scholarly journals Impacts of Inflammatory Microenvironment on the Development of Cancer Relapse after Combined Treatment

2021 ◽  
Vol 6 (5) ◽  
pp. 204-213
Author(s):  
O. V. Movchan ◽  
◽  
I. Yu. Bagmut ◽  
Keyword(s):  
Breast Cancer ◽  
Colorectal Cancer ◽  
Stomach Cancer ◽  
Inflammatory Breast Cancer ◽  
Combined Treatment ◽  
Esophagus Cancer ◽  
Inflammatory Microenvironment ◽  
Cancer Relapse ◽  
Her 2 ◽  
The Impact

The purpose of the work was to study the impact of certain elements of the inflammatory microenvironment of the tumor on the development of cancer relapse of main localizations with the amplification of ERBB2 after combined treatment. Materials and methods. 80 patients, who had been treated for the period from 2016 to 2021 in National Cancer Institute, Kyiv, Ukraine. They were 42-78 (average 60) years old, ECOG 0-2, female. All patients histologically proved adenocarcinoma GIII-GIV. Everyone was studied for the level of chitinase-like proteins, cryoglobulins, tumor-associated macrophages in the preoperative (with the first identified disease for the first time, prior to the beginning of the neoadjuvant chemotherapy) and in the postoperative period. 1st block: with a confirmed mutation of HER-2/neu gene (amplification ERBB2 (3+)): a) inflammatory breast cancer (primary-edema form) – 10 people, b) diffuse-infiltrative stomach cancer – 10 people; c) diffuse-infiltrative esophagus cancer – 10 people; d) diffuse-infiltrative colorectal cancer – 10 people. 2nd block: without a confirmed mutation of HER-2/neu gene: a) inflammatory breast cancer (primary edema form) – 10 people; b) a diffuse-infiltrative stomach cancer – 10 people; c) diffuse-infiltrative esophageal cancer – 10 people; d) diffuse-infiltrative colorectal cancer – 10 people. Results and discussion. In patients with infiltrative breast cancer, diffuse-infiltrative stomach cancer, and diffuse-infiltrative esophagus cancer, and diffuse-infiltrative colorectal cancer there was a tendency to an increase in the expression of YKL-39 with the ERBB2 amplification during inflammatory tumor infiltration in the stroma. High expression of Stabilin-1 (2.1±0.70, n = 22) was found compared to patient tumors that did not reveal the amplification of ERBB2 (1.46±0.67, n = 13, p = 0.015). In most patients with amplification ERBB2, the cryoglobulin content was average (298.6±2.5 mg/l; 1.3±0.08%) – 20 (50%), which corresponds to cryoglobulinemia type II; with conditioned cryoglobulinemia (79.4±1.01 mg/l) in 10 (25%); high content (477.3±48 mg/l; 3.4±0.2%) was recorded in 10 (25%), which indicates the type III of cryoglobulinemia [the hazard ratio (HR) = 0.71, 95%, сonfidence interval (CI): 0.22-0.83, p = 0.005] Conclusion. Amplification of ERBB2 and macrophages surroundings markers CD68, M2 subpopulation RS1 (Stabilin-1), chitinase-like proteins YKL-39 and SI-CLP independently identified subgroups of patients with inflammatory breast cancer, diffuse stomach and diffuse esophageal, diffuse colorectal cancer with a bad forecast. In patients with the presence of the amplification of ERBB2 in the inflammatory tumor infiltrate, in the stroma, the higher expression of the chitinase-like protein YKL-39 and M2-polarization RS1 of the marker Stabilin-1, was detected compared to the patient's tumors without amplifying ERBB2. This study shows an important role of quantitative values associated with the tumor phenotype and macrophages in tumor progression, depending on the presence of ERBB2 gain. In patients with cryoglobulinemia with inflammatory cancer the secondary immunodeficiency is developed. This is determined by anomalies in the cell and humoral immune system, and leads to the development of postoperative inflammatory complications and relapses

