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Introduction: The plant alkaloid Maytansine and its derivatives with anti-microtubule activity failed in early trials due to significant toxicity.When linked to trastuzumab as an antibody-drug conjugate (ADC), emtansine can be delivered directly into the target cell with little systemic toxicity since the emtansine is inactive before the linker of the ADC is cleaved inside the tumor cells. Systemic toxicities with trastuzumab-emtansine (T-DM1) include thrombocytopenia and transaminase elevations, unlike trastuzumab alone. We hypothesized that systemic toxicities of this ADC are in part the result of emtansine released from the lysed tumor cells, and if so, that they may predict its tumor response. To evaluate this hypothesis, the correlation between early toxicity and initial tumor response, as well as progression free survival, are examined in a retrospective multi-center study. Methods: Records of women with metastatic or locally advanced/inoperable HER2+ breast cancer who received at least one dose of T-DM1 were retrospectively abstracted from 3 centers with IRB approval. Eighty-two patients were identified. Nine were excluded—one due to a diagnosis of idiopathic thrombocytopenic purpura and eight due to lack of follow-up imaging after starting T-DM1. Platelet count, AST, and ALT results from baseline up to the 8th cycle were graded with the NCI CTCAEv5.0 toxicity scale and grades were summed as a toxicity score for the 73 evaluable patients. Sequential CT or PET/CT response to therapy were defined by RECIST criteria with the addition of a mixed response category. Results: A significant association between improved ordinal imaging response (complete, partial, stable, mixed, progression) and higher toxicity sum score was observed by the Jonckheere-Terpstra two-sided test (Z=-2.194, p=0.028). 66% of the progression free patients (29/44) had toxicity sum scores ≥2 compared to 45% with disease progression (13/29), Z=-1.89, p=0.059 by two-sided Cochran-Armitage Trend Test. Progression free survival (PFS) was significantly longer with toxicity score ≥ 2 compared to score ≤ 1, p = 0.012 by log-rank test. Further, longer PFS was significantly associated with higher toxicity sum score with HR= 0.67 (β= -0.418, SE(β) = 0.169, χ2 = 6.08, d.f.=1, p = 0.014) indicating a 33% decrease in hazard of progression for each one-point increase in toxicity score. Discussion: This small, retrospective study demonstrates a significant association between higher toxicity sum score and more favorable tumor response as well as progression free survival in women with metastatic or locally advanced/inoperable HER2+ breast cancer treated with T-DM1. Further study in large-scale trials is warranted to confirm this association and determine the clinical utility of toxicity score as a predictor of therapeutic response. Our finding does not exclude systemic toxicity from the possible ADC linker cleavage prior to endocytosis. However, when T-DM1 was studied in the metastatic setting, 48% of patients experienced a Grade 3 or higher adverse event leading to dose reductions or discontinuation of the drug in 19% and 10% of patients, respectively. In the adjuvant setting, with only residual tumor that can account for ADC-related tumor lysis, only 25% had a Grade 3 or higher adverse event leading to 18% of patients discontinuing the drug. Should our observation prove predictive in further studies, it may have ramifications for many more antibody-drug conjugates. Citation Format: Shou-Ching Tang, Carter Louis Capra, Germame H Ajebo, Simon Mairs, Judith Meza-Junco, William B. Hillegass, Barbara S. Craft, Xiaofu Zhu. Systemic toxicities of trastuzumab-emtansine predict tumor response in HER2+ metastatic breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-08-52.

