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1102 Background: Inflammatory breast cancer (IBC) is a rare and aggressive form of breast cancer typically presenting with early metastasis. Optimal outcomes are achieved with multimodality treatment strategies in the non-metastatic setting. Data is limited, however, on the benefit of surgery in patients with metastatic IBC. We evaluated the effect of primary tumor resection on outcomes in patients with newly diagnosed stage IV IBC. Methods: We reviewed records of 172 patients with metastatic IBC treated at our institution from 1994 - 2009. All patients received systemic therapy with or without locoregional therapy (LRT). Patient demographics, receptor (ER) and HER2-neu status, grade, histology, presence of lymphovascular invasion, margin status, number of distant disease sites, pathologic response of primary tumor and clinical response to systemic therapy (CRS) at distant disease sites were recorded. Overall survival (OS), distant progression-free survival (DPFS), and chest/skin involvement at last follow-up were evaluated. Kaplan-Meier survival analyses, univariate (UV) and multivariate (MV) logistic regression models were used. Chest/skin involvement was compared between groups using Kruskal-Wallis test. Results: Seventy-nine (45%) patients underwent primary tumor resection. Average age was 51 (22-78). Median live-patient follow-up was 33 months. OS and DPFS were significantly better for patients who underwent LRT versus none (p

594 Background: IBC is a rare disease but the most aggressive form of locally advanced breast cancer with a higher frequency of HER2 neu amplification (HER2+) compared to non-IBC. The EGFR pathways are also important therapeutic targets in IBC. (Zhang D, 2009). Lap is an oral reversible dual kinase inhibitor of epidermal growth factor receptor of EGFR and HER2. Our objective was to determine the efficacy of Lap in combination with paclitaxel as NAC in pts with previously untreated HER2+ IBC. The primary end-point was to determine the rate of pathological complete response (pCR) defined as no residual invasive disease in the breast and the axillary lymph nodes or Residual Cancer Burden (RCB) of 0. (Symmans FW, 2008). The second endpoint was to assess general safety and cardiac toxicity of this combination therapy. Methods: From October 2008 to May 2011, 15 chemo-naïve pts were treated with Lap 1,250 mg/day as a single agent for 2 weeks, followed by 12 weeks of paclitaxel (80 mg/m2 weekly) plus Lap (1,000 mg/day), and finally with 4 cycles of FEC-75 mg/m2 regimen plus Lap (1,000 mg/day) before surgery. Among 12 first pts enrolled, 6 pts had grade 3 diarrhea (CTCAC v3.0) and the protocol was amended to reduce the Lap dose to 750 mg/day. After modified radical mastectomy (MRM), patients received radiation therapy and one year of adjuvant trastuzumab. Results: Median age was 53.8 (range, 39 -70), performance status was 0 (13 pts), 1 (2 pts), 4 pts had metastatic disease at diagnosis. 10 of 15 pts had MRM. One pt achieved pCR. Five pts did not complete the NAC due to grade 2 cardiomyopathy (1), liver dysfunction (2), diarrhea (1), and insurance denial after pt started treatment (1). The trial was stopped early due to severe toxicity (>15%) and lack of efficacy. Conclusions: Lap in combination with chemotherapy as NAC has a limited anti-tumor activity in pts with HER2+ IBC with a pCR rate of 6.6%. Lap and paclitaxel was associated with severe diarrhea toxicity and required multiple dose reductions of Lap. With the recent promising results in HER2+ NAC studies, the role of Lap should continue to be explored in combination with other anti-HER2 agents in IBC patients.

Angiogenesis plays an important role in the biology of tumour progression and therapies that target the vascular endothelial growth factor (VEGF) pathways – ligands, receptors and co-receptors – have become an important treatment for many types of cancer. Bevacizumab, a monoclonal antibody against VEGF, was explored in several randomised Phase III studies conducted in patients with metastatic breast cancer. However, despite bringing improvements in progression-free survival, the use of bevacizumab has not been associated with improvements in overall survival. Further improvements in predictive biomarkers and the development of biology-driven Phase II trials will be critical to help us understand which patients would benefit the most from anti-angiogenic therapy.