The impact of the COVID-19 pandemic on stage at diagnosis of breast and colorectal cancers.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 6501-6501
Author(s):  
Jade Zhou ◽  
Shelly Kane ◽  
Celia Ramsey ◽  
Melody Ann Akhondzadeh ◽  
Ananya Banerjee ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Colorectal Cancer ◽  
Cancer Screening ◽  
Late Stage ◽  
Stage Iv ◽  
Stage I ◽  
Screening Programs ◽  
Stage Distribution ◽  
Number Of Patients ◽  
The Impact

6501 Background: Effective cancer screening leads to a substantial increase in the detection of earlier stages of cancer, while decreasing the incidence of later stage cancer diagnoses. Timely screening programs are critical in reducing cancer-related mortality in both breast and colorectal cancer by detecting tumors at an early, curable stage. The COVID-19 pandemic resulted in the postponement or cancellation of many screening procedures, due to both patient fears of exposures within the healthcare system as well as the cancellation of some elective procedures. We sought to identify how the COVID-19 pandemic has impacted the incidence of early and late stage breast and colorectal cancer diagnoses at our institution. Methods: We examined staging for all patients presenting to UCSD at first presentation for a new diagnosis of malignancy or second opinion in 2019 and 2020. Treating clinicians determined the stage at presentation for all patients using an AJCC staging module (8th edition) in the electronic medical record (Epic). We compared stage distribution at presentation in 2019 vs 2020, both for cancers overall and for colorectal and breast cancer, because these cancers are frequently detected by screening. Results: Total numbers of new patient visits for malignancy were similar in 2019 and 2020 (1894 vs 1915 pts), and stage distribution for all cancer patients was similar (stage I 32% in 2019 vs 29% in 2020; stage IV 26% in both 2019 and 2020). For patients with breast cancer, we saw a lower number of patients presenting with stage I disease (64% in 2019 vs 51% in 2020) and a higher number presenting with stage IV (2% vs 6%). Similar findings were seen in colorectal cancer (stage I: 22% vs 16%; stage IV: 6% vs 18%). Conclusions: Since the COVID-19 pandemic, there has been an increase in incidence of late stage presentation of colorectal and breast cancer, corresponding with a decrease in early stage presentation of these cancers at our institution. Cancer screening is integral to cancer prevention and control, specifically in colorectal and breast cancers which are often detected by screening, and the disruption of screening services has had a significant impact on our patients. We plan to continue following these numbers closely, and will present data from the first half of 2021 as it becomes available.

scholarly journals Antiangiogenic therapy for breast cancer with triple negative phenotype

2021 ◽  
Vol 23 (1) ◽  
pp. 88-92
Author(s):  
Inna P. Ganshina ◽  
Kristina A. Ivanova ◽  
Olga O. Gordeeva ◽  
Aleksandr V. Arkhipov ◽  
Liudmila G. Zhukova
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Malignant Tumors ◽  
Antiangiogenic Therapy ◽  
Treatment Strategies ◽  
Her 2 ◽  
Triple Negative Phenotype ◽  
The Impact ◽  
Negative Phenotype

Triple-negative breast cancer is 1024% of all cases of breast cancer and is characterized by the absence of estrogen, progesterone, and HER-2 receptors in the tumor. The therapy of this illness is a difficult clinical case. In contrast to hormone-positive and HER-2-positive phenotypes, in which we successfully use targeted drugs (antiestrogens and anti-HER-2 drugs), for triple-negative breast cancer we have not had such targets for a long time. Thus, despite the impressive results of immunotherapy of triple-negative breast cancer, there remains a fairly large group of patients with negative PD-L1 status, for whom it is necessary to develop other treatment strategies. One of the approaches in the treatment of malignant tumors includes not the impact on tumor cells, but the process of angiogenesis. Antiangiogenic drugs have positively proven themselves in the treatment of a large number of malignant tumors but are underestimated for breast cancer (including triple-negative phenotype). The use of bevacizumab in combinations with cytostatic drugs in breast cancer therapy (including triple-negative breast cancer) has been studied in a large number of clinical trials but was undeservedly forgotten in some countries due to the revoked FDA registration. This review presents the role of bevacizumab in the treatment of patients with triple-negative breast cancer and suggests the conditions when the administration of this drug is justified and leads to better results.