Background Triple negative breast cancer (TNBC) (estrogen receptor (ER) – negative, progesterone receptor (PR) - negative, and human epidermal growth factor receptor 2 (HER2) -negative) is an aggressive subtype of breast cancer that is more common in younger women, carries a poorer prognosis and has a greater metastatic potential than receptor positive subtypes. Radiation therapy’s ability to improve outcomes, especially the overall survival is controversial, more so among African American patients. The objective of this study is to evaluate local control and survival rates of TNBC patients treated with radiotherapy (RT) in our institution with a sizeable cohort of African American women. Methods This is a retrospective analysis of 67 TNBCs (2007–2017) at an academic state institution who underwent a lumpectomy and /or mastectomy (surgery) followed by adjuvant irradiation to a median total dose of 50 Gy (range 40.5–50.40 Gy). Chemotherapy was administered in a neoadjuvant (32) or adjuvant setting (35). For all 67 TNBCs, local control (LC), overall survival (OS), and disease-free survival (DFS) were estimated using the Kaplan-Meier method. The significance of survival variables was analyzed using the Cox univariate and multivariate proportional hazards model. A p-value of less than 0.05 was considered statistically significant. The SPSS 24.0 software was used for data analysis. Results The baseline characteristics of all 67 TNBCs were measured with median follow up of 58 months (range 10–142 months). Patients were stratified into two groups (neoadjuvant chemotherapy-RT (32) vs. adjuvant chemotherapy-RT (35)). The five-year rates for LC, DFS and OS were 14.8 % vs. 47.9 % (p = 0.002), 24.2% vs. 53.1 % (p = 0.015), and 65.1% vs. 92.2% (0.002) respectively. On Cox multivariate analysis, patients who received adjuvant chemotherapy were associated with statistically improved significant LC (p = 0.002) and OS (p = 0.002). The variables included were: BMI (p = 0.050), distance travelled (p = 0.027), 8th AJCC TNM staging (p = 0.018) and tumor grade (p = 0.022). Conclusion In this hypothesis-generating report, among TNBC patients undergoing RT, adjuvant chemotherapy appears to be better than neoadjuvant chemotherapy in determining the clinical outcomes.

The mechanism by which trastuzumab‐emtansine (T‐DM1) causes systemic toxicities apart from trastuzumab alone is currently unknown. We hypothesized that the systemic toxicities from T‐DM1 may have been caused by the free and active maytansine released from the lysed HER2+ tumor cells, and if so, they may correlate with the response to treatment and eventually disease‐free survival or patient outcome. In a retrospective, observational study, we evaluated 73 patients from three centers in the United States and Canada with advanced HER2+ breast cancer that received at least one dose of T‐DM1. Toxicity grades were summed to create a corresponding toxicity sum score (TSS), and its association with clinical outcomes was analyzed. A higher TSS was significantly associated with longer progression‐free survival with an HR = 0.66 [95% confidence interval [CI]: 0.47‐0.92], P = .014, for each 1‐point increase in the TSS score. Adjusted for baseline platelet count, aspartate transaminase and alanine transaminase, higher TSS remains significantly associated with longer progression‐free survival with adjusted HR = 0.67 [95% CI: 0.47‐0.93], P = .020. The analysis suggests that the systemic toxicities of T‐DM1 were significantly correlated with its clinical efficacy. This is the first report to correlate the systemic toxicities of T‐DM1 with clinical outcome. Further, this suggests that systemic toxicities of antibody‐drug conjugates (ADCs) may serve as a predictive biomarker, particularly if noncleavable linkers are used. If confirmed in larger prospective studies, the present finding is significant because most ADCs do not have a biomarker predictive of clinical outcome other than the presence or absence of the antibody target., What's new? Linkage of trastuzumab to emtansine (T‐DM1), a tumor‐antigen specific antibody, is associated with improved survival in patients with metastatic HER2+ breast cancer. Relative to trastuzumab alone, however, trastuzumab‐emtansine (T‐DM1) has unique side effects, including throbocytopenia and transaminitis. In this investigation of systemic toxicities, tumor response, and patient outcome, higher toxicity sum score for T‐DM1 was significantly associated with improved tumor response and increased progression‐free survival in metastatic HER2+ breast cancer patients. The findings suggest that emtansine freed from lysed HER2+ breast cancer cells potentially influences T‐DM1 toxicity and that systemic toxicities of antibody‐drug conjugates function as predictive biomarkers.

