[Show abstract][Hide abstract] ABSTRACT: This prospective, controlled study evaluated the safety, tolerability, and efficacy of the mixture of botanical compounds known as LCS101 in preventing chemotherapy-induced hematological toxicity in breast cancer patients.
Female patients diagnosed with localized breast cancer were randomly allocated to receive treatment with either LCS101 or placebo capsules, in addition to conventional chemotherapy. The study intervention was initiated 2 weeks prior to the initiation of chemotherapy and continued until chemotherapy was completed, with participants receiving 2 g of LCS101 capsules thrice daily. Subjects were assessed for the development of hematological and nonhematological toxicities, as well as the tolerability and safety of the study intervention.
Sixty-five breast cancer patients were recruited, with 34 allocated to LCS101 and 31 allocated to placebo treatment. Patients in the treatment group developed significantly less severe (grades 2-4) anemia (p < .01) and leukopenia (p < .03) when comparing grades 0-1 with grades 2-4, with significantly less neutropenia (p < .04) when comparing grades 0-2 with grades 3-4. This effect was more significant among patients undergoing a dose-dense regimen. No statistically significant effect was found with respect to nonhematological toxicities, and side effect rates were not significantly different between the groups, with no severe or life-threatening events observed in either group.
The addition of LCS101 to anthracycline- and taxane-based chemotherapy is safe and well tolerated, and may significantly prevent some chemotherapy-induced hematological toxicities in early breast cancer patients. These results should encourage further larger and more extensive clinical trials.
[Show abstract][Hide abstract] ABSTRACT: The inflammatory chemokines CCL2 (MCP-1) & CCL5 (RANTES) and the inflammatory cytokines TNFα & IL-1β were shown to contribute to breast cancer development and metastasis. In this study, we wished to determine whether there are associations between these factors along stages of breast cancer progression, and to identify the possible implications of these factors to disease course.
The expression of CCL2, CCL5, TNFα and IL-1β was determined by immunohistochemistry in patients diagnosed with: (1) Benign breast disorders (=healthy individuals); (2) Ductal Carcinoma In Situ (DCIS); (3) Invasive Ducal Carcinoma without relapse (IDC-no-relapse); (4) IDC-with-relapse. Based on the results obtained, breast tumor cells were stimulated by the inflammatory cytokines, and epithelial-to-mesenchymal transition (EMT) was determined by flow cytometry, confocal analyses and adhesion, migration and invasion experiments.
CCL2, CCL5, TNFα and IL-1β were expressed at very low incidence in normal breast epithelial cells, but their incidence was significantly elevated in tumor cells of the three groups of cancer patients. Significant associations were found between CCL2 & CCL5 and TNFα & IL-1β in the tumor cells in DCIS and IDC-no-relapse patients. In the IDC-with-relapse group, the expression of CCL2 & CCL5 was accompanied by further elevated incidence of TNFα & IL-1β expression. These results suggest progression-related roles for TNFα and IL-1β in breast cancer, as indeed indicated by the following: (1) Tumors of the IDC-with-relapse group had significantly higher persistence of TNFα and IL-1β compared to tumors of DCIS or IDC-no-relapse; (2) Continuous stimulation of the tumor cells by TNFα (and to some extent IL-1β) has led to EMT in the tumor cells; (3) Combined analyses with relevant clinical parameters suggested that IL-1β acts jointly with other pro-malignancy factors to promote disease relapse.
Our findings suggest that the coordinated expression of CCL2 & CCL5 and TNFα & IL-1β may be important for disease course, and that TNFα & IL-1β may promote disease relapse. Further in vitro and in vivo studies are needed for determination of the joint powers of the four factors in breast cancer, as well as analyses of their combined targeting in breast cancer.
[Show abstract][Hide abstract] ABSTRACT: TNFa and IL-1b up-regulate the release of CCL5 by human breast tumor cells. T47D (A) and MCF-7 (B) human breast tumor cells were stimulated for 24-48 hr with human TNFa or IL-1b. CCL5 levels were determined in the cell supernatants by ELISA, at the linear range of absorbance. The results are representatives of n ≥ 3. **p < 0.01, ***p < 0.001 in comparison to unstimulated cells.
