Collaborative Initiatives in the Care of Early Stage Breast Cancer: Reduction in Variation of Breast-Conserving Therapy

The Breast Journal. Mar, 2000  |  Pubmed ID: 11348345

Breast-conserving therapy (BCT) has survival results comparable to those obtained with modified radical mastectomy (MST). However, studies suggest variations in the rates of breast-conserving therapy that are not explained by comorbidities or age. The Virginia Health Quality Center collaborated with 40 Virginia hospitals to address patterns of breast cancer treatment. Medicare Peer Review Organization data files were used to identify all Medicare beneficiaries with a primary diagnosis of breast cancer from January 1, 1992, through June 30, 1993. Explicit chart review was performed on a random sample of patients with early stage disease receiving either BCT or MST. At baseline, the BCT rate was 21.1% after controlling for access to radiation facilities, medical conditions, and demographic variables. Hospitals with the highest rates of appropriate BCT served as resources for the project. We provided data on BCT rates to 40 participating hospitals. Hospitals then submitted comprehensive plans to address the performance of BCT. A four-step cooperative improvement intervention was employed to initiate and sustain changes at the hospital level. Interventions included individual hospital feedback, dissemination of model cancer care processes at high-performing institutions, and integration of oncology services for breast cancer treatment decisions. One year after implementation, the overall BCT rate in Virginia increased to 25.5%. Hospitals with the lowest BCT rates increased their average rate from 6.6% to 21.2%. Middle tercile hospitals increased BCT rates by 10%. Variation between the lowest and highest terciles was reduced to 9%. Variation in BCT rates can be reduced by a collaborative program centered on addressing processes of care for breast cancer treatment for Medicare patients with early stage disease.

Sentinel Node Mapping Identifies Vaccine-draining Lymph Nodes with Tumor-specific Immunological Activity

Annals of Surgical Oncology. Jan-Feb, 2002  |  Pubmed ID: 11829435

Adoptive immunotherapy (AIT) with 4T07-IL2 vaccine-draining lymph node (DLN) cells induced regression of established 4T07 mammary carcinomas, but contralateral non-DLN were inactive. These experiments were performed to determine whether mapping with isosulfan blue (IB), as described for identification of sentinel nodes, would identify vaccine-DLN with antitumor activity.

Earlier Chemotherapy for Breast Cancer: Perhaps Too Late but Still Useful

Annals of Surgical Oncology. May, 2003  |  Pubmed ID: 12734078

Taking Action on the Volume-quality Relationship: How Long Can We Hide Our Heads in the Colostomy Bag?

Journal of the National Cancer Institute. May, 2003  |  Pubmed ID: 12759377

Partial Breast Brachytherapy After Lumpectomy: Low-dose-rate and High-dose-rate Experience

International Journal of Radiation Oncology, Biology, Physics. Jul, 2003  |  Pubmed ID: 12788173

The use of partial breast brachytherapy (PBB) after lumpectomy for selected patients with early-stage breast cancer reduces the adjuvant radiotherapy treatment time to <1 week. Despite the advantages of accelerated treatment, maintaining an acceptable cosmetic outcome is important. In a cohort of patients who received low-dose-rate (LDR) or high-dose-rate (HDR) PBB after lumpectomy, the clinical characteristics and treatment parameters were analyzed to identify predictors for an unfavorable cosmetic outcome.

Successful Adoptive Immunotherapy with Vaccine-sensitized T Cells, Despite No Effect with Vaccination Alone in a Weakly Immunogenic Tumor Model

Cancer Immunology, Immunotherapy : CII. Dec, 2003  |  Pubmed ID: 12827306

Tumor cell vaccines have been successful at inducing immunity in naïve mice, but only in a few reports has vaccination alone induced regression of established tumors and, generally, only when they are very small. Clinically, vaccinations alone may not be able to cause regression of established human cancers, which tend to be weakly immunogenic. We hypothesized that pharmacologic ex vivo amplification of a vaccination-induced immune response with subsequent adoptive immunotherapy (AIT) to tumor-bearing animals would be more effective in treatment of these animals than vaccination alone. The 4T1 and 4T07 mammary carcinomas are derived from the same parental cell line, but 4T1 is much less immunogenic and more aggressive than 4T07. Vaccination with either 4T1, 4T1-IL-2, or 4T07-IL-2 was not effective as treatment for established 4T1 tumors. However, 4T1 or 4T07-IL-2-vaccine-sensitized draining lymph node (DLN) cells, activated ex vivo with bryostatin 1 and ionomycin and expanded in culture, induced complete tumor regressions when adoptively transferred to 4T1 tumor-bearing animals. This was effective against small tumors as well as more advanced tumors, 10 days after tumor cell inoculation. Furthermore, as would be required for this approach to be used clinically, vaccine-DLN cells obtained from mice with established progressive 4T1 tumors (inoculated 10 days before vaccination) also induced regression of 4T1 tumors in an adoptive host. In none of these experiments was exogenous IL-2 required to induce tumor regression. The response to tumor cell vaccine can be amplified by ex vivo pharmacologic activation of sensitized T cells, which can then cure an established, weakly immunogenic and highly aggressive tumor that was resistant to vaccination alone.

