bluuebunny/crossref_metadata_2025 huggingface dataset:
Preventive Effect of Crocin on Osteoporosis in an Ovariectomized Rat Model
Authors: Cao Peng-Chong , Xiao Wen-Xing , Yan Ya-Bo , Zhao Xiong , Liu Shuai , Feng Jing , Zhang Wei , Wang Jun , Feng Ya-Fei , Lei Wei
Published: August 2014

The purpose of this study was to investigate the therapeutic effects of crocin on ovariectomy‐induced osteoporosis in rats. Female Sprague‐Dawley rats were randomly assigned to a sham‐operated group (sham) and five ovariectomy (OVX) subgroups, that is, OVX with vehicle (OVX), OVX with 17β‐estradiol (E2, 25 μg/kg/day), and OVX with graded crocin doses (5, 10, or 20 mg/kg/day). Daily oral administration of E2 or crocin started 4 weeks after OVX and lasted for 16 weeks. Our results showed that crocin dose‐dependently inhibited the BMD reduction of L4 vertebrae and femurs caused by OVX and prevented the deterioration of trabecular microarchitecture, which were accompanied by a significant decrease in skeletal remodeling as evidenced by the lower levels of bone turnover markers. Furthermore, crocin reversed the oxidative stress status in both serum and bone tissue. The present study indicates that the administration of crocin at higher doses over a 16‐week period can prevent OVX‐induced osteoporosis in rats without hyperplastic effects on the uterus, which may, at least partially, be attributed to crocin’s antioxidative property. In brief, crocin is a natural alternative for postmenopausal osteoporosis treatment in elderly women.
A Class of Volterra-Fredholm Type Weakly Singular Difference Inequalities with Power Functions and Their Applications
Authors: Huang Yange , Wang Wu-Sheng , Huang Yong
Published: August 2014

We discuss a class of Volterra-Fredholm type difference inequalities with weakly singular. The upper bounds of the embedded unknown functions are estimated explicitly by analysis techniques. An application of the obtained inequalities to the estimation of Volterra-Fredholm type difference equations is given.
Krein Space-BasedH∞Fault Estimation for Discrete Time-Delay Systems
Authors: Song Xinmin , Yan Xuehua
Published: August 2014

This paper investigates the finite-timeH∞fault estimation problem for linear time-delay systems, where the delay appears in both state and measurement equations. Firstly, the design of finite horizonH∞fault estimation is converted into a minimum problem of certain quadratic form. Then we introduce a stochastic system in Krein space, and a sufficient and necessary condition for the minimum is derived by applying innovation analysis approach and projection theory. Finally, a solution to theH∞fault estimation is obtained by recursively computing a partial difference Riccati equation, which has the same dimension as the original system. Compared with the conventional augmented approach, the solving of a high dimension Riccati equation is avoided.
CNS Involvement in AML Patient Treated with 5-Azacytidine
Authors: Vasilatou Diamantina , Papageorgiou Sotirios , Bazani Efthymia , Prasouli Athina , Economopoulou Christina , Roumpakis Christoforos , Karakitsos Petros , Dimitriadis George , Pappa Vasiliki
Published: August 2014

Central nervous system (CNS) involvement in acute myeloid leukemia (AML) is a rare complication of the disease and is associated with poor prognosis. Sometimes the clinical presentation can be unspecific and the diagnosis can be very challenging. Here we report a case of CNS infiltration in a patient suffering from AML who presented with normal complete blood count and altered mental status.
Abstract BL-2: Brinker Award Lecture: Older Women and Breast Cancer: Challenges and Opportunities
Authors: Muss HB
Published: August 2014

In the United States and other developed nations breast cancer incidence and mortality rates rise dramatically with increasing age. This fact, coupled with the aging of the U.S population is leading to a tsunami of older women with breast cancer. Most oncologists lack training in geriatrics and the frequent comorbidities in older patients along with a new diagnosis of breast cancer makes treatment selection challenging. Little data from clinical trials are available to guide physicians in treatment selection and a paucity of geriatricians makes it difficult to develop comprehensive treatment plans for many older patients. Newer tools that are validated, fast, and user-friendly are now available to help busy clinicians do meaningful geriatric assessments which are necessary for evaluating the medical, functional, cognitive, psychological, and social status of older patients. Such tools can be used to accurately estimate survival in older patients and more recently to predict chemotherapy related toxicity. For older patients, maintenance of independent living and cognitive function are their major goals and such preferences must be taken into consideration when planning treatment. Older women, like younger women, are interested in body image and when possible should be offered breast preservation with lumpectomy and radiation. In some older women treated with lumpectomy and adjuvant endocrine therapy for small tumors that are hormone-receptor positive and lower grade, breast radiation may be omitted with only a small increase in the risk of in-breast recurrence. The majority of older patients with early stage breast cancer have hormone receptor positive, HER-2 negative breast cancers and are excellent candidates for endocrine therapy. The major issue in these patients is defining the potential added value of chemotherapy. Elders with HER-2 positive tumors may be good candidates for chemotherapy and trastuzumab, while for many with “triple-negative” lesions, chemotherapy is the option of choice. Older patients with metastatic breast cancer whose tumors have progressed after endocrine therapy can be considered for palliative chemotherapy and many single agent regimens are well tolerated in this setting. In these patients, making sure they are offered “structured” palliative care as part of their treatment program is integral to maximizing quality of life and possibly even prolonging survival. Lastly, eligible elders should be offered clinical trials participation. Although getting elders on trials remains a challenge, it's essential we work diligently on recruitment so as to obtain meaningful data on outcomes and toxicities of newer treatment regimens. Opportunities for trials of all types abound, not only for testing new treatments, but for defining interventions that minimize toxicity and loss of function. All of us in oncology will need to learn how to care for older cancer patients to provide them with optimal treatment.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr BL-2.
Abstract MS1-3: Clinical Development of mTOR Inhibitors in Breast Cancer
Authors: André F
Published: August 2014

