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575 Background: Approximately 15% of breast cancers (BC) are diagnosed in reproductive aged women. Management of the disease in this age group frequently includes chemotherapy and hormonal therapy, which can both affect fertility. Considering that age at first delivery has been steadily increasing, young women may face BC before completion of childbearing. Methods: In this prospective study, women referred to our institution for surgical treatment of BC were asked, before their first visit, to fill out a questionnaire regarding their reproductive history and fertility preservation knowledge. Eligible patients included women between the ages of 18 and 45, with a newly diagnosed BC, who had not yet started treatment. Results: Sixty women were eligible with a median age of 40 (range 20-45). 98% of responders (59 out of 60) had been diagnosed within the previous 2 months. 78% (47/60) had a college or post-graduate degree. 80% (48/60) had been pregnant before, while 86.5% (45/52) reported having had children. 81% (47/58) were premenopausal, and only 3 patients reported not having had periods for more than 1 year. 50% of responders (30/60) declared no interest in future childbearing, 25% were definitely interested, and 25% were undecided. However, only 9% (5/57) reported having received information on fertility preservation options before the survey. Women who have been pregnant were significantly less likely to consider fertility preservation options prior to treatment (egg/embryo/ovarian tissue cryopreservation [6% vs. 50%, p=0.001]), or after treatment (egg/embryo donation, surrogacy or adoption [6% vs. 58%, p

10514 Background: Retrospective and preclinical studies suggest that smokers are at increased risk for LM from BC, possibly mediated by lung inflammation and the bioactive lipid, PGE2. To investigate this link in pts, we examined urinary PGE-M, a stable end metabolite of PGE2. Methods: A translational study was conducted, consisting of pts with LM (n=100), pts with mets but no known lung mets (NKL, n=100) and controls (CTRLS) with a history of BC (n=200). Pts receiving steroids and radiotherapy were excluded. Pts gave urine (PGE-M), blood (biomarkers), had BMI measured, and completed a validated questionnaire (smoking, NSAIDs, confounders). PGE-M was measured by mass spectrometry, normalized to urinary creatinine and compared between grps in both univariate and multivariate models, correcting for covariates. Results: From 09/2010 to 06/2011, 400 pts, med age 58 yrs (range 24-88) enrolled. There were no significant differences between grps in smoking and NSAID exposure (table). PGE-M (med; range) was highest among pts with LM (6.7; 0.7 - 43.4) compared to pts with NKL (4.6; 0.7 - 26.8) and CTRLS (4.2; 0.9 – 62.6, P24 pack year smoking history and LM had the highest co-variate-adjusted log PGE-M (P=0.03). In this model, age (P

Background Patients (pts) with residual breast cancer after neoadjuvant chemotherapy are at increased risk of recurrence; no proven risk-reduction strategies exist, supporting exploration of novel therapies in the post-preoperative setting. Bevacizumab (B) combined with chemotherapy is active in metastatic disease; ongoing studies are exploring the efficacy of adjuvant combination chemotherapy and B. DFCI 05–055 (Mayer et al, ASCO 2007, 2008) demonstrated the feasibility of 1 year B after preoperative chemotherapy. Also, increasing data support risk reduction through lifestyle interventions (Segal, Ligibel et al, ASCO 2011). The ABCDE trial was designed to evaluate extended adjuvant B in a high risk post-preoperative cohort, and also assess the contribution of exercise to a dietary intervention. Eligibility Criteria Eligible pts have HER2− breast cancer and have received preoperative anthracycline and/or taxane-based chemotherapy with residual invasive disease at surgery. Acceptable stages include: triple negative if preop stages I-III, or ER+/PR+ if stage III preop or IIB postop. Acceptable organ function and standard B exclusions apply. Registration must occur between 28–180 days after last surgery. Specific Aims Primary endpoint is recurrence-free survival at a median follow-up of 6 years. Secondary endpoints include B pharmacogenomics, evaluation of the impact of exercise on quality of life and biomarkers associated with recurrence, and prospective examination of cardiac toxicity. Residual tissue-based predictors of outcome will be extensively explored, including PAM50, Ki67, and VEGF hypoxia signature. Methods This is a 2 × 2 randomized study with a first randomization to 6 months (mo) B 15 mg/kg every 3 weeks (wks) plus 6 mo CM (C 50 mg daily, M 2.5 mg twice daily days 1, 2 each wk), followed by 2.5 years B 15 mg/kg every 6–8 wks, versus observation. A second randomization is to a 1 year telephone-based lifestyle intervention, offering dietary modification alone, or in combination with a structured exercise program. Statistical Methods and Accrual Total sample size is 660 pts within the Translational Breast Cancer Research Consortium. Overall power is 0.80 to detect a hazard ratio of 0.59−0.68, depending on pt population. Accrual initiated early 2011 and is expected to continue for the next 36 months. Conclusions Patients with residual disease after preoperative chemotherapy are at high risk of recurrence and have unmet medical needs. To our knowledge, this is the only trial testing a prolonged but less intensive adjuvant B schedule in this clinical setting. Results of this study could have critical implications for the management of this patient population and for the design of future clinical trials with anti-angiogenic agents. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr OT3-02-04.

Background: Sexual dysfunction is reported after chemotherapy and endocrine therapies. However, the prevalence and severity of sexual dysfunction in premenopausal women undergoing therapy for both local and metastatic disease is not well defined. This study was performed in order to understand the impact of contemporary breast cancer treatment on the prevalence and severity of sexual health in premenopausal women. Methods: We developed a survey that includes a previously validated questionnaire, the Female Sexual Function Index (FSFI), as well as an established measure of health-related quality of life (the EuroQol EQ-5D), and disease-specific items to characterize sexual dysfunction and its causes based on literature review and expert consultations. Anonymous administration of the surveys was conducted in outpatient clinic waiting areas of the Breast Cancer Center at Memorial Sloan-Kettering Cancer Center (MSKCC), under an IRB waiver of consent. Results: 372 consecutively approached premenopausal women with breast cancer of any stage, undergoing treatment were each queried once. The mean age was 47. 87% reported current or past hormonal treatment, and 86% reported current or past chemotherapy (76% adjuvant; 24% for metastatic disease). Sexual dysfunction attributed to breast cancer or its treatment, defined as an FSFI score =5/10). In a multivariate analysis, metastatic disease, development of amenorrhea from cancer treatment, antidepressant use and poorer overall health were each significantly associated with worse FSFI scores. Lower FSFI scores were also significantly associated with worse health-related quality of life. Conclusion: Sexual dysfunction is prevalent in premenopausal women treated for breast cancer and should be discussed with patients as a potential adverse effect of therapy. Assessment of sexual symptoms throughout treatment and beyond may facilitate the use of potential interventions such as lubricants, dilators, treatment modification and counseling. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD04-03.