Emerging Role of Taxanes in Adjuvant and Neoadjuvant Therapy for Breast Cancer: the Potential and the Questions

The Surgical Clinics of North America. Aug, 2003  |  Pubmed ID: 12875604

Adjuvant chemotherapy has gained increasing prominence in the treatment of nonmetastatic breast cancer, producing gradual improvement in the survival of these patients. The taxanes offer great hope for adding to the progress in adjuvant treatment, but data have been conflicting. Early results of multi-center trials testing the sequential addition of paclitaxel to anthracycline-based adjuvant chemotherapy have perhaps been prematurely reported, but have already made a major impact on patterns of care for node-positive and even some node-negative patients. The early dramatic improvements in CALG 9344 are fading with time, however, and have not been confirmed by a second similar trial, NSABP B-28. Moreover, it cannot be stated with certainty whether the modest improvements observed by sequential addition of paclitaxel reflect the ability of this drug to kill anthracycline-resistant cancer cells or the increased total duration and amount of treatment. By contrast, the early results of the BCIRG 001 trial suggest that combining docetaxel with doxorubicin may significantly increase survival, but these early results should be viewed with caution and do not necessarily mean that docetaxel is superior to paclitaxel. The role of neoadjuvant chemotherapy for breast cancer has also expanded over the past 2 decades, from its initial use for inoperable locally advanced breast cancer (LABC) to its current use for patients with large operable tumors to make BCT feasible. The neoadjuvant approach also has an important role in clinical trials, where it will allow more rapid comparison of treatment regimens than can be accomplished in the adjuvant setting and provides an opportunity to analyze biologic markers as predictors of response. The value of this approach, however, will ultimately depend on a clear demonstration, not yet available, that a change in therapy that increases primary tumor response will also lead to improved long-term survival. The roles of docetaxel and paclitaxel in the neoadjuvant setting has been actively investigated over the past 5 to 10 years, and exciting results are beginning to emerge. Clearly, docetaxel has potent antitumor activity against breast cancer. Several preliminary results suggest that addition of docetaxel to an anthracycline-based regimen, particularly when added sequentially, as in NASBP B-27 and the Aberdeen trial, results in higher clinical and pathologic response rates. Whether this will translate into increased long-term survival, as suggested by the early results of the Aberdeen trial, remains to be seen. Whether sequential addition of docetaxel to doxorubicin is more or less effective than combining these drugs also has not been established. The results from M.D. Anderson suggesting that paclitaxel given on a weekly schedule was more effective than the same drug given every 3 weeks are particularly intriguing, and they may help to explain why the adjuvant studies with paclitaxel given every 3 weeks have not produced more dramatic results, whereas several studies with docetaxel (also given every 3 weeks) seem so positive. It may be that paclitaxel, with activity that is highly schedule-dependent and for which cell killing is more dependent on the duration of exposure, works best when given weekly, whereas the efficacy of docetaxel depends less on scheduling. If this is the case, then weekly paclitaxel may turn out to be equally effective as docetaxel appears to be even when given every 3 weeks. Alternatively, if docetaxel is simply a more active drug, then giving docetaxel weekly may be the most effective taxane regimen. Whether routine use of weekly chemotherapy administration in the adjuvant or neoadjuvant setting is practical or not is largely subjective, but at least it appears that the toxicity of this approach is acceptable. These issues are also being addressed in ongoing trials. Finally, taxanes have produced dramatic increases in response rates in the neoadjuvant setting, but, except for the Aberdeen trial, survival benefits have not yet been shown. If, however, the high pCR rates do translate into overall survival benefits that are greater than adding taxanes to postoperative adjuvant therapy, it might suggest that, unlike other drugs, taxanes are actually more effective before surgery than after, as predicted originally based on laboratory experiments. Clearly, much work remains to be done in this area of research on breast cancer therapy.

The Impact of Physician and Hospital Volume on the Quality of Surgical Outcomes

Journal of Surgical Oncology. Oct, 2003  |  Pubmed ID: 14502775

Breast Conservation Therapy Rates Are No Different in Medically Indigent Versus Insured Patients with Early Stage Breast Cancer

Journal of Surgical Oncology. Oct, 2003  |  Pubmed ID: 14502777

Multiple prospective, randomized studies show that breast conservation therapy (BCT) results in survival rates equal to mastectomy (Mx) for patients with early stage breast cancer (ESBC). Nevertheless, BCT remains underused in certain areas of the nation, without clearly definable reasons. Several studies have implicated socioeconomic status as one potential cause for this disparity in BCT usage. We sought to compare BCT rates in the medically indigent versus insured patients, within the same institution.

The Effect on Tumor Response of Adding Sequential Preoperative Docetaxel to Preoperative Doxorubicin and Cyclophosphamide: Preliminary Results from National Surgical Adjuvant Breast and Bowel Project Protocol B-27

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. Nov, 2003  |  Pubmed ID: 14559892

The National Surgical Adjuvant Breast and Bowel Project Protocol B-27 was designed to determine the effect of adding docetaxel after four cycles of preoperative doxorubicin and cyclophosphamide (AC) on clinical and pathological response rates and on disease-free and overall survival of women with operable breast cancer.

