Prior Neoadjuvant Research Articles

Abstract P5-20-04: Eribulin mesylate + trastuzumab as first-line therapy for locally recurrent or metastatic HER2-positive breast cancer: results from a phase 2, multicenter, single-arm study

Abstract Background: Eribulin mesylate, a novel non-taxane microtubule dynamics inhibitor, has been approved for patients with metastatic breast cancer (MBC) who have previously received at least two chemotherapeutic regimens for MBC. This study evaluates efficacy and safety of eribulin + trastuzumab (TRAZ) as first-line therapy for human epidermal growth factor receptor 2 positive (HER2+) locally recurrent or MBC. Methods: Patients received eribulin mesylate at 1.4 mg/m2 IV on days 1, 8 and TRAZ initial dose of 8 mg/kg IV on day 1 every 21 days, followed by 6 mg/kg on day 1 of each subsequent cycle. For study inclusion, patients could have been previously treated with TRAZ, but at least 12 months should have passed since any prior neoadjuvant or adjuvant chemotherapy was used. Endpoints include objective response rate (ORR) (primary), safety, progression free survival (PFS), time to response (TTR), and duration of response (DOR). Tumor assessments are evaluated every 6 weeks for the first 6 cycles and every 6–12 weeks thereafter per RECIST 1.1. Results: Updated results presented here as of June 1, 2012; 37 of 52 planned patients have been treated. Patient characteristics are as follows: median age: 58 years (range, 31–81), 70% have luminal subtype, 95% are stage IV disease, and 73% have visceral disease, 46% had prior neo/adjuvant, 22% had prior anthracycline and 32% had prior taxane, 35% had original diagnosis of MBC. Patients received median of 7 (1,20) cycles for eribulin and 9 (1,23) cycles for TRAZ. The most common treatment related AEs are reported in Table 1. Treatment-related serious AEs were reported for 4 (11%) patients; neutropenia 3 (8%) and febrile neutropenia 2 (6%) patients each. Eight patients have discontinued treatment due to disease progression (PD). Best patient responses are found in Table 2. Conclusions: Based on the updated preliminary results of this Phase II study, the combination of eribulin + trastuzumab as first-line therapy for HER2+ locally recurrent or MBC appears to demonstrate an acceptable safety profile with considerable tumor responses, including in patients with ER/PR+ disease. Accrual is ongoing and study completion is anticipated prior to SABCS 2012. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-20-04.

Intermittent (IAD) versus continuous androgen deprivation (CAD) in hormone sensitive metastatic prostate cancer (HSM1PC) patients (pts): Results of S9346 (INT-0162), an international phase III trial.

4 Background: Castration resistance occurs in the vast majority of HSM1PC pts treated with AD, with a median survival of 2.5 years (y). It is in part an adaptive process with activation of genes resulting in the production of autocrine/paracrine growth factors that contribute to maintaining the viability of PC cells. Replacing androgens before castration resistance is hypothesized to maintain PC androgen-dependence. Preclinically IAD prolonged time to castration resistance and early clinical data indicated feasibility and potential for better quality of life. Methods: HSM1PC pts with performance status (PS) 0-2, PSA ≥ 5 ng/ml were treated with 7 months (m) of goserelin + bicalutamide. Pts achieving PSA ≤4 ng/ml on m 6 and 7 were stratified by prior neoadjuvant AD/finasteride, PS and disease extent (minimal, extensive) and randomized to CAD or IAD. Primary objective: To assess if overall survival (OS) with IAD is noninferior to CAD using a one-sided test with an upper bound hazard ratio=1.20, adjusting for stratification factors. Sample size: 756 pts/arm, type I and II error rates of 0.05 and 0.10. Results: 3,040 pts were accrued by SWOG, CALGB, ECOG, NCIC, and EORTC (5/95- 9/08). After 7 m of CAD, 1535 eligible pts achieved PSA ≤4.0 (median age 70 yrs, 4% PS 2, 48% extensive disease, 12% prior neoadjuvant AD) and were randomized to CAD (759 pts) or IAD (770 pts). Grade 3/4 related adverse events: IAD 30.3%, CAD 32.6%. Median follow-up was 9.2 yrs. Median and 10 yr OS: All eligible pts from study entry: 3.6 yrs, 17%; from randomization CAD: 5.8 yrs, 29%; IAD: 5.1 yrs, 23%, HR (IAD/CAD) = 1.09 (95% CI 0.95, 1.24). No interaction with therapy was significant (p>0.25) except suggestion with disease extent (p=0.08): extensive disease HR=0.96 (95% CI 0.79, 1.15, p=0.64); minimal disease: HR=1.23 (95% CI 1.02, 1.48, p=0.035). PC was cause of death in 56% of CAD and 64% IAD pts. OSby race was not different (p=0.44). Conclusions: In HSM1PC, IAD is not proven to be noninferior to CAD. For extensive disease pts IAD was noninferior; however, IAD was statistically inferior in minimal disease pts suggesting that CAD is the preferred treatment in this group.