Background: MicroRNAs (miRs) have oncogenic and tumor-suppressor functions. MiR-21, miR-19a and miR-10b are overexpressed in breast cancer and regulate tumor cell migration, invasion and angiogenesis. We assessed the levels of miR-21, -19a, and -10b in sera of breast cancer patients and their association with the stage, histological type, hormonal receptor (HR) status and HER2 amplification in the primary tumor. Since circulating tumor cells (CTC) detected by CellSearch® are an independent and strong predictor of overall survival in metastatic breast cancer (MBC), we assessed the relationship between circulating miRs and CTCs. Methods: The study consisted of 30 healthy donors (HD) and 95 breast cancer (BC) patients. Patients’ sera were collected before starting a new line of treatment. Total RNA was isolated, reverse transcribed to cDNA and then subjected to qRT-PCR for the detection of miR-21, -19a, -10b and -192 using the TaqMan MicroRNA Assay (Applied Biosystems, Foster City, CA). Mir-192 was used to normalize the expression levels of the other miRs. Fold-changes in expression of miRs were calculated using the 2−DCt method, where DCt= mean CTtarget-miRNA -mean CTmiR-192. CTCs were enumerated using CellSearch™ (Veridex LLC, Warren, NJ). Mann-Whitney U test was used to determine differences in serum miR expression levels between patients and HD. Results: Of the 95 BC patients, 39 were non-MBC and 56 MBC. Patients grouped according to the receptor expression by immunohistochemical staining consisted of 27 HR+HER2−, 30 HR+HER2+, 20 HRHER2+, and 18 HRHER2− triple negative BC (TNBC). MiR-21 and miR-19a were higher in non-MBC patients than in HD (p=.001, p Discussion: High expression levels of miR-21, miR-19a and miR-10b in sera are observed in breast cancer patients, especially with advanced disease. HER2+ BC patients had higher serum levels of miR-21 and miR-10b than HER2−. IBC patients had a higher serum level of miR-19a than non-IBC patients. Moreover, patients with Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-03-02.

e11133 Background: Inflammatory breast cancer (IBC) is a rare and aggressive form of invasive breast cancer accounting for 3-6% of all cases. IBC patients have higher rates of distant recurrence. We hypothesized that circulating tumor cells (CTCs) can be identified in patients with IBCs and may correlate with primary tumor characteristics. Methods: All patients had blood samples taken at the time of primary surgery. CTCs (per 7.5 ml blood) were detected using the Cell Search system (Veridex) and were defined as nucleated cells lacking CD45 but expressing cytokeratins (CK) 8, 18, or 19. The presence of ≥ 1 epithelial cells meeting morphologic criteria for malignancy was considered a positive result. Statistical analyses used Chi square and Fisher's exact tests. Results: We prospectively evaluated 38 IBC patients enrolled in an IRB approved protocol undergoing surgery for stage I-III breast cancer. Median follow-up was 27 months and mean age was 51 years. Eleven patients (29%) were ER +ve, 10 (26%) were PR ...

610 Background: Breast cancer is now recognized to be a heterogeneous disease with differences in outcome among various molecular subtypes. Approximately 30-40% of patients diagnosed with primary breast cancer eventually die of recurrent disease indicating the need for identification of prognostic factors. Several retrospective studies suggested that obesity adversely affects outcome particularly in hormone-receptor (HR) positive early breast cancer. Detection of circulating tumor cells (CTCs) by CellSearch before treatment is an independent predictor of survival in metastatic breast cancer (MBC). We therefore investigated the value of CTCs and body mass index (BMI) as independent prognostic factors in MBC. Methods: We retrospectively analyzed 255 consecutive MBC patients treated between 2004 and 2010 who had baseline CTC enumeration by CellSearch and BMI measurements. OS was calculated from the date of CTC measurement and analyzed with Kaplan-Meier survival plots. Patients with a BMI ≥ 30 were considered...

623 Background: The detection of ≥ 5 CTCs by CellSearch in women with metastatic breast cancer (MBC) is predictive of early recurrence and poor survival. Whereas CTC enumeration appears to be predi...