Bryostatin 1/ionomycin (B/I) Ex Vivo Stimulation Preferentially Activates L-selectinlow Tumor-sensitized Lymphocytes

International Immunology. Sep, 2004  |  Pubmed ID: 15262898

We have shown that tumor vaccine-sensitized draining lymph node (vDLN) cells activated ex vivo with bryostatin and ionomycin (B/I) were capable of inducing antigen-specific regression of a murine mammary tumor, 4T07. vDLN cells not activated with B/I were ineffective. We hypothesized that B/I selectively activates tumor-sensitized (CD62Llow) lymphocytes, to account for the highly potent and tumor-specific activity. We hypothesized that CD8+ CD62Llow cells may be preferentially activated by B/I treatment, infiltrate the tumors and mediate tumor regression in mice. 4T07-IL2 tumor cells were injected into one hind footpad of BALB/c mice. Ten days later, vDLN were harvested and separated based on CD62L expression. After separation, cells were activated with B/I, expanded with IL2 (40 IU/ml) for 10 days, and adoptively transferred to 4T07 tumor bearing mice. Naive mice were also treated with different subsets of T cells and later were challenged with 4T07 tumor cells. To test in vitro responses to antigen, expanded lymphocytes were cultured either alone or with irradiated 4T07 tumor cells. Supernatants were harvested after 24 h and tested by ELISA for IFN-gamma. The importance of the host immune response was tested by AIT into 4T07-bearing nude athymic mice. Host mice were depleted in vivo of CD4 or CD8 T cells after vDLN AIT to ascertain the mediators of tumor regression. In order to track B/I activated vDLN cells, they were prestained with CFSE prior to adoptive transfer into tumor-bearing hosts. At various time points, tumors, spleens and lymph nodes of host mice were harvested, dual stained for activation marker expression and analyzed by flow cytometry. CD62Llow cells expanded 12-fold more than CD62Lhigh lymphocytes during the 10 day culture period. Supernatant from CD62Llow cells + 4T07 cultures contained 33-fold more IFN-gamma than supernatant from CD62Lhigh cells + 4T07 cultures (843.9 pg/ml +/- 135.8 vs 25.89 pg/ml +/- 0.01). Adoptive transfer of CD62Llow lymphocytes induced complete tumor regressions in all mice, while tumors regressed in only 17% of mice treated with CD62Lhigh lymphocytes. Naive mice that received B/I-activated CD62Llow cells were protected from future tumor challenges, while mice given CD62Lhigh cells did not exhibit the same resistance to tumor growth. Tumors in nude host mice regressed after AIT treatment. In vivo depletion of CD4 T cells after AIT did not inhibit tumor regression, but CD8 T cell depletion abrogated tumor regression. vDLN cells tracked preferentially to tumor draining lymph nodes and proliferated in vivo, persisting for at least 21 days, and were 95% CD44+ and 39% CD69+. Bryostatin 1 and ionomycin, by increasing PKC activity and intracellular calcium, respectively, mimic intracellular signals that result in T cell activation. CD62Llow cells are preferentially activated by B/I, leading to a highly effective anti-tumor T cell population.

Sentinel Node Biopsy After Neoadjuvant Chemotherapy in Breast Cancer: Results from National Surgical Adjuvant Breast and Bowel Project Protocol B-27

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. Apr, 2005  |  Pubmed ID: 15837984

Experience with sentinel node biopsy (SNB) after neoadjuvant chemotherapy is limited. We examined the feasibility and accuracy of this procedure within a randomized trial in patients treated with neoadjuvant chemotherapy.

Walter Lawrence, Jr.: a Tribute to a Surgical Oncologist. "Been There, Done That"

Journal of Surgical Oncology. Jun, 2005  |  Pubmed ID: 15895456

Sentinel Node Micrometastases and Non-sentinel Nodes in Breast Cancer: How Much Do We Need to Know?

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. Apr, 2006  |  Pubmed ID: 16567763

Sequential Preoperative or Postoperative Docetaxel Added to Preoperative Doxorubicin Plus Cyclophosphamide for Operable Breast Cancer:National Surgical Adjuvant Breast and Bowel Project Protocol B-27

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. May, 2006  |  Pubmed ID: 16606972

This study was designed to determine the effect of adding docetaxel (T) to preoperative doxorubicin and cyclophosphamide (AC) on breast cancer response rates and disease-free survival (DFS) and overall survival (OS).

Tumor Bed Boost Omission After Negative Re-excision in Breast-conservation Treatment

Annals of Surgical Oncology. Jun, 2006  |  Pubmed ID: 16614879

We evaluated the necessity of a tumor bed boost after whole-breast radiotherapy for early-stage breast cancer after breast-conserving surgery and negative re-excision.