[Show abstract][Hide abstract] ABSTRACT: TNFa and IL-1b up-regulate the release of CCL2 by human breast tumor cells. T47D (A) and MCF-7 (B) human breast tumor cells were stimulated for 24-48 hr with human TNFa or IL-1b. CCL2 levels were determined in the cell supernatants by ELISA, at the linear range of absorbance. The results are representatives of n ≥ 3. *p < 0.05, **p < 0.01 in comparison to unstimulated cells.
[Show abstract][Hide abstract] ABSTRACT: Despite the widespread use of medicinal herbs to prevent and treat many diseases, including cancer, there are insufficient scientific data on the safety and efficacy of the majority of herbal therapies. The aim of this study was to assess the effect of a unique Chinese herbal therapy (CHT) from controlled manufactured concentrated powders, on an in vitro model of breast cancer. Three breast adenocarcinoma cell lines (MDA-231, MDA-453, T47D) were exposed to CHT for 72 h. Cell viability was assessed by XTT (sodium 3'-[1-(phenylaminocarbonyl)-3, 4-tetra zolium]-bis(4-methoxy-6-nitro) benzene sulphonic acid hydrate) assay. Apoptosis and cell cycle stage were determined by fluorescence-activated cell sorting (FACS) analysis. CHT decreased cell survival in a dose-dependent manner in all tested cell lines. FACS analysis of treated and non-treated T47D cells demonstrated that the inhibitory effect of CHT was associated with an increase in apoptosis. A randomized clinical trial is currently underway to investigate CHT as supplementary therapy for breast cancer patients receiving chemotherapy.
Preview · Article · Dec 2010 · The Journal of international medical research
[Show abstract][Hide abstract] ABSTRACT: The chemokines RANTES (CCL5) and MCP-1 (CCL2) were suggested to contribute, independently, to breast malignancy. In the present study, we asked if the two chemokines are jointly expressed in clinical samples of breast cancer patients, and do they interact in breast tumor cells. We found that RANTES and MCP-1 were expressed by breast tumor cells in primary tumors of Ductal Carcinoma In Situ and of Invasive Ductal Carcinoma, but minimally in normal breast epithelial duct cells. The chemokines were also detected in metastases and pleural effusions. Novel findings showed that co-expression of RANTES and MCP-1 in the same tumor was associated with more advanced stages of disease, suggesting that breast tumors “benefit” from interactions between the two chemokines. Accordingly, MCP-1 significantly promoted the release of RANTES from endogenous pre-made vesicles, in an active process that depended on calcium from intracellular and extracellular sources, and on intracellular transport of RANTES towards exocytosis. Our findings show a chemokine-triggered release of stored pro-malignancy chemokine from breast tumor cells. These observations support a major tumor-promoting role for co-expression of the chemokines in breast malignancy, and agree with the significant association of joint RANTES and MCP-1 expression with advanced stages of breast cancer.
[Show abstract][Hide abstract] ABSTRACT: To correlate p53 and ErbB receptors status with disease-free survival (DFS) and overall survival (OS) in locally advanced breast cancer.
Sixty patients were included in a single-center, open-label, phase II trial (1998-2003). Analysis of Erb receptors and p53 status and estrogen receptor/progesterone receptor data were available for 33 patients. Neoadjuvant epirubicin 75 mg/m2 and paclitaxel 175-200 mg/m2 were administered every 21 days. The patients underwent surgery and radiation therapy and adjuvant chemo/hormonotherapy.
Approximately two thirds of the patients demonstrated overexpression of ErbB receptors and had mutant p53 overexpression. The disease recurred in 11/33 patients and 7 died (median follow-up 56 months). Detrimental effects on OS were established in cases of combined defective p53 expression and ErbB1-ErbB3 heterodimeric receptor overexpression. In contrast, normal p53 together with the same overexpressed heterodimeric combination of ErbB receptors showed no statistically significant effect.