Background: The detection of more than 5 CTCs/7.5 ml of blood in MBC pts predicts worse progression-free survival (PFS) and overall survival (OS). We investigated time-related clinical trend of CTCs according to types of 1st line therapy (hormonal therapy, HTx; chemotherapy CTx, anti-HER2 therapy; CTx with Bevacizumab) and immunohistochemical (IHC) subtypes of disease. Methods: Enumeration of CTCs was performed by the CellSearch™ technology as standard of care for 235 MBC pts receiving 1st line treatment for MBC. The evaluation of CTCs was performed as follow: baseline CTC value defined as assay taken within 30 days before starting therapy, post-treatment CTC value defined as the lowest CTC value after starting therapy; progression CTC value defined as assay taken within 30 days before documented radiological progression of disease (PD). We analyzed the effect of treatments on CTC count by Wilcoxon matched pair test and the progression CTC value within all subtypes by Kruskal-Wallis one-way analysis of variance. Results: A total of 1,052 CTC assays were performed from September 2004 to June 2010 in 235 MBC pts. One hundred thirty pts (55%) had HR+/HER2- MBC, 20 (9%) HR+/HER2+, 23 (10%) HR-/HER2-, and 62 (26%) triple-negative MBC (TNBC). Forty-seven pts received HTx (25 with available post-treatment CTC, median PFS for all group: 10.6 months), 41 pts were treated with anti-HER2 treatment (30 post-treatment CTC, median PFS: 12 months), 39 received Bevacizumab (31 post-treatment CTC, median PFS: 7.3 months), 87 CTx combination with taxanes/anthracyclines or other (epothilone or platinum salts) (57 post-treatment CTC, median PFS: 9.4 months) and 21 mono-chemotherapy (16 post-treatment CTC, median PFS: 3.6 months). Table 1 describes treatment distribution among subtypes. All administrated 1st line treatments decreased the CTC number with exception of HTx (66% patients decreased post-treatment CTCs value after HTx, p=.31). According to IHC subtypes, post-treatment CTC value decreased in all subtypes, while progression CTC at radiological PD increased in pts with HR+/HER2- and TNBC (45% and 51% pts had < 5 progressing CTCs, respectively, p.05). Conclusion: This large retrospective study showed that monitoring of CTCs is an appropriate tool for predicting response to different types of treatments, but is least useful for pts receiving HTx. Clinical trend of CTC value consistently reflects disease course in pts with HR+/HER2- and TNBC, while pts with HER2+ MBC treated with trastuzumab or lapatinib presented a low number of CTCs at PD. Our data may suggest phenotypical heterogeneity of CTCs in pts with HER-2 amplified and HR+ disease. Table 1 Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD04-02.

Background: Circulating tumor cells (CTCs) are an independent predictor of survival in metastatic breast cancer patients and patients with ≥5 CTC per 7.5 mL of whole blood (WB) have a poor prognosis and overall survival than patients with fewer than 5 CTC. Dendritic cells (DCs), the most efficient antigen presenting cells (APC), are essential for a robust host immune response. Therefore, we investigated the relationship between CTCs and the immunophenotype and function of DCs in breast cancer (BC) patients. Methods: This ongoing prospective study consists of 47 patients, 26 with metastatic breast cancer, 19 with inflammatory breast cancer; and 2 with locally advanced breast cancer, with a median age of 52 years (range: 34-71 years). Primary tumor characteristics of patients included 28 hormone receptor positive, 18 HER2 amplified, and 12 triple receptor negative. Fluorescence-activated cell sorting analysis was used to enumerate circulating DC subsets, myeloid (mDC) and plasmacytoid (pDC), that express costimulatory molecules (CD40, CD80, and CD86). Additionally, we assessed the ability of DCs to synthesize interleukin (IL)-10, IL-12, interferon-alpha (IFN-a) and tumor necrosis factor (TNF)-a constitutively and following activation with toll-like receptor (TLR) agonists. CTCs were enumerated in 7.5 mL of WB using CellSearch (Raritan, NJ). Results: CTCs were detected in 26 patients (range from 1 to 1009) including 12 patients with ≥5 CTCs. Compared with patients with < 5 CTCs, those with ≥5 CTCs have a significantly higher median number of mDC (P = 0.007) and higher median percentages (%) of TLR-activated mDC that expressed CD80 (P = 0.047) and CD86 (P = 0.063). Additionally, compared with patients who had < 5 CTCs, patients with ≥5 CTCs had a lower median % of TLR-activated mDC that synthesized IL-12 (P=0.028), TNF-α (P=0.006), or IL-10 (P = 0.031); and there was a higher median % of TLR-activated pDC that synthesized IL-10 (P = 0.000). Conclusions: Even though BC patients with ≥5 CTCs have more mDC, activated mDCs are less capable of synthesizing inflammatory factors (TNF-a and IL-12) responsible for adaptive immunity. Moreover, there was increased % of activated pDC that synthesized IL-10, a cytokine responsible for downregulating adaptive immune responses. These preliminary data suggest that activated DCs from BC patients with ≥5 CTCs are likely to have a suboptimal ability to sustain an efficient adaptive immune response compared with activated DCs of BC patients with < 5 CTCs. This is the first report linking CTCs, a proven poor prognostic indicator, with potential dysfunctional APC in BC patients. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-02-04.