LUX-breast 2: Phase II, open-label study of oral afatinib in HER2-overexpressing metastatic breast cancer (MBC) patients (pts) who progressed on prior trastuzumab (T) and/or lapatanib (L).

TPS651 Background: Management of HER2-overexpressing MBC has improved over the past decade. However, pts still develop resistance to currently available HER2-targeted therapies and novel effective treatments are increasingly required as dual targeted combinations are given in early treatment lines already. Current therapies focus on targeting HER2 and do not inhibit all relevant ErbB Family dimers. Afatinib is an oral, irreversible ErbB Family Blocker that inhibits signaling through activated EGFR (ErbB1), HER2 (ErbB2) and ErbB4 receptors and transphosphorylation of ErbB3. Preclinical studies have demonstrated efficacy in T-sensitive and T-resistant human BC xenograft models dependent on ErbB signaling. Efficacy of afatinib in a T-resistant SUM 190 xenograft model has been shown to be increased by addition of IV vinorelbine (V). Afatinib monotherapy has shown promising clinical benefit in 46% of HER2-overexpressing MBC pts who progressed on prior T, with 10% of pts achieving PR. Methods: This open-label Phase II trial (NCT01271725) investigates efficacy and safety of afatinib alone (40 mg/d) followed by afatinib ‘beyond progression’ plus chemotherapy in 120 pts with HER2-overexpressing MBC, who progressed on prior neoadjuvant and/or adjuvant T and/or L. Pts who progress on afatinib monotherapy receive afatinib plus either weekly paclitaxel (P) 80 mg/m2 or V 25 mg/m2. Eligible pts have confirmed HER2-overexpressing BC, stage IV disease measurable by RECIST 1.1, progressed on T and/or L therapy in either neoadjuvant and/or adjuvant setting, are eligible for retreatment with P or V and should not have been pretreated with P (≤12 months) or V, respectively. Exclusion criteria: inadequate cardiac, renal, hepatic and hematological function, pre-existing gastrointestinal dysfunction, rapidly progressing visceral disease, ILD and active brain metastases. The primary endpoint is objective response (OR) and secondary endpoints include best overall response, duration of OR and PFS; safety will be assessed separately for afatinib mono- and combination therapy. Patient enrollment began in May 2011 in ~35 sites and 5 countries.

A multicenter randomized controlled trial (RCT) of adjuvant chemotherapy (CT) in nasopharyngeal carcinoma (NPC) with residual plasma EBV DNA (EBV DNA) following primary radiotherapy (RT) or chemoradiotherapy (CRT).