Reaping the Harvest from Neoadjuvant Therapy for Breast Cancer: Reducing Morbidity with Sentinel Lymph Node Biopsy

Journal of Surgical Oncology. Jun, 2007  |  Pubmed ID: 17192916

Imaging Multidrug Resistance with 4-[18F]fluoropaclitaxel

Nuclear Medicine and Biology. Oct, 2007  |  Pubmed ID: 17921033

Multidrug resistance (MDR) is a cause of treatment failure in many cancer patients. MDR refers to a phenotype whereby a tumor is resistant to a large number of natural chemotherapeutic drugs. Having prior knowledge of the presence of such resistance would decrease morbidity from unsuccessful therapy and allow for the selection of individuals who may benefit from the coadministration of MDR-inhibiting drugs. The Tc-99m-labeled single-photon-emitting radiotracers sestamibi and tetrofosmin have shown some predictive value. However, positron-emitting radiotracers, which allow for dynamic quantitative imaging, hold promise for a more accurate and specific identification of MDRtumors.MDR-expressing tumors are resistant to paclitaxel, which is commonly used as a chemotherapeutic agent. 4-[18F]Fluoropaclitaxel (FPAC) is a PET-radiolabeled analogue of paclitaxel. Preclinical studies have shown the uptake of FPAC to be inversely proportional to tumor MDR expression. FPAC PET imaging in normal volunteers shows biodistribution to be similar to that in nonhuman primates. Imaging in a breast cancer patient showed FPAC localization in a primary tumor that responded to chemotherapy, while failure to localize in mediastinal disease corresponded with only partial response.FPAC PET imaging shows promise for the noninvasive pretreatment identification of MDR-expressing tumors. While much additional work is needed, this work represents a step toward image-guided personalized medicine.

Preoperative Chemotherapy: Updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. Feb, 2008  |  Pubmed ID: 18258986

National Surgical Adjuvant Breast and Bowel Project (NSABP) Protocol B-18 was designed to determine whether four cycles of doxorubicin and cyclophosphamide (AC) administered preoperatively improved breast cancer disease-free survival (DFS) and overall survival (OS) compared with AC administered postoperatively. Protocol B-27 was designed to determine the effect of adding docetaxel (T) to preoperative AC on tumor response rates, DFS, and OS.

Statement of the Science Concerning Locoregional Treatments After Preoperative Chemotherapy for Breast Cancer: a National Cancer Institute Conference

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. Feb, 2008  |  Pubmed ID: 18258988

To review the state of the science with respect to diagnostic imaging and locoregional therapy for patients with breast cancer receiving preoperative chemotherapy.

Measuring Circulating Tumor Cells As a Surrogate End Point for Adjuvant Therapy of Breast Cancer: What Do They Mean and What Should We Do About Them?

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. Mar, 2008  |  Pubmed ID: 18323543

Signatures Associated with Rejection or Recurrence in HER-2/neu-positive Mammary Tumors

Cancer Research. Apr, 2008  |  Pubmed ID: 18381452

We have previously shown T-cell-mediated rejection of the neu-overexpressing mammary carcinoma cells (MMC) in wild-type FVB mice. However, following rejection of primary tumors, a fraction of animals experienced a recurrence of a neu antigen-negative variant (ANV) of MMC (tumor evasion model) after a long latency period. In the present study, we determined that T cells derived from wild-type FVB mice can specifically recognize MMC by secreting IFN-gamma and can induce apoptosis of MMC in vitro. Neu transgenic (FVBN202) mice develop spontaneous tumors and cannot reject it (tumor tolerance model). To dissect the mechanisms associated with rejection or tolerance of MMC tumors, we compared transcriptional patterns within the tumor microenvironment of MMC undergoing rejection with those that resisted it either because of tumor evasion/antigen loss recurrence (ANV tumors) or because of intrinsic tolerance mechanisms displayed by the transgenic mice. Gene profiling confirmed that immune rejection is primarily mediated through activation of IFN-stimulated genes and T-cell effector mechanisms. The tumor evasion model showed combined activation of Th1 and Th2 with a deviation toward Th2 and humoral immune responses that failed to achieve rejection likely because of lack of target antigen. Interestingly, the tumor tolerance model instead displayed immune suppression pathways through activation of regulatory mechanisms that included in particular the overexpression of interleukin-10 (IL-10), IL-10 receptor, and suppressor of cytokine signaling (SOCS)-1 and SOCS-3. These data provide a road map for the identification of novel biomarkers of immune responsiveness in clinical trials.