scholarly journals Molecular Mechanisms of Antitumor Activity of PAMAM Dendrimer Conjugates with Anticancer Drugs and a Monoclonal Antibody

Polymers ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 1422 ◽  
Author(s):  
Marcinkowska ◽  
Stanczyk ◽  
Janaszewska ◽  
Gajek ◽  
Ksiezak ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Monoclonal Antibody ◽  
Antitumor Activity ◽  
Molecular Mechanisms ◽  
Pamam Dendrimer ◽  
Breast Cancer Cell Lines ◽  
Cytotoxic Action ◽  
Her 2 ◽  
The Impact ◽  
Dendrimer Conjugates

Taxanes are considered fundamental drugs in the treatment of breast cancer, but despite the similarities, docetaxel (doc) and paclitaxel (ptx) work differently. For this reason, it is interesting to identify mechanisms of antitumor activity of PAMAM dendrimer conjugates that carry docetaxel or paclitaxel and monoclonal antibody trastuzumab, specifically targeted to cells which overexpressed HER-2. For this purpose, the impact on the level of reactive oxygen species, the mitochondrial membrane potential, cell cycle distribution and the activity of caspases-3/7, -8 and -9 of PAMAM-doc-trastuzumab and PAMAM-ptx-trastuzumab conjugates was determined and compared with free docetaxel and paclitaxel toward HER-2-positive (SKBR-3) and negative (MCF-7) human breast cancer cell lines. Moreover, apoptosis and necrosis were studied using flow cytometry and confocal microscopy, respectively. Our studies show the complexity of the potential mechanism of cytotoxic action of PAMAM-drug-trastuzumab conjugates that should be sought as a resultant of oxidative stress, mitochondrial activation of the caspase cascade and the HER-2 receptor blockade.

scholarly journals Histone deacetylase inhibitors valproic acid and vorinostat enhance trastuzumab-mediated antibody-dependent cell-mediated phagocytosis

2020 ◽  
Vol 8 (1) ◽  
pp. e000195 ◽  
Author(s):  
Johannes Laengle ◽  
Julijan Kabiljo ◽  
Leah Hunter ◽  
Jakob Homola ◽  
Sophie Prodinger ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Flow Cytometry ◽  
Valproic Acid ◽  
Cancer Cells ◽  
Histone Deacetylase ◽  
Breast Cancer Cells ◽  
Histone Deacetylase Inhibitors ◽  
Combined Treatment ◽  
Dependent Cell ◽  
The Impact

BackgroundThe monoclonal antibody (mAb) trastuzumab is part of the standard of care for patients with human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancer. Antibody-dependent cell-mediated phagocytosis (ADCP) and cytotoxicity (ADCC) are major mechanisms of action of the mAb trastuzumab. Histone deacetylase inhibitors (HDACi), such as valproic acid (VPA) or vorinostat (SAHA), exert several immunostimulatory properties, which contribute at least in part to their anticancer effect. However, the impact of HDACi-induced immunostimulatory effects on trastuzumab-mediated anti-tumor immune response is not well characterized.MethodsWe analyzed the ADCP and ADCC activity of peripheral blood mononuclear cells (PBMCs) from age and gender-matched healthy volunteers (n=5) against HDACi-treated HER2-overexpressing breast cancer cells (SKBR3), using a well-established in vitro three-color imaging flow cytometry and flow cytometry approach.ResultsVPA and SAHA enhanced trastuzumab-mediated ADCP and trastuzumab-independent cytotoxicity. Mechanistically, VPA upregulated the activating antibody-binding receptor Fc-gamma receptor (FcγR) IIA (CD32A) on monocytes (CD14+). Moreover, VPA and SAHA downregulated the anti-apoptotic protein myeloid leukemia cell differentiation 1 (MCL1) in breast cancer cells. Additionally, VPA and SAHA induced an immunogenic cell death, characterized by the exposure of calreticulin (CALR), as well as decreased the “do not eat me” signal CD47 on tumor cells.ConclusionsHDACi VPA and SAHA increase trastuzumab-mediated phagocytosis and trastuzumab-independent cytotoxicity. The immunomodulatory activities of those HDACi support a rationale combined treatment approach with mAb for cancer treatment.

