1133 Background: Epithelial growth factor receptor pathway (EGFR) is expressed in TNBC and may be important in a subset of this heterogeneous disease. We evaluated the efficacy and toxicity of an anti-EGFR antibody (cetuximab) combined with ixabepilone given to the TNBC patients (pts) in the neoadjuvant setting. This study was designed to detect an increase in pathological complete response (pCR) rate, defined as no residual disease in the breast, from 20% to 40% in each arm, using a Simon optimal two stage design, with one-sided alpha=10% and power=80%. At least three responses out of 12 patients were needed to proceed with second stage for each arm. Methods: All pts received 4 cycles of preoperative ixabepilone 40 mg/m2 every 3 weeks. In addition, patients were randomized to receive either 12 infusions of weekly cetuximab (400mg/m2 on week 1, then 250 mg/m2) or not. Race, proliferation rate, and TILs was correlated with pCR. Results: To date, a total of36 pts with stage II-IIIA TNBC were enrolled. Median age was 54 years (range 35-79 years) with median tumor size of 6.1 cm (range 2-18 cm). The median proliferation rate (Ki-67) was 67.2% (range 8%-95%). Pts were Hispanic (36%), White (39%), African-American (19%) and others (6%). In ixabepilone alone arm, pCR was observed in only 14.3%, and this monotherapy arm did not progress to second stage. To date, pCR was observed in 31.3% in ixabepilone/cetuximab arm, with 6 patients still on treatment. Adverse events for the combination arm were modest, mainly grade 1-2 (neutropenia: 4%, skin: 83 %, GI: 50 %, fatigue: 100 %). Grade 3 febrile neutropenia in 3 % were observed. No statistically significant correlation with race, Ki67, and TILs with pCR rate was observed. Conclusions: The addition of cetuximab to ixabepilone may improve the rate of pathological complete response in TNBC pts. There was no association between race or proliferation and response to ixabepilone and cetuximab. Evaluation of EGFR, p-EGFR and EGFR pathway -associated genes, PTEN, mutational analysis of PI3K/mTOR pathway and next generation genomic analysis is underway to evaluate for potential predictive biomarkers of response to EGFR inhibition. Clinical trial information: NCT01097642.

Based on a modified dosing protocol designed to optimize efficacy, an open-label EFL vs. capecitabine (4:3 randomization) Phase 2 trial for metastatic breast cancer is in progress. Eniluracil inactivates dihydropyrimidine dehydrogenase, thereby preventing the formation of α-fluoro-β-alanine, and conferring 100% oral bioavailability and a 5 hr half-life on 5-fluorouracil (5-FU). Study drugs are administered orally for 1st- or 2nd-line treatment for metastatic disease in patients previously treated with an anthracycline and a taxane. Arm 1: eniluracil (40 mg) taken 11–16 hr before 5-FU (30 mg/m2); leucovorin (30 mg) taken with 5-FU and the next day. The regimen is administered once/week for 3 weeks/4 weeks. Arm 2: capecitabine (1000 mg/m2) taken bid for 14 days/21days. Arm 2 patients with disease progression could crossover to take EFL in Arm X. Two sites in the USA and 19 in Russia are enrolling. Currently, 115 patients (21% are 1st-line, 70% had previous 5-FU treatment) are enrolled and 83 have had tumor assessments. EFL was well tolerated with no unexpected toxicities. As of May 2012, there were 11, 7, & 1 partial responses in Arms 1, 2, & X, respectively. The primary endpoint, progression-free survival, will be determined approximately 7.5 months after the trial is enrolled with 140 evaluable patients. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr OT3-3-01.

PURPOSE:To compare breast cancer subtyping with the three centrally assessed microarray-based assays BluePrint, MammaPrint, and TargetPrint with locally assessed clinical subtyping using immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH).METHODS:BluePrint, MammaPrint, and TargetPrint were all performed on fresh tumor samples. Microarray analysis was performed at Agendia Laboratories, blinded for clinical and pathological data. IHC/FISH assessments were performed according to local practice at each institution; estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) assessments were performed on 132 samples, and Ki-67 on 79 samples.RESULTS:The concordance between BluePrint and IHC/FISH subtyping was 94 % for the Luminal-type, 95 % for the HER2-type, and 94 % for the Basal-type subgroups. The concordance of BluePrint with subtyping using mRNA single gene readout (TargetPrint) was 96 % for the Luminal-type, 97 % for the HER2-type, and 98 % for the Basal-type subgroups. The concordance for substratification into Luminal A and B using MammaPrint and Ki-67 was 68 %. The concordance between TargetPrint and IHC/FISH was 97 % for ER, 80 % for PR, and 95 % for HER2.CONCLUSIONS:The implementation of multigene assays such as TargetPrint, BluePrint, and MammaPrint may improve the clinical management of breast cancer patients. High discordance between Luminal A and B substratification based on MammaPrint versus locally assessed Ki-67 or grade indicates that chemotherapy decisions should not be based on the basis of Ki-67 readout or tumor grade alone. TargetPrint serves as a second opinion for those local pathology settings where high-quality standardization is harder to maintain.