Completion Axillary Lymph Node Dissection for Breast Cancer: Immediate Versus Delayed Versus None

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. Jul, 2008  |  Pubmed ID: 18640928

Adoptive Transfer of HER2/neu-specific T Cells Expanded with Alternating Gamma Chain Cytokines Mediate Tumor Regression when Combined with the Depletion of Myeloid-derived Suppressor Cells

Cancer Immunology, Immunotherapy : CII. Jun, 2009  |  Pubmed ID: 18979098

Adoptive immunotherapy (AIT) using ex vivo-expanded HER-2/neu-specific T cells has shown initial promising results against disseminated tumor cells in the bone marrow. However, it has failed to promote objective responses against primary tumors. We report for the first time that alternating gamma chain cytokines (IL-2, IL-7 and IL-15) ex vivo can expand the neu-specific lymphocytes that can kill breast tumors in vitro. However, the anti-tumor efficacy of these neu-specific T cells was compromised by the increased levels of myeloid-derived suppressor cells (MDSC) during the premalignant stage in FVBN202 transgenic mouse model of breast carcinoma. Combination of AIT with the depletion of MDSC, in vivo, resulted in the regression of neu positive primary tumors. Importantly, neu-specific antibody responses were restored only when AIT was combined with the depletion of MDSC. In vitro studies determined that MDSC caused inhibition of T cell proliferation in a contact-dependent manner. Together, these results suggest that combination of AIT with depletion or inhibition of MDSC could lead to the regression of mammary tumors.

Gemcitabine Directly Inhibits Myeloid Derived Suppressor Cells in BALB/c Mice Bearing 4T1 Mammary Carcinoma and Augments Expansion of T Cells from Tumor-bearing Mice

International Immunopharmacology. Jul, 2009  |  Pubmed ID: 19336265

Myeloid derived suppressor cells (MDSCs) accumulate in 4T1 mammary carcinoma bearing mice and present a barrier to the success of adoptive immunotherapy (AIT) by suppressing T cell immunity. In this study, we investigated the inhibition of MDSCs by gemcitabine (GEM), a chemotherapy agent that may have favorable immunologic effects. BALB/c mice were inoculated with 4T1 mammary carcinoma cells and treated with GEM either once a week starting 5 days after tumor inoculation (EARLY GEM) or as a single dose at days 20-25 (LATE GEM). Splenic mononuclear cells were isolated, activated in vitro, expanded, and stimulated with tumor antigen. T cells were then used for AIT to treat tumor-bearing mice. EARLY GEM treatment of 4T1 tumor-bearing mice significantly inhibited tumor growth, reduced splenomegaly, and significantly decreased MDSC proportion in the spleen. Support for a direct effect was demonstrated through suppression of MDSCs in spleens, bone marrow, and blood harvested 24 and 48 h after LATE GEM treatment, despite no significant decrease in tumor burden. Interestingly, treatment of tumor-bearing mice with GEM augmented in vitro expansion of splenic T cells and boosted IFN-gamma secretion in response to stimulation by tumor antigen. However, despite GEM-mediated inhibition of MDSC suppression, splenic T cells from mice with advanced tumors were ineffective in vivo against established tumors. This study provides support for direct inhibition of MDSCs and direct reduction of tumor burden by GEM in 4T1 tumor-bearing mice. GEM treatment of mice with advanced tumors improves T cell function and growth in vitro.

Human T Cells Express CD25 and Foxp3 Upon Activation and Exhibit Effector/memory Phenotypes Without Any Regulatory/suppressor Function

Journal of Translational Medicine. 2009  |  Pubmed ID: 19849846

Foxp3 has been suggested to be a standard marker for murine Tregs whereas its role as marker for human Tregs is controversial. While some reports have shown that human Foxp3+ T cells had no regulatory function others have shown their role in the inhibition of T cell proliferation.

Radiofrequency Thermal Ablation of Breast Tumors Combined with Intralesional Administration of IL-7 and IL-15 Augments Anti-tumor Immune Responses and Inhibits Tumor Development and Metastasis

Breast Cancer Research and Treatment. Apr, 2009  |  Pubmed ID: 18425677

Tumor development or recurrence is always a matter of concern following radiofrequency thermal ablation (RFA) of tumors. To determine whether combining RFA with immunologically active cytokines might induce tumor-specific immune responses against mammary carcinoma and inhibit tumor development or metastasis, we evaluated intralesional injection of IL-7 and IL-15 in RFA-treated murine tumors. We used two different breast carcinoma models: neu-overexpressing mouse mammary carcinoma (MMC) in FVBN202 transgenic mouse and 4T1 tumors in Balb/c mouse. MMC tend to relapse even in the presence of neu-specific immune responses, and 4T1 is a weakly immunogenic, aggressive and highly metastatic transplantable tumor. In vivo growth of both of these tumors is also associated with increased numbers of CD11b+Gr1+ myeloid-derived suppressor cells (MDSC). We showed for the first time that unlike RFA alone, RFA combined with the administration of intralesional IL-7 and IL-15 (after RFA), induced immune responses to tumors, inhibited tumor development and lung metastasis, and reduced MDSC.