In terms of the clinical impact of combinations of ErbB receptors with or without mutant p53, only the overexpressed various ErbB1-ErbB3 dimeric combinations and the ErbB1/ErbB2/ErbB3 triplet combination with mutated p53 were related to a significantly poorer outcome. This observation may help in the development of new strategies required for blocking these molecular pathways and improving the outcome of patients with locally advanced breast cancer.
Preview · Article · Sep 2008 · Anticancer research
[Show abstract][Hide abstract] ABSTRACT: A reverse transcriptase (RT) cDNA, designated HERV-K-T47D-RT, was isolated from a hormonally treated human breast cancer cell line. The protein product putative sequence is 97% identical to the human endogenous HERV-K retroviral sequences. Recombinant T47D-RT protein was used to generate polyclonal antibodies. The expression of HERV-K-T47D-RT protein increased in T47D cells after treatment with estrogen and progesterone. The RT-associated DNA polymerase activity was substantially increased after over-expressing a chimeric YFP-HERV-K-T47D-RT protein in cells. This RT-associated polymerase activity was significantly reduced by mutating the active site sequence YIDD to SIAA. Moreover, the endogenous RT activity observed in T47D cells was decreased by HERV-K-T47D-RT-specific siRNA, confirming the dependence of the endogenous enzymatic activity. To assess HERV-K-T47D-RT expression in human breast tumors, 110 paraffin sections of breast carcinoma biopsies were stained and subjected to confocal analysis. Twenty-six percent (28/110) of the tumor tissues and 18% (15/85) of the adjacent normal tissue, from the same patients, expressed the RT. HERV-K-T47D-RT expression significantly correlates with poor prognosis for disease-free patients and their overall survival. These results imply that HERV-K-T47D-RT might be expressed in early malignancy and might serve as a novel prognostic marker for breast cancer. Furthermore, these results provide evidence for the possible involvement of endogenous retrovirus in human breast carcinoma.
Full-text · Article · Jul 2008 · Neoplasia (New York, N.Y.)
[Show abstract][Hide abstract] ABSTRACT: Over 75% of postmenopausal patients with metastatic breast cancer have hormone receptor-positive tumors. Endocrine therapy, with its more favorable toxicity profile than chemotherapy, is the preferred treatment modality for these patients.
To assess our experience with fulvestrant, an antiestrogen, in an advanced phase of treatment, after progression on the classical anti-estrogen (tamoxifen) and aromatase inhibitors
The study group comprised 46 patients with metastatic breast cancer treated with fulvestrant during the years 2002-2006. Fulvestrant was given monthly until disease progression or unacceptable toxicity.
The median number of fulvestrant cycles was 4.14 (range 1-32). Four patients are still on the treatment. The reasons for treatment discontinuation include disease progression (n=40), refusal (n=1), and allergic reaction (n=1). Ten patients (22%) achieved partial response and 22 (47%) had stable disease. Fourteen (30%) had disease progression with a response rate of 22% and a clinical benefit of 67%, and 14 (30%) had stable disease for > 6 months. Twenty-five patients (54%) are still alive, 4 (9%) without and 21 (45%) with disease progression. With a median follow-up of 15 months (range 1-30.1), the median time to progression was estimated to be 4 months (95% confidence interval 3.1-4.9), and the estimated overall survival 20.1 (95% CI 13.6 to upper limit; not reached yet). The 1 year estimated survival is 67%.
In terms of late-phase administration, fulvestrant still appears to have a good clinical effect, with a time to progression of 4 months and a clinical benefit > 60%, notably accompanied by only very mild toxicity. Irrespective of the line of treatment the patients received, the 4 month time to progression was constant and the medication was still working effectively in a very late line of treatment in metastatic breast cancer. Fulvestrant offers clinical benefit with very mild toxicity in a very heavily pretreated population and the medication is recommended, even in patients who received many lines of chemotherapy.