mTOR is a serine/threonine kinase involved in cancer cell metabolism and protein synthesis. mTOR induces phosphorylation of estrogen receptor and resistance to endocrine therapy in preclinical models. Based on this rationale, clinical trials have evaluated whether first generation of mTOR inhibitors could reverse resistance to endocrine therapy. Two randomized trials, including one registration trial, have reported that everolimus improves progression-free survival in patients resistant to non-steroidal aromatase inhibitors. These data are consistent with a phase II randomized trial performed in the neoadjuvant setting. One large phase III trial performed with temsirolimus failed, mainly due to dose intensity of the drug and patient population. Overall, these finding suggest that rapalogs could reverse resistance to endocrine therapy. These data open several avenues in the field of breast cancer.

First, two trials are starting that evaluate the efficacy of everolimus in the adjuvant setting. These trials evaluate everolimus either frontline or after 2–3 years of endocrine therapy.

Second, rapalogs are being tested in other breast cancer subtypes including Her2-overexpressing breast cancers and triple negative breast cancers. Indeed, mTOR has been shown to be involved in trastuzumab resistance in preclinical studies. Early trials have suggested that mTOR inhibition could reverse trastuzumab resistance. mTOR inhibitors have also been shown to synergize with cisplatin in preclinical models, and this combination is currently being evaluated in a phase II randomized trial.

Finally, several mechanisms of resistance to rapalogs have been identified. This includes positive feedback loops and lack of optimal bioactivity on p4EBP1. Rapalogs indeed mediate activating feedback loops that in turn induce a paradoxical activation of kinase pathways. Based on this observation, several trials have started that evaluate the combination between Rapalogs and IGF1R inhibitors. Preliminary results from phase I trial suggest that this combination is active in ER+/highly proliferative disease. Although they induce optimal inhibition of pS6K, several studies have reported that rapalogs could be suboptimal to inhibit p4EBP1, a protein downstream of mTORC1. 4EBP1 is involved in protein synthesis. Second generation mTOR inhibitors (mTORC1/C2 inhibitors) present an increased bioactivity on 4EBP1, in addition to avoid mTORC2-mediated feedback loop. This second generation mTOR inhibitor is being tested in early phase trials.

Overall, rapalogs have opened the path for the development of mTOR inhibitors in the field of breast cancer. This will further improve outcome by exploring new indications and by developing strategies to reverse resistance. Finally, the development of mTOR inhibitors will dramatically increase our knowledge on the role of metabolism and protein translation in cancer progression.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr MS1-3.
Abstract OT1-1-12: NSABP FB-7 Trial: A Phase II Randomized Clinical Trial Evaluating Neoadjuvant Therapy Regimens with Weekly Paclitaxel and Neratinib or Trastuzumab or Neratinib and Trastuzumab Followed by Doxorubicin and Cyclophosphamide with Postoperative Trastuzumab in Women with Locally Advanced HER2-Positive Breast Cancer
Authors: Lu J , Jacobs SA , Buyse ME , Paik S , Wolmark N
Published: August 2014

Neratinib is an oral, small molecule which acts as an irreversible inhibitor of the pan ErbB receptor tyrosine kinase. Dual ErbB blockade combined with chemotherapy improves efficacy in Her-2 positive breast cancer. Both NeoALTTO (Lancet 2012) and Neosphere (Lancet Oncol 2012) trials demonstrated higher pCR for Her-2 positive breast cancer receiving dual anti-Her-2 neoadjuvant blockade therapy. The purpose of this trial is to determine the activity and safety profile of Neratinib as mono-blockade or in combination with Trastuzumab as dual blockade in neoadjuvant therapy of locally advanced breast cancer (stage IIB, III A, B and C).

Methods: This NSABP Foundation Research Program study (FB-7) is designed as a Phase II, multi-center, three arm clinical trial for patients with Her-2 positive locally advanced breast cancer. 126 patients will be enrolled. The initial two- arm study of Neratinib or Trastuzumab in combination with Paclitaxel began in December 2010. 30 patients were enrolled by December of 2011 at which time the study was placed on hold awaiting the recommended phase II dose of the three drug combination, Neratinib, Trastuzamab and Paclitaxel (NSABP FB-8 trial), which is a Phase I dose-escalation study in women with metastatic Her-2 positive breast cancer. The amended FB −7 trial is now a three arm trial of weekly Paclitaxel and Neratinib or Trastuzumab or Neratinib and Trastuzumab for 4 cycles followed by Doxorubicin and Cyclophosphamide for 4 cycles prior to surgical resection. Patients will then receive postoperative Trastuzumb to complete one total year of Her-2 blockade therapy. The primary goal of this study is to determine the pathologic complete response in breast and axillary lymph nodes following completion of neoadjuvant therapy.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr OT1-1-12.
Abstract OT2-2-02: Prospective multicentre study evaluating the effect of impaired tamoxifen metabolization on efficacy in breast cancer patients receiving tamoxifen in the neo-adjuvant or metastatic setting - The CYPTAM-BRUT 2 trial.
Authors: Lintermans A , Dieudonné A-S , Blomme C , Lambrechts D , Wildiers H , Christiaens M-R , Timmerman D , Van Calster B , Decloedt J , Berteloot P , Joerger M , Zaman K , Dezentjé V , Neven P
Published: August 2014

Background: Tamoxifen is often used for the prevention and treatment of hormone receptor positive breast cancer. It is metabolized in the liver through cytochrome P450 (CYP) enzymes to more active metabolites, of which endoxifen is considered the most important. It is known that certain genetic variants in CYP enzymes result in lower serum endoxifen levels, but their effect on tamoxifen efficacy is not yet clear as results remain contradictory.

