifen plus goserelin (n = 99). The best overall tumor response was better for the anastrozole group compared with the tamoxifen group both among patients who had a baseline Ki-67 index ≥20% and among those who had a baseline Ki-67 index <20%. There was no apparent correlation between baseline ER status and the Ki-67 index in either group. Positive PgR status was reduced from baseline to week 24 in the anastrozole group. CONCLUSIONS: In premenopausal women with ER-positive breast cancer, anastrozole produced a greater best overall tumor response compared with tamoxifen regardless of the baseline Ki-67 index.

The detection of pCR after PST by contrast-enhanced ultrasonography for breast cancer.

BACKGROUND: Primary systemic therapy (PST; such as chemotherapy) has been approved as the standard therapy. Breast-conserving surgery is involved in 60-70% of breast cancer operations, and cancer can spread in the period between the initial treatment and preoperative chemotherapy. To reduce the residual tumor in persistent disease of breast tissue, determining the margin including normal tissue when removing the tumor is very difficult. With the development of the color Doppler method, contrast-enhanced ultrasonography (CEUS) allows visualization of the tumor bloodstream. The availability and efficacy of CEUS for setting the resection margin in breast-conserving surgery were examined and compared with MRI imaging as tools for making decisions for breast-conserving surgery. METHODS: One hundred seventy patients underwent breast cancer operations: 59 were PST(+) and 111 PST(-). Imaging studies, ultrasonography and MRI, to measure the size of the tumor were performed twice, before and after chemotherapy, for PST patients. This was carried out not only to measure the residual tumor size after PST, but also to detect whether pathologically complete response (pCR) had been achieved or not. Fifty-nine patients received CEUS after PST, and we determined the precision of CEUS and conventional US. RESULTS: The sensitivity of CEUS for pCR was 80.0% (95% CI 0.571-0.88), specificity 98.0% (95% CI 0.933-0.996), positive predictive value 88.9% (95% CI 0.635-0.978) and negative predictive value 96.0% (95% CI 0.914-0.976). The difference between the pathological examination and ultrasonography, conventional ultrasonography and CEUS was -4.455 ± 2.02 and 2.582 ± 2.298 cm (95% CI -13.11 to -0.96, p = 0.0235); CEUS was near the diameter of the actual pathological examination. CONCLUSION: Contrast-enhanced ultrasonography is suitable for the preoperative examination, especially after PST, to determine the resection margin before breast-conserving surgery and detects pCR, which can help to avoid surgical procedures in the future.