Background: Hyperactivation of the PI3K-AKT-mTOR pathway is a postulated mechanism of resistance to anti-HER2 therapies and has also been described in triple-negative breast tumors. In HER2−amplified (HER2+) laboratory models, inhibition of this pathway induces activation of upstream receptor tyrosine kinases such as HER3. In triple-negative breast cancer (TN), HER1 overexpression has been identified and models show sensitivity to combined HER1 and mTOR inhibition. We hypothesize that dual inhibition of the PI3K pathway, HER1/2, and induced HER3 may be highly effective in patients with HER2+ or TN breast cancer (BC). This phase I/II trial is designed to determine the tolerability and possible efficacy of the mTOR inhibitor temsirolimus (T) plus the HER1/2 inhibitor neratinib (N) in patients with trastuzumab-refractory, HER2+ or TN BC. We will also explore mutational activation of the PI3K pathway in trastuzumab-refractory tumors as it relates to response to the T-N combination. Methods: The phase I dose-escalation study evaluated T (flat dose IV weekly) plus N (240 mg oral daily) in patients with metastatic HER2+ or TN BC. Cycle length was 4 weeks. Phase I end points included definition of maximum tolerated dose (MTD) and response rate (RR) per RECIST. The phase II study has a Simon two-stage design and evaluates the HER2+ and TN patients separately. Phase II endpoints include progression free survival and duration of response. Response was evaluated radiographically every 8 weeks, toxicity assessed every 2 weeks. All patients underwent biopsy of metastatic disease for biomarker assessment. Activating mutations in PIK3CA were assayed using the Sequenom MassARRAY system. Expression of PTEN was assessed by immunohistochemistry utilizing a published scoring system. Results: The phase I study enrolled 8 HER2+ patients who received a median of 5 (1-13) cycles of therapy. All patients had received trastuzumab and a median of 5.5 (2-12) prior lines of therapy. Frequent treatment-related grade 2 events were: hyperglycemia (4/8), elevated CPK (3/8), diarrhea (2/8), and rash (2/8). Grade 3 diarrhea was the dose-limiting toxicity. Other grade 3 toxicity was hyperglycemia (1/8); hematologic toxicities were not observed. The MTD of temsirolimus with neratinib is 8 mg IV weekly. Six patients treated at MTD were evaluable for response; 4 patients had PR, 1 had SD for a RR of 67%. PI3K pathway activation, through PIK3CA mutational activation or PTEN loss, was identified in 4/6 tumors analyzed and did not preclude response to temsirolimus and neratinib. Updated results reflecting the phase II patients will be reported. Conclusions: Temsirolimus plus neratinib is active in trastuzumab-refractory HER2+ patients. The phase II study is ongoing and additional efficacy and safety data in both HER2−amplified and triple-negative breast cancer patients will be presented. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD09-08.

1100 Background: PTC299, an oral investigational drug, suppresses tumor growth by selective posttranscriptional inhibition of tumor VEGF and angiogenic cytokine synthesis. Alone, PTC299 shows antit...

e19657 Background: Over 125,000 patients of reproductive age are diagnosed with cancer annually in the US. Many have not yet started or completed their families at the time of diagnosis and are dis...

1092 Background: Tivozanib (T; AV-951) is a potent and selective oral small molecule tyrosine kinase inhibitor (TKI) of VEGFR-1, -2, and -3. This phase Ib open-label, multicenter study investigated...

e19525 Background: More than 2.5 million individuals of child-bearing age are currently survivors of cancer. Many of these patients wish to become parents after treatment, and are concerned about p...

1156 Background: Inhibition of SRC is a novel approach for MBC. Preclinically, the SRC inhibitor D + P had superior antitumor activity to either agent alone. We designed this phase I-II study to translate this observation. Methods: For phase I: pts with MBC, ECOG PS 0-1, normal hepatic, renal, marrow function were eligible. Pts with pleural/pericardial effusions were excluded. For phase II: pts had measurable, HER2-negative MBC, ≤2 prior rx for MBC. Cycle (C) consisted of wP 80 mg/m2 IV 3/4 weeks + D 70mg orally daily; escalating to 100 mg, 120 mg, and 150 mg in cohorts of 3 pts. Toxicity was assessed by CTCAE v3.0, response by RECIST. Results: 15 pts (14 females, 1 male) enrolled; median age 54 (range 35-74), median PS=1 (range 0-1). 11 (73%) pts rcvd prior adjuvant chemoRx. Pts rcvd a median of 3 prior rx for MBC (range 0-12). Pts rcvd median of 2 C of D + P (range 1-10). One DLT occurred at 150 mg (G3 fatigue); this cohort was expanded with no further DLTs to date. However, 1 pt had a skin reaction to ...

579 Background: Women with high risk ESBC remain at substantial risk of relapse despite adjuvant chemotherapy (AT). Current testing does not completely stratify individual risk of relapse, or asses...

9128 Background: Cancer patients report significant levels of unmet communication needs. Attending to these needs is crucial for optimal care. Communication skills training (CST) programs have been shown to improve clinical communication. However, advanced CST programs in oncology have lacked institutional integration, and thus have not attended to institutional norms and cultures, the “hidden curriculum”, that may counteract explicit communication skills training. The goals of this project were to 1. Develop an evidenced-based CST curriculum; 2. Address the “hidden curriculum” through faculty development; 3. Implement the program for the institution's fellows, residents and faculty; 4. Assess the effectiveness of the program. Methods: We developed an advanced CST program, made up of nine teaching modules, at Memorial Sloan-Kettering Cancer Center through systematic review of the literature which identified commonly used strategies, skills, and behaviors that enhance effective communication in the oncolog...

e13537 Background: PTC299 is a novel oral investigational drug designed to inhibit tumor expression of VEGF and other angiogenic cytokines. PTC299 also induces a parallel interruption of tumor cell...

Background: Sexual dysfunction is reported after chemotherapy and endocrine therapies, and causes a substantial burden on women with breast cancer. However, the prevalence and severity of sexual dysfunction in women undergoing therapy for both local and metastatic disease is not well defined. Improved understanding of sexual dysfunction may facilitate enhanced treatment and interventions in patients with breast cancer undergoing active treatment, and in survivors of this disease.Methods: We developed a survey that includes a previously validated questionnaire, the female sexual function index (FSFI), as well as an established measure of health-related quality of life (the EuroQol EQ-5D), and disease-specific items to characterize sexual dysfunction and its causes based on literature review and expert consultations. Anonymous administration of the surveys was conducted in outpatient clinic waiting areas of the Breast Cancer Center at Memorial Sloan-Kettering Cancer Center (MSKCC) and two community centers, under an IRB waiver of consent.Results: During November 2008 through May 2009, 509 women undergoing treatment for breast cancer of all stages were each queried once. The mean age was 51 (range 26-91). 87% reported current or past hormonal treatment, and 82% reported current or past chemotherapy (76% adjuvant; 24% for metastatic disease). Sexual dysfunction attributed to breast cancer or its treatment, defined as an FSFI score =5/10). Patients attributed their sexual dysfunction to chemotherapy in 318/373 (85%) of cases; to hormonal therapy in 221/298 (74%) of cases; and to surgery in 331/442 (66%) of cases. Other reported contributors to sexual dysfunction include a new diagnosis of breast cancer by 81% of respondents, anxiety by 82% of respondents, and change in relationship with a partner by 55% of respondents.Conclusion: Sexual dysfunction is prevalent in women treated for breast cancer and should be discussed with patients as a potential adverse effect of therapy. Assessment of sexual symptoms throughout treatment and beyond may facilitate the use of potential interventions such as lubricants, dilators, treatment modification, topical estrogens, and counseling. Future work includes a longitudinal prospective trial to further characterize the etiologies of these symptoms and a randomized controlled trial to evaluate interventions for sexual dysfunction. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1056.