Trial design: CYPTAM-BRUT 2 is a prospective multicentre open label single arm non randomized observational trial approved by the UZ Leuven Ethics Committee. Eligibility criteria are postmenopausal women with estrogen receptor positive invasive breast cancer receiving tamoxifen as first line therapy in the metastatic or neo-adjuvant setting. Prior adjuvant endocrine therapy is allowed if there is more than 12 months after completion of the adjuvant therapy.

Primary endpoint is the relation between endoxifen levels and objective response rate. Secondary endpoints are the relation between endoxifen levels and the proportion of patients who are failure-free at 6 months, clinical benefit, tolerability of tamoxifen and the predictive value of the tamoxifen activity score, based on the presence of genetic variants and CYP inhibiting drugs. Patients with bone-only lesions will only be included in the analysis of the secondary endpoints.

The trial is designed to show an improvement of the objective tumor response rate from 5% in patients with an unfavorable endoxifen profile (steady-state concentrations < 90nM) to 20% in patients with a favorable endoxifen profile (steady-state concentrations ≥ 90nM). With a type I error of 5% and a power of 90%, 231 patients have to be included into the study. The main secondary study endpoint is progression-free survival (PFS) at 6 months. With a total number 260 patients eligible for PFS, the study has a power of 80% to detect a 20% improvement of PFS at 6 months (i.e. from 50% to 70%) in patients with a favorable endoxifen as compared to patients with an unfavorable endoxifen profile, and a type-I error of 5%.

Patient accrual: Total sample size is 260 and currently 202 patients from 22 participating centres in Belgium and Switzerland are included (May 2012).

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr OT2-2-02.
Abstract OT2-3-10: Phase II study of panitumumab, nab-paclitaxel, and carboplatin for patients with primary inflammatory breast cancer (IBC) without HER2 overexpression
Authors: Willey JS , Alvarez RH , Valero V , Lara JM , Parker CA , Hortobagyi GN , Ueno NT
Published: August 2014

Background: Inflammatory breast cancer (IBC) is the most aggressive form of primary breast cancer. The outcome for patients with IBC is bleak despite multimodality treatment approaches. 10-year disease-free survival rates after combined anthracycline and taxane-containing chemotherapy, surgery, and radiation are only 20%–25%. Our recent study found EGFR overexpression, a predictive factor of poor outcome, in 12 of 40 (30%) patients with IBC. Panitumumab has shown activity against EGFR overexpressing breast cancer xenograft model.

Trial design: This is a single center, open-label, phase II study to evaluate the safety and efficacy of panitumumab in combination with preoperative chemotherapy. The treatment regimen consists panitumumab 2.5 mg/Kg given intravenously alone for the first week, followed by weekly panitumumab, nab-paclitaxel (100mg/m2) and carboplatin (2 AUC) (PNC) for 12 weeks. Patients then will receive 5-FU, epirubicin, and cyclophosphamide (FEC) every 3 weeks for 4 cycles prior to surgery.

Eligibility criteria: 1) Histological confirmation of breast carcinoma with pathologic evidence of dermal lymphatic invasion and clinical diagnosis of IBC, including diffuse erythema, heat, ridging, and peau d'orange; 2) Normal HER2 expression; 3) No prior therapies for IBC; 4) Adequate hematologic, cardiac, renal and hepatic functions.

Specific aims: 1) Primary objective is to determine the pathologic complete response (pCR) rate in patients with primary IBC without HER2 overexpression; 2) Secondary objectives are to determine the disease-free survival (DFS), overall survival (OS), the safety and tolerability of PNC regimens and the correlates of pathologic response rate and EGFR expression level.

Statistical methods: 1) Previous studies have shown that this IBC patient population achieved a 13% pCR rate on the standard of care. We assume a beta (0.26, 1.74) prior distribution for the pCR rate. This prior distribution has a mean of 13% and a standard deviation of 19%. 2) We will stop the trial early if P (pCR rate >/= 13%) is < 0.01. If we determine that there is less than a 1% chance that the pCR rate is 13% or more we will consider stopping the trial. 3) Once we have completed the study we will estimate the pCR rate with a 90% credible interval. If we have pCR in 4 of the 40 patients (10%), then our 90% credible interval for the pCR rate will be 4.0–19.6%. If we have pCR in 8 of the 40 patients (20%), then our 90% credible interval for the pCR rate will be 10.6–30.4%. We will also report the posterior probability that the pCR rate is 13% or more. For example, if we have pCR in 8 of the 40 patients (20%), then the probability that the pCR rate is 13% or more is 0.869.

