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Although metastatic breast cancer (MBC) survival is improving, symptoms remain a significant burden. Returning to a cancer center for symptom management can be challenging. Technology-enabled supportive care platforms are worth exploration. Seventeen patients with MBC were randomized to immediate or delayed start for a 3-month intervention that included daily tablet-based guideline-concordant self-care for pain, distress, fatigue, and sleep disturbance, as well as weekly calls with a patient navigator. The primary outcome was patient acceptability. We also assessed feasibility, patient satisfaction, and cost and compared between group differences for symptoms. RM-ANOVA examined between group differences over time. Hedges’ d effect sizes quantified magnitude of differences in change between immediate and delayed start. Sixty-eight percent of patients approached accepted the tablet-based intervention. Patients interacted with the tablet 48% of possible days. Patient satisfaction ranged from 83 for walking to 49% for the psychological interventions. The cost of delivering Nurse AMIE for 3 months was $570.23. Small nonsignificant improvements were found for fatigue (d=0.24). Nonsignificant, but potentially clinically meaningful, moderate reductions were found for sleep (d=0.65) and distress (d=0.74). A tablet-based supportive care platform that offers guideline-concordant self-care for pain, fatigue, sleep, and distress was observed to be highly acceptable and feasible for patients with metastatic breast cancer. Patient satisfaction scores and initial evaluation of efficacy are promising, and the platform warrants further investigation. Technology-based self-care is a promising option to address symptoms in patients with metastatic breast cancer.

Background The purpose of this retrospective biomarker study of the Canadian Cancer Trials Group (CCTG) MA.31 randomized phase 3 trial (lapatinib vs trastuzumab) of HER2-positive metastatic breast cancer (MBC) was to evaluate the prognostic and predictive biomarker utility of pretreatment serum programmed death ligand 1 (PD-L1) levels. Methods CCTG MA.31 accrued 652 HER2-positive patients; 387 had serum available (185 in the trastuzumab arm and 202 in the lapatinib arm). The Ella immunoassay platform (ProteinSimple, San Jose, California) was used to quantitate serum PD-L1 levels. Stepwise forward Cox multivariable analyses were performed for progression-free survival and overall survival (OS). Results In the whole trial population, continuous pretreatment serum PD-L1 levels were not associated with OS. However, within the trastuzumab arm, a higher continuous pretreatment serum PD-L1 level was significant for shorter OS (hazard ratio [HR], 3.85; P = .04), but within the lapatinib arm, pretreatment serum PD-L1 was not associated with OS (P = .37). In the whole trial, in a multivariable analysis for OS, serum PD-L1 (median cut point) remained a significant independent covariate (HR, 2.38; P = .001). There was a significant interaction between treatment arm and continuous serum PD-L1 (bootstrap method; P = .0025): at or above 214.2 pg/mL (the 89th percentile), serum PD-L1 was associated with significantly shorter OS with trastuzumab treatment versus lapatinib treatment. Conclusions In the CCTG MA.31 trial, serum PD-L1 was a significant predictive factor: a higher pretreatment serum PD-L1 level was associated with shorter OS with trastuzumab treatment but with longer OS with lapatinib treatment. Immune evasion may decrease the effectiveness of trastuzumab therapy. Further evaluation of elevated serum PD-L1 in advanced breast cancer is warranted to identify patients with HER2-positive MBC who may benefit from novel immune-targeted therapies in addition to trastuzumab.