5511 Background: The benefit of adjuvant CT in NPC is unclear. Administering CT after full-dose CRT presents challenges in treatment compliance and toxicity. Post-RT EBV DNA predicts poor survival and may be a biomarker of subclinical residual disease. We conducted a biomarker driven RCT using EBV DNA to select high risk NPC patients (pts) for adjuvant CT while sparing low risk pts from unnecessary toxicity. Methods: Biopsy proven NPC, AJCC stage IIB-IVB, detectable EBV DNA at 6-8 wks post-RT, no persistent locoregional disease or distant metastasis, ECOG 0 or 1, adequate organ function. Randomised with stratification for primary therapy (RT Vs CRT) and tumor stage (II/III Vs IV) to arm A (adjuvant cisplatin 40 mg/m2 and gemcitabine 1000mg/m2, both given on D1+8 q3w x 6 cycles) or arm B (clinical follow-up). EBV DNA and PET scan were performed before and 6 months after randomization. Primary endpoint was relapse free survival and secondary endpoints included toxicity of adjuvant CT. With a hazard ratio of 2, 100 pts were required with a power of 0.8 and an alpha at 0.05. This safety analysis was approved by DMSC. Results: From 9/2006 to 12/2011, 514 pts consented for EBV DNA screening, 95 with detectable EBV DNA consented for adjuvant study. After work-up, 74 were eligible for randomization (37 to arm A; 37 to arm B). The two arms were well balanced in baseline characteristics. 80% received prior neoadjuvant and/or concurrent CT. Staging: IIB (36.5%), III (29.7%), IVA (18.9%), IVB (14.8%). Five pts refused adjuvant CT after randomization. Overall 65% and 57% completed 5 and 6 cycles respectively. Mean dose intensity (DI): 84% for cisplatin (22.5 mg/m2/wk, range 0.0-26.7), 92% for gemcitabine (612.8 mg/m2/wk, range 333.3-777.8). Treatment related adverse events above CTC G2 were summarized in Table. Conclusions: Delivery of 6 cycles of adjuvant CT is feasible with acceptable toxicity after full dose RT or CRT. [Table: see text]

S5-5: A Phase III, Randomized, Double-Blind, Placebo-Controlled Registration Trial To Evaluate the Efficacy and Safety of Pertuzumab + Trastuzumab + Docetaxel vs. Placebo + Trastuzumab + Docetaxel in Patients with Previously Untreated HER2−Positive Metastatic Breast Cancer (CLEOPATRA).

Abstract Background: Pertuzumab (P) is a fully humanized investigational monoclonal antibody that binds to human epidermal growth factor receptor 2 (HER2), preventing dimerization of HER2 with other HER family members and inducing antibody-dependent cell-mediated cytotoxicity. Its mechanisms of action are complementary to those of the anti-HER2 antibody trastuzumab (H) and the two antibodies combined have superior activity compared with either antibody alone in preclinical and clinical studies. In patients with advanced disease, P in combination with H has been shown to be active in patients whose disease has progressed while on H therapy (Baselga et al. J Clin Oncol 2010). Furthermore, P has been shown to improve the activity of H and docetaxel (T) in a randomized neoadjuvant study (Gianni et al. SABCS 2010, S3-2). No increase in overall toxicity and, in particular, no increase in cardiac events was observed with the addition of P to H and HT regimens. Methods: In this double-blind Phase III study patients with centrally confirmed HER2−positive metastatic or locally recurrent, unresectable breast cancer were randomized to receive either placebo+H+T or P+H+T. Patients could have received one prior hormonal treatment for metastatic breast cancer and/or prior systemic neoadjuvant or adjuvant therapy including prior H and T. Patients had to have a baseline left ventricular ejection fraction ≥50% and no history of declines to <50% during or after prior H therapy. Study medication was as follows: P 840 mg loading dose followed by 420 mg q3w; H 8 mg/kg loading dose followed by 6 mg/kg q3w; T 75 mg/m2 q3w (with subsequent dose escalation to 100 mg/m2 if 75 mg/m2 was well tolerated). Patients were recommended to receive at least 6 cycles of T. In the case of chemotherapy discontinuation due to cumulative toxicity, antibody therapy was continued until disease progression, unacceptable toxicity, or withdrawal of consent. Patients were stratified according to region and prior treatment status (adjuvant therapy or de novo metastatic breast cancer). The primary endpoint for the study was progression-free survival (PFS) as determined by independent review. The primary analysis was planned to take place when approximately 381 independently confirmed PFS events had occurred. This would provide 80% power to detect a 33% improvement in PFS (HR=0.75) at the two-sided significance level of 5%. Secondary endpoints included overall survival, investigator-determined PFS, overall response rate, duration of response, safety, and quality of life. Patient safety was monitored throughout the study by an independent data monitoring committee and a cardiac review committee. This study is registered at ClinicalTrials.gov: NCT00567190. Results: 808 patients were recruited between February 2008 and July 2010. The required number of PFS events for analysis of the primary endpoint has been reached and independent assessment PFS is currently being performed. Results of the primary analysis of efficacy and safety will be presented. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr S5-5.