Present accrual and target accrual: To date, 13 patients have been enrolled. Target accrual is 40 patients.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr OT2-3-10.
Abstract OT3-2-01: Influence of strength and endurance training on selected physical and psychological parameters and on immune system, metabolism and circulating tumor cells during adjuvant chemotherapy
Authors: Mundhenke C , Weisser B , Keller L , Sanders L , Summa B , Duerkop J , Schmidt T , Jonat W
Published: August 2014

Background: Reduced quality of life, limited performance and fatigue are commonly observed side effects of breast cancer systemic treatment. In previous studies sport therapy could improve these symptoms. Sport has also been reported to positively impact the clinical course of the disease. So far it has remained unclear if these influences on clinical outcome are caused by alterations in the immune system or in tumor biology or in glucose or fat metabolism.

The aim of this study is to analyse the implications of individual interventions in exercise therapy on endurance, muscle strength, fatigue and quality of life, alterations in the immune system or in tumor biology or in glucose or fat metabolism for breast cancer patients during chemo therapy.

Method: The trial is prospectively randomised and controlled and will involve 60 breast cancer patients receiving adjuvant chemotherapy. 20 patients each are randomized into a strength training group, an endurance training group or a control group (with standard care). At the beginning and after 12 weeks the following tests are undertaken: isometric maximum strength test, a PWC 150 test to determine the endurance of patients. The standardised questionnaire EORTC QLQ C30 including module BR23 to measure quality of life and the questionnaire MFI-20 to determine symptoms of fatigue are filled in. Questionnair D2 measures ability to concentrate. Immunologic parameters as CD4, CD8 and T-REG-cells (FACS-Analysis), the number of the circulating tumour cells (measured by density gradient centrifugation) and also the concentration of glucose, insulin, leptin and adiponectin are being measured at study entry and after 12 weeks.

Momentarily patients are being screened, recruited and randomised into the trial. The final evaluation of the results is planned II/ 2013.

Discussion: The purpose of this study is to show if additional value can be added by individualized strength- or endurance training. Stabilisation or improvement of maximum strength and endurance during chemotherapy, as well as increase of quality of life and reduction of symptoms of fatigue would be a major improvement. Knowledge about effects of physical activity on circulating tumour cells as well as on immunologic alterations and on glucose and fat metabolism under chemotherapy could lead to a more specific counseling of patients and an individualized training program during chemotherapy.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr OT3-2-01.
Abstract OT3-3-01: Eniluracil + 5-fluorouracil + leucovorin (EFL) vs. capecitabine phase 2 trial for metastatic breast cancer
Authors: Rivera E , Chang JC , Semiglazov V , Gorbunova V , Manikhas A , Krasnozhon D , Kirby G , Spector T
Published: August 2014

Based on a modified dosing protocol designed to optimize efficacy, an open-label EFL vs. capecitabine (4:3 randomization) Phase 2 trial for metastatic breast cancer is in progress. Eniluracil inactivates dihydropyrimidine dehydrogenase, thereby preventing the formation of α-fluoro-β-alanine, and conferring 100% oral bioavailability and a 5 hr half-life on 5-fluorouracil (5-FU). Study drugs are administered orally for 1st- or 2nd-line treatment for metastatic disease in patients previously treated with an anthracycline and a taxane. Arm 1: eniluracil (40 mg) taken 11–16 hr before 5-FU (30 mg/m2); leucovorin (30 mg) taken with 5-FU and the next day. The regimen is administered once/week for 3 weeks/4 weeks. Arm 2: capecitabine (1000 mg/m2) taken bid for 14 days/21days. Arm 2 patients with disease progression could crossover to take EFL in Arm X. Two sites in the USA and 19 in Russia are enrolling. Currently, 115 patients (21% are 1st-line, 70% had previous 5-FU treatment) are enrolled and 83 have had tumor assessments. EFL was well tolerated with no unexpected toxicities. As of May 2012, there were 11, 7, & 1 partial responses in Arms 1, 2, & X, respectively. The primary endpoint, progression-free survival, will be determined approximately 7.5 months after the trial is enrolled with 140 evaluable patients.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr OT3-3-01.
Abstract P1-01-19: Prediction of axillary lymph node status in male breast carcinoma
Authors: Vaysse C , Sroussi J , Mallon P , Feron J-G , Rivain A-L , Ngo C , Belichard C , Lasry S , Pierga J-Y , Couturaud B , Fitoussi A , Laki F , Fourchotte V , Alran S , Kirova YM , Vincent-Salomon A , Sastre-Garau X , Sigal-Zafrani B , Rouzier R , Reyal F
Published: August 2014

Background: To evaluate whether predictive factors of axillary lymph node metastasis in female breast cancer (BC) are similar in male BC.

Patients and methods: From January 1994 to May 2011, we recorded 80 non-metastatic male BC treated at Institut Curie. We analysed the calibration and discrimination performance of two nomograms (Institut Curie (IC), Memorian Sloan-Kettering Cancer Center (MSKCC)) originally designed to predict axillary lymph node metastases in female BC.

Results: 55% and 24% of the tumours were pT1 and pT4 respectively. 46% demonstrated axillary lymph node metastasis. 99% were estrogen receptor positive and 94% HER2 negative. Lymph node status was the only significant prognostic factor of overall survival (p = 0.012). The area under curve (AUC) of IC and MSKCC nomograms were 0.66 (95%CI, 0.54–0.79) and 0.64 (95% CI, 0.52–0.76) respectively. The calibration of these two models was inadequate (Table 1).