Background: Cancer cells have altered metabolism, which contributes to their ability to proliferate, survive in unusual microenvironments, and invade other tissues. Measuring the complete set of metabolites in an individual (i.e. the metabolome) provides a functional readout for cellular pathways. Further, changes in the metabolome can be correlated with disease status, prognosis and progression. Using a metabolomics platform and machine learning algorithms, biomarker signatures can be identified to predict response to therapy. Metabolite analysis of pretreatment plasma has shown promise for predicting response in a small retrospective study of the CDK 4/6 inhibitors palbociclib and ribociclib in hormone receptor-positive metastatic breast cancer (Zhang B et al, ASCO 2019 Abstr 3043). HER2-positive metastatic breast cancer patients have significant heterogeneity in response and progression-free survival (PFS) to HER2-targeted therapy. Here we retrospectively evaluated the pretreatment serum metabolome for association with PFS in a cohort of trastuzumab-treated metastatic breast cancer patients from a single institution. Methods: Pretreatment serum from 26 HER2-positive trastuzumab-naive metastatic breast cancer patients who were treated with first-line trastuzumab and chemotherapy were included in this exploratory analysis. Metabolites were extracted from previously frozen serum (1 mL) using ice-cold methanol and chloroform. The resulting metabolites were isolated and quantified using an unbiased, non-destructive, nuclear magnetic resonance (NMR)-based profiling platform (Olaris, Inc., Cambridge, MA). The serum was analyzed via 1D 1H NMR and 2D 13C-1H heteronuclear single quantum coherence spectroscopy (HSQC) using customized non-uniform sampling (NUS) techniques and processed with proprietary Olaris software. Supervised and unsupervised machine learning algorithms were used to identify patients with shorter and longer PFS to trastuzumab-based therapy. Results: The median PFS for this cohort was 301 days. Patients were subdivided into early progressors (PFS < 301 days) and late progressors (PFS ≥ 301 days). 23 metabolite resonance levels were statistically different between the two groups (KW test p Citation Format: Elizabeth O'Day, Kim Leitzel, Suhail M Ali, Bo Zhang, Chen Dong, Haiwei Gu, Xiajian Shi, Joseph J Drabick, Leah Cream, Monali Vasekar, Hyma V Polimera, Vinod Nagabhairu, Prashanth Moku, Ashok Maddukuri, Harry Menon, Neha Pancholy, Walter P Carney, Wolfgang Koestler, Allan Lipton. Pretreatment serum metabolome predicts PFS in first-line trastuzumab-treated 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 P4-10-25.

Highlights • The role and efficacy of chemotherapy in angiosarcoma treatment remains uncertain. • Doxorubicin, paclitaxel, and cisplatin may be an effective alternative to surgery. • Chemotherapy may limit the need for debilitating, radical excision in extremity. • Neoadjuvant chemotherapy may increase chances of curative surgery in the breast., Introduction Angiosarcoma is a rare soft tissue malignancy of endothelial cells, generally associated with a poor prognosis. Due to its rarity, randomized trials are difficult to conduct and a consensus on the treatment of angiosarcoma has not been reached. The role, efficacy, and timing of chemotherapy in AS treatment remain uncertain, and as stated, no large-scale trials have been able to establish definitive recommendations. Case descriptions Here we describe the successful use of chemotherapy followed by radiation for a case of lower extremity angiosarcoma, and a case of breast angiosarcoma treated with neoadjuvant chemotherapy followed by surgical resection. Systemic therapy consisted of weekly doxorubicin, paclitaxel, and cisplatin. This regimen resulted in a full clinical remission in the first patient and a pathologic complete response in the second. Discussion These cases suggest that the use of the doxorubicin, cisplatin and paclitaxel combination could be an effective alternative to radical surgical excision in extremity sarcomas, and an effective adjuvant treatment to mastectomy in cutaneous radiation-associated angiosarcoma of the breast due to their independent efficacy against angiosarcoma. A randomized trial utilizing neoadjuvant combined doxorubicin, paclitaxel and cisplatin followed by either surgery or radiation, with endpoints assessing pathologic and overall response as well as progression free survival is warranted based on these cases. Conclusion The role of neoadjuvant chemotherapy in the treatment of angiosarcoma should be reconsidered considering its ability to provide important prognostic information and improve the likelihood of curative surgery.