Preview · Article · May 2008 · The Israel Medical Association journal: IMAJ
[Show abstract][Hide abstract] ABSTRACT: The 21-gene recurrence score (RS) assay has been reported to accurately predict the risk of disease recurrence and chemotherapy benefit in women with estrogen receptor (ER)-positive, lymph node (LN)-negative breast cancer who are treated with tamoxifen. To the authors' knowledge, the association between the RS and clinicopathologic characteristics has been studied in randomized and case-control trials, but not in the general population.
The authors analyzed the correlation between clinicopathologic breast cancer characteristics and RS among 300 consecutive Israeli patients who were referred to undergo the test between October 2004 and October 2006.
Low, intermediate, and high RS were noted in 109 patients (36%), 134 patients (45%), and 57 patients (19%), respectively. The median age of the patients was 54 years and the median tumor size was 1.6 cm. High tumor grade, low progesterone receptor expression, infiltrating ductal histology, and high HER-2 expression were found to be associated with a high RS, whereas patient age, tumor size, ER expression, and lymph node micrometastasis were found to correlate poorly with the RS. The ability of any of these variables, either alone or in combination, to predict the RS was limited. Similarly, neither commonly used guidelines nor the Adjuvant! Online software were found to be able to predict the RS.
The results of the current study suggest that neither standard clinicopathologic features nor commonly used assessment tools can reliably predict the RS among referred breast cancer patients compared with a clinical trial population. These data also may indicate the need for additional studies regarding the role of the RS among certain subsets of breast cancer patients, including those with noninfiltrating ductal carcinoma histology and the presence of lymph node micrometastasis.
[Show abstract][Hide abstract] ABSTRACT: The imaging parameters that mandate further diagnostic workup in focal asymmetric breast densities are not clearly defined.
To identify indications for further workup in FABD by comparing mammographic and ultrasonographic findings with the pathology results of women with FABD.
Ninety-four women (97 FABD) were referred for core needle biopsy after incidental discovery of FABD on routine mammograms (n=83) or on diagnostic mammograms performed for palpable masses (n=11). Clinical data included the patient's age, use of hormone replacement therapy, family history of breast cancer, and the presence of a palpable mass. Mammograms and sonograms were evaluated for lesion size and location, associated calcifications, architectural distortion, and change from previous examinations when available. Two patient groups emerged according to the pathological findings and the data were compared.
The average age, size and location of the lesions in the malignant (n=5) and benign (n=92) groups were similar. There was a significant difference (P<0.05) for the presence of a clinically palpable mass (60% vs. 9%, respectively), a cluster of calcifications (60% vs. 12%), associated architectural distortion (exclusively in the malignant group) and a solid mass on sonography (50% vs. 9%). The malignant group had a higher rate of family history of breast cancer and HRT use.
FABD usually present a benign etiology and can safely be managed by follow-up. The presence of an architectural distortion, a cluster of malignant-appearing or indeterminate calcifications, a sonographic mass with features of possible malignancy, or a clinically palpable mass mandates tissue diagnosis.
Full-text · Article · Oct 2007 · The Israel Medical Association journal: IMAJ
[Show abstract][Hide abstract] ABSTRACT: To determine the frequency of visually asymptomatic choroidal metastases in patients with disseminated breast and lung carcinomas in order to establish optimal patient management policies.
All patients with confirmed metastatic disease treated in our institution between January 2002 and December 2003 were invited to undergo a funduscopic examination and a B-scan ultrasound evaluation.
Of the 169 study participants, 77 had breast cancer (64 with metastases in one organ and 13 with multiple-organ involvement) and 92 had lung cancer (85 with metastases in one organ and 7 with multiple-organ involvement). No patient with metastatic breast cancer and two patients with metastatic lung disease (each with multiple-organ involvement) were found to have choroidal metastases. The choroidal metastases were detected by both the funduscopic and ultrasound examinations.
The 2.17% incidence of choroidal metastasis in disseminated lung cancer and the 0% incidence in disseminated breast cancer speaks against the practicality of screening for early detection of choroidal metastasis among these patients, even though it would lead to early implementation of appropriate, often vision saving, therapeutic management. Its low incidence probably testifies to progress achieved by enhanced systemic oncological treatment policies that have been introduced into routine patient management over the past few years.