Background: We previously reported that dose dense (dd) q2wk AC-nab-P with concurrent bevacizumab (B) in early stage breast cancer is safe (McArthur, SABCS 2008). Prospective randomized studies of adjuvant B-containing, anthracycline-based regimens are ongoing with stringent cardiac monitoring strategies. However, accurate predictors of cardiotoxicity, including congestive heart failure (CHF), are lacking. Currently, treatment-related CHF is monitored by measuring left ventricular ejection fraction (LVEF) changes at various time points. Cardiac troponins (cTn) are myocardial contractile proteins that are released into the circulation after cardiac injury. As highly specific biomarkers of myocardial damage, cTns may augment existing cardiac monitoring strategies by providing earlier and more reliable evidence of myocyte damage. Consequently, we investigated cTnI as a potential biomarker of cardiotoxicity in our pilot study of cardiac safety with ddAC-nab-P+B.Methods: In this phase II study, B was administered concurrently (10 mg/kg IV q2wk x 8) with pegfilgrastim-supported chemotherapy (AC at 60/600 mg/m2 q2wk x4 then nab-paclitaxel at 260 mg/m2 q2wk x4) and continued at 15 mg/kg q3wk thereafter for a total one year of B therapy. The primary endpoint was cardiac safety. A secondary endpoint was the prospective exploration of TnI as a potential predictor of cardiotoxicity. Peripheral blood for TnI was collected at baseline; weeks 2, 4, 6, 8, 10, 12, and 14; and months 6, 9, and 18. In this pre-planned analysis, TnI values over time were examined as continuous variables by institution and as categorical variables. TnI values were categorized as undetectable (UN; 0.31ng/ml MSKCC or >0.16ng/ml UCSF). Baseline and maximum TnI values were compared with the maximum change in left ventricular ejection fraction (LVEF) values for all 80 enrolled patients over the study period using ANOVA or regressionResults: Median age: 48y (range, 27–75y). Median follow-up: 24.5mo (range, 1–32mo). Median baseline LVEF: 68% (range, 53–82%). The baseline TnI was MD for 1 pt and UN for 79 pts. Overall, 57 pts developed MD TnIs and 6 pts developed EL TnIs. There was no significant association between TnI and LVEF for the 6 pts who developed protocol-defined asymptomatic LVEF declines and the 1 pt who developed CHF versus not, or for 6 pts who develop EL TnI versus not. Furthermore, there was no significant association between continuous TnIs and the maximum % LVEF change [(max-min)/min)].Conclusions: In this prospective study, TnIs do not appear to predict for LVEF changes with B + ddAC-nab-P. Long-term follow-up continues for late CHF events. Accurate biomarkers of cardiotoxicity in this setting are needed. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3087.

Estrogen deprivation therapy with aromatase inhibitors has been hypothesized to paradoxically sensitize hormone-receptor-positive breast cancer tumor cells to low-dose estradiol therapy.To determine whether 6 mg of estradiol (daily) is a viable therapy for postmenopausal women with advanced aromatase inhibitor-resistant hormone receptor-positive breast cancer.A phase 2 randomized trial of 6 mg vs 30 mg of oral estradiol used daily (April 2004-February 2008 [enrollment closed]). Eligible patients (66 randomized) had metastatic breast cancer treated with an aromatase inhibitor with progression-free survival (or = 24 wk) or relapse (afteror = 2 y) of adjuvant aromatase inhibitor use. Patients at high risk of estradiol-related adverse events were excluded. Patients were examined after 1 and 2 weeks for clinical and laboratory toxicities and flare reactions and thereafter every 4 weeks. Tumor radiological assessment occurred every 12 weeks. At least 1 measurable lesion or 4 measurable lesions (bone-only disease) were evaluated for tumor response.Randomization to receive 1 oral 2-mg generic estradiol tablet 3 times daily or five 2-mg tablets 3 times daily.Primary end point: clinical benefit rate (response plus stable disease at 24 weeks).toxicity, progression-free survival, time to treatment failure, quality of life, and the predictive properties of the metabolic flare reaction detected by positron emission tomography/computed tomography with fluorodeoxyglucose F 18.The adverse event rate (or = grade 3) in the 30-mg group (11/32 [34%]; 95% confidence interval [CI], 23%-47%) was higher than in the 6-mg group (4/34 [18%]; 95% CI, 5%-22%; P = .03). Clinical benefit rates were 9 of 32 (28%; 95% CI, 18%-41%) in the 30-mg group and 10 of 34 (29%; 95% CI, 19%-42%) in the 6-mg group. An estradiol-stimulated increase in fluorodeoxyglucose F 18 uptake (or = 12% prospectively defined) was predictive of response (positive predictive value, 80%; 95% CI, 61%-92%). Seven patients with estradiol-sensitive disease were re-treated with aromatase inhibitors at estradiol progression, among which 2 had partial response and 1 had stable disease, suggesting resensitization to estrogen deprivation.In women with advanced breast cancer and acquired resistance to aromatase inhibitors, a daily dose of 6 mg of estradiol provided a similar clinical benefit rate as 30 mg, with fewer serious adverse events. The efficacy of treatment with the lower dose should be further examined in phase 3 clinical trials.clinicaltrials.gov Identifier: NCT00324259.

9558 Background: Sexual dysfunction (SD) is reported after chemotherapy and endocrine therapies, and causes a substantial burden on women with breast cancer. However, the prevalence and severity of SD in this population is not well defined. Improved understanding of SD may allow for enhanced treatment and interventions in patients with breast cancer undergoing active treatment, and in survivors of this disease. Methods: We developed a survey that includes a previously validated questionnaire, the female sexual function index (FSFI), and disease-specific items to characterize SD and its causes based on literature review and expert consultations. Anonymous administration of the surveys was conducted in outpatient clinic waiting areas of the M64/Breast Center Memorial Sloan-Kettering Cancer Center (MSKCC), under an IRB waiver of consent. Results: During November-December 2008, 100 women with breast cancer of any stage were each queried once. The mean age was 52 (range 26–75). 68% reported current or past hormonal treatment, and 63% reported current or past chemotherapy (84% adjuvant; 16% for metastatic disease). SD attributed to breast cancer or its treatment, defined as an FSFI score =5/10). Patients attributed their SD to chemotherapy in 52/63 (83%) of cases; to hormonal therapy in 56/68 (82%) of cases; and to surgery in 68/92 (74%) of cases. Other contributors to SD were felt to include anxiety by 83% of respondents, and change in relationship with a partner by 46%. Conclusions: SD is prevalent in women treated for breast cancer and should be discussed with patients as a potential adverse effect of therapy. Assessment of sexual symptoms throughout treatment and beyond may facilitate the use of potential interventions such as lubricants, dilators, treatment modification, topical estrogens, and counseling. A longitudinal prospective trial is planned to further characterize the etiologies of these symptoms. No significant financial relationships to disclose.