scholarly journals Regulatory Crosstalk of Doxorubicin, Estradiol and TNFα Combined Treatment in Breast Cancer-derived Cell Lines

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Isar Nassiri ◽  
Alberto Inga ◽  
Erna Marija Meškytė ◽  
Federica Alessandrini ◽  
Yari Ciribilli ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Lines ◽  
Differentially Expressed Genes ◽  
Combination Treatment ◽  
Combined Treatment ◽  
Enrichment Analysis ◽  
Differentially Expressed ◽  
Transcriptional Responses ◽  
Predisposing Factor ◽  
Inflammatory Microenvironment

Abstract We present a new model of ESR1 network regulation based on analysis of Doxorubicin, Estradiol, and TNFα combination treatment in MCF-7. We used Doxorubicin as a therapeutic agent, TNFα as marker and mediator of an inflammatory microenvironment and 17β-Estradiol (E2) as an agonist of Estrogen Receptors, known predisposing factor for hormone-driven breast cancer, whose pharmacological inhibition reduces the risk of breast cancer recurrence. Based on the results of transcriptomics analysis, we found 71 differentially expressed genes that are specific for the combination treatment with Doxorubicin + Estradiol + TNFα in comparison with single or double treatments. The responsiveness to the triple treatment was examined for seven genes by qPCR, of which six were validated, and then extended to four additional cell lines differing for p53 and/or ER status. The results of differential regulation enrichment analysis highlight the role of the ESR1 network that included 36 of 71 specific differentially expressed genes. We propose that the combined activation of p53 and NF-kB transcription factors significantly influences ligand-dependent, ER-driven transcriptional responses, also of the ESR1 gene itself. These results provide a model of coordinated interaction of TFs to explain the Doxorubicin, E2 and TNFα induced repression mechanisms.

Abstract A96: The impact of the inflammatory microenvironment on breast cancer metastasis and chemotherapy responsiveness

2013 ◽  
Author(s):  
Kelly Kersten ◽  
Metamia Ciampricotti ◽  
Chris W. Doornebal ◽  
Cheei-Sing Hau ◽  
Seth B. Coffelt ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Metastasis ◽  
Breast Cancer Metastasis ◽  
Inflammatory Microenvironment ◽  
The Impact

Prospective monitoring of circulating tumor cells in breast cancer patients treated with primary systemic therapy—A translational project of the German Breast Group study GeparQuattro

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 21085-21085 ◽  
Author(s):  
V. Mueller ◽  
S. Riethdorf ◽  
S. Loibl ◽  
M. Komor ◽  
J. Houber ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Metastatic Breast ◽  
Primary Diagnosis ◽  
Breast Cancer Patients ◽  
Primary Systemic Therapy ◽  
Her 2 ◽  
The Impact

21085 Background: The impact of circulating tumor cells (CTC) in patients with primary breast cancer is still unclear. Primary systemic treatment (PST) allows the assessment of therapeutic efficacy in breast cancer patients without long follow-up periods. Here we present first results on the presence of CTC in peripheral blood of patients enrolled in the “GeparQuattro” study. Methods: This study incorporates three different chemotherapy approaches and additional Trastuzumab (Herceptin®) treatment for patients with HER-2/neu-positive tumors. Recruitment finished in November 2006 and not all patients have completed therapy yet. We used the CellSearch™ system to evaluate CTC before PST from 245 patients and after PST from 67 patients. CTC from 45 samples were also examined for HER-2/neu expression by immunocytochemistry in the CellSearch™ system. Results: Before PST we detected CTC in 54/245 patients (22%). CTC numbers in 7.5 mL blood ranged between 1 and 200 (mean 6.5). In 8 CTC-positive samples (3.3%) = 5 CTC were found. Her-2/neu-positive CTC were observed in 25/45 cases (55.6%). CTC could be detected in 7/67 patients (10.4%) after PST (1 or 2 CTC). Before and after PST blood was analyzed from 43 patients, 27 of them were CTC-negative at both time points. Ten initially CTC-positive cases were CTC-negative after PST whereas 6 cases were detected CTC-positive after PST although no CTC could be found before PST. Conclusions: With the CellSearch™ system CTC can be detected in non-metastatic breast cancer patients at primary diagnosis and also after PST. To our knowledge, this is the largest study evaluating the presence of CTC in this context. With the availability of response information from more patients, it will be possible to examine the correlation between the incidence of CTC and response as well as kinetics of HER-2/neu expression during Trastuzumab treatment. [Table: see text]