The selective estrogen receptor modulators (SERM), Tamoxifen and raloxifen reduce risk breast cancer. Patient acceptance of SERMs for breast cancer prevention is low due to toxicities. New agents with a better toxicity profile are needed. Aromatase inhibitors (AI) reduce the risk of contralateral breast cancer and risk of new breast cancer in high risk women. However, the mechanism by which AIs reduce breast risk is not known. Surrogate biomarkers are needed to evaluate the effect of preventive agents. The objective of this prospective short-term prevention study was to evaluate the effect of anastrozole on biomarkers in breast tissue and serum of women at increased risk for developing a contralateral breast cancer. Women with a history of stage I, II breast cancer who started anastrozole for standard adjuvant treatment were eligible. Patients underwent baseline fine needle aspiration of the unaffected breast and serum collection for biomarker analysis before starting anastrozole at 1 mg per oral/day and again at 6 months. Biomarkers included changes in cytology, insulin-like growth factor 1 (IGF-1), IGF-binding protein 1 (IGFBP-1), and IGFBP-3. Thirty-seven patients were enrolled. There was a significant modulation in serum IGFBP-1 levels between pre- and postsamples (P = 0.02). No change was observed in IGF-1, IGFBP-3, and breast cytology.We showed a significant modulation of IGFBP-1 levels with six months anastrozole. Anastrozole is currently being studied as a prevention agent in a large phase III trial and our results provide support for continued evaluation of IGFBP-1 as a surrogate endpoint biomarker in prospective breast chemoprevention studies. Cancer Prev Res; 5(2); 276–82. ©2011 AACR.

47 Background: MammaPrint (MP) is a powerful predictor of disease outcome in early stage breast cancer. In addition, TargetPrint (TP), a microarray-based test that measures the mRNA expression level of ER, PR and HER2 and an 80 gene expression Molecular Subtyping profile BluePrint (BP) were developed. In the present study, MP, BP and TP were measured in a prospective U.S. breast cancer patient cohort. Methods: MP results were evaluated in fresh tumor samples from 127 breast cancer patients (T1-4N0-2; median age 62 [39-97 yr]) collected by core needle biopsy or from a surgical specimen between July 2008 and January 2011. We compared treatment advice as recommended by NCCN guidelines and classification according to MP. In addition, we compared IHC/FISH ER, PR and HER2 assessments with TP. The MP and BP results were used to subtype the patients into molecular subgroups. Results: For the group of patients (n=59) for which NCCN recommends the use of a multi-gene signature for determining chemotherapy treatment recommendations, 42 patients were classified as High Risk and 17 as Low Risk by MP. Comparison of TP with IHC/FISH indicated a concordance of 98% for ER, 94% for PR, and 98% for HER2. For a subgroup of 53 patients combined MP and BP results were available; 18 patients were Luminal-type/MP Low Risk, 27 patients were Luminal-type/MP High risk, 1 patient was Her2-type/MP Low Risk, 1 patient was Her2-type/MP High Risk and 6 patients were Basal-type/MP High Risk. Conclusions: Adding the multi-gene signature MammaPrint, as well as BluePrint and TargetPrint provides additional information for treatment guidance. By combining MammaPrint with the BluePrint molecular subtyping profile, specific groups of patients can be recognized that are at high risk of recurrence and that would possibly benefit from specific treatment. This study shows that TargetPrint provides high quality second opinion for local IHC/FISH assessment.