Conclusion: Multivariate models designed to predict axillary lymph node metastases for female BC weren't effective in our male BC series. Our results may be explained by a) small sample size b) different biological determinants influencing axillary metastasis in male BC compared to female BC.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-01-19.
Abstract P1-01-20: Clinicopathlogic Analysis of Invasive Breast Carcinoma with Micropapillary Component
Authors: Yamanaka T , Suganuma N , Yamanaka A , Kojima I , Nishiyama S , Mukaibashi T , Nakayama H , Matsuura H , Matsuzu K , Chiba A , Inaba M , Rino Y , Yoshida A , Shimizu S , Masuda M
Published: August 2014

Background: Invasive micropapillary carcinoma(IMPC) is a rare variant of invasive breast cancer that is associated with a high incidence of lymph node(LN) metastasis. But, the meaning of focal micropapillary component has not been fully elucidated.

Methods: We retrospectively reviewed 88 invasive breast carcinoma cases with IMPC and focal micropapillary component.

Results: Sixty-four cases had micropapillary component only in operative specimens, 18 cases had only in core-needle specimens, and 6 cases had in both. Sixteen were diagnosed as IMPC, and 72 cases had focal micropapillary component with other histological type of invasive breast carcinoma; 65 cases with invasive ductal carcinoma, 6 cases with mucinous carcinoma and one with metaplastic carcinoma. There was one male patient. Mean age was 56.5 years old. Median tumor size was 2.5 cm. Forty two (47.7%) cases were nuclear grade(NG)1, 16 (18.2%) were NG2 and 30 (34.1%) were NG3. Seventy eight cases (90%) were ERand/orPgR positive and 18.5% were HER2 positive. Six cases had distant metastasis at initial diagnosis. LN metastases were observed in 63.6% of all cases, and this high rate of LN metastasis could be seen even in small tumor group; 45.5% in cases with tumor equal or less than 2 cm. In the group of IMPC, 40.0% had LN metastasis, and 56.9% in cases with focal micropapillary component. There was no significant difference between IMPC and focal micropapillary component by univariate analysis(p = 0.055). Multivariate analysis of all cases showed that tumor size(>2cm)(p = 0.047), NG(1 vs 2&3, p = 0.017), and lymphatic invasion(p = 0.001) were significantly associated with LN metastasis. No significant difference between IMPC and focal micropapillary component was showed by multivariate analysis also (p = 0.60). Hormone receptor status or HER2 status were also not correlated(p = 0.92, p = 0.27 respectively). Among female patients without neoadjuvant chemotherapy, sentinel lymph node biopsy(SLNB) were underwent in 38 cases, and 16 cases (42.1%) had positive sentinel lymph node(SLN). Fourteen patients underwent additional axillary dissection and 7 cases (50%) had non-SLN metastases. Among patients with SLNB, 12 patients had micropapillary component in needle biopsy specimens, and 6 (50%) cases had positive SLN.

Conclusion: Our data showed very high rate of LN metastasis in patients with micropapillary component, and this tendency still exists in cases with only focal micropapillary pattern. High positivity of SLNB was observed in these groups, and our data suggests that the findings of micropapillary component in CNB specimen could be used as a predictor of SLN metastasis.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-01-20.
Abstract P1-01-23: Increased Diagnostic Performance of Sentinel Lymph Node Biopsy Combined with Radiologic-pathologic Factors After Neoadjuvant Chemotherapy in Breast Cancer Patients with Cytologically Proven Node Metastasis at Diagnosis
Authors: Park S , Koo JS , Kim MJ , Park JM , Cho JH , Hwang H , Park HS , Kim E-K , Kim SI , Park B-W
Published: August 2014

Background: It is undetermined whether sentinel lymph node biopsy (SLNB) is feasible and accurate for predicting final nodal status after neoadjuvant chemotherapy (NCT) in breast cancer patients with cytologically proven node metastasis at the time of diagnosis, although currently completion node dissection is a standard surgical procedure for the management of axilla. The aim of this study was to investigate diagnostic performance of SLNB after NCT in this subgroup.

Methods: Of 374 patients with T1-T3 breast cancer who received NCT, 178 had initially biopsy proven axillary/supraclavicular metastasis and subsequently underwent SLNB using radioisotope alone followed by completion node dissection between 2008 and 2011. Detection rate, sensitivity, false negative rate (FNR), negative predictive value (NPV), and accuracy of SLNB were retrospectively analyzed and it was explored using regression analysis whether combination with clinicopathologic factors improved performance.

Results: At initial presentation, 60.7% of patients were cT2 stage and 88.2% treated with concurrent or sequential anthracycline plus taxane preoperatively. SLNB was successfully performed in 169 (94.9%) patients. The mean number of sentinel and regional nodes retrieved was 2.1 ± 1.6 and 12.8 ± 6.3, respectively. Tumoral non-responder and extensive residual nodal disease were significantly associated with detection failure of SLNB. Conversion to node-negative disease was noted in 69 (40.8%) patients. Sensitivity, FNR, NPV, and accuracy of SLNB were 78.0%, 22.0%, 75.8%, and 87.0%, respectively and diagnostic performance increased when ≥ 3 sentinel nodes were evaluated. By logistic regression model, tumoral and nodal responder, absent lymphovascular invasion (LVI), estrogen receptor (ER)-negativity, and HER2-positivity were significantly associated with node-negative disease after NCT. Area under the receiver operating characteristic curve increased from 0.890 to 0.949 when considering radiologic-pathologic factors and FNR was the lowest value of 14.3% in 46 patients with tumoral responder, absent LVI, and ER-negative tumor.