Background: In the CCTG (Canadian Clinical Trials Group) MA.31 randomized phase 3 trial, the trastuzumab-taxane combination led to longer PFS than lapatinib-taxane in HER2-positive metastatic breast cancer (MBC). We previously reported the prognostic utility of pretreatment serum PD-L1 in the trastuzumab arm of MA.31 (ASCO 2018, #1031), and here we evaluate serum PD-L1 in the lapatinib arm, and in the whole trial. Higher serum PD-L1 has been reported to be associated with reduced response to treatment with the immune checkpoint inhibitors in melanoma and lung cancer. Methods: MA.31 accrued 652 centrally and/or locally-identified HER2-positivepatients; 186 in the trastuzumab arm, and 202 in the lapatinib armhad pretreatment serum available. TheELLA immunoassay platform (ProteinSimple, San Jose, CA) was used to quantitate serum PD-L1. Step-wise forward Cox multivariate analysis was used for PFS and OS, and testing for treatment-biomarker interaction was based on the local partial-likelihood method (Liu Y, Jiang W, and Chen BE, Statistics in Medicine 34, 3516-3530, 2015). Results: In the total study population, pretreatment serum PD-L1 concentration had a median of 86.2 pg/ml, and 25% and 75% interquartiles of 64.1 and 134.3 pg/ml, respectively. In univariate analysis in the whole trial, and within both treatment arms, serum PD-L1 was not a significant biomarker for PFS. For OS, higher serum PD-L1 (as a continuous variable) was significant for shorter OS within the trastuzumab arm (HR=3.84, p=0.04), but was not associated with OS in the lapatinib arm (p=0.37). In the whole trial, in multivariate analysis for OS [15 covariates included: age, race, ECOG status, anthracyclines, other chemo, endocrine, radio, other prior adjuvant therapy, disease status, ER status, PR status, Ki67 (log transformed), CK5, EGFR, treatment arm, and serum PD-L1 (with median cut point)], serum PD-L1 remained a significant independent covariate (HR= 2.27, p= 0.001 (Table).There was significant interaction between treatment arm and continuous serum PD-L1 (Bootstrap method, p=0.0025); above 214.2 pg/ml serum PD-L1 (89% percentile), higher pretreatment serum PD-L1 was associated with a shorter OS to trastuzumab treatment, but longer OS to lapatinib treatment. Conclusions: In the CCTG MA.31 trial, serum PD-L1 was a significant predictive factor: higher pretreatment serum PD-L1 was associated with a shorter OS to trastuzumab treatment, but longer OS to lapatinib treatment. Immune evasion may decrease the effectiveness of trastuzumab therapy. Further evaluation of elevated serum PD-L1 in the advanced breast cancer setting is warranted to identify HER2-positive MBC patients who may benefit from novel immune-targeted therapies in addition to trastuzumab. Multivariate Analysis (whole trial): Significant Independent CovariatesCovariateP-ValueHRLower 95% CIHigher 95% CISerum PD-L1 (pretreatment) (>median vs Citation Format: Moku PR, Shepherd LE, Ali SM, Leitzel K, Parulekar WE, Zhu L, Virk S, Nomikos D, Aparicio S, Gelmon KA, Drabick JJ, Cream L, Halstead SE, Umstead T, Mckeone D, Maddukuri A, Polimera HV, Ali A, Poulose J, Pancholy N, Spiegel H, Nagabhairu V, Chen BE, Lipton A. Higher serum PD-L1 predicts for increased overall survival to lapatinib vs trastuzumab in the phase 3 CCTG MA.31 trial [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD3-10.

Women with metastatic breast cancer desire interventions that would allow them to self‐manage symptoms, but which do not require additional clinic appointments. We used a community based participatory research approach to develop a tablet based supportive care intervention called Nurse AMIE to address this need. The intervention modules are drawn from published evidence based clinical guidelines from ASCO and NCCN, including physical activity, soothing music, mindfulness meditation, guided imagery, cognitive behavioral therapy, and psychoeducation. Preliminary results include 61% and 55% acceptability from clinicians and patients, respectively, as well as 86% feasibility, defined as using the tablet for at least 30 of the 90‐day intervention. These preliminary results warrant additional research, particularly given the potential for this intervention to address needs of rural and medically underserved patients.

Mental health programs to improve problem-solving skills and reduce stress through social gameplay can improve psychiatric outcomes, but little is known about whether adult patients are interested in using them. Primary care patients (n = 467) completed a cross-sectional survey to assess interest in using 2 types of group programs for mental health. A significantly greater percentage (23.7%) of patients expressed interest in a gameplay-based program than in interpersonal therapy (17.6%) (P < .001). Lonely patients and younger patients were more likely to report interest in gameplay. Results suggest that diverse patient populations are interested in using gameplay programs for mental health.