GM-CSF is One of the Main Breast Tumor-derived Soluble Factors Involved in the Differentiation of CD11b-Gr1- Bone Marrow Progenitor Cells into Myeloid-derived Suppressor Cells

Breast Cancer Research and Treatment. Aug, 2010  |  Pubmed ID: 19898981

Recent reports have shown the involvement of tumor burden as well as GM-CSF in supporting myeloid-derived suppressor cells (MDSC). However, it is not known what progenitor cells may differentiate into MDSC in the presence of GM-CSF, and whether FVBN202 transgenic mouse model of spontaneous breast carcinoma may exhibit distinct subset distribution of CD11b+Gr1+ cells. In addition, it is not known why CD11b+Gr1+ cells derived from tumor-free and tumor-bearing animals exhibit different functions. In this study, we determined that GM-CSF was one of the tumor-derived soluble factors that induced differentiation of CD11b-Gr1- progenitor cells from within monocytic/granulocytic bone marrow cells into CD11b+Gr1+ cells. We also showed that CD11b+Gr1+ cells in FVBN202 mice consisted of CD11b+Ly6G-Ly6C+ suppressive and CD11b+Ly6G+Ly6C+ non-suppressive subsets. Previously reported variations between tumor-free and tumor-bearing animals in the function of their CD11b+Gr1+ cells were found to be due to the variations in the proportion of these two subsets. Therefore, increasing ratios of CD11b+Gr1+ cells derived from tumor-free animals revealed their suppressive activity on T cells, in vitro. Importantly, GM-CSF supported the generation of CD11b+Ly6G-Ly6C+ suppressor subsets that inhibited proliferation as well as anti-tumor function of neu-specific T cells. These findings suggest revisiting the use of GM-CSF for the expansion of dendritic cells, ex vivo, for cell-based immunotherapy or as an adjuvant for vaccines for patients with cancer in whom MDSC play a major role in the suppression of anti-tumor immune responses.

Influence of the Phosphodiesterase-5 Inhibitor, Sildenafil, on Sensitivity to Chemotherapy in Breast Tumor Cells

Breast Cancer Research and Treatment. Nov, 2010  |  Pubmed ID: 20155316

Studies were performed to determine the influence of the phosphodiesterase-5 inhibitor, sildenafil, on sensitivity to adriamycin (doxorubicin) in four human breast tumor cell lines and one murine breast tumor line. Sildenafil did not interfere with the effectiveness of adriamycin in any of the cell lines tested. Sildenafil also failed to protect MDA-MB231 cells against the cytotoxicity of cisplatin, taxol or camptothecin. Sildenafil enhanced sensitivity to adriamycin markedly in the p53 mutant MDA-MB231 and p53 null MCF-7/E6 cells and moderately in the MCF-7/caspase 3 and 4T1 cell lines. In the MDA-MB231 cells, sildenafil increased the extent of DNA damage induced by adriamycin as well as the extent of apoptotic cell death. Sildenafil did not influence sensitivity to adriamycin in bone marrow cells or macrophages. In an immunocompetent model of breast cancer (4T1 mammary carcinoma in Balb/c mice), sildenafil did not attenuate the antitumor effects of adriamycin; furthermore, the combination of sildenafil with adriamycin was no more toxic to the animals than adriamycin alone. Given that sildenafil has been shown to have the potential to protect the heart against the toxicity of adriamycin, these studies suggest that the inclusion of sildenafil with conventional chemotherapeutic protocols involving adriamycin (and possibly cisplatin, camptothecin and/or paclitaxel) should not compromise the antitumor effectiveness of these drugs nor enhance their toxicity to the patient.

Neoadjuvant Chemotherapy for Operable Breast Cancer: Individualizing Locoregional and Systemic Therapy

Surgical Oncology Clinics of North America. Jul, 2010  |  Pubmed ID: 20620930

Neoadjuvant chemotherapy (NAC) is being used with increasing frequency in the multidisciplinary care of women with breast cancer. NAC can increase the chances for successful breast conservation and may decrease the need for axillary node dissection in selected patients. Some patients with chemoresistant tumors may benefit more from hormonal neoadjuvant therapy. The greatest potential for this approach is to predict responses of different breast cancers to therapy based on molecular profiles. This will accelerate better understanding of breast cancer biology and progress toward improved and more individualized therapy.

Phenotype, Functions and Fate of Adoptively Transferred Tumor Draining Lymphocytes Activated Ex Vivo in Mice with an Aggressive Weakly Immunogenic Mammary Carcinoma

BMC Immunology. 2010  |  Pubmed ID: 21050466

Regression of established tumors can be induced by adoptive immunotherapy with tumor draining lymph node lymphocytes activated with bryostatin and ionomycin. We hypothesized that tumor regression is mediated by a subset of the transferred T lymphocytes, which selectively infiltrate the tumor draining lymph nodes and proliferate in vivo.

Effects of Surgical Excision on Survival of Patients with Stage IV Breast Cancer

The Journal of Surgical Research. Jun, 2010  |  Pubmed ID: 19375721

Non-palliative resection of the primary tumor in stage IV breast cancer is controversial. Our aim was to determine whether surgery improves survival in stage IV patients.