Background The Will Rogers phenomenon [WRP] describes an apparent improvement in outcome for patients’ group due to tumor grade reclassification. Staging of cancers is important to select appropriate treatment and to estimate prognosis. The WRP has been described as one of the most important biases limiting the use of historical cohorts when comparing survival or treatment. The main purpose of this study is to assess whether the WRP exists with the move from the AJCC 7th to AJCC 8th edition in breast cancer [BC] staging, and if racial differences are manifested in the expression of the WRP. Methods This is a retrospective analysis of 300 BC women (2007–2017) at an academic medical center. Overall survival [OS] and disease-free survival [DFS] was estimated by Kaplan-Meier analysis. Bi and multi-variate Cox regression analyses was used to identify racial factors associated with outcomes. Results Our patient cohort included 30.3% Caucasians [Whites] and 69.7% African-Americans [Blacks]. Stages I, II, III, and IV were 46.2, 26.3, 23.1, and 4.4% of Whites; 28.7, 43.1, 24.4, and 3.8% of Blacks respectively, in anatomic staging (p = 0.043). In prognostic staging, 52.8, 18.7, 23, and 5.5% were Whites while 35, 17.2, 43.5, and 4.3% were Blacks, respectively (p = 0.011). A total of Whites (45.05% vs. 47.85%) Blacks, upstaged. Whites (16.49% vs. 14.35%) Blacks, downstaged. The remaining, 38.46 and 37.79% patients had their stages unchanged. With a median follow-up of 54 months, the Black patients showed better stage-by-stage 5-year OS rates using 8th edition compared to the 7th edition (p = 0.000). Among the Whites, those who were stage IIIA in the 7th but became stage IB in the 8th had a better prognosis than stages IIA and IIB in the 8th (p = 0.000). The 8th showed complex results (p = 0.176) compared to DFS estimated using the 7th edition (p = 0.004). Conclusion The WRP exists with significant variability in the move from the AJCC 7th to the 8th edition in BC staging (both White and Black patients). We suggest that caution needs to be exercised when results are compared across staging systems to account for the WRP in the interpretation of the data.

Purpose: The objective of this study is to evaluate local control and survival rates of node negative triple negative breast cancer patients (TNBCs) treated with radiotherapy (RT) in our institution. Methods: This is a retrospective analysis of 67 TNBCs (2007 - 2017) at an academic state institution who underwent lumpectomy and /or mastectomy (surgery) followed by adjuvant irradiation to median total dose of 50 Gy (range 40.5-50.40 Gy). Chemotherapy was administered in a neoadjuvant (31) or adjuvant setting (36). For all 67 TNBCs, local control (LC), overall survival (OS) and disease free survival (DFS) were estimated using the Kaplan-Meier method. The significance of survival variables were analyzed using the Cox univariate and multivariate proportional hazards model. A p-value of less than 0.05 was considered statistically significant. The SPSS 24.0 software was used for data analysis. Results: The baseline characteristics of all 67 TNBCs were measured with median follow up of 58 months (range 10-142 months). Patients were stratified into two groups (neoadjuvant chemotherapy-RT (31) vs. adjuvant chemotherapy-RT (36)). The median rates for LC, DFS and OS were 27 % vs. 68 % (p= 0.001), 27.2% vs. 63.2 % (p= 0.034), and 63.4% vs. 92.5% (0.001) respectively. On Cox multivariate analysis, patients who received adjuvant chemotherapy were associated with statistically improved significant LC (p= 0.002) and OS (p=0.005). The variables included were: ethnicity (p=0.251), age (p=0.984), BMI (p=0.032), lump boost (p=0.300), TNM (p=0.162) and tumor grade (p=0.336). Conclusion: Among TNBC patients undergoing RT, adjuvant chemotherapy appears to be better than neoadjuvant chemotherapy in determining the clinical outcomes. Citation Format: Mary R. Nittala, Eswar K. Mundra, Satya Packianathan, Divyang Mehta, Maria L. Smith, William C. Woods, Shawn McKinney, Barbara S. Craft, Srinivasan Vijayakumar. Triple negative breast cancer patients treated with radiation therapy: Improvement in survival and local control with adjuvant chemotherapy compared to neoadjuvant chemotherapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6177.