Conclusions: SLNB was technically feasible but solely showed higher FNR in this study. Improved diagnostic performance of SLNB combined with radiologic-pathologic characteristics suggests possible clinical value of SLNB after NCT in highly selected patients with node metastasis at diagnosis.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-01-23.
Abstract P1-01-24: Which combinations are helpful to predict axillary lymph node metastasis in T1 breast cancer with ultrasonography and contrast-enhanced MRI and contrast-enhanced 18F-FDG PET-CT?
Authors: Hwang SO , Park HY , Jung JH , Kim WW , Lee YH , Lee JJ , Choi HH , Hwangbo SM
Published: August 2014

Backgrounds: Axillary lymph node(ALN) status has been important factor of treatment and prognosis for patients with breast cancer. Even though the better ultrasonographic instruments have been developed, it is still difficult to predict axillary lymh node metastasis (ALNM) with only ultrasonography(US) in T1 breast cancers which most of newly diagnosed breast cancers are recently since T1 breast cancers have low rate and less tumor burden of ALNM. This study evaluated the accuracy of prediction of ALNM in T1 breast cancer with US, contrast-enhanced MRI (cMRI) and contrast-enhanced 18F-FDG PET/CT (cPET/CT) and found out adequate combinations of these modalities.

Method: Retrospectively, we reviewed 351 breast cancer patients with tumors(T1) ≤2cm in size between January 2008 and December 2011 who were preoperatively examined with US, cMRI, and cPET/CT and underwent pathologic evaluation of axillary lymph nodes acquired by sentinel lymph node biopsy or axillary dissection.

Results: 94(26.8%) patients of 351 had ALNM. The sensitivity, specificity, positive predictive value(PPV), negative predictive value (NPV), and accuracy of ALNM with US were 0.457, 0.887, 0.597, 0.817, 0.772, respectively. cMRI had similar results with US. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of ALNM with cPET/CT were 0.447, 0.942, 0.737, 0.823, 0.809, respectively. The sensitivity if any one or more modalities were suspicious was 0.563. The specificity if all modalities were suspicious was 0.992. The PPV if cMRI and cPET/CT were suspicious was highest than if other combinations were suspicious.

Conclusion: US, cMRI, and cPET/CT are helpful in prediction of ALNM of T1 breast cancers. However, there are no definite modality and combination of modalites to predict ALNM of T1 breast cancers.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-01-24.
Abstract P1-01-28: What is the actual impact of micrometastases in sentinel lymph nodes in regards to global survival and disease free survival
Authors: Barbosa EM , Araujo Neto JT , Filho EC , Infante KP , Felzener MM , Matielle CR , Modesto MG , Basso R , Goes JCS
Published: August 2014

OBJECTIVE: Assess the clinical relevance of micro metastasis in sentinel lymph nodes in the overall survival and disease free survival of 1,211 patients undergoing sentinel lymph node biopsy.

METHODS: Retrospective cohort study including 1,211 patients undergoing consecutive SLB from 1998 to 2010. SLB were performed in patients with invasive carcinoma of the breast with clinically negative axilla. Age, tumor size, and histologic grades, estrogen and progesterone receptors expression, HER-2, lymphovascular invasion and size of metastases in lymph nodes were assessed. Tumor sizes were divided according to pathologic staging into pT1(< 2,0mm) and pT2(>2,0mm). Lymph nodes were classified as negative (pN0), positive with micro metastases with diameter ranging from 0,21mm to 2,0mm(pN1mi) and positive with macro metastases with diameter greater than 2,0mm(pN1). Statistical analyses were performed by the Likelihood ratio test or Chi-square test for insufficient samples between macro metastases and micro metastases in SLB. Time was considered in months and the overall follow-up time was 125 months and mean time was 65 months. Local regional and distant recurrences were considered as events for disease free survival and Kaplan-Meier survival functions were constructed, testing time between metastases sizes in SLB using the Log-rank test, with a significance level of 5%.

RESULTS: Of the studied variables, lymphovascular invasion(p = 0,068) and local regional and distant metastases(p = 0,002) had a statistically significant association with overall survival. Tumor size(p = 0,016); lymph vascular invasion(p = 0,002) and metastases types in sentinel lymph node(p < 0,001) were associated to disease free survival. In the association tests with types of metastases in sentinel lymph node, the following were statistically significant: age(p = 0,004), tumor size(p < 0,001), lymph vascular invasion(p < 0,001) and local regional and distant recurrences. In the interim and final Cox regression analysis, macro metastases were the only statistically relevant factor for disease free survival(p < 0,001).

CONCLUSION: The presence of micro metastases(pN1mi) in sentinel lymph node is associated to a prognosis similar to that of negative axilla patients(pN0), indicating that other risk factors for local regional and systemic recurrences should be taken into account.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-01-28.
Abstract P1-04-02: The role of the mTORC1/S6K1 signaling pathway in ER-positive breast cancer.
Authors: Holz MK , Unger HA , Sedletcaia A
Published: August 2014

The mammalian target of rapamycin complex 1 (mTORC1) is a central signaling node in mediating cellular responses to mitogens, hormones and nutrients. The 40S ribosomal S6 kinase 1 (S6K1) is a conserved serine/threonine protein kinase that belongs to the AGC family of protein kinases, which also includes Akt, RSK and many others. S6K1 is the principal kinase effector downstream mTORC1. S6K1 is sensitive to a wide range of signaling inputs, including growth factors, amino acids, energy levels, and hypoxia. S6K1 relays these signals to regulate a growing list of substrates and interacting proteins in control of oncogenic processes, such as cell growth and proliferation, cell survival and apoptosis, and cell migration and invasion.