IL-7 + IL-15 Are Superior to IL-2 for the Ex Vivo Expansion of 4T1 Mammary Carcinoma-specific T Cells with Greater Efficacy Against Tumors in Vivo

Breast Cancer Research and Treatment. Jul, 2010  |  Pubmed ID: 19826947

Regression of established tumors can be induced by adoptive immunotherapy (AIT) with tumor draining lymph node (DLN) lymphocytes activated with bryostatin and ionomycin (B/I). Tumor antigen-sensitized DLN lymphocytes from BALB/c mice with 10-day 4T1 mammary carcinomas were harvested, activated with B/I, and expanded in culture with either interleukin-2 (IL-2) or IL-7 + IL-15. Cell yields, proliferation, phenotypes, and in vitro responses to tumor antigen were compared for cells grown in different cytokines. These T cells were also tested for antitumor activity against established 4T1 mammary carcinomas after inoculation of tumor cells subcutaneously (s.c.). IL-7/15 resulted in much faster and more prolonged proliferation of B/I-activated T cells than culturing the same cells in IL-2. This resulted in approximately 5-10-fold greater yields of viable cells. Culture in IL-7/15 yielded higher proportions of CD8(+) T cells and a higher proportion of cells with a central memory phenotype. T cells grown in IL-2 had higher interferon-gamma (IFN-gamma) release responses to tumor antigen than cells grown in IL-7/15. Adoptive transfer of B/I-activated T cells grown in IL-7/15 demonstrated much greater efficacy against 4T1 tumors in vivo. Activation of tumor antigen-sensitized T cells with B/I and culture in IL-7 + IL-15 is a promising modification of standard regimens for production of T cells for use in AIT of cancer.

Tumor Escape and Progression of HER-2/neu Negative Breast Cancer Under Immune Pressure

Journal of Translational Medicine. 2011  |  Pubmed ID: 21453513

Emerging data from pre-clinical and clinical studies suggest that HER-2/neu-specific T cell responses could induce HER-2/neu antigen loss in the tumor cells. These data suggest that patients with HER-2/neu negative breast cancer might have had HER-2/neu positive premalignant lesions in the past that progressed to HER-2/neu negative breast cancer under HER-2/neu-specific immune pressure.

Activated NKT Cells and NK Cells Render T Cells Resistant to Myeloid-derived Suppressor Cells and Result in an Effective Adoptive Cellular Therapy Against Breast Cancer in the FVBN202 Transgenic Mouse

Journal of Immunology (Baltimore, Md. : 1950). Jul, 2011  |  Pubmed ID: 21670315

Attempts to cure breast cancer by adoptive cellular therapy (ACT) have not been successful. This is primarily due to the presence of tumor-induced immune-suppressive mechanisms as well as the failure of tumor-reactive T cells to provide long-term memory responses in vivo. To address these clinically important challenges, we developed an ex vivo protocol for the expansion of tumor-reactive immune cells obtained from tumor-bearing animals prior to or after local radiation therapy. We used an Ag-free protocol that included bryostatin 1/ionomycin and sequential common γ-chain cytokines (IL-7/IL-15 + IL-2). The proposed protocol expanded tumor-reactive T cells as well as activated non-T cells, including NKT cells, NK cells, and IFN-γ-producing killer dendritic cells. Antitumor efficacy of T cells depended on the presence of non-T cells. The effector non-T cells also rendered T cells resistant to myeloid-derived suppressor cells. Radiation therapy altered phenotypic distribution and differentiation of T cells as well as their ability to generate central memory T cells. ACT by means of the expanded cells protected animals from tumor challenge and generated long-term memory responses against the tumor, provided that leukocytes were derived from tumor-bearing animals prior to radiation therapy. The ex vivo protocol was also able to expand HER-2/neu-specific T cells derived from the PBMC of a single patient with breast carcinoma. These data suggest that the proposed ACT protocol should be studied further in breast cancer patients.

Methyl-binding Domain Protein 2-dependent Proliferation and Survival of Breast Cancer Cells

Molecular Cancer Research : MCR. Aug, 2011  |  Pubmed ID: 21693597

Methyl cytosine binding domain protein 2 (MBD2) has been shown to bind to and mediate repression of methylated tumor suppressor genes in cancer cells, where repatterning of CpG methylation and associated gene silencing is common. We have investigated the role of MBD2 in breast cancer cell growth and tumor suppressor gene expression. We show that stable short hairpin RNA (shRNA)-mediated knockdown of MBD2 leads to growth suppression of cultured human mammary epithelial cancer lines, SK-BR-3, MDA-MB-231, and MDA-MB-435. The peak antiproliferative occurs only after sustained, stable MBD2 knockdown. Once established, the growth inhibition persists over time and leads to a markedly decreased propensity for aggressive breast cancer cell lines to form in vivo xenograft tumors in Bagg Albino (BALB)/C nu/nu mice. The growth effects of MBD2 knockdown are accompanied by derepression of tumor suppressor genes, including DAPK1 and KLK10. Chromatin immunoprecipitation assays and bisulfite sequencing show MBD2 binding directly to the hyper methylated and CpG-rich promoters of both DAPK1 and KLK10. Remarkably, the promoter CpG island-associated methylation of these genes remained stable despite robust transcriptional activation in MBD2 knockdown cells. Expression of a shRNA-resistant MBD2 protein resulted in restoration of growth and resilencing of the MBD2-dependent tumor suppressor genes. Our data suggest that uncoupling CpG methylation from repressive chromatin remodeling and histone modifications by removing MBD2 is sufficient to initiate and maintain tumor suppressor gene transcription and suppress neoplastic cell growth. These results show a role for MBD2 in cancer progression and provide support for the prospect of targeting MBD2 therapeutically in aggressive breast cancers.