Purpose: To assess whether the Will Roger’s phenomenon [WRP] exists with the move from the AJCC 7th to AJCC 8th edition in Breast Cancer staging and if racial differences are manifested in the expression of the WRP. Methods: A retrospective analysis of 300 women diagnosed with breast cancer between 2007 and 2017 at an academic medical center was performed. Pearson’s square test was used to compare the proportional differences between the anatomic staging system represented by the 7th edition and the prognostic staging of the 8th edition among Caucasian [C] and African-American [AA] women. Kaplan- Meier analysis was used to estimate overall survival [OS] and disease-free survival [DFS] between the races and compared using the log-rank test. Bi and multi-variate Cox hazard regression analyses were used to identify any racial factors associated with outcomes. The SPSS v.24.0 was used for all statistical analyses. Results: Our patient cohort included 30.3% C and 69.7% AA (median age, 62 y; range 34- 92 y). Stages I, II, III, and IV accounted for 46.2%, 26.3%, 23.1%, and 4.4% of C and 28.7%, 43.1%, 24.4%, and 3.8% of AA respectively, in anatomic staging (p= 0.043). In prognostic staging, 52.8%, 18.7%, 23%, and 5.5% were C while 35%, 17.2%, 43.5%, and 4.3 % were AA, respectively (p=0.011). A total number of 41 C (45.05 %) were upstaged compared to 100 AA (47.85 %) patients. Fifteen C patients (16.49 %) and 30 AA patients (14.35 %) were down-staged. Of the remainder, 35 C (38.46 %) and 79 AA (37.79 %) patients had their stages unchanged (P=0.859). The median follow-up duration for this cohort was 58 months (range 4- 235 months). The AA patients showed better stage -by- stage 5- year OS rates using 8th edition compared to the 7th edition, suggesting a manifestation of the WRP. Among the C patients, those who were stage IIIA in the 7th edition but became stage IB in the 8th had a better prognosis than stages IIA and IIB in the 8th edition (p=0.000). For AA patients, stage IIIA, IIIB, IIIC, and IV all demonstrated better prognoses in the 8th edition when compared to the 7th edition (p=0.000). In terms of DFS, the 8th edition’s clinical staging showed complex results (p=0.176) compared to DFS estimated using the 7th’s anatomic staging system (p=0.004). For C patients, stages IA, IB, IIB, and IIIC all recorded better DFS when using the 8th edition while for AA patients, only those with stages IB and IIIC showed better DFS in the 8th edition compared to the 7th. Conclusion: Our analyses suggest that the WRP exists in the move from the AJCC 7thto the 8th edition in breast cancer staging in both C and AA patients. However, there was significant variability between the races in the extent of its manifestation. We suggest that caution needs to be exercised when results are compared across staging systems to account for the WRP in the interpretation of the data. Citation Format: Mary R Nittala, Eswar K Mundra, SatyaSeelan Packianathan, Divyang Mehta, William C Woods, Shawn Mckinney, Barbara S Craft, Srinivasan Vijayakumar. The Will Rogers phenomenon in breast cancer: The AJCC 8th Ed. and the importance of caution in the interpretation of outcomes differences for overall population and race-specific cohorts [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr B126.

In the United States, about 11% (26,393) of those diagnosed with breast cancer in 2016 will be young or less than 45 years old. Young breast cancer survivors, compared to older cancer survivors, are a disparate group that experience higher incidence of advanced disease, greater mortality, and poorer quality of life, and are often faced with difficulty locating support that meet the unique needs of young women. The Gulf States Young Breast Cancer Survivor Network, composed of three sister networks, formed a partnership aimed at harnessing the power of social media to reach and impact the lives of young women with breast cancer. The collaborative partnership framework and the power of synergy are shown in merging two existing programs and incorporating a third new program.

We aimed to examine the use of circulating tumor cells (CTCs) as an effective measure of treatment efficacy and immune system function in metastatic breast cancer patients. CTCs are believed to be indicators of residual disease and thus pose an increased risk of metastasis and poorer outcomes to those patients who are CTC-positive. We obtained peripheral blood samples from 45 patients previously diagnosed with metastatic disease originating in the breast. Using TLR agonists that bind TLR ligands and upregulate immune effects versus unstimulated cells, we calculated a percent specific lysis using chromium-51 assay to illustrate the functional abilities of patient natural killer (NK) cells. We found those with greater than 5 CTCs per 7.5 mL blood had significantly decreased responses by their immune cells when compared with those patients who had 5 CTCs or less. We furthermore found a correlation between disease progression and CTC-positive patients, indicating that those who have a positive test should be closely monitored by their clinician. CTCs represent an exciting new clinical opportunity that will ideally utilize their low invasiveness and quick turnaround time to best benefit clinical scenarios.