Background. The formation of distant metastases in each tissue is a tightly regulated biological event. The characteristic organ distribution of metastasis in the various cancers was first recognized in 1889 by Paget and gave rise to the “ seed and soil “ hypothesis. Several reports demonstrate that the presence of more than 5 circulating tumor cells (CTC) in peripheral blood is associated with short survival in patients (pts) with metastatic breast cancer (MBC). Interestingly, pts with bone metastasis had higher absolute number and percentage of ≥5 CTC (De Giorgi et al. 2010). Because of the correlation between CTC detection, metastatic site and prognosis, we hypothesized that the baseline detection of ≥5 CTC at the time of initial recurrence can predict the development of new metastatic sites, when progression of disease occurs. Methods. We retrospectively evaluated a cohort of 516 MBC pts who had a CTC assessment before starting systemic treatment at the M.D. Anderson Cancer Center between September 2004 and November 2009. CTC were enumerated using the CellSearch™ technology. Among all pts, we selected 408 women with documented radiological progression of disease defined according to RECIST. Pts were divided in 2 categories: subjects who experienced progression of the pre-existing metastatic site(s) and those who developed new metastatic site(s). The rate of development of new metastatic sites was compared between groups according to baseline value of CTC ( Results. At a median follow-up of 16 months (range, 1-58), 168 (41%) pts had died. The estimated overall survival was 28.6 months for pts with Conclusions. Our analysis indicates that the presence of a high number of CTC before starting systemic treatment can predict for a higher probability to develop new metastatic sites on progression. This finding seems to be largely limited to pts with bone involvement at baseline. Our results may suggest the need to evaluate more effective bone-directed therapies for MBC pts with ≥5 CTC in order to prevent further progression of disease. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD04-03.

Background Transforming growth factor (TGF)-b1 has pleiotropic effects in cancer. In the early stages of breast cancer, TGF-b may be responsible for immune tolerance through the activation of T-Regulatory cells (TR). On the other hand, in the late stages of disease, it may induce angiogenic factors [vascular endothelial growth factor (VEGF), interleukin-8 (IL-8) (in Bonnomet J Mammary Gland Biol Neoplasia 2010); and IL-17 (Pickens J Immunol 2010)], and epithelial to mesenchymal transition (EMT) which may lead to an increase in the number of circulating tumor cells (CTC) (Kim, Cell 2009). Therefore, we investigated the possible correlation between TGF-b1, CTC count, angiogenic factors and T-cell function of patients with locally advanced or metastatic breast cancer. Methods As an interim analysis of an on-going prospective study, sera and peripheral blood mononuclear cells (PBMC) were collected from breast cancer patients starting a new line of therapy. At analysis, study enrollment included 78 patients with breast cancer [19 with locally advance disease (LABC), 23 with non-metastatic inflammatory breast cancer (IBC), and 32 with metastatic disease (MBC) including 19 with IBC features], and 28 healthy donors (HD). Serum TGF-b1, VEGF, and IL-8 levels were measured by Milliplex Luminex kits (Millipore, Billerica, MA). CD4+CD25+CD127dim TR cells were enumerated in whole blood by FACS (BD Biosciences, San Jose, CA). PBMC were used to study the ability of T cells to synthesize cytokines following activation of the T-cell receptor by immobilized anti-CD3 antibodies. CTC were enumerated by CellSearch (Veridex, Raritan, NJ). The Spearman Rho was calculated for nonparametric correlations and the Mann-Whitney U test was used to determine significant differences between median values. Results LABC patients and HD had a median serum TGF-b1 that was significantly higher than that of MBC patients (P = 0.042). There were statistically significantly positive correlations between serum TGF-b1 and the number of CD4+ T cells (rho = .226, P = .029) and IL-10 produced by %CD4+ (rho = .388, P = .002) and %CD8+ (rho = .459, P < .001) T cells. Furthermore, there was a positive correlation between serum TGF-b1 and the % of CD8+, but not CD4+, T cells that produced IL-17 (rho = .250, P = .022). Serum TGF-b1 levels did not correlate with either % or number of TR cells. Although serum TGF-b1 level of MBC patients was independent of CTCs (24.4 ng/mL vs. 24.0 ng/mL, P = .317), MBC patients with CTC had significantly higher serum levels of angiogenic factors such as VEGF (530 ng/mL vs. 240 ng/mL, P=0.037) and IL-8 (45.6 pg/ml vs. 20.0 pg/ml P= .006) than those of patients with no CTC. Even so, MBC patients with or without CTC have similar % of CD4 and CD8 T-cell subsets that could be activated to produce IFN-g, IL-2, TNF-a, IL-17, or IL-10. Conclusion: The concomitant presence of elevated serum TGF-ß1 levels and IL-10 producing T cells suggest immune suppression could facilitate disease progression of breast cancer. T-cell function is independent of CTC in MBC patients; however, serum VEGF and IL-8 levels were significantly elevated in MBC patients with CTC suggesting that vascular changes can facilitate tumor dissemination. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-02-07.