Phase II trial combining nab-paclitaxel (NP), gemcitabine (G), and bevacizumab (B) in patients (pts) with metastatic breast cancer (MBC): NCCTG N0735.

1126 Background: In N0531 (Roy et al, Ann Oncol 2009) NP+G was effective and tolerable in MBC, with complete + partial response rate (CR+PR) 50%, proportion with 6-month progression free survival (6-mo PFS) 60%, median PFS 7.9 mo, 14% with grade (gr) 4 adverse events (AE). N0735 studied addition of B to NP+G to improve response rate and PFS without reducing tolerability. Methods: Single stage phase II study enrolled pts with measurable MBC eligible for 1st line chemotherapy (chemo). Pts received NP 125 mg/m2 followed by G 1000 mg/m2 days 1 and 8; followed by B 15 mg/kg day 1 of 21 day cycles. Dose modifications allowed for NP and G. Primary endpoint was proportion of pts with PFS 6 months from registration. 47 evaluable pts required to test null hypothesis that 6-mo PFS was at most 60% against alternative of at least 77.5%. Results: 48 evaluable pts enrolled 11/08 - 3/10. Median age 56 (27-77). 30 pts (63%) ER- and 25 (52%) PgR-positive, 2 (4%) HER2 positive. 29 (60%) had prior neoadjuvant or adjuvant chemo. Median follow-up 10.6 mos (5-19.6). Median of 9.5 cycles completed (1-27). 39 pts discontinued, due to progression (36%), pt refusal (26%), adverse events (31%), alternate therapy (3%). 6-mo PFS was 81% (95% CI: 67-91%). Confirmed CR+PR was 69% (95% CI: 54-81%): 2 CR, 31 PR. Median duration of response was 9.9 mos (95% CI: 7.3-12.6). Median PFS was 11.7 mos (95% CI: 8.9-13.1); median overall survival (OS) was not reached. 12-mo OS rate was 84% (95% CI: 73-97%). Gr 4 AE occurred in 18 pts (38%), gr 3/4 AE in 43 (90%). Most common gr 3/4 AEs: neutropenia (71%), fatigue (21%), thrombocytopenia (19%), anemia (15%), leukopenia (10%), dyspnea (10%). Four pts had gr 3 neuropathy. Conclusions: The combination of NP+G+B is active in patients with MBC, and met study’s prespecified endpoint (6-mo PFS >60%) to warrant further study of this regimen. Toxicities were manageable, permitting long duration therapy to achieve high response and PFS rates. This regimen should be further evaluated in phase III trials comparing regimens of chemotherapy + targeted agents in MBC.

Prediction of gemcitabine benefit after curative-intent resection of pancreatic adenocarcinoma using HENT1 and dCK protein expression.