Abstract #16 Rationale: It has been postulated that aromatase inhibitor (AI) therapy may sensitize ER+ breast cancer to lower doses of estrogen therapy as second-line endocrine treatment for advanced breast cancer (ABC). We therefore conducted a randomized trial of 30mg generic estradiol daily (10 mg t.i.d.- "recommended" dose) versus 6 mg (2 mg t.i.d - "experimental" dose). Materials and Methods: Major eligibility: Postmenopausal ER+ ABC treated with an AI with 24+ wks progression free survival, or relapse after 2+ yrs of adjuvant AI; RECIST measureable non-bone metastases or WHO assessable bone lesions, with elevated tumor markers >2X ULN. Major exclusions: History venous thrombosis, heart disease, uncontrolled hypercalcemia and fulvestant in the last 12 months. FDG PET scans were conducted at baseline and after 24 hours to assess metabolic flare as a predictor of response (pre-defined as a ≥12% increase in FDG uptake). Results: Sixty-six patients were enrolled (82% White, 15% Black); mean age 59 years, range 36-84. 34 received 6 mg and 32 received 30 mg. Estradiol levels will be provided at the meeting. There were more patients experiencing grade 3+ SAE on the 30 mg arm versus the 6 mg arm (11 vs. 4; P=0.06) with one venous thrombosis on each arm. There was no difference in total FACT-B QOL scores at one month by treatment arm, QOL decline was associated with more severe estrogen side effects, especially amongst patients on the 30 mg arm (P=0.006). Uterine bleeding was successfully controlled with intermittent progestin therapy. Clinical benefit rates (stable disease at least 24 weeks plus response - intent to treat population) were 25% (CI: 15-37%, 1PR and 7SD out of 32) on the 30 mg arm and 29% (CI: 19-42%, 3PR and 7SD out of 34) on the 6 mg arm. Patients with clinical benefit to estradiol could be retreated with original AI after progression and to date one PR out of three patients with repeat AI therapy noted. There were 44 patients evaluable for the interaction between PET -flare and response. Flare was seen in all responders (3/3), 9 of 13 patients with SD and only 3 of 30 patients with PD (p Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 16.

Abstract #5007 Background: The accurate detection of osseous metastases frequently has significant prognostic and therapeutic implications at metastatic breast cancer (MBC) diagnosis. However, the ideal paradigm for accurate detection of osseous metastases has not yet been determined. In this retrospective, single-institution study, we compare the diagnostic performance of integrated positron emission tomography/computed tomography (PET/CT) versus bone scintigraphy (BS) for women undergoing extent-of-disease (EOD) evaluation for suspected MBC. Methods: Women undergoing EOD evaluation for suspected MBC with integrated PET/CT and bone scintigraphy (BS) between January 1, 2005 and Dec 31, 2007 were identified through institutional databases. Patients with PET/CT and BS imaging completed within 30-days of each other were included. Women with a prior history of MBC or an active second malignancy were excluded. Electronic medical record (EMR) reports were reviewed and classified as positive, negative or equivocal for detecting osseous metastases. All EMR reports deemed potentially equivocal were reviewed by 2 investigators and consensus reached regarding the final classification. Bone biopsy data, where available, was also recorded. Results: The median age of the 62 eligible women was 54y (33-90y). Overall, PET/CT and BS demonstrated a high degree of concordance. Of the 41 concordant studies, 13 (21%) and 28 (45%) were reported as positive and negative for osseous metastases, respectively. No studies were classified as equivocal by both modalities. Ten positive PET/CT studies were negative by BS, but no PET/CT-negative studies were positive by BS. Of the 10 patients with PET/CT-positive, BS-negative studies, 4 had subsequent bone biopsies, all of which confirmed osseous metastases. Conclusions: This study supports the diagnostic performance of integrated PET/CT in detecting osseous metastases when EOD evaluation for suspected MBC is considered. Whether PET/CT may supplant BS entirely in this setting has not yet been determined. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5007.

Abstract #3154 Background: Overexpression of both HER2 and VEGF is associated with worse outcome than overexpression of either receptor alone. In preclinical models, combination anti-HER2 and anti-VEGF therapy has been shown to be more effective than either treatment alone. Bevacizumab (B) plus trastuzumab and lapatinib (L) plus pazopanib have shown activity in patients (pts) with HER2+ MBC. We evaluated the combination of L+B in a phase 2 trial in HER2+ MBC pts. To explore new biomarkers of treatment effect, we measured circulating tumor cells (CTCs) with two different methods of CTC enumeration: CellSearch (Veridex LLC), and immunomagnetic enrichment followed by flow cytometry (IE/FC), as well as circulating endothelial cells (CECs) in pts receiving study treatment. Methods: This study evaluated L (1500 mg PO daily) plus B (10 mg/kg IV q2wk) in 50 HER2+ MBC pts. The primary endpoint is crude progression-free survival (PFS) at 12 wks. Serial evaluation of CTC and CEC was performed. Blood was obtained from consenting pts at baseline, weeks 2, 6 then every 12 weeks until end of study. CellSearch assay was performed as previously described using 7.5 cc blood in a CellSave tube and the CellSpotter analyzer. For IE/FC, 20 ml of blood was subjected to IE using anti-EpCAM ferrofluid, followed by FC for EpCAM, CD45, and nucleic acid content. CTC data were correlated with assay method and with best response. CECs were defined as CD34/31+, CD45-, or CD34/146+, CD45-, and were assayed by FC. Results: Enrollment to this study ended in March 2008 (n=52). Clinical data is presented at this meeting (Dickler et al). 47 patients have evaluable CTC and CEC data at baseline and/or first follow-up; 32 patients have response data. CTC determined by CellSearch or IE/FC showed significant correlation at baseline (R=0.58; P=0.012). CTC by CellSearch at first followup correlated with treatment response (P=0.01) with levels above 5 CTC/sample associated with progression; there was no correlation with baseline values. There were too few positive IE/FC values to evaluate correlation with outcome. The change in CEC/CD146 from baseline to first followup for is of borderline significance in this preliminary analysis (P=0.07) between PR (N=2, Mean Change Score/MCS=-4.345) and SD/PD (N=18, MCS=0.8); a decrease of CEC/CD146 from baseline to first followup suggests greater likelihood of response. Conclusions: L+B is an active regimen in pts with MBC. CTC measurements correlated between two separate methodologies, and for the CellSearch assay predicted response to therapy. A decrease in CEC from baseline to first followup correlated with response to this combined targeted therapy, consistent with our previous results with other B-based therapy. PFS and response correlations for the full study cohort will be presented. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3154.

9588 Background: ONJ is diagnosed with increasing frequency among IV bisphosponate (IVBP)-treated cancer pts, in the range of 1–10 per 100 treated pts depending on duration of therapy (Khosla 2007)...