Background. Detection of ≥5 CTC per 7.5 mL of blood before starting systemic treatment is a strong and independent predictor of worse progression-free survival (PFS) and overall survival (OS) in MBC. Trastuzumab (Herceptin®) was shown to be highly effective in reducing CTC number in all HER-2 amplified MBC cases after the first dose (De Giorgi et al., SABCS 2009). Furthermore, trastuzumab can target chemotherapy-resistant CTC in pts with breast cancer (Bozionellou et al. 2004). To date no significant analysis exploring the effect of another anti-HER2 therapy, lapatinib (Tykerb®) on CTC has been published.We hypothesized that anti-HER2-based therapy may modify the detection rate and prognostic value of CTC in pts with HER-2 amplified MBC. Patients and Methods. We retrospectively evaluated 91 HER-2 positive MBC pts, treated at the M. D. Anderson Cancer Center with trastuzumab-based (n=59), or lapatinib-based therapy (n=32). In all pts, CTC were enumerated before starting systemic treatments, using CellSearch™. Follow-up CTC counts were available for 41 (69%) pts treated with trastuzumab and 25 (78%) pts treated with lapatinib. PFS and OS were estimated by Kaplan-Meier product limit, and compared between groups according to baseline CTC count ( Conclusions. According to previously published data, our study confirms that trastuzumab-based therapies can drastically reduce the number of CTC and neutralize their negative prognostic value. Furthermore, we found that lapatinib had a limited effect on the detection rate and prognostic value of CTC, although the low number of pts and the high percentage of pre-treated women do not allow us to draw definitive conclusions. Table 1 Table 2 Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-02-03.

548 Background: Taxane (T) and anthracycline (A) based regimens are commonly used sequentially in the PST setting in BC. It is unknown whether the efficacy of such combinations is affected by their sequence of administration. The purpose of this analysis was to assess the clinical relevance of different sequences of T and A in pts receiving PST. Methods: 1,414 pts with stage I-III BC were treated at MDACC between 1994-2009 with sequential PST T→A (84%) or A→T (16%). T-based and A-based regimens included only paclitaxel, and FAC/FEC regimens, respectively. Pts treated with trastuzumab or docetaxel were excluded. Results: The median follow up was 48.5 months and median age 50.2 years (range 23-83). 530 pts (37.4%) had stage I-IIA, 541 (38.2%) stage IIB-IIIA, and 343 (24.2%) stage IIIB-IIIC BC. 958 pts (67.7%) had hormone-receptor (HR) positive BC and 161 (11.3%), HER-2 positive. Because the two groups of patients were not identical in the distribution of prognostic factors at baseline, multivariate regressi...

1033 Background: The detection of ≥5 circulating tumor cells (CTC)/7.5 ml of blood in patients (pts) with metastatic breast cancer (MBC) predicts worse progression-free survival (PFS) and overall s...