4024 Background: In resected pancreatic adenocarcinoma (PA), gemcitabine was shown to improve both DFS and OS, equally to 5FU. In vitro, gemcitabine efficacy is linked to expression of the human equilibrative nucleoside transporter 1(hENT1), deoxycytidine kinase (dCK) and ribonucleotide reductase subunit1 (RRM1) proteins. This study evaluated association of these three proteins with efficacy of gemcitabine in resected PA. Methods: Patients with resected PA and no prior neoadjuvant therapy were accrued in 5 university hospitals. hENT1, dCK and RRM1 protein expression were semi-quantitatively assessed by immunohistochemistry using tissue microarray analysis and applying scoring systems as previously reported. The primary clinical end-point was overall survival (OS). The association of clinico-pathological parameters and protein expression with OS was evaluated by log-rank testing and Cox proportional regression. For statistical analysis, biomarkers expression was dichotomized as followed: hENT1 high vslow, dCK high vs low, RRM1 positive vs negative. Results: 434 patients with resected PA were analysed with a median OS of 30.4 months (95% CI: 26.0-34.8); 142 patients (32.7%) did not receive any adjuvant treatment; 243 (56%) were treated with an adjuvant gemcitabine-based therapy (Gem), and 49 (11.3%) with an adjuvant non gemcitabine-based therapy. In patients who did not received Gem (n=191), hENT1, RRM1 and dCK expression were not associated with OS in univariate and multivariate analysis. There was a significant interaction for OS between Gem and hENT1 (p=0.001), and Gem and dCK (p=0.001). In multivariate models adjusted for center, tumor grade, maximum tumor size, lymph nodes, and resection margins, Gem was associated with better OS in hENT1 high (n=163; HR: 0.44, 95%CI: 0.28-0.69, p<0.001) and in dCK high tumors (n=302; HR: 0.57, 95% CI:0.41-0.78, p=0.001). By contrast, in dCK low (n= 114, p=0.73) and in hENT1 low (n=249, p=0.66) tumors, patients derived no benefit from gemcitabine. Conclusions: In this multicenter study, hENT1 and dCK high expressions may predict benefit from gem-based chemotherapy after curative-intent surgery in PA.

Abstract P1-01-05: Clinical Significance of Tumor Burden in the Sentinel Nodes after Neoadjuvant Therapy Differs from Sentinel Nodes in the Adjuvant Setting and This May Influence the Management of the Axilla

Abstract Background. Lymph node metastases are the most significant prognostic factor for breast cancer patients. The use of sentinel node biopsy (SLN) has generated an increased detection of positive nodes through the identification of isolated tumor cells (ITC) and micrometastasis. The objective of this study is to evaluate the significance of SLN micrometastasis and ITC for patients undergoing neoadjuvant chemotherapy versus patients undergoing surgery first. Material and Methods. A total of 571 patients with clinically node negative T1-T3 breast cancer underwent SLN surgery from 2004 to 2008. Clinicopathological data were reviewed and comparison was made between results in the adjuvant and neoadjuvant setting. Results. Of the 571 patients, 71 patients (12.5%) underwent SLN biopsy after neoadjuvant chemotherapy and 500 (87.5%) underwent surgery first. The SLN identification rate in the adjuvant and neoadjuvant therapy groups were similar (96.2% vs 95.8%). Mean number of sentinel nodes removed were 2,2 (range 1-15) in the adjuvant group and 2.2 (range 1-7) in the neoadjuvant group. The SLN was positive in the adjuvant group in 151 patients (30%) while in 27 patients (37.5%) in the neoadjuvant group. The SLN was the only positive node in 106 patients (70.1%) in the adjuvant group and in 6(26%) in the neoadjuvant group. Micrometastasis in the SLN was found in 39 patients (7.8%) in the adjuvant group and in 7 (9.8%) patients in the neoadjuvant group. In the adjuvant group, 7 patients (17.9%) had additional non SLN positive in the axillary dissection (ALND), while 3 (49%) in the neoadjuvant group. ALND was performed in all patients with ITC in the SLN in the neoadjuvant setting and 50% of them had additional nonSLN. Discussion. The significance of micrometastasis or ITC in the sentinel node seems to differ in patients with neoadjuvant therapy or surgery first. Micrometastsis or ITC in patients with prior neoadjuvant therapy may reflect residual disease in the axilla, as 50% of patients will have additional positive nodes. Completion axillary node dissection should be considered in this group of patients. Even more, the majority of patients with a positive SLN in the neoadjuvant group harbored additional positive axillary nodes. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-01-05.