Purpose: We aimed to establish the MTD of the poly (ADP-ribose) (PAR) polymerase inhibitor, veliparib, in combination with carboplatin in germline BRCA1- and BRCA2- (BRCA)-associated metastatic breast cancer (MBC), to assess the efficacy of single-agent veliparib, and of the combination treatment after progression, and to correlate PAR levels with clinical outcome. Experimental Design: Phase I patients received carboplatin (AUC of 5–6, every 21 days), with escalating doses (50-20 mg) of oral twice-daily (BID) veliparib. In a companion phase II trial, patients received single-agent veliparib (400 mg BID), and upon progression, received the combination at MTD. Peripheral blood mononuclear cell PAR and serum veliparib levels were assessed and correlated with outcome. Results: Twenty-seven phase I trial patients were evaluable. Dose-limiting toxicities were nausea, dehydration, and thrombocytopenia [MTD: veliparib 150 mg po BID and carboplatin (AUC of 5)]. Response rate (RR) was 56%; 3 patients remain in complete response (CR) beyond 3 years. Progression-free survival (PFS) and overall survival (OS) were 8.7 and 18.8 months. The PFS and OS were 5.2 and 14.5 months in the 44 patients in the phase II trial, with a 14% RR in BRCA1 (n = 22) and 36% in BRCA2 (n = 22). One of 30 patients responded to the combination therapy after progression on veliparib. Higher baseline PAR was associated with clinical benefit. Conclusions: Safety and efficacy are encouraging with veliparib alone and in combination with carboplatin in BRCA-associated MBC. Lasting CRs were observed when the combination was administered first in the phase I trial. Further investigation of PAR level association with clinical outcomes is warranted. Clin Cancer Res; 23(15); 4066–76. ©2017 AACR.

Cells disseminated from primary epithelial tumors into peripheral blood, called circulating tumor cells (CTCs), can be monitored to assess metastases and to provide a surrogate marker of treatment response. Here, we demonstrate how the flexible micro spring array (FMSA) device—a novel microfluidic device that enriches CTCs by two physical parameters: size and deformability—could be used in the rational development of treatment intervention and as a method to study the fundamental biology of CTCs. Cancer cells of different origins were spiked into healthy samples of donor blood to mimic blood samples of metastatic cancer patients. This spiked human blood was filtered using the FMSA device, and the recovered cells were successfully expanded in vitro and in a novel in vivo system. A series of experiments were performed to characterize these cells and to investigate the effect of chemotherapy on the resulting cultures. As few as 20 colon cancer cells in 7.5 mL blood could be isolated with the FMSA device, expanded both in vitro and in vivo and used at 25 cells per well to obtain significant and reliable chemosensitivity data. We also show that isolating a low number of viable patient CTCs and maintaining them in culture for a few weeks is possible. The isolation of viable cancer cells from human blood using the FMSA device provides a novel and realistic means for studying the biology of viable CTCs and for testing drug efficacy on these rare cells—a hypothesis that can be tested in future clinical trials.

e12534Background: Genetic polymorphisms in drug metabolizing enzymes can have significant impact on drug toxicity and/or efficacy. Exemestane (Exe), a steroidal aromatase inhibitor, is extensively ...

1031Background: In MA.31 the lapatinib-taxane combination led to shorter PFS than trastuzumab-taxane in HER2+ metastatic breast cancer. We previously reported the positive prognostic utility of pre...

INTRODUCTION: Single-agent chemotherapy was abandoned decades ago in favor of multi-agent regimens for nearly all malignancies, but single-agent intraventricular chemotherapy remains the standard of care for patients with neoplastic meningitis (NM). In the five decades since Ommaya reservoirs became available, overall survival has remained dismal, and NM remains the most devastating and feared complication of cancer. METHODS: For the last five years, we have treated patients with NM with multi-agent intraventricular chemotherapy regimens tailored to the histology of the underlying cancer. From a list of 12 cytotoxic and targeted drugs which can safely be administered into the cerebrospinal fluid (CSF) we select the 4 most appropriate agents, and treat patients with two drugs at a time in alternating weekly cycles. We queried our multinational NM registry to identify patients with NM treated with this multi-agent regimen. We collected detailed demographic, treatment, and outcome data, and compared these characteristics with corresponding patient level data acquired from 6 of the 7 randomized controlled trials (RCTs) conducted in patients with NM, all of which used single-agent intraventricular therapies. RESULTS: Two-hundred and three patients with NM (139 with solid tumors, 44 with lymphoma, 20 with leukemia) were identified from our registry, and were compared to 300 patients from the RCTs (238 with solid tumors, 62 with lymphoma). RCT data for adults with leukemic meningitis are not available. Age, gender, KPS at the start of treatment, tumor histology, status of the primary cancer, and frequency of concurrent systemic chemotherapy or radiation did not differ between registry and RCT patients, or were less favorable in the registry patients. All patients from the registry patient group were included for analysis regardless of how many cycles of intraventricular therapy they received (intent-to-treat model). Median survival for the solid tumor, lymphoma, and leukemia groups (multi-agent vs. single-agent treatment) were 211 vs. 93.1 days (p