Phase 1 studies in cancer have changed in recent years. Now, with the advent of new, less toxic, targeted agents, more patients may be candidates for new drug studies earlier in the course of their disease. It is to the advantage of the members of the oncology community to know more regarding the details and requirements for participation in early-phase clinical trials so they can advocate for their patients and help them decide when such trials may be an appropriate choice. To examine the work intensity of early phase cancer clinical trials, the authors of this report compared the study requirements of phase 1 and 2 protocols. Five parameters were studied as a surrogate of study complexity-the number of physical examinations, vital sign determinations, electrocardiograms (ECGs), nonpharmacokinetic laboratory tests, and pharmacokinetic (PK) sampling-in the first 4 weeks of protocol in 90 studies (49 phase 1 studies and 41 phase 2 studies). From July 2004 through March 2007, there were 49 phase 1 trials in the phase 1 Program, 9 phase 2 studies that were conducted by physicians appointed in that program, and 32 phase 2 trials with accessible data in the Department of Thoracic/Head & Neck Medical Oncology. In the phase 1 trials versus the phase 2 trials, there were significantly more (P < .05) physical examinations (mean +/- standard error, 3.16 +/- 0.24 vs 2.22 +/- 0.13), vital sign determinations (5.63 +/- 0.61 vs 2.80 +/- 0.26), ECGs (4.36 +/- 1.16 vs 0.80 +/- 0.17), nonpharmacokinetic laboratory tests (18.08 +/- 1.31 vs 10.12 +/- 0.65), and PK sampling (15.14 +/- 1.79 vs 1.02 +/- 0.53). These values also differed significantly (P < .005 for each) when the median values were compared in nonparametric tests. Although both phase 1 and phase 2 trials had substantial study requirements, those for the phase 1 studies were significantly higher. The successful conduct of early-phase clinical trials requires significant research infrastructure.

Although significant advances have been made in the treatment of breast cancer using chemotherapy, less than half of the patients treated for localized breast cancer benefit from adjuvant chemotherapy and most patients with metastatic cancer eventually develop disease that is chemotherapy resistant. Targeted agents, such as inhibitors of tyrosine kinases, offer the opportunity to reverse chemotherapy resistance and enhance response in patients with localized and advanced breast cancer. Such combined approaches have been established for the treatment of advanced breast cancer and are now demonstrating benefit in the adjuvant arena. This review summarizes the results of several trials involving the use of tyrosine kinase inhibition in combination with chemotherapy for the treatment of breast cancer and discusses future directions for breast cancer biotherapy.

Breast cancer continues to be a major health problem despite a decrease in mortality rates over the past 2 decades. Although many advances have been made in the treatment of breast cancer, drug therapy for the disease continues to evolve as more is learned about cell biology and cellular signaling pathways. The development of targeted agents offers the hope of new therapies with better efficacy and tolerability. Biologic therapy has been a cornerstone of targeted therapy for the treatment of advanced breast cancer and is now entering the adjuvant arena. This review summarizes the results of several adjuvant studies and discusses future directions for breast cancer biotherapy.

Breast cancer (BC) is a major health problem for women around the world. Although advances in the field of molecular therapy have been achieved, the successful therapeutic management of BC, particularly metastatic disease, remains a challenge for patients and clinicians. One of the areas of current investigation is the circulating tumor cells (CTCs), which have a determinant role in the development of distant metastasis. At the present, many of the available treatment strategies for metastatic disease are of limited benefit. However, the elucidation of the mechanisms of tumor progression and metastasis may help to identify key molecules/components that may function as therapeutic targets in the future. In the present study, the functional analysis of CTCs revealed their ability to grow and proliferate to form colonies. Immunofluorescence staining of the CTCs' colonies exhibits elevated expression of cell growth and survival associated proteins such as, survivin, ERK and Akt1. More importantly, the functional screening of the chemokine profile in BC patients' sera revealed an HR-independent elevation of the chemokine CXCL10 when compared to healthy controls. The analysis of chemokines CXCL9 and CXCL11 demonstrated an HR-dependent production pattern. The levels of both CXCL9 and CXCL11 were markedly high in HR + patients' sera when compared to HR − patients and healthy controls. The functional analysis of HR + and HR − BC derived cell lines when cultivated in media supplemented with patients' sera demonstrated the alteration of tumor progression and metastasis related proteins. We noted the induction of survivin, β-catenin, MKP-1, pERK, CXCR4 and MMP-1 both at the protein and mRNA levels. The induction of those proteins was in keeping with patients' sera induced cell proliferation as measured by the MTT assay. In conclusion, our data emphasizes the role of chemokines, especially CXCL10, in BC progression and metastasis via the induction of signaling pathways, which mainly involve survivin, β-catenin, MKP-1 and MMP-1.