Growing evidence indicates that there exists a close interaction between the mTORC1/S6K1 pathway and estrogen receptor (ER) signaling. Notably, endocrine resistance is often associated with ligand-independent activation of ERα signaling due to hyperactivation of the mTORC1 signaling pathway, and can be reversed by the mTORC1 inhibitor everolimus in vitro.

Several lines of evidence suggest an important role for S6K1 in ER-positive breast cancer. We demonstrated that S6K1 directly phosphorylates ERα on Ser167, leading to activation of its transcriptional activity. While the MAPK-regulated p90 RSK also contributes to phosphorylation of this site, its contribution is early and transient, while the phosphorylation of Ser167 by S6K1 is prolonged and sustained. Intriguingly, we also found that S6K1 expression is estrogenically regulated. This regulation involves the transcription factor GATA-3 and others. Thus it appears that S6K1 expression is maintained in two modes: a basal level of expression, typical of normal cells, and an estrogen/ERα-dependent specific upregulation. Therefore, there exists a feed-forward regulatory loop whereby S6K1 activates ERα transcriptional activity, leading to increased expression of S6K1. This finding is of great interest since it not only sheds light on the mode of transcriptional regulation of S6K1 expression, but may help understand the role of S6K1 overexpression and activation in the development and progression of breast cancer.

Therefore, hyperactivation of mTORC1/S6K1 signaling may be closely related to ER-positive status in breast cancer, and may be utilized as a marker for prognosis and a therapeutic target.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-04-02.
Abstract P1-05-13: CLIC3 is associated with invasive behaviour and poorer prognosis in estrogen receptor-negative breast cancer.
Authors: Macpherson IR , Dozynkiewicz M , Kalna G , Speirs C , Chaudhary S , Edwards J , Timpson P , Norman J
Published: August 2014

Background: We previously described a Chloride Intracellular Channel-3 (CLIC3)-dependent recycling pathway which trafficked active integrins from late endosomes to the cell surface and which was required for the migratory and invasive behaviour of A2780 ovarian cancer cells in vitro. We also demonstrated that elevated expression of CLIC3 was associated with poor prognosis in pancreatic cancer. We therefore set out to investigate the role of CLIC3 in breast cancer.

Materials and Methods: CLIC3 expression was assessed by immunohistochemistry and the weighted histoscore method in a tissue microarray (TMA) consisting of triplicate cores from 141 patients diagnosed with invasive estrogen receptor (ER)-negative early breast carcinoma between 1995 and 1998. Full clinicopathological and follow-up data were available. Further data were obtained from publicly available gene expression datasets (Desmedt, GSE7390) and Oncomine™. Knockdown of CLIC3 in the ER-ve MDA-MB231 breast cancer cell line was achieved by nucleofection of 2 different siRNA sequences (Dharmacon). Inverse invasion assays measured invasion into a plug of matrigel supplemented with fibronectin over 72 hours whilst organotypic invasion assays measured invasion into a fibroblast-containing collagen matrix over 6 days.

Results: CLIC3 mRNA expression was significantly elevated in breast cancer in comparison to normal breast tissue in two independent data sets. High CLIC3 protein levels were associated with significantly shorter breast cancer specific survival (p = 0.026) in a TMA of 141 ER-ve patients. This finding was corroborated by the observation that high CLIC3 mRNA levels were associated with shorter overall survival in 198 patients in the Desmedt dataset (p = 0.038). Transient silencing of CLIC3 expression using two independent siRNA sequences had no effect on proliferation of MDA-MB231 cells but significantly reduced their invasiveness by 46% and 93% respectively in an inverse invasion assay and by 36% and 42% respectively in an organotypic invasion assay. CLIC3 was found to co-localise with Rab7 and LAMP1 in late endosomes/lysosomes in MDA-MB231 cells.

Conclusions: Our clinical and in vitro data indicate an important role for CLIC3 in the invasive and metastatic behaviour of some breast cancers. Further work to elucidate molecular mechanisms is underway and will be presented.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-05-13.
Abstract P1-05-14: Multiscale computational modeling of breast cancer invasion: Towards a predictive patient-based tool
Authors: Trucu D , Thompson A , Chaplain MAJ
Published: August 2014

Background: Understanding the mechanisms of the growth and spread of cancer cells in the human breast and providing effective treatment continues to remain a significant challenge. Cancer cell invasion of breast tissue plays a pivotal role in the metastatic cascade through complex, coupled dynamics of the constituent processes occurring over a range of spatial and temporal scales, ranging from genetic events through intracellular signaling pathways through cell-matrix interactions to tissue scale changes.

Method: While most previous computational modeling has been carried out at the level of a single spatial or temporal scale, the work presented here has developed a novel multiscale modeling and computational simulation framework. Formulated in both two and three spatial dimensions, this approach is based on a new type of multiscale moving boundary computational model that explores the crucial role that matrix degrading enzymes, secreted by individual cancer cells (micro-scale) along the invasive edge of the tumour, play in the overall dynamics of the tissue-scale invasion (macro-scale).

Results: The computational simulation results we have obtained reveal a rich variety of cancer invasion patterns that emerge in the vicinity of a primary breast cancer. In the presence of heterogeneous tissue, our computational simulation results show well-defined “lobular” and “fingering” invasion patterns, consistent with the spread of a breast carcinoma, and which remain robust with respect to any changes made in the model parameters. These patterns are found to be compatible with respect to both the dynamic heterogeneity of cancer cell macro-scale distributions and to the evolution of the heterogeneity of the surrounding breast tissue.