Patients with advanced or metastatic breast cancer commonly develop disease resistant to chemotherapy (typically anthracyclines and taxanes), which presents a major obstacle to therapy and leaves few effective treatment options. Drug resistance can occur due to various mechanisms including modification of drug efflux membrane transporters such as P-glycoprotein, as well as alterations in beta-tubulin. The novel epothilone B analog, ixabepilone, which has low susceptibility to various drug-resistance mechanisms, has demonstrated preclinical activity in drug-resistant breast cancer. The clinical activity of ixabepilone was evaluated in metastatic breast cancer patients with highly pretreated and/or resistant/refractory disease. Results were reviewed from three phase II trials in which ixabepilone was administered as monotherapy and one phase III trial that evaluated ixabepilone in combination with capecitabine. As a single agent, ixabepilone demonstrated activity in women who were heavily pretreated and resistant to an anthracycline, a taxane, and/or capecitabine. The combination of ixabepilone and capecitabine was significantly more active than capecitabine alone in patients with prior treatment or resistance to anthracyclines and taxanes. Treatment-related adverse events were generally low grade except for grade 3/4 toxicities, including neutropenia (53-54%) and reversible peripheral sensory neuropathy (14-16%). Ixabepilone has significant activity in patients with heavily pretreated metastatic breast cancer who are disease resistant or refractory to anthracyclines and taxanes. Further clinical evaluation of this agent in patients with drug-resistant breast cancer and in specific patient subsets is warranted.

PURPOSE To explore the antitumor activity of the aromatase inhibitor, anastrozole, in the treatment of premenopausal women with hormone receptor-positive, metastatic breast cancer who have been rendered functionally postmenopausal with the use of the luteinizing hormone-releasing hormone agonist, goserelin. PATIENTS AND METHODS Premenopausal women with estrogen and/or progesterone receptor-positive, metastatic or recurrent breast cancer were enrolled in this prospective, single-arm, multicenter phase II trial. Patients were treated with goserelin 3.6 mg subcutaneous monthly and began anastrozole 1-mg daily 21 days after the first injection of goserelin. Patients continued on treatment until disease progression or unacceptable toxicity. RESULTS Thirty-five patients were enrolled of which 32 were evaluable for response and toxicity. Estradiol suppression was assessed, with mean estradiol levels of 18.7 pg/mL at 3 months and 14.8 pg/mL at 6 months. One participant (3.1%) experienced a complete response, 11 (34.4%) experienced partial response, and 11 (34.4%) experienced stable disease for 6 months or longer for a clinical benefit rate of 71.9%. Median time to progression was 8.3 months (range, 2.1 to 63+) and median survival was not been reached (range, 11.1 to 63+). The most common adverse events were fatigue (50%), arthralgias (53%), and hot flashes (59%). There were no grade 4 to 5 toxicities. CONCLUSION The combination of goserelin plus anastrozole has substantial antitumor activity in the treatment of premenopausal women with hormone receptor-positive metastatic breast cancer.

Resistance to chemotherapy is a major obstacle to the effective treatment of many tumor types. Although many anticancer therapies can alter tumor growth, in most cases the effect is not long lasting. Consequently, there is a significant need for new agents with low susceptibility to common drug resistance mechanisms in order to improve response rates and potentially extend survival. Approximately 30% of the women diagnosed with early-stage disease in turn progress to metastatic breast cancer, for which therapeutic options are limited. Current recommendations for first-line chemotherapy include anthracycline-based regimens and taxanes (paclitaxel and docetaxel). They typically give response rates of 30 to 70% but the responses are often not durable, with a time to progression of 6 to 10 months. Patients with progression or resistance may be administered capecitabine, gemcitabine, vinorelbine, albumin-bound paclitaxel, or ixabepilone, while other drugs are being evaluated. Response rates in this setting tend to be low (20 to 30%); the median duration of responses is <6 months and the results do not always translate into improved long-term outcomes. The present article reviews treatment options in taxane-resistant metastatic breast cancer and the role of ixabepilone in this setting.

Resistance to chemotherapeutic agents is a significant obstacle to the effective treatment of metastatic breast cancer (MBC). Anthracycline- and taxane-based regimens are active as first-line treatment for MBC; however, MBC often progresses because of primary or acquired resistance to anthracyclines and taxanes. There are few options for the treatment of patients with anthracycline- and taxane-resistant or taxane-refractory MBC. This article reviews several single agents that have demonstrated activity as treatment for patients with MBC who progress during, or rapidly following, treatment with anthracyclines and taxanes. Results from clinical trials evaluating agents such as ixabepilone, albumin-bound paclitaxel, capecitabine, vinorelbine, pemetrexed, and irinotecan are presented. Single-agent capecitabine is approved for the treatment of patients after failure of anthracyclines and taxanes. Ixabepilone has demonstrated efficacy in patients with MBC resistant to multiple chemotherapeutic agents and is the only agent approved by the Food and Drug Administration as monotherapy for anthracycline-, taxane-, and capecitabine-resistant MBC. Improved treatment strategies and further evaluation of newer agents may reduce the current burden of treatment-resistant or treatment-refractory MBC.