20745 Background: More than three million people in the United States are infected with hepatitic C virus (HCV) and over 200,000 women are diagnosed with breast cancer each year. There is little da...

11003 Background: Bevacizumab, a monoclonal antibody to vascular endothelial growth factor, has shown a survival advantage in treating several solid tumors. Reported serious side effects include hy...

1047 Background: The addition of carboplatin (Cb) to paclitaxel (P) and trastuzumab (T) improves response rate and time to progression (TTP) in HER2+ MBC (Robert N, JCO 2006). Weekly P+Cb+T is acti...

589 Background: DD q2week (wk) AC-P is superior to q3wk AC-P (Citron, JCO 2003). In metastatic BC (MBC), q3wk nab-P is more active than q3wk P (Gradishar, JCO 2005), and B improves PFS when added to wkly P (E2100, Miller, NEJM 2007). AC-P + B is currently under phase III study as adjuvant therapy (E5103), and nab-P may offer superior efficacy to P in this setting. However, grade (gr) 3 SN was greater with q3wk nab-P (260 mg/m2) than P (175 mg/m2) (10% vs 2%) in MBC and B may increase SN of P (E2100). Without B, ddAC-nab-P caused 2–14% gr 3 SN (Burstein, ASCO 2007; Robert, SABCS 2005). We assessed the incidence and severity of SN over time in pts treated on a pilot trial of adjuvant B + ddAC-nab-P. Methods: Eligible pts had resected HER2(-) BC. 80 pts enrolled and received B (10mg/kg IV q 2wks x 8 cycles) concurrent with chemoRx (AC 60/600 mg/m2 x 4, followed by nab-P 260 mg/m2 x 4). B continued at 15mg/kg IV q3wks x 12. Pegfilgrastim was given day 2 after each chemoRx. Radiation and endocrine Rx were admi...

1042 Background: In a preclinical HER2+ BC model, combination anti-HER2 and anti-VEGF therapy was more effective than either treatment alone, and increased VEGF expression is associated with worse outcome in HER2+ disease. B plus trastuzumab (T) has shown promising activity in patients (pts) with HER2+ MBC, however the cardiac toxicity of this regimen requires further evaluation. L, an oral dual inhibitor of EGFR and HER2, is approved in combination with capecitabine after T-based therapy for HER2+ MBC. L may have less cardiac toxicity and may be a safer and more effective alternative to T+B. This hypothesis was evaluated in a phase 2 trial of L+B in HER2+ MBC pts. Methods: This 50-patient single-arm study evaluated L (1,500 mg PO daily) plus B (10 mg/kg IV q2wk). The primary endpoint is progression-free survival (PFS) at 12 weeks with 84% power to detect a clinically significant PFS rate of 60%; secondary endpoints include toxicity and response per RECIST. Efficacy was assessed at Week 6, 12, and q12wks ...

518 Background: We showed that dd q 2 weekly (w) AC → P + T×1 year (y) as adjuvant treatment (Rx) for patients (pts) with HER2 (+) BCA is safe with a congestive heart failure (CHF) rate of 1/70 pts...

637 Background: ddAC-paclitaxel (P) is superior to q3w AC-P. Both are associated w/ a 50%). Pts w/ unstable angina, CHF, or recent MI were excluded. MUGA was repeated after completion of ddACx4. Subsequent therapy (Rx) was determined per protocol guidelines of LVEF. Results: From Jan ‘05 to Dec ‘07, 185 pts were enrolled in 3 trials. Median age was 49yrs (range 27...

9569 Background: Bevacizumab (BEV) improves response and PFS when added to weekly paclitaxel in patients (pts) with metastatic breast cancer (MBC). Known toxicities include hypertension (HTN), thro...

1036 Background: E2100 was an open-label, multi-center, randomized, Phase III trial comparing P to P+B as initial chemotherapy for MBC. The original analysis based on investigator-assessed progress...

567 Background: Dose dense, q2 wk AC-paclitaxel (T) is superior to q3 wk therapy (Rx) (Citron, JCO 2003). The risk of congestive heart failure (CHF) with ddAC-T is not increased at 2) ×4 then nab-p (260 mg/m2) x4 with pegfilgrastim on Day 2 plus B for one year (10mg/kg IV q2wk ×8 with chemoRx then B 15mg/kg q3wk); radiation & endocrine Rx per standard of care. MUGA obtained at baseline & mos. 2, 6, 9, 18. Pts with significant asymptomatic ↓LVEF during Rx may have B held per protocol. These pts are not counted as CEs but will have long-term cardiac monitoring. Accrual goal is 75 pts. If ≥3 CE (∼4.7%) or >1 cardiac death from LV dysfunction, B + ddAC-nab-p will not be considered safe. Results: 44 pts have enrolled, median (med) age 46.5 yrs (33–67). 28 pts have baseline & month 2 LVEF data: med baseline LVEF 68% (61–82), med LVEF at mo. 2 after ddAC+B 68% (53–75); 1 pt had an 18 point asymptomatic drop to 53% - B held but reinitiated in 4 wks with repeat LVEF 63%. 12 pts completed nab-p+B but none have reached the 6 mo. MUGA. Rx-related Gr 3/4 toxicity: neutropenia gr4 (6.8%), diarrhea gr3 (2.3%), hypertension gr3 (2.3%), neuropathy gr 3 (2.3%), fatigue gr 3 (2.3%), mucositis gr 3 (2.3%). 4 pts have withdrawn from study Rx, but only 1 due to toxicity including gr3 fatigue, mucositis & neuropathy. Conclusions: No LV dysfunction has been observed with B + ddAC-nab-p; this trial is on-going. Long-term follow-up and analysis of troponin, renin and circulating endothelial & tumor cells are planned. No significant financial relationships to disclose.

10650 Background: The combination of carboplatin (C), paclitaxel (P) and trastuzumab (T) is active in HER2+ metastatic breast cancer (MBC) (Robert N et al. Proc ASCO 2003), and safer with weekly administration of all 3 agents (Perez E et al. Proc ASCO 2004). The superiority of nanoparticle paclitaxel (Abraxane, AB) over Cremophor-based paclitaxel (Gradishar W et al. JCO 2005), and the efficacy and safety of weekly AB in MBC (Blum J et al. Proc ASCO 2005) motivated us to conduct this study. Materials/Methods: To date 10 of 50 planned patients (pts) with measurable, HER2+ MBC have entered. After we established the safety of AB at 75 mg/m2 on days 1, 8, and 15 every 28 days (n = 4 pts), all subsequent pts received AB at 100 mg/m2. C was dosed at AUC = 2 on the same schedule, and T was weekly at 2 mg/kg without interruption, after a 4 mg/kg load. Initially, no prophylactic anti-allergy medication was given. Treatment is until disease progression (PD) or prohibitive toxicity. Pts without PD at 6 months may opt to continue T alone. Median age: 42 yrs (29–66), ECOG PS 0/1 (70/30%); 6 pts had prior adjuvant chemotherapy; 1 with anthracycline (A) and 4 with A + taxane (> 1 yr prior). Results: 68 cycles have been delivered to date (median: 8, range 1–9). Dose reductions of AB and C have been necessary in 4 pts (to 80 mg/m2 and AUC of 1.5 weekly), with delays in 4 pts. 3 pts had hypersensitivity reactions (HSR) to C and continued protocol therapy without C (n = 2) or with C and the addition of anti-HSR premeds (n = 1). Grade ¾ toxicities include neutropenia (44/11%) with 1 episode of febrile neutropenia. Grade ¾ anemia or thrombocytopenia has not occurred. Grade ¾ non-hematologic toxicity has been rare: 1 instance of grade 3 neuropathy (2 pts with grade 2). 7 partial responses have been observed in the first 9 evaluable pts (78%, 95% CI 44–93%), in liver, lung, bone and soft tissue sites, including 4 pts with prior adjuvant taxane. The median time to PD is not reached at 9.9+ months (7.3–9.9+). Accrual continues as the trial expands to additional study sites. Conclusions: The weekly administration of AB, C, and T demonstrates promising preliminary efficacy as 1st-line treatment for HER2+ MBC. With the exception of HSRs due to weekly C, a very favorable toxicity profile is observed. [Table: see text]