A Gene Transcription Signature of Obesity in Breast Cancer

Breast Cancer Research and Treatment. Jul, 2011  |  Pubmed ID: 21750966

Obesity is thought to contribute to worse disease outcome in breast cancer as a result of increased levels of adipocyte-secreted endocrine factors, insulin, and insulin-like growth factors (IGFs) that accelerate tumor cell proliferation and impair treatment response. We examined the effects of patient obesity on primary breast tumor gene expression, by profiling transcription of a set of 103 tumors for which the patients' body mass index (BMI) was ascertained. Sample profiles were stratified according to patients' obesity phenotype defined as normal (BMI < 25), overweight (BMI 25-29.9), or obese (BMI ≥ 30). Widespread gene expression alterations were evident in breast tumors from obese patients as compared to other tumors, allowing us to define an obesity-associated cancer transcriptional signature of 662 genes. In multiple public expression data sets of breast cancers (representing > 1,500 patients), manifestation of the obesity signature patterns correlated with manifestation of a gene signature for IGF signaling and (to a lesser extent) with lower levels of estrogen receptor. In one patient cohort, manifestation of the obesity signature correlated with shorter time to metastases. A number of small molecules either induced or suppressed the obesity-associated transcriptional program in vitro; estrogens alpha-estradiol, levonorgestrel, and hexestrol induced the program, while several anti-parkinsonian agents targeting neurotransmitter receptor pathways repressed the program. Obesity in breast cancer patients appears to impact the gene expression patterns of the tumor (perhaps as a result of altered body chemistry). These results warrant further investigation of obesity-associated modifiers of breast cancer risk and disease outcome.

Human Dosimetry and Preliminary Tumor Distribution of 18F-fluoropaclitaxel in Healthy Volunteers and Newly Diagnosed Breast Cancer Patients Using PET/CT

Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine. Sep, 2011  |  Pubmed ID: 21849404

(18)F-fluoropaclitaxel is a radiolabeled form of paclitaxel, a widely used chemotherapy agent. Preclinical data suggest that (18)F-fluoropaclitaxel may be a reasonable surrogate for measuring the uptake of paclitaxel. As a substrate of P-glycoprotein, a drug efflux pump associated with multidrug resistance, (18)F-fluoropaclitaxel may also be useful in identifying multidrug resistance and predicting tumor response for drugs other than paclitaxel.

Bevacizumab Added to Neoadjuvant Chemotherapy for Breast Cancer

The New England Journal of Medicine. Jan, 2012  |  Pubmed ID: 22276821

Bevacizumab and the antimetabolites capecitabine and gemcitabine have been shown to improve outcomes when added to taxanes in patients with metastatic breast cancer. The primary aims of this trial were to determine whether the addition of capecitabine or gemcitabine to neoadjuvant chemotherapy with docetaxel, followed by doxorubicin plus cyclophosphamide, would increase the rates of pathological complete response in the breast in women with operable, human epidermal growth factor receptor 2 (HER2)-negative breast cancer and whether adding bevacizumab to these chemotherapy regimens would increase the rates of pathological complete response.

A Signature of Immune Function Genes Associated with Recurrence-free Survival in Breast Cancer Patients

Breast Cancer Research and Treatment. Feb, 2012  |  Pubmed ID: 21479927

The clinical significance of tumor-infiltrating immune cells has been reported in a variety of human carcinomas including breast cancer. However, molecular signature of tumor-infiltrating immune cells and their prognostic value in breast cancer patients remain elusive. We hypothesized that a distinct network of immune function genes at the tumor site can predict a low risk versus high risk of distant relapse in breast cancer patients regardless of the status of ER, PR, or HER-2/neu in their tumors. We conducted retrospective studies in a diverse cohort of breast cancer patients with a 1-5 year tumor relapse versus those with up to 7 years relapse-free survival. The RNAs were extracted from the frozen tumor specimens at the time of diagnosis and subjected to microarray analysis and real-time RT-PCR. Paraffin-embedded tissues were also subjected to immunohistochemistry staining. We determined that a network of immune function genes involved in B cell development, interferon signaling associated with allograft rejection and autoimmune reaction, antigen presentation pathway, and cross talk between adaptive and innate immune responses were exclusively upregulated in patients with relapse-free survival. Among the 299 genes, five genes which included B cell response genes were found to predict with >85% accuracy relapse-free survival. Real-time RT-PCR confirmed the 5-gene prognostic signature that was distinct from an FDA-cleared 70-gene signature of MammaPrint panel and from the Oncotype DX recurrence score assay panel. These data suggest that neoadjuvant immunotherapy in patients with high risk of relapse may reduce tumor recurrence by inducing the immune function genes.