558Background: Despite considerabletreatment advances,resistance to hormone therapy remains a major clinical problem. We correlated the protein levels of multiple tyrosine kinase receptors, signal ...

2549Background: PARP inhibitor therapy of BRCA-associated cancer exploits the concept of synthetic lethality, yet there have been limited PD markers of efficacy. We report here on baseline PAR and ...

Breast cancer is the most commonly diagnosed cancer in women in United States. From data of American Cancer Society from 2007 reported total of 178,480 women diagnosed with breast cancer. The death rate from breast cancer has decreased in North America over time, but still accounts for second highest cancer death, following lung cancer. Breast cancer is staged based on tumor size, nodal involvement, and distant metastasis like any other solid tumors. However clinical staging is not the only important factor in management of breast cancer. Various molecular features divides breast cancer into many subgroups – that act differently, and respond differently from therapy. Thus the focus of breast cancer treatment has evolved focusing on specific targets. The most important biologic markers in subtyping of breast cancer so far are hormone receptor positivity and HER2/neu protein expression. Five molecular subtypes using intrinsic gene set include Basal mRNA, HER2 + mRNA, Luminal AmRNA, Luminal B mRNA, and Normal-like mRNA. In addition, better understanding of genetic target of breast cancer has given us arsenal of personalized, and more effective treatment approach.

Breast cancer is a highly osteotropic neoplasm, and as many as 75% of patients with metastatic disease will have involvement of the bony skeleton. On radiologic examination, these metastases are predominantly osteolytic but can be osteoblastic or mixed. The mechanisms by which metastases are formed are complex, involving many steps that include angiogenesis, invasion, and proliferation in the bone microenvironment. Tumor cells in the bone microenvironment produce a large number of cytokines that stimulate osteoclastic activity. Increased osteoclastic activity, in turn, leads to production of a variety of lymphokines and growth factors that can increase tumor cell proliferation. Thus, a cytokine network is established, which results in an imbalance of the processes of bone formation and bone resorption. As tumor burden in bone increases, osteoclast-mediated bone resorption is accelerated, resulting in loss of bone strength, fractures, pain, and other morbidities. Tumor cells metastatic to bone can also secrete growth factors, leading to increased osteoblastic activity. Osteoblasts lay down an excess of new bone that is structurally weak. There is considerable crosstalk between osteoclasts, osteoblasts, macrophages, and other cellular elements within the bone environment. The increasing understanding of the biology of bone metastases has opened the door to improved management of this important clinical problem. Current treatment strategies include approaches to reduce tumor burden and developing treatments that directly inhibit osteoclast function. The bisphosphonates are a class of drugs that inhibit osteoclast recruitment and function. Several highly potent bisphosphonates are now available for clinical use and represent an important adjunct in the management of bone metastases from breast cancer, multiple myeloma, and several other types of malignancies. Some newer therapeutic approaches include agents designed to inhibit the osteoclast-osteoblast signaling interactions or alter processes of adhesion and invasion.

520 Background: Based on the concept of synthetic lethality combining platinum agents and PIs should benefit patients (pts) with BRCA-associated MBC. We report mature outcomes with vel alone, or wi...