Background: Growth of breast cancer is dependent upon sustained angiogenesis, of which vascular endothelial growth factor (VEGF) is a major stimulant. Increased expression of VEGF in breast cancers is associated with poor prognosis and disease recurrence, and anti-angiogenic agents are being developed as potential new therapies. Motesanib is an oral inhibitor of VEGF receptors 1, 2 and 3, platelet-derived growth factor receptor, and stem cell factor receptor (c-Kit). This study determined the effects of motesanib on the growth of human basal-like breast cancer cell lines in immunodeficient mice, alone and in combination with paclitaxel.Materials and Methods: Breast cancer cells BT-549 and GILM2 were injected into the mammary fatpad (MFP) of mice; HCC1187 cells were injected on the subcutaneous flank. Mice with established tumors (150-200 mm3) received motesanib orally BID, at 7.5, 25 or 75 mg/kg for three weeks. Tumors were collected for analysis of blood vessels (CD-31 staining), viable tumor area, and for markers of proliferation (Ki67) and apoptosis (cleaved caspase-3). GILM2 cells were injected into the tibia of mice to model growth in bone; mice with GILM2 MFP or tibia tumors received motesanib (25 mg/kg BID) or paclitaxel (24 mg/kg Q4Dx5), or the combination. Intratibial GILM2 tumors expressing luciferase were monitored by bioluminescence and radiography to evaluate osteolysis. Analyses of tumor size were assessed by ANOVA, and immunohistochemical tests by Student's t tests.Results: Motesanib produced dose-dependent inhibition of growth of BT-549, GILM2 and HCC1187 tumors. All doses of motesanib significantly inhibited the growth of BT-549 tumors (>55% inhibition, P25mg/kg had smaller viable tissue areas (P Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5057.

11007 Background: Chemosensitization is the ability to augment the effects of standard chemotherapy. One of the possible mechanisms for chemosensitization is improving intratumoral chemotherapy concentrations by increasing total or regional delivery of chemotherapy to the tumor. This mechanism potentially leads to a decreased tumor interstitial fluid pressure (IFP). This study evaluates the interaction between tumor IFP, intra-tumor drug accumulation and blood vessel perfusion. Methods: GILM2 human breast cancer (triple negative phenotype) cells were injected into the mammary fat pad of female nude mice. Mice were randomized to 4 arms: Control, Pac 24 mg/Kg, Bev 10 mg/Kg, and the same dose for the combination Pac + Bev, twice a week for 3 weeks. Tumor IFP was assessed using an ultraminiature catheter-tip technique (Ozerdem 2005). Concentration of Pac in tumor tissue was measured using liquid chromatography mass spectrometry (LC/MS) and blood vessel perfusion was assessed by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Ultrastructural morphology changes were assessed by electron microscopy (EM). Results: Treatment started 35 days after implantation; tumor tissue concentration of Pac was significantly increased when combined with Bev (P = 0.03). In mice treated with the combination of Pac + Bev, IFP values decreased more gradually, with sustained and significant reduction at the end of the treatment (P = 0.0068; mean SEM day 0: 28,44 ± 6,1; mean SEM day 21: 7,41 ± 2,0). The IFP changes in the other 3 experimental arms did not reach statistical significance. The combination of Pac and Bev produced substantial changes to the proportions of endothelial cell/pericytes and increased apoptosis in tumor cells by 75% (detected by immunostaining for cleaved-caspase 3). Conclusions: The combination of Pac and Bev produces significant tumor reduction and increases three-fold the concentration of Pac in the tumor. This intra-tumor augmentation of Pac was correlated with the decrease of tumor IFP, which was independent of the action of Bev alone. Results of DCE-MRI and EM analyses of the treated tumors will also be presented. No significant financial relationships to disclose.

611 Background: PST is the principal component of a multidisciplinary treatment of LABC. One of the aims of this study was to evaluate if an improvement in survival could be achieved if pts were given an alternate non-cross resistant CT regimen, based on their pathologic response to anthracycline and taxane. Methods: After multidisciplinary evaluation pts had PST: D 60 mg/m2 IV and T 60 mg/m2 IV, with GM-CSF support. Pts received q3-week DT x4. Pts with inoperable disease after DT x4 received CMF chemotherapy x4 (C: 600 mg/m2, M: 40 mg/m2, F: 600 mg/m2) day 1 and 8 q 28 days, followed by S. Pts received adjuvant CT as follows: Pts with pathologic complete response (pCR) received adjuvant DT x2; Pts with pathologic partial response (pPR) and 4+ LN after DT received CMF x 6. All pts received adjuvant RT and hormonotherapy (HT) if ER+ and/or PR+. Results: 88 pts were enrolled from 1/1998 to 6/2000: 86 with LABC, 2 with infl...