CARDIAC TOXICITY OF TRASTUZUMAB: EXPERIENCE AT THE GHENT UNIVERSITY HOSPITAL, BELGIUM

Introduction Trastuzumab (TRAS) is a humanised monoclonal antibody that is targeted against the HER2 growth factor receptor. Over-expression of the receptor occurs in around 15-25% of women with early breast cancer (CA). Four major adjuvant trials compared trastuzumab treatment with observation after neoadjuvant or adjuvant chemotherapy in women with high risk HER2-positive breast cancer. Results of these trials showed that trastuzumab treatment given every 3 weeks for 1 year achieved a significant improvement of disease free survival and overall survival. However, cardiac toxicity occurred more in the trastuzumab arm than in the observation arm resulting in symptomatic congestive heart failure and a significant drop in left ventricular ejection function (LVEF).Aim of the study The purpose of this analysis is to evaluate cardiac toxicity of adjuvant trastuzumab treatment in 30 breast cancer patients. Study parameters were cardiac toxicity assessed by LV function, disease free survival and overall survival.Materials and methods Based on the adjuvant trials and in expectation of the reimbursement of trastuzumab in the adjuvant setting, a convention was set up between the Belgian National Institute for Health and Disability Insurance and hospital centres specialized in the treatment of breast cancer. In this convention, trastuzumab was offered to patients diagnosed with invasive, non-metastatic breast cancer with an over-expression of HER2 proven by a positive FISH test. Metastatic lymph nodes or a tumour measuring more than 10 mm had to be present. At least 4 cycles of adjuvant or neoadjuvant chemotherapy had to be given to the patient. Radiotherapy could be administered. The time interval between chemotherapy or radiotherapy and treatment with trastuzumab could not be more than 6 months. LVEF determined by MUGA scan or by ultrasonography at the start of trastuzumab treatment had to be more than 55%.Results 30 breast cancer patients were treated with adjuvant trastuzumab in our hospital between June 2006 and July 2007. All patients met the inclusion criteria. Six patients stopped trastuzumab treatment because of cardiac toxicity. All these patients had received prior anthracycline neoadjuvant or adjuvant chemotherapy. Five of these patients were found to have a LVEF < 55%, one showing symptoms of congestive cardiomyopathy. The sixth patient was diagnosed with a newly developed tricuspid valve insufficiency grade 3.Follow-up data of 20 months since the start of trastuzumab treatment showed that 27 patients were disease-free. Two patients died because of progressive breast cancer disease. One patient was lost of follow-up.Conclusion In this small group of breast cancer patients, treated with adjuvant trastuzumab, cardiac toxicity expressed as a decreased left ventricular function seems to have a higher incidence compared to the other adjuvant trials. Therefore, a close cardiac monitoring for several years should be recommended in patients treated with trastuzumab.

Are there differences in zonal distribution and tumor volume of prostate cancer in patients with a positive family history?

To determine if there are any differences in the zonal distribution and tumor volumes of familial and sporadic prostate cancers (PC) in men undergoing radical prostatectomy. 839 patients underwent a radical prostatectomy in the absence of prior neoadjuvant therapy between 1987 and 1996. Telephone interviews were conducted to obtain an updated family history. A positive family history was defined as the diagnosis of PC in at least one first degree relative. Prostatectomy specimens were examined to determine the number of tumor foci, zonal origin of the dominant tumor focus, tumor volume of the largest cancer focus, total tumor volume, Gleason score and stage, and the surgical margin status. Results were stratified according to family history and ethnicity. We successfully contacted 437 patients (52%). Prostatectomy specimens from 55 patients were excluded from review due to a history of prior transurethral resection of the prostate (n = 26) or uncertain pathological stage (n = 29). Of the remaining 382 patients, 76 (20%) reported having a first-degree relative with PC. Statistical analysis revealed no significant differences in the pathologic variables between the two groups of patients with or without a family history of PC. Familial and sporadic PC share similar characteristics. No histopathological differences account for the increased positive predictive value of PC screening tests among patients with a family history of PC.