3050 Background: Bevacizumab added to chemotherapy (CRx) prolongs PFS in pts with MBC. Data suggest that estrogen (E2) modulates VEGF-induced angiogenesis in physiologic and pathologic conditions. E2-induced VEGF expression may promote breast cancer growth therefore combination therapy with an aromatase inhibitor (AI) and an antibody to VEGF may be more effective than either agent alone. We performed a feasibility study testing B with L for the treatment (tx) of hormone receptor-positive MBC. Methods: Eligible pts have MBC and are candidates for AI therapy. Prior non-steroidal AI (NSAI) use without progression is permitted. Premenopausal pts undergo ovarian suppression/oophorectomy prior to tx. Therapy consists of L (2.5 mg daily) and B (15 mg/kg IV q3 weeks). The primary endpoint is frequency of Grade (Gr) 4 toxicity. Secondary endpoints include response rate, stable disease (SD) ≥ 6 mo and time to tumor progression. Using a two-stage design, 19 pts were accrued. Because nd stage is now enrolling an additional 23 pts. If [Table: see text]

3039 Background: Antiangiogenic therapy has demonstrated efficacy in the treatment (tx) of metastatic breast cancer. Mechanism-based biomarkers of antiangiogenic therapy, if clinically validated, offer the potential to optimize this novel therapy. CECs have been proposed as a marker of tumor progression and/or response to antiangiogenic therapy with B. We performed a feasibility study testing B combined with L for the tx of hormone receptor-positive MBC. To explore markers of activity and response, we assayed CECs and circulating tumor cells (CTCs) at weeks (wks) 0 (baseline), 3, 12, and then Q 12 wks. Methods: CECs were defined as CD34/31+, CD45-. Progenitor (CD133+) (CECp) and activation markers (CD106+) were also measured. For CECs, 50 ul of blood was stained with the indicated MAbs; after RBC lysis, flow cytometry (FC) was performed for total CEC and CECp. For CTCs, 20 ml of blood was subjected to immunomagnetic capture using anti-EpCAM ferrofluid, followed by FC for EpCAM, CD45, and nucleic acid content. The log rank test was used to test for significant differences related to response. Results: 32 of 42 pts have been enrolled. As separately reported, prior non-steroidal AI (NSAI) use without progression is permitted; median (med) time on L before start of B was 6 mo (1–52). 28 pts have at least baseline and week 3 CEC and CTC along with clinical response data. Med CEC level at baseline was 10.4 CEC/ul (4–38); the peak value at any time point was 107. CTC levels were much less frequent with a med of 0.3 CTC/ml (0–95, and highest value 1153). An increase in CECs at wk 3 compared to wk 0 predicted worse PFS (p = 0.015). CTCs were ≤ 0.1 at study start in 40% of pts and ≥ 1.0 in only 17%, likely due to length of prior L; change in values at wk 3 did not correlate with PFS in this pretreated group. Conclusions: Consistent with our previous results in a separate trial of B containing treatment in MBC, changes in CEC levels appear to be a biomarker of response/progression on antiangiogenic therapy. CTCs did not reflect response or progression in this population of patients, likely due to lengthy prior exposure to letrozole. Supported in part by Genentech and Novartis. [Table: see text]

796 Background: In DMBA-induced animal models of breast cancer, estrogen (E) induced expression of VEGF whereas AI therapy (Rx) had the opposite effect (Nakamura, 1996). We hypothesize that E-induc...

525 Background: The antivascular effects of antiangiogenic therapy for cancer are not well understood. Identifying clinically relevant intermediate markers for angiogenesis that might predict response has been difficult; CECs have been proposed as a marker of tumor progression and/or response to antiangiogenic therapy with bevacizumab. We performed a phase II study of erlotinib and bevacizumab in pts with MBC based on preclinical data suggesting that EGFR blockade may inhibit angiogenesis, and that combined blockade may increase anti-tumor activity. To explore markers of activity and response, we assayed CECs and CTCs at weeks 0 (baseline), 3, 9, and then Q 9 weeks. Methods: CECs were defined as CD34/31+, CD45-. Progenitor (CD133+) (CECp) and activation markers (CD106+) were also measured. For CECs, 50 ul of blood was stained with the indicated MAbs; after RBC lysis, flow cytometry (FC) was performed for total CEC and CECp. For CTCs, 20 ml of blood was subjected to immunomagnetic capture using anti-EpCAM ...

2001 Background: Aberrant VEGFR expression in breast tumor cells and EGFR expression in endothelial cells may contribute to tumor growth and progression (Baker, 2002; Kranz, 1999). Preclinical evidence suggests that EGFR blockade may inhibit angiogenesis (Hirata, 2002), and combined blockade of the VEGFR and EGFR pathways may increase anti-tumor activity in xenograft models (Jung, 2002). We performed this two stage phase II study to explore the activity of erlotinib and bevacizumab in MBC, as a phase I/II trial in lung ca showed no pharmacokinetic interaction (Mininberg, ASCO 2003). Methods: Erlotinib (150 mg orally/day) and bevacizumab (15mg/kg IV q3 weeks) is given to pts with measurable MBC following 1–2 prior chemotherapy regimens (CRx). The primary endpoint is response rate; secondary endpoints include safety and time to tumor progression. Markers of the EGFR and VEGFR pathways will be evaluated in archival tumor tissue and in pre/post treatment tumor biopsies in several pts. Levels of circulating en...