Conclusions: By exploring the dynamics of the molecular processes of matrix degrading enzymes and of tissue-scale spatio-temporal cancer tissue evolution, this novel multiscale computational modeling framework faithfully replicates the cancer invasion process. Development of this computational tool should allow pre-operative breast cancer patient data to be used to predict the extent of breast cancer invasion and hence the extent of surgical resection.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-05-14.
Abstract P1-13-07: Association Between Delayed Initiation of Adjuvant Chemotherapy and Survival in Breast Cancer: A Single-institution Study and A Systematic Review and Meta-analysis
Authors: Yu K-D , Fan L , Yang C , Shao Z-M
Published: August 2014

Objective: Adjuvant chemotherapy (AC) improves survival among patients with operable breast cancer. However, the effect of delay in AC initiation on survival is unclear. We performed a single-institution data analysis and a systematic review and meta-analysis to determine the relationship between time to AC and survival outcomes.

Methods: PubMed, EMBASE, Cochrane Database of Systematic Reviews, and Web-of-Science databases (before March-20, 2012) were searched to identify relevant eligible studies. An additional retrospective analysis including 1,408 patients from the prospectively maintained database of Shanghai Cancer Center was performed and results were also included. Hazard ratios (HRs) for overall survival (OS) and disease-free survival (DFS) from each study were converted to a regression coefficient (β) and its standard error corresponding to a continuous representation per 4-week delay of AC. Individual adjusted β were combined using a fixed-effects or random-effects model depending on heterogeneity.

Results: We included 8 eligible studies with 10 independent analytical groups involving 21,221 patients, 1 prospective observational study, 2 secondary analyses in randomized trials (4 analytical groups), and 5 hospital-/population-based retrospective studies. In our single-institution study, every 4-week delay in initiation of AC significantly decreased OS (HR = 1.38; 95% confidence interval [CI], 1.03–1.87) and DFS (HR = 1.35; 95% CI, 1.08–1.69) after adjustment for other prognostic variables. The overall meta-analysis demonstrated that a 4-week increase in time to AC was associated with a significant decrease in both OS (HR = 1.20; 95% CI, 1.03–1.39; random-effects model) and DFS (HR = 1.21; 95% CI, 1.08–1.36; fixed-effects model). One study caused a significant between-study heterogeneity for OS (p = 0.001; I2=74.1%); after excluding that single study, there was no heterogeneity (p = 0.345; I2=11.1%) and the HR was more significant (HR = 1.24; 95% CI, 1.14–1.35; P < 0.001; fixed-effects model). Our single-institution data did not fundamentally influence the positive outcomes, since the HR of OS was 1.17 (95% CI, 1.00–1.37; random-effects model) after removing our study. No evidence of publication bias was observed either in OS or in DFS.

Conclusion: The present meta-analysis suggests that longer time to AC was associated with worse survival in breast cancer patients.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-13-07.
Abstract P1-13-09: A multicenter randomized study comparing the dose dense G-CSF-supported sequential administration of FEC followed by docetaxel versus paclitaxel as adjuvant chemotherapy in women with axillary lymph node positive breast cancer.
Authors: Mavroudis D , Malamos N , Boukovinas I , Kakolyris S , Kourousis C , Athanasiadis A , Ziras N , Makrantonakis P , Polyzos A , Christophylakis C , Georgoulias V
Published: August 2014

Purpose: To compare the efficacy of dose dense docetaxel versus paclitaxel following FEC as adjuvant chemotherapy in node positive early breast cancer.

Patients and treatment: Women 18–75 years old with histologically confirmed HER2-negative invasive breast carcinoma surgically resected with at least one infiltrated axillary lymph node and absence of metastatic disease were randomized to receive 4 cycles of fluorouracil (700mg/m2), epirubicin (75mg/m2), cyclophosphamide (700mg/m2) followed by 4 cycles of either docetaxel (75mg/m2) or paclitaxel (175mg/m2). All chemotherapy cycles were administered every 14 days with G-CSF support. Stratification was based on menopausal status, number of involved nodes and hormone receptor expression. The primary endpoint of the study was to compare the disease-free survival (DFS) at 3 years and 239 patients were scheduled to enroll on each arm.

Results: Between 2004–2007, 481 women were randomized and received FEC followed by docetaxel (arm A; n=240) or paclitaxel (arm B; n=241). The median age was 55 years in both arms, premenopausal status 31.3% versus 32.8%, more than 10 involved axillary nodes in 12.9% versus 12.4%, histological grade 3 tumor in 36.3% versus 35.3% and hormone receptor negative disease in 14.6% versus 12% of patients in arms A and B, respectively. After a median follow up of 56.3 and 55.6 months (p = 0.3) for arms A and B, respectively, there were 42 (17.5%) versus 47 (19.5%) disease relapses (p = 0.5) and 20 (8.3%) versus 22 (9.1%) disease-related deaths (p = 0.7), respectively. The 3-year DFS rates were 88.1% versus 87.3% for arms A and B, respectively. Toxicity included grade 2–4 neutropenia in 31% versus 21% (p = 0.01), thrombocytopenia 3.5% versus 0.8% (p = 0.06), febrile neutropenia 2.1% versus 1.2% (p = 0.5), diarrhea 3.7% versus 2.5% (p = 0.4), neurotoxicity 2.9% versus 4.6% (p = 0.3) of patients in arms A and B, respectively. There were no toxic deaths.

Conclusion: The dose dense administration with G-CSF support of FEC followed by either docetaxel or paclitaxel as adjuvant chemotherapy in women with node positive early breast cancer is well tolerated and results in a similar 3-year DFS rate.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-13-09.