Tipifarnib is a non-peptidomimetic farnesyl transferase inhibitor (FTI) with clinical activity in hematologic malignancies, including AML, MDS and CML. Pre-clinical data suggests that tipifarnib may be synergistic with some chemotherapeutic agents. We designed a phase I/II study where pts age 15 to 70 years with previously untreated AML or high-risk MDS (blasts >10%) received induction with Ida 12 mg/m2/d on days 1–3, ara-C 1.5 g/m2 IV over 24 hours daily on days 1–4 (days 1–3 only if age ≥ 60 years) and Z with first cohort (6 pts) receiving 200mg orally twice daily (BID), and all others 300 mg BID x 21 days every 28 days. Pts achieving CR received consolidation (5 courses) with Ida 8 mg/m2/d, days 1–2, ara-C 0.75 g/m2/d, days 1–3, and Z 300 mg BID x14 days every 4–6 weeks. Maintenance was with Z 300 mg BID x 21 d every 4–6 wk for 6 months. We have treated 74 pts, median age 50 yrs (17–61 yrs). All pts are evaluable for response. Fifty seven pts (77%) responded: 48 (65%) achieved CR and 9 (12%) CRp. Overall response rate (CR+CRp) in a similar historical population treated with the same chemotherapy regimen (IA) without Z was 68% (p=0.29). Response by cytogenetics was: 26/30 (86%) for diploid, 12/16 (76%) with -5/-7, 1/2 with t(8;21), and 17/25 (68%) with other abnormalities. Response by Flt3 was 11/15 (73%) for unmutated Flt3, 39/46 (85%) for mutated Flt3. Response by age was 26/34 (76%) if ≤50yrs, 9/13 (69%) if >50yrs with diploid karyotype and 13/27 (48%) if >50yrs with abnormal karyotype. With median follow-up of 22 weeks, 34 pts are still on study. Of the 48 pts that achieved CR, 2 died in CR of unrelated causes and 9 pts have relapsed after 5, 11 13, 14, 16, 26, 29, 34, and 39 weeks, respectively. The most common grade 3 adverse events include diarrhea in 31 (42%) and hyperbilirrubinemia in 10 (14%), both transient. Thirty nine (53%) pts have required treatment interruptions/dose reductions during induction, 17 (16%), and 2 (7%) during consolidation and maintenance respectively. We conclude that Z combined with Ida and ara-C induces a high rate of CR in AML, with increased incidence of diarrhea and hyperbilirrrubinemia. Direct comparison with chemotherapy alone is warranted in a randomized trial.

Background. Myelofibrosis in the setting of CML has been historically associated with poor prognosis and with transformation. Its significance in the context of imatinib therapy is unknown. Study Aims. To evaluate the prognostic relevance of myelofibrosis in patients with chronic phase CML post interferon-a failure treated with imatinib. Patients and Methods. 110 patients with Philadelphia chromosome (Ph)-positive CML were analyzed. Imatinib was given at 400 mg orally daily. Marrow biopsies obtained prior to imatinib were subjected to Snook’s reticulin staining and graded on a scale of 1 to 4 for the degree of reticulin fibrosis as previously reported (Dekmezian.Cancer 59:1739, 1987). Severe fibrosis included grades 3–4. Results. Patients’ median age was 57 years (24 to 81). Median duration of chronic phase was 31 months (range 6–148). Reticulin fibrosis was grade 1 in 4%, grade 2 in 35%, grade 3 in 28% and grade 4 in 33%. Splenomegaly was more frequent with grade 3–4 fibrosis (p=0.04). However, patients with severe fibrosis had a similar incidence of complete cytogenetic response and survival as those with lesser degrees of fibrosis. | Parameter | Fibrosis Grade | | |:---------------------------- | -------------- | ------ | ------ | | | 1–2 | 3–4 | pvalue | | No. analyzed | 43 | 67 | | | No. cytogenetic CR (%) | 25(58) | 45(67) | .45 | | Estimated cytogenetic CR (%) | 88% | 80% | .27 | Conclusions. Imatinib, being a highly effective therapy in CML, may have reduced or eliminated the previously known prognostic impact of myelofibrosis in CML.