Philadelphia chromosome-positive acute lymphoblastic leukemia occurs in two molecular forms, those with and those without rearrangement of the breakpoint cluster region on chromosome 22. The molecular abnormality in the former group is similar to that found in chronic myelogenous leukemia. To characterize the abnormality in the breakpoint cluster region-unrearranged form, we have mapped a 9;22 translocation from the Philadelphia chromosome-positive acute lymphoblastic leukemia cell line SUP-B13 by using pulsed-field gel electrophoresis and have cloned the DNA at the translocation junctions. We demonstrate a BCR-ABL fusion gene on the Philadelphia chromosome. The breakpoint on chromosome 9 is within ABL between exons Ia and II, and the breakpoint on chromosome 22 is approximately equal to 50 kilobases upstream of a breakpoint cluster region in an intron of the BCR gene. This upstream BCR breakpoint leads to inclusion of fewer BCR sequences in the fusion gene, compared with the BCR-ABL fusion gene of chronic myelogenous leukemia. Consequently, the associated mRNA and protein are smaller. The exons from ABL are the same. Analysis of leukemic cells from four other patients with breakpoint cluster region-unrearranged Philadelphia chromosome-positive acute lymphoblastic leukemia revealed a rearrangement on chromosome 22 close to the breakpoint in SUP-B13 in only one patient. These data indicate that breakpoints do not cluster tightly in this region but are scattered, possibly in a large intron. Given the large size of BCR and the heterogeneity in breakpoint location, detection of BCR rearrangement by standard Southern blot analysis is difficult. Pulsed-field gel electrophoresis should allow detection at the DNA level in every patient and thus will permit clinical correlation of the breakpoint location with prognosis.

A 2.3 kb single-copy genomic EcoRI-BamHI fragment was isolated from the putative first intron of the human BCR gene and subcloned into the Bluescribe vector pBS M13+ (pA-EB2.3). Multiple enzymes resolve a two-allele deletion/insertion type RFLP. A 1 kb difference between the alleles is seen in BamHI, Bg1II and HindIII digests. The deleted/inserted material includes EcoRI and TaqI sites; thus, using these enzymes the fragment lengths corresponding to the alleles do not differ by 1 kb. The BCR gene is within chromosome band 22q11. A family was studied in which the parents represented both homozygotes. The child was heterozygous as expected.

Abstract #2108 Background: DD q 2 weekly (w) AC → P + T x 1 year (y) has an acceptable safely profile w/ congestive heart failure (CHF) rate of 1/70 pts (Dang, JCO 2008). Lapatinib (L) is effective in HER2 (+) BC. We conducted a pilot study of dd AC → w P + T + L to determine its feasibility and cardiac safety. Methods: Enrolled pts had HER2 (+) BC; LVEF > 50%. Rx consisted of AC at 60/600 mg/m2 x 4 q 2 w (w/ pegfilgrastim 6 mg day 2) → P at 80 mg/m2 x 12 q w + T x 1 y; L (1000 mg daily beginning w/ P + T and continued x 1 y). MUGA is obtained at baseline and at months (mo) 2, 6, 9, and 18. Rx is considered feasible if 1) > 80% pts can complete the PTL phase without a dose delay or reduction and 2) the cardiac event rate (CHF or cardiac death) is < 4%. Pts can remain on-Rx w/ one dose reduction of L (1000 mg → 750 mg) for a G 3 event or < G 3 toxicity (unacceptable). Results: From March 2007 to April 2008, we enrolled 95 pts. Median (med) age was 45 years (range, 28-73). At a med follow-up of 7 months, 90 are evaluable. Of the 90 pts, 34 (37%) withdrew from study during the PTL phase; 29 for a 2nd event of G 3 or unacceptable < G 3 toxicities (15 G 3 diarrhea, 4 G 1/2 diarrhea, 1 G 3 rash, 2 G 2 rash, 1 G 3 dyspnea and also had G 3 diarrhea, 1 G 3 ↑QTc also had G 3 diarrhea, 1 G 3 ↑ALT also had G 3 diarrhea, 1 G 3 paronychia, 1 G 3 pneumonitis, 1 asymptomatic LVEF ↓, 1 myocarditis) and 5 for other reasons (2 personal reason, 1 PCP pneumonia, 1 progression, 1 P hypersensitivity). Overall, 25/90 (27%) pts had G 3 diarrhea and 31/90 (34%) pts required a dose reduction of lapatinib. Med LVEF at baseline is 67% (N=95), at mo 2 is 68% (N=90), at mo 6 is 65% (N=53), and mo 9 is 65% (N=28). To date there are no patient drop-outs due to significant LVEF declines after dd AC; one patient dropped during PTL out due to an asymptomatic LVEF decline. Discussion: L at 1000 mg/day is not feasible combined w/ weekly P and T by protocol stipulation (> 20% pts required L dose reduction) primarily due to excessive G 3 diarrhea. These results have led to the modification of Design 2 (Arm D) of ALTTO. We will report updated results. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2108.

e24059 Background: As societal shifts have led to more women delaying childbearing, a diagnosis of breast cancer is increasingly more likely to occur prior to the completion of family building. Therefore, understanding impact of chemo on future fertility is of the utmost importance. This study evaluates the trends in AMH over time in women receiving different chemo regimens for breast cancer. Methods: This is an IRB approved prospective study of 164 women, < 45 years old with non-metastatic breast cancer who were enrolled at time of diagnosis. Patients received chemo and had prospective serum AMH measured at baseline,12, 18 & 24 mos post-chemo. Of those, 99/164 completed 2-yr follow up. Pts were divided according to their chemotherapy regimen: ddAC-T, CMF and other (e.g. TH). Results: Mean age in ddAC-T (n = 118), CMF (n = 22) and other (n = 23) chemo groups were 37.1±4.6, 41.1±3.2 and 37.6±4.3 yrs, respectively (p = 0.001). AMH sharply declined between baseline & 12 mos post-chemo in all groups (p = 0.005). There was no difference in rate of decline between the groups, after adjusting for age. Age was an important predictor of AMH. Older age at study entry was associated with lower AMH with a decrease of 9% per life year (p = 0.0005). AMH recovered from 12 to 18 mos post-chemo in all groups. 18 mos after chemo, AMH recovery was observed in 61%, 59% & 65% in ddAC-T, CMF & other groups, respectively. In the ddAC-T arm there was a 1.9 fold increase in AMH while there was a 1.4 and 3.3 fold increase in the CMF and other arms, respectively. At 2-yrs post-chemo, AMH recovery rate reached 67%, 69% & 77% in ddAC-T, CMF & other groups, respectively. However, 12% in ddAC-T and 23% in CMF had undetectable AMH. Baseline AMH was 1.59 fold higher in pts whose AMH increased compared to those whose AMH decreased between 12 & 18 mos (p = 0.035). AMH recovery was associated with higher baseline AMH. Age, BMI & chemo type did not correlate with AMH recovery and tamoxifen treatment did not impact AMH recovery. Conclusions: Our data show that anthracycline plus taxane, taxane-based and CMF chemo regimens compromise ovarian reserve in breast cancer patients in similar fashion. As surviving ovarian follicles resume production of AMH, most of ovarian reserve recovery occurs by 18 mos post-chemo with some minor recovery from 18-24 mos. Baseline AMH level is the most important predictor of AMH recovery. Hence in women undergoing gonadotoxic chemo, ovarian reserve should be assessed by AMH before and 12 months after treatment to determine extent of damage. The novel information provided in this study is valuable for counseling cancer pts about fertility preservation. Clinical trial information: NCT00823654 .