Full-text · Article · Feb 2007 · British Journal of Ophthalmology
[Show abstract][Hide abstract] ABSTRACT: Five-year survival of patients with stage IV epithelial ovarian carcinoma not treated after recurrence is almost non-existent in oncological literature. The authors report a patient almost 30 years after surgery of the primary epithelial ovarian carcinoma lesion and 15 years after recurrent disease and incomplete chemotherapy who is alive without evidence of disease. She received no conventional oncological therapy during the past 15 years but rather used many types of alternative medicine, predominantly mind body therapies. The authors review the relevant literature on this subject and describe what they believe to be the first report of long-term survival of such a patient.
No preview · Article · Jan 2007 · Integrative Cancer Therapies
[Show abstract][Hide abstract] ABSTRACT: The aim of this study was to determine the prognostic value of the chemokine CCL5, considered as a promalignancy factor in breast cancer, in predicting breast cancer progression and to evaluate its ability to strengthen the prognostic significance of other biomarkers.
The expression of CCL5, alone and in conjunction with estrogen receptor (ER)-alpha, ER-beta, progesterone receptor (PR), and HER-2/neu (ErbB2), was determined in breast tumor cells by immunohistochemistry. The study included 142 breast cancer patients, including individuals in whom disease has progressed.
Using Cox proportional hazard models, univariate analysis suggested that, in stage I breast cancer patients, CCL5 was not a significant predictor of disease progression. In contrast, in stage II patients, the expression of CCL5 (CCL5(+)), the absence of ER-alpha (ER-alpha(-)), and the lack of PR expression (PR(-)) increased significantly the risk for disease progression (P = 0.0045, 0.0041, and 0.0107, respectively). The prognostic strength of CCL5, as well as of ER-alpha(-), improved by combining them together (CCL5(+)/ER-alpha(-): P = 0.0001), being highly evident in the stage IIA subgroup [CCL5(+)/ER-alpha(-) (P = 0.0003); ER-alpha(-) (P = 0.0315)]. In the stage II group as a whole, the combinations of CCL5(-)/ER-alpha(+) and CCL5(-)/PR(+) were highly correlated with an improved prognosis. Multivariate analysis indicated that, in stage II patients, ER-alpha and CCL5 were independent predictors of disease progression.
CCL5 could be considered as a biomarker for disease progression in stage II breast cancer patients, with the CCL5(+)/ER-alpha(-) combination providing improved prediction of disease progression, primarily in the stage IIA subgroup.
No preview · Article · Sep 2006 · Clinical Cancer Research
[Show abstract][Hide abstract] ABSTRACT: The current methods for pre- and post-chemotherapy examination of the extent of disease in the breast and lymph nodes do not provide sufficiently accurate information and, not infrequently, the surgeon has to re-operate.
To correlate the findings between three methods of examination (physical examination, ultrasonography, mammography), all performed by the same oncologic and radiologic team, in patients with locally advanced breast cancer or a tumor/breast tissue ratio that precludes breast-conserving surgery.
Forty patients (median age 48 years, range 24-73) with locally advanced breast cancer or with a tumor/breast ratio that precluded breast-conserving surgery were evaluated by the same medical team and received neoadjuvant chemotherapy. Surgery was performed in all, and the pathologic specimen was correlated with the results of the other examinations.
In the pre-chemotherapy evaluation, the imaging findings of the breast correlated with the physical findings in 78% of the patients and with the axilla examination in 66.7%. In the post-chemotherapy analysis, imaging agreed with the physical findings of the breast in 62.2% and in 76.3% of the axilla. Sonography best detected occult breast disease and axillary lymph nodes but correlated with pathology in only 58% of the patients in diagnosing breast tumor and in 65.8% in diagnosing axillary lymph nodes. Mammography correlated with breast and lymph node pathology in half the patients.
None of the classical methods of post-neoadjuvant chemotherapy evaluations could adequately delineate the actual extent of the disease in the breast and axillary lymph nodes. More exacting techniques of imaging combined with the classical methods are required.
Preview · Article · Jun 2006 · The Israel Medical Association journal: IMAJ