A retrospective study of inflammatory breast cancer patients from seven hospitals in the United Kingdom.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e11062-e11062
Author(s):  
Saeed Rafii ◽  
Christopher John Poole ◽  
Adele Francis ◽  
Shalini Chaudhri ◽  
Daniel Rea
Keyword(s):  
Breast Cancer ◽  
United Kingdom ◽  
Neoadjuvant Chemotherapy ◽  
Cancer Patients ◽  
Inflammatory Breast Cancer ◽  
Triple Negative ◽  
Breast Cancer Patients ◽  
The United Kingdom ◽  
Her 2 ◽  
Clinical Records

e11062 Background: Inflammatory breast cancer (IBC) is an aggressive form of locally advanced breast cancer characterised by rapidly progressive breast erythema, pain and tenderness, oedema and paeu d’orange. It is estimated that between 1-4 % of all newly diagnosed breast cancer patients in the United Kingdom have IBC. Methods: We retrospectively identified 51 patients who were treated for IBC at 7 hospitals in the West midlands area of the United Kingdom between 1997 and 2011. Data including patients’ demographics, clinical, radiological and histopathological characteristics were collected from electronic clinical records. The test for HER-2 over-expression was not carried out routinely before 2002, therefore HER-2 status of such patients were assessed retrospectively on the archived tissues. A cox regression analysis was used for statistical assessment of survival and prognostic factors. Results: Median age at diagnosis was 55 years (range 34-83 yrs). Median overall (OS) and progression free survival (PFS) were 32 months (range 7-97 months) and 27 months (range 2-53 months) respectively. The 3–year survival rate for the entire cohort was 32%. Majority of patients were ER and HER-2 positive (49% and 52% respectively). The rate of complete pathological response (pCR) after neoadjuvant chemotherapy was 14%. All cases who had achieved pCR were HER-2 positive who had received anti HER-2 treatment during the neoadjuvant chemotherapy. The OS for the HER-2 positive patients with pCR was not statistically different from the whole cohort (49 vs 32 months, p=0.09) or from the patients with residual disease (49 vs 26 months, p=0.13). Although the triple negative IBC patients consisted 20% of the cohort, no patients in this group had achieved pCR. The OS and PFS for the triple negative patients were 20 and 14 months respectively. Although the rate of pCR was higher in patients treated with taxane compared to those treated with anthracycline containing chemotherapy (35% vs 7%), there was no significant difference in OS between either of these regimens (29 vs 27 months). Conclusions: HER-2 positive IBC patients had higher rate of achieving pCR after neo-adjuvant anti HER-2 therapy. However higher rate of pCR did not improve the OS.

Factors associated with local control in inflammatory breast cancer.

2012 ◽  
Vol 30 (27_suppl) ◽  
pp. 126-126
Author(s):  
Lindsay C. Brown ◽  
Miran J. Blanchard ◽  
Nadia N. Laack
Keyword(s):  
Breast Cancer ◽  
Adjuvant Chemotherapy ◽  
Chest Wall ◽  
Inflammatory Breast Cancer ◽  
Pathologic Complete Response ◽  
Regional Lymph Nodes ◽  
Trimodality Therapy ◽  
Once Daily ◽  
Factors Associated ◽  
The Impact