Introduction Circulating tumor cells (CTCs) are an independent prognostic factor for progression-free survival (PFS) and overall survival (OS) in patients with metastatic breast cancer. Inflammatory breast cancer (IBC) is one of the most aggressive forms of breast cancer. The prognostic value of a CTC count in newly diagnosed IBC has not been established. The aim of this study was to assess the prognostic value of a baseline CTC count in patients with newly diagnosed IBC. Methods This retrospective study included 147 patients with newly diagnosed IBC (77 with locally advanced and 70 with metastatic IBC) treated with neoadjuvant therapy or first-line chemotherapy during the period from January 2004 through December 2012 at The University of Texas MD Anderson Cancer Center. CTCs were detected and enumerated by using the CellSearch system before patients were started with chemotherapy. Results The proportion of patients with ≥1 CTC was lower among patients with stage III than among patients with metastatic IBC (54.5% versus 84.3%; P = 0.0002); the proportion of patients with ≥5 CTCs was also lower for stage III than for metastatic IBC (19.5% versus 47.1%; P = 0.0004). Patients with fewer than five CTCs had significantly better progression-free survival (PFS) (hazard ratio (HR) = 0.60; P = 0.02) and overall survival (HR = 0.59; P = 0.03) than patients with five or more CTCs. Among patients with stage III IBC, there was a nonsignificant difference in PFS (HR = 0.66; 95% confidence interval (CI), 0.31 to 1.39; P = 0.29) and OS (HR = 0.54; 95% CI, 0.24 to 1.26; P = 0.48) in patients with no CTCs compared with patients with one or more CTCs. In multivariate analysis, CTC was prognostic for PFS and OS independent of clinical stage. Conclusions CTCs can be detected in a large proportion of patients with newly diagnosed IBC and are a strong predictor of worse prognosis in patients with newly diagnosed IBC.

1087Background: EGFR overexpression is an independent poor prognostic factor in patients with inflammatory breast cancer (IBC). Our IBC animal model indicated that EGFR-targeted therapy inhibited IBC tumor progression via reversing EMT and suppression of CSC phenotype. We hypothesized that the combination of an anti-EGFR monoclonal antibody to neoadjuvant chemotherapy for IBC produce higher pathological complete response (pCR; including breast and axilla) rates compared with our historic rates (triple-negative [TN], 12%; HR+/HER2-, 7%) of 527 patients. Methods: In this single-arm, phase II study (47 patients enrolled, closed in June 2015), patients received 1 dose of panitumumab in a window period followed by 4 cycles of the combination of panitumumab (2.5 mg/kg), nab-paclitaxel (100 mg/m2), and carboplatin (AUC 2) on a weekly (PNC) followed by 4 cycles of FEC (5-fluorouracil, 500 mg/m2; epirubicin, 100 mg/m2; cyclophosphamide, 500 mg/m2) was administered, followed by surgical resection, radiation, and ho...

Introduction Circulating tumor cells (CTCs) represent an independent predictor of outcome in patients with metastatic breast cancer (MBC). We assessed the prognostic impact of CTCs according to different first-line systemic treatments, and explored their potential predictive value in MBC patients. Methods We retrospectively evaluated 235 newly diagnosed MBC patients, treated at the University of Texas MD Anderson Cancer Center. All patients had a baseline CTC assessment performed with CellSearch®. Progression-free survival and overall survival were compared with the log-rank test between groups, according to CTC count (< 5 vs. ≥ 5) and type of systemic therapy. We further explored the predictive value of baseline CTCs in patients receiving different treatments. Results At a median follow-up of 18 months, the CTC count was confirmed to be a robust prognostic marker in the overall population (median progression-free survival 12.0 and 7.0 months for patients with CTC < 5 and ≥ 5, respectively; P < 0.001). Conversely, in patients with human epidermal growth factor receptor-2-overexpressed/amplified tumors receiving trastuzumab or lapatinib, the baseline CTC count was not prognostic (median progression-free survival 14.5 months for patients with CTC < 5 and 16.1 months for those with CTC ≥ 5; P = 0.947). Furthermore, in patients with human epidermal growth factor receptor-2 normal tumors, a baseline CTC count ≥ 5 identified subjects who derived benefit from more aggressive treatments, including combination chemotherapy and chemotherapy plus bevacizumab. Conclusions This analysis suggests that the prognostic information provided by CTC count may be useful in patient stratifications and therapeutic selection, particularly in the group with positive CTCs, in which various therapeutic choices may procure differential palliative benefit.

1586 Background: Inflammatory breast cancer (IBC) is associated with a poor prognosis and high risk of central nervous system (CNS) metastases. We determined the cumulative incidence rate of develo...