Introduction Intrinsic or acquired chemoresistance is a major problem in oncology. Although highly responsive to chemotherapies such as paclitaxel, most triple negative breast cancer (TNBC) patients develop chemoresistance. Here we investigate the role of BRCA1-IRIS as a novel treatment target for TNBCs and their paclitaxel-resistant recurrences. Methods We analyzed the response of BRCA1-IRIS overexpressing normal mammary cells or established TNBC cells silenced from BRCA1-IRIS to paclitaxel in vitro and in vivo. We analyzed BRCA1-IRIS downstream signaling pathways in relation to paclitaxel treatment. We also analyzed a large cohort of breast tumor samples for BRCA1-IRIS, Forkhead box class O3a (FOXO3a) and survivin expression. Finally, we analyzed the effect of BRCA1-IRIS silencing or inactivation on TNBCs formation, maintenance and response to paclitaxel in an orthotopic model. Results We show that low concentrations of paclitaxel triggers BRCA1-IRIS expression in vitro and in vivo, and that BRCA1-IRIS activates two autocrine signaling loops (epidermal growth factor (EGF)/EGF receptor 1 (EGFR)-EGF receptor 2 (ErbB2) and neurogulin 1 (NRG1)/ErbB2-EGF receptor 3 (ErbB3), which enhances protein kinase B (AKT) and thus survivin expression/activation through promoting FOXO3a degradation. This signaling pathway is intact in TNBCs endogenously overexpressing BRCA1-IRIS. These events trigger the intrinsic and acquired paclitaxel resistance phenotype known for BRCA1-IRIS-overexpressing TNBCs. Inactivating BRCA1-IRIS signaling using a novel inhibitory mimetic peptide inactivates these autocrine loops, AKT and survivin activity/expression, in part by restoring FOXO3a expression, and sensitizes TNBC cells to low paclitaxel concentrations in vitro and in vivo. Finally, we show BRCA1-IRIS and survivin overexpression is correlated with lack of FOXO3a expression in a large cohort of primary tumor samples, and that BRCA1-IRIS overexpression-induced signature is associated with decreased disease free survival in heavily treated estrogen receptor alpha-negative patients. Conclusions In addition to driving TNBC tumor formation, BRCA1-IRIS overexpression drives their intrinsic and acquired paclitaxel resistance, partly by activating autocrine signaling loops EGF/EGFR-ErbB2 and NRG1/ErbB2-ErbB3. These loops activate AKT, causing FOXO3a degradation and survivin overexpression. Taken together, this underscores the need for BRCA1-IRIS-specific therapy and strongly suggests that BRCA1-IRIS and/or signaling loops activated by it could be rational therapeutic targets for advanced TNBCs.

The risk posed by breast cancer represents a complex interaction among factors affecting tumor immunity of the host. Toll-like receptors (TLRs) are members of the innate immune system and generally function to attract host immune cells upon activation. However, the good intentions of TLRs are sometimes not transferred to positive long-term effects, due to their involvement in exacerbating inflammatory effects and even contributing to continued inflammation. Chronic inflammatory states are considered to favor an increased predisposition to cancer, with continuous activation of inflammatory cytokines and other hallmarks of inflammation exerting a deleterious effect. Circulating tumor cells (CTCs) are neoplastic cells present in the peripheral blood circulation that have been found to be an indicator of disease progression and long-term survival. In the present study, we examined the expression of TLRs on dendritic cells, which play a major role in eliciting anti-tumor immunity, in metastatic breast cancer patients with CTCs. Flow cytometric data showed significant differences between circulating tumor cell (CTC) positive patients and CTC negative patients in their expression of TLR2 by CD8 positive cytotoxic T cells and TLR2, TLR4, TLR3, and TLR8 by CD11c positive dendritic cells (p0.05). Expression of TLR2, TLR4, and TLR8 was increased in CTC positive patients, whereas TLR3 expression was decreased in the dendritic cell population.