PURPOSE: This phase II study evaluated weekly trastuzumab and paclitaxel therapy in women with HER2-normal and HER2-overexpressing metastatic breast cancer. Efficacy was correlated with immunohistochemical and fluorescent in situ hybridization (FISH) assay results. PATIENTS AND METHODS: Eligible patients had bidimensionally measurable metastatic breast cancer. Up to three prior chemotherapy regimens, including prior anthracycline and taxane therapy, were allowed. Trastuzumab 4 mg/kg and paclitaxel 90 mg/m2 were administered on week 1, with trastuzumab 2 mg/kg and paclitaxel 90 mg/m2 administered on subsequent weeks. HER2 status was evaluated using four different immunohistochemical assays and FISH. RESULTS: Patients received a median of 25 weekly infusions (range, one to 85 infusions). Median delivered paclitaxel dose-intensity was 82 mg/m2/wk (range, 52 to 90 mg/m2/wk). The intent-to-treat response rate for all 95 patients enrolled was 56.8% (95% confidence interval, 47% to 67%). A response rate of 61.4% (4.5% complete response, 56.8% partial response) was observed in 88 fully assessable patients. In patients with HER2-overexpressing tumors, overall response rates ranged from 67% to 81% compared with 41% to 46% in patients with HER2-normal expression (ranges reflect the different assay methods used to assess HER2 status). Differences in response rates between patients with HER2-overexpressing tumors and those with normal HER2 expression were statistically significant for all assay methods, with CB11 and TAB250 antibodies and FISH having the strongest significance. Therapy was generally well tolerated, although three patients had serious cardiac complications. CONCLUSION: Weekly trastuzumab and paclitaxel therapy is active in women with metastatic breast cancer. Therapy was relatively well tolerated; however, attention to cardiac function is necessary.

Abstract #3133 Background: HER2 overexpression has been shown to upregulate VEGF expression in pre-clinical breast cancer models. Overexpression of both HER2 and VEGF has been associated with worse clinical outcome than overexpression of either receptor alone. In pre-clinical models, combination anti-HER2 and anti-VEGF therapy has been shown to be more effective than either treatment alone. B plus trastuzumab (T) has shown promising activity in patients (pts) with HER2+ MBC, however the cardiac toxicity of this regimen requires further study. L, an oral dual tyrosine kinase inhibitor of EGFR and HER2, is approved in combination with capecitabine after T-based therapy for HER2+ MBC. L may have less cardiac toxicity and may be a safer and more effective alternative to T. This hypothesis was evaluated in a phase 2 trial of L+B in HER2+ MBC pts. Methods: This single-arm study was designed to evaluate L (1500 mg PO daily) plus B (10 mg/kg IV q2wk) in 50 HER2+ MBC patients. The primary endpoint is crude progression-free survival (PFS) rate at 12 weeks with 84% power to detect a clinically significant PFS rate of 60%; secondary endpoints include toxicity and response per RECIST. Efficacy was assessed at Week 6, 12, and q12wks thereafter. HER2-overexpression was defined as local FISH-positive or IHC 3+ results. Serial evaluation of circulating tumor and endothelial cells and HER2 extracellular domain was performed. Results: Enrollment to this study ended in March 2008 (n=52). Data are presently available on 32 of 52 pts enrolled before January 1, 2008. Pts received a median of 5 prior MBC therapies (range 0-15); 88% received prior T (median 19.7 months; range 1.2-56.8 months). The most frequently reported AEs included diarrhea (81%), rash (66%), nausea (56%), fatigue (56%), and emesis (46%). Four asymptomatic LVEF declines were reported (three grade 2 events; one grade 1 event), as were nine cases of hypertension (eight grade 1 or 2 events; one grade 3 event) and one grade 3 GI hemorrhage. 27/32 patients were evaluable for response; five withdrew prior to first radiologic assessment (two due to toxicity, three due to investigator/pt request). The crude 12-week PFS rate was 63% (20/32 did not progress by Week 12); overall response rate (complete/partial response) was 13%, and the clinical benefit rate (complete/partial response or stable disease for ≥ 24 weeks) was 34%. Conclusions:L+ B is well tolerated and has shown promising activity in heavily pretreated HER2+ MBC pts. Final efficacy and safety data will be presented on the full study cohort. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3133.

Background. Imatinib mesylate is a potent inhibitor of Abl, KIT, and PDGFR tyrosine kinases. Breast cancer has variable expression of KIT and PDGFR therefore we conducted a phase II trial to evaluate the safety and efficacy of imatinib in patients with metastatic breast cancer (MBC). Patients and methods. Eligible patients had measurable and progressive MBC, with no limits on prior chemo- or hormonal therapy. Imatinib was initially administered at a dose of 400 mg orally twice a day with provisions for dose reductions based on toxicities. The primary endpoint was clinical benefit based on RECIST criteria. Tumor specimens were tested for expression of KIT and PDGFR tyrosine kinases. Results. Sixteen patients were enrolled and treated. Median age was 55 years (range: 35–73); median number of prior chemotherapy regimens for MBC was 4 (range 1–8). The main non-hematologic toxicities were (Grades 1/2; Grade 3): fatigue (56%; 6%), edema (38%; 19%), nausea (31%; 19%), vomiting (38%; 0%), anorexia (38%; 0%), diarrhea (19%; 6%), and rash (25%; 6%). Grade 3/4 hematologic and biochemical abnormalities were minimal. There was no evidence of clinical benefit. The median duration of therapy on trial was 28 days (range 2–71). Of the 13 testable cases: 1 was KIT positive and 4 were PDGFR positive. Conclusion. Imatinib therapy at doses of 800 mg/day was associated with significant toxicity in patients with heavily pre-treated MBC. Our results do not indicate activity for imatinib monotherapy in these unselected patients.

e12004 Background: PERCIST is a framework for the evaluation of tumor response to therapy by 18F-FDG-PET (FDG PET/CT). As primary analysis to quantify tumor response to therapy PERCIST recommends t...

Abstract #4104 Background: Dose dense (dd) q2wk AC-paclitaxel (P) is superior to q3wk AC-P. Both regimens are associated with a 1 cardiac death from LV dysfunction occur, B + ddAC-nab-P will not be considered safe. Results: The target accrual of 80 pts has been met. Median age is 47y (27-75). As of May 31, 2008, median follow-up is 14 mo (1-21) and 51 pts have completed 1y of planned therapy. No patients have developed symptomatic LV dysfunction at any point during study therapy. Sixteen pts have discontinued treatment due to toxicity: asymptomatic LVEF decline (N=3), hypertension (N=3), wound healing (N=3), headache (N=2), sensory neuropathy (N=2), pain (N=1), hypersensitivity reaction (N=1), and pneumonitis (N=1). Three pts had disease progression, and 8 pts withdrew consent. Conclusions: At the time of this analysis, no symptomatic LV dysfunction has been observed with B + ddAC-nab-P. Follow-up is ongoing. Correlative studies, including analysis of troponin, renin, and circulating endothelial and tumor cells, are underway. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4104.

9522 Background: In prior studies, menses was used as a surrogate for fertility. But, anti-mullerian hormone (AMH) may be a better surrogate for ovarian reserve. The goal of this study is to deline...