BACKGROUND: A combination of uracil and ftorafur (UFT) was developed to combine the cytotoxic effects of 5-fluorouracil (5-FU) with convenient oral dosing. Leucovorin was combined with LIFT to further potentiate the effect of 5FU on tumor cells. Orally administered LIFT and leucovorin provided higher peak plasma concentrations of S-FU and prolonged therapeutic 5-FU concentrations compared with continuous infusion of 5-FU. METHODS: Ninety-one patients with metastatic breast cancer who had been previously treated with anthracyclines and/or taxanes were treated with LIFT and leucovorin, given orally, for the first 28 days of a 35-day cycle. The total daily dose of LIFT was 300 mg/m(2), administered in 3 doses of 100 mg/m(2) each every 8 hours. The primary endpoint was time to disease progression (TTID). Secondary objectives included overall tumor response rate (overall response equals complete response plus partial response) and overall survival. RESULTS: Of the 91 patients enrolled, 70 were evaluable for efficacy. Although no complete responses were observed, 7 patients had partial responses, for an overall response rate of 10% in the evaluable population. The median TTP for the evaluable population was 10 weeks, and the proportion of patients who were free of disease progression at 6 months was 23%. The median overall survival was 59.4 weeks for all patients enrolled. Common, drug-related >= grade 3 adverse events (graded according to National Cancer Institute Common Toxicity Criteria, version 2) included diarrhea, vomiting, abdominal pain, and nausea. CONCLUSIONS: The combination of LIFT and leucovorin administered orally in a 3-times-daily regimen was found to have modest activity. Grade 3 toxicities were manageable with appropriate dose adjustments in patients with metastatic breast cancer previously treated with anthracyclines and/or taxanes. Cancer 2010;116:1440-5. (C) 2070 American Cancer Society.

This study evaluated whether expressive writing (EW) was an effective stress management intervention for breast cancer patients. Women were recruited at the end of neoadjuvant chemotherapy and assigned to write about their cancer experience (EW group; n = 24) or neutral topics (neutral writing [NW] group; n = 25). Women were asked to write for 20 minutes a day for a total of four writing sessions that were completed over a 7-day period. Participants were reassessed approximately 3 days before and 2 weeks after surgery. The intervention did not significantly decrease women's distress, perceived stress, sleep disturbance, or pain. There was some evidence that the EW group used more sleep medication at the presurgical assessment than the NW group. Social constraints moderated the effect of the intervention. Among women with high social constraints, the EW group reported lower average daily pain than the NW group. Among women with low social constraints, the EW group reported higher average daily pain than the NW group. EW was not broadly effective as a stress management intervention for women with breast cancer. These data do not support the use of EW as a presurgical mind-body complementary medicine program for this population.

Chemotherapy efficacy in patients with solid tumors is influenced by primary and acquired multidrug resistance (MDR). Epothilones represent a novel class of microtubule inhibitors with lower susceptibility to drug resistance and efficacy in taxane-resistant tumors. While other epothilones are currently under investigation, ixabepilone is the first epothilone B analogue approved by the U. S. Food and Drug Administration. Ixabepilone has been shown to have preclinical activity in chemotherapy-sensitive and chemotherapy-resistant tumor models, and synergistic antitumor activity with other chemotherapeutic and targeted agents. Single-agent ixabepilone has demonstrated clinical activity in multiple solid tumors including advanced breast, lung, prostate, pancreatic, renal cell, and ovarian cancers. Most notably, efficacy has been demonstrated in patients with metastatic breast cancer (MBC) progressing after treatment with anthracyclines and taxanes. A phase III trial in anthracycline-and taxane-resistant MBC showed superior disease control with ixabepilone plus capecitabine versus capecitabine monotherapy, resulting in its approval. Ixabepilone is also active in chemotherapy-naive and taxane-resistant hormone-refractory prostate cancer and platinum-resistant non-small cell lung cancer. Neutropenia and peripheral sensory neuropathy are the most common adverse events associated with treatment. This review discusses the challenges of MDR and the data that support the use of epothilones in this setting, focusing on ixabepilone. The Oncologist 2008; 13: 1207-1223