Advances in early detection and treatment have improved survival in common adult cancers. Surveillance for late recurrence and secondary primary malignancies is recommended for most patients. Initial treatment with surgery, radiation, chemotherapy, or hormonal therapy can result in both local and systemic sequelae, including treatment-related new cancers. Patients with head and neck, lung, breast, colorectal, and prostate cancers constitute the largest groups requiring long-term monitoring and follow-up care.

Targeted drugs are active as single agents for the treatment of breast cancer and offer the opportunity to reverse resistance to chemotherapy and hormonal therapy. Targeted therapies have been established for the treatment of advanced breast cancer and are now demonstrating benefit in the adjuvant arena. This review summarizes the results of several trials involving the use of targeted therapy for the treatment of breast cancer and discusses future directions for breast cancer therapy.

3061 Background: We have studied our recent experience in the MDACC Clinical Translational Research Center (CTRC), the Phase I Program, and the Dept. of Thoracic/Head & Neck Medical Oncology to compare the extent of regulatory and other requirements for current phase I and II cancer clinical trials. Methods: We developed a comprehensive database, together with a Microsoft Excel spreadsheet matrix to analyze the number and extent of diagnostic and therapeutic requirements for each protocol. We then examined the demands for pharmacokinetic (PK) sampling as well as electrocardiography (ECG) in the first cycle of a protocol as a surrogate for study complexity. Results: Since October, 2002, 250 protocols have been conducted in the CTRC; 54.6% were Phase I clinical trials. We reviewed 65 trials, approximately one quarter of the total. Of these, 48 were phase I trials carried out by the Phase I Program. For comparison, we identified 17 phase II trials managed by the Dept. of Thoracic/Head & Neck Medical Oncology during the same time period. In the phase I trials there were significantly more PKs (mean ± SE = 16.69 ± 1.93) than in the phase II trials (mean ± SE = 1.82 ± 1.17) (p No significant financial relationships to disclose.

Purpose The development of new, targeted, less toxic agents is one of the highest priorities for progress in cancer treatment. Many of these new agents have fewer severe side effects but may require more detailed and subtle testing to assess biologic effects. Recent literature has focused on the cost and intensity of late phase II and III clinical trials, but little has been written about the requirements of current early-phase drug development. We are carrying out a study of our recent experience in the M.D. Anderson Cancer Center Clinical Translational Research Center (CTRC) and the Phase I Program to document the extent of regulatory and other requirements for current developmental cancer clinical trials. Methods We have developed an access database of virtually all studies, together with a Microsoft Excel spreadsheet matrix for each study that defines the number and extent of the diagnostic and therapeutic requirements for each protocol. RESULTS We initially analyzed demands for pharmacokinetic (PK) sampling in the first 4 weeks of a protocol as a representative marker for study complexity. Since October 2002, over 250 protocols have been conducted in the CTRC and the Phase I Program; 54.6% were phase I clinical trials. We picked a random sample of 67 trials, which is approximately a quarter of the total. Twenty-seven of these were phase I, 12 phase I/II, 24 later phase II, and four phase III trials. Our analysis demonstrates that in phase I trials, there was a median of 23 (range 1-58) PKs per patient. Phase I/II protocols had a median of 18.5 (range 8-53) PKs per patient. In contrast, later phase II studies had a median of 12 (range 1-51) samples per patient. Conclusions PK collection in phase I trials is complex and labor intensive and reflects just the tip of the iceberg, with increasingly complicated correlates and monitoring (electrocardiograms, physical examinations, and other tests). We will present an overview of this issue, as analyzed by our database. Successful and accurate phase I clinical trials will require resources and commitment for research infrastructure considerably greater than later-phase studies.