1021 Background: We reported on a phase I trial showing 54% confirmed partial response (PR) with carb + vel. Here we describe single agent vel activity and, upon progression, the feasibility and ef...

e11015 Background: Breast cancer is the most commonly diagnosed malignancy among women in the United States. Among various subtypes of breast cancer, tumors that overexpress the human epidermal gro...

e11595 Background: Paclitaxel (P) is an important part of chemotherapy regimens for early breast cancer. Breast cancer survivors may be left with iaotrogenic peripheral neuropathy which can affect their quality of life. Methods: We conducted a retrospective, IRB approved, medical chart review to determine the rate of peripheral neuropathy in a tertiary care practice in central Pennsylvania. Patients had biopsy proven, newly diagnosed, high risk breast cancer. Patients were treated with a standard dose dense (DD) regimen where 4 cycles of adriamycin (A) 60 mg/m2/cyclophosphamide (C) 600 mg/m2 were followed by four cycles of paclitaxel (P) 175 mg/m2 every 2 weeks (Citron et al) between 7/2006 to7/2008 at Penn State Cancer Institute. All patients who received dose dense chemotherapy by a single provider were included (n=23). No peripheral neuropathy (PN) was reported before initiating paclitaxel, but 3 of 23 patients had type II diabetes. Electronic medical charts were reviewed and data was abstracted to analyze incidence of peripheral neuropathy. These data were compared to reported published data. Results: 22 pts received dose dense AC followed by P chemotherapy. 100% completed 4 cycles of AC and 87% complete 4 cycles of P. Overall, 82% developed neuropathy (32% with grade 1, 41 % with grade 2, 9 % with grade 3). Almost 30% of patients required gabapentin for control of neuropathic pain. 35% of patients with PN had symptoms persisting >3 months after chemotherapy. Conclusions: A considerable percentage of high risk, early breast cancer patients treated with AC followed by DD paclitaxel developed at least mild neurotoxicity. Rates of Grade 3 neurotoxicity were much higher (9%) than the previous CALGB-9741 study (4%). This may be related to regional pharmacogenomic differences. Although dense dose paclitaxel has been shown to improve disease free survival, PN affects most patients treated with paclitaxel and for some patients can have a prolonged impact on their quality of life. Future studies should attempt identify which patients are at risk for severe peripheral neuropathy. No significant financial relationships to disclose.

e11631 Background: P, a chemotherapeutic agent, extensively used in management of solid tumors. Although hypersensitivity reactions from P are common; HSP is rarely reported. We report 3 pts with early stage, high risk breast cancer, who developed HSP while receiving dose dense (DD) P with PF support. Methods: C#1 51 yr old woman (W) was diagnosed (Di) with triple negative (TN), infiltrating duct carcinoma (ca) with nodal metastasis. Neoadjuvant chemo (NC) with DD adriamycin 60 mg/m2 (A) and Cyclophosphamide 600 mg/m2 (C) was started. She completed 4 cycles of AC with PF 6 mg SQ given day 2 of each cycle without complications. Several days after her first dose of P with PF, she experienced dyspnea on exertion (DOE) and a non productive cough (NPC). CT of chest (CC) revealed ground glass opacity more in upper lungs, suggestive of HSP, and echocardiogram (echo) was within normal limits (WNL). She rapidly improved with steroid (S). C#2 46 yr w was Di with hormone positive, her 2 negative, infiltrating duct ca with nodal involvement. NC with DD AC followed by P was started. She completed 4 cycles of AC with minimal toxicity followed by DDP. After the third P infusion, she developed NPC with DOE. CC revealed diffuse interstitial prominence and echo was WNL. She rapidly improved with S. C#3 63 yr W was Di with 2.3 cm, TN, invasive duct carcinoma of left breast. NC with DD AC followed by P was started. After 2nd infusion of P, she developed hypoxia and cough; CC revealed diffuse groundglass opacities throughout lungs bilaterally, suggestive of HSP. She rapidly improved with S. Results: All 3 cases occurred in non-smoking pts without known lung/cardiac disease, treated with PF on day 2 of each cycle. Pts had abnormal CCs, were afebrile and responded quickly to steroids. Published DD experience (Citron et al) uses daily filgrastim (F), not the pegylated form which our pts received. We believe that HSP in these pts may be related to long acting growth factor stimulation of white cells and causing reversible HSP. Conclusions: Future prospective studies on taxanes using DD regimens should include a randomized design where pts given PF are compared to pts who receive F. No significant financial relationships to disclose.