126 Background: Inflammatory breast cancer (IBC) is an aggressive breast cancer variant, with 5-yr overall survival (OS) typically reported at 40-45%. We recently presented our results with once-daily radiotherapy (RT) as a component of trimodality therapy, with 5-yr OS of 64%. Herein we report patient and treatment factors associated with locoregional control (LRC). Methods: With permission of the IRB, review of medical records at the Mayo Clinic in Rochester, MN was performed to identify patients treated with RT for IBC from 2000-2010. Patients with non-metastatic, clinically diagnosed IBC were included. OS, LRC and distant metastasis-free survival (DMFS) were assessed using the Kaplan-Meier method. First recurrence in the chest wall or regional lymph nodes was defined as a locoregional recurrence (LRR). Results: 52 women were included in the analysis. Median age at diagnosis was 54 years (range 23-83). Median follow-up for the population was 3.6 years (range 0.7 – 11.9). All patients were treated with adjuvant RT to the chest wall and draining nodal basins in once-daily fractions of 1.8-2.25 Gy (median 2 Gy), to a median of 50 Gy (range 46-60 Gy). Actuarial 5-yr LRC was 85%. LRR was associated with poorer DMFS and OS (p < 0.01). Factors significantly associated with improved LRC included lack of extracapsular extension (ECE) and use of adjuvant chemotherapy (p < 0.05). Factors associated with a trend towards LRC included use of bolus, absence of boost, node negativity at time of surgery and pathologic complete response (pCR). Daily bolus was employed in 90% of patients and was most commonly (68%) 1 cm in thickness. There was a trend towards improved 5-yr LRC when bolus ≥ 1 cm was employed daily (93% v. 67%, p = 0.06). Patients who received a boost to the mastectomy scar (62% of the population, median of 10 Gy, range 10-16 Gy) had poorer LRC (78% v. 100%, p = 0.08), but superior 5-yr DMFS (78% v. 34%, p = 0.035) and OS (77% v. 34%, p = 0.04). Conclusions: LRC is associated with improved OS in IBC. Lack of ECE and use of adjuvant chemotherapy are associated with improved LRC in women with IBC. Node negativity, pCR and use of daily bolus ≥1 cm in thickness are associated with a trend towards improved LRC. The impact of boost requires further analysis.

Biomarker Changes During Neoadjuvant Anastrozole, Tamoxifen, or the Combination: Influence of Hormonal Status and HER-2 in Breast Cancer—A Study from the IMPACT Trialists

2005 ◽  
Vol 23 (11) ◽  
pp. 2477-2492 ◽  
Author(s):  
Mitch Dowsett ◽  
Steve R. Ebbs ◽  
J. Michael Dixon ◽  
Anthony Skene ◽  
Clive Griffith ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Progesterone Receptor ◽  
Treated Group ◽  
Growth Factor Signaling ◽  
Tumor Biopsy ◽  
Tamoxifen Group ◽  
Her 2 ◽  
The Difference ◽  
Induced Changes ◽  
The Impact

Purpose To investigate the relationships between biomarker changes in breast cancer during neoadjuvant (preoperative) endocrine therapy. Patients and Methods The IMPACT trial compared the preoperative use of tamoxifen with anastrozole alone or in combination in postmenopausal women (n = 330) with primary breast cancer. Biomarkers were measured in tumor biopsy specimens taken at baseline, and after 2 and 12 weeks of treatment. Results A decrease in the proliferation marker Ki67 occurred in the majority of patients: 52 (93%) of 56, 46 (85%) of 54, and 37 (84%) of 44 patients in the anastrozole, tamoxifen, and combination groups, respectively. There was a significantly greater suppression of Ki67 in the anastrozole-treated group than in the tamoxifen- or combination-treated groups, which is parallel to the greater efficacy seen for anastrozole over these two treatments in the Arimidex, Tamoxifen, Alone or in Combination adjuvant trial. A positive relationship was noted between estrogen-receptor level and Ki67 suppression in all patients. Ki67 was reduced to a greater extent in progesterone receptor-positive tumors compared with progesterone receptor-negative tumors. HER-2-negative tumors tended to show a greater reduction in Ki67 compared with HER-2-positive tumors, but the difference was only significant in the tamoxifen group after 2 weeks, and in the anastrozole group after 12 weeks. Conclusion These results confirm the value of Ki67 as a molecular marker, and provide information regarding the relationships between treatment-induced changes in Ki67 and other important biomarkers. Studies such as this should help integrate agents targeted at growth factor signaling with endocrine agents in breast cancer.

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