BACKGROUND. Previous studies have evaluated 3-week and weekly docetaxel schedules in patients with metastatic breast cancer (MBC). The varying efficacy results and toxicity profiles noted in these earlier studies led to a comparison of the schedules to determine which was safer and more efficacious.METHODS. A phase 3 clinical trial was conducted in patients with MBC who were treated with docetaxel either every 3 weeks or once weekly to determine and compare response rate and duration, time to disease progression, progression-free survival (PFS), overall survival (OS), and toxicity. Patients were randomized to receive docetaxel at a starting dose of either 75 mg/m(2) every 3 weeks or 35 mg/m(2) weekly for 3 consecutive weeks followed by 1 week of rest.RESULTS. A total of 118 patients underwent efficacy analysis; 59 patients were randomized to the every-3-week treatment arm and 59 to the weekly arm. The response rate was 35.6% (95% confidence interval [95% CI], 23.6-49.1%) for the every-3-week arm versus 20.3% (95% CI, 11.0-32.8%) for the weekly arm. There was no statistical difference between the every 3-week and the weekly treatment arms with regard to median PFS (5.7 months vs 5.5 months; P = .46) or OS (18.3 months vs 18.6 months, respectively; P = .34). There was a higher overall toxicity rate (grades 3 and 4, according to the National Cancer Institute Common Toxicity Criteria [version 2.0]) in the every-3-week treatment arm versus the weekly treatment arm (88.1% vs 55.9%, respectively; P = .0001).CONCLUSIONS. Compared with patients who received weekly docetaxel, those who received docetaxel every 3 weeks had a higher response rate but experienced similar PFS and OS and a more pronounced toxicity.

PURPOSE:Ixabepilone (BMS-247550) is an epothilone analog that optimizes the properties of naturally occurring epothilone B. Natural epothilones and their analogs promote tumor cell death by binding to tubulin and stabilizing microtubules, causing apoptosis. This international phase II trial assessed the activity of ixabepilone in patients with metastatic breast cancer (MBC) that was resistant to taxane therapy.PATIENTS AND METHODS:MBC patients, who had experienced disease progression while receiving or within 4 months of taxane therapy (6 months if adjuvant taxane only), and who had a taxane as their last regimen, received ixabepilone (1- or 3-hour infusion of 50 mg/m(2) or 3-hour infusion of 40 mg/m(2) every 3 weeks).RESULTS:Of 49 patients treated with 40 mg/m(2) ixabepilone during 3 hours, 35 (73%) had experienced disease progression within 1 month of their last taxane dose. The response rate was 12% (95% CI, 4.7% to 26.5%). All responses (n = 6) were partial; five of six patients had not responded to prior taxane therapy. In responders, the median response duration was 10.4 months. In 20 patients (41%), stable disease was the best outcome. Median time to progression was 2.2 months (95% CI, 1.4 to 3.2 months); median survival was 7.9 months. For treated patients across all cohorts (intent-to-treat population), the response rate was also 12% (eight of 66). Treatment-related adverse events in the study were manageable and primarily grade 1/2. Treatment-related neuropathy was mostly sensory and mild to moderate.CONCLUSION:Ixabepilone (40 mg/m(2) as a 3-hour infusion every 3 weeks) demonstrates promising antitumor activity and an acceptable safety profile in patients with taxane-resistant MBC.

Purpose: Short-term phase I and phase II breast cancer prevention trials require tissue acquisition at baseline and after intervention to evaluate modulation of potential biomarkers. Currently used tissue acquisition methods include ductal lavage (DL), random periareolar fine needle aspiration (RPFNA), and core needle biopsy. The optimum method to retrieve adequate samples and the most accepted method by study participants is not known. Experimental Design: We compared RPFNA and DL as breast tissue acquisition methods for short-term breast cancer prevention trials by evaluating sample adequacy and tolerability in subjects who participated in two prospective phase II breast cancer prevention trials. Eighty-six women at increased risk for breast cancer were included in this study and underwent baseline DL and RPFNA. High risk was defined as having a 5-year Gail score of >1.67% or a history of atypical hyperplasia (AH), lobular carcinoma, or breast cancer. Results: Median age was 54.5 years (range, 39-75 years); 75% of the women were postmenopausal. About 51% of the women yielded nipple aspiration fluid, and breast fluid samples via DL were retrieved in 73% of these subjects. Of these samples, 71% were adequate samples (greater than 10 epithelial cells). However, when the entire cohort was considered, only 31% of the subjects had adequate samples. RPFNA was also attempted in all subjects, and sample retrieval rate was 100%. Out of these, 96% of the subjects had adequate samples. In DL samples, AH rate was 3.7% was and hyperplasia (H) rate was 11.1%. In RPFNA samples, AH rate was 12.9%, and H rate was 24.7%. Cytology findings in RPFNA samples correlated with age, menopausal status, and breast cancer risk category (previous history of lobular carcinoma in situ). Both procedures were well tolerated, and no complications occurred among participants. Conclusions: Considering that the main end point for short-term prevention trials is the modulation of biomarkers, it is important to optimize adequate sample acquisition; therefore, RPFNA is a more practical option for future phase I and II breast cancer prevention trials compared with DL.