Ixabepilone plus capecitabine for Chinese patients with metastatic breast cancer progressing after anthracycline and taxane treatment

Effective treatment options for patients with metastatic breast cancer pretreated with or resistant to anthracyclines and taxanes are limited. Ixabepilone has single-agent activity in these patients and has demonstrated synergy with capecitabine in this setting. This study was designed as a prospective clinical trial to evaluate the efficacy and safety of ixabepilone plus capecitabine in both anthracycline-pretreated and resistant and taxane-resistant metastatic breast cancer of Chinese women. Patients with measurable disease who had anthracycline and taxanes as prior neoadjuvant, adjuvant or metastatic therapy were treated with ixabepilone at 40 mg/m(2) intravenously on day 1 of 21-day cycle plus capecitabine 2,000 mg/m(2) orally on day 1 through 14 of a 21-day cycle. The primary end point was the objective response rate. The secondary end points were time to progression, overall survival, and toxicity profiles. Twenty-one patients received 146 cycles with a median of 5 cycles (range 1-13 cycles) per patients. Fourteen patients (66.7%) had partial response, 5 patients (23.8%) had stable disease, and 2 patients (9.5%) had progressive disease. Median time to progression and duration of response were 6.2 and 6.0 months, respectively. The median overall survival was 16.7 months. Eight (38.1%) patients required dose reduction and 14 (66.7%) patients discontinued treatment for adverse effect. Grade 3/4 treatment-related events included fatigue (28.6%), peripheral sensory neuropathy (33.3%), neutropenia (61.9%), anemia (4.7%), hypokalemia (4.7%), hand and foot syndrome (19.0%) and infection (9.5%). Resolution of grade 3/4 peripheral neuropathy was reversible after a median period of 6 weeks. Ixabepilone plus capecitabine demonstrated a clear activity and an acceptable safety profile in Chinese patients with anthracycline-pretreated/resistant and taxane-resistant metastatic breast cancer, and the majority of patients completed 6 cycles of the therapy with manageable neuropathy toxicities.

A phase II trial of the Src kinase inhibitor AZD0530 in patients with metastatic or locally advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma: A trial of the PMH phase II consortium.

e14544 Background: AZD0530is an oral, anilinoquinazolone, non-receptor tyrosine kinase inhibitor targeting c-SRC, c- Yes, Lck and Bcr-abl. Src family kinases have been implicated in transformation and gastric cancer progression. Methods: The aim of this multi-centre, 2-stage design, phase II study was to assess the activity of AZD0530 in patients (pts) with unresectable or metastatic gastric or GEJ adenocarcinoma. Eligibility criteria included: ECOG PS ≤ 2; prior neoadjuvant or adjuvant chemo radiation and ≤ 1 prior line of chemotherapy for metastatic disease were allowed. Primary endpoint was objective response and/or prolonged stable disease rate (pSD ≥ 16 weeks). Secondary endpoints included time to progression (TTP), overall survival (OS) and tolerability. Pts received AZD0530 175 mg/day of a 28 day cycle. Tumor response was assessed by RECIST criteria every 8 weeks. ≥ 1 pt(s) with response, or ≥ 3 pts with pSD out of the first 18 evaluable pts was required to proceed to second stage accrual. Results: 20 pts with gastric cancer, median age 64 (range 43-83) years received a total of 38 cycles of treatment, median 2 (range 1 to 5) cycles/pt. 7 pts had received prior chemotherapy and 6 prior radiotherapy for advanced disease. Best response was pSD (1 pt). 3 pts had SD, 10 progressive disease and 3 were inevaluable. 3 pts remain on treatment. The most common drug related adverse events any grade (% of patients) were fatigue (40%), elevated phosphate (40%), lymphopenia (35%), anorexia (30%), hypocalcaemia (30%) and elevation of aminotransferases (30%). Grade 3 events possibly related to AZD0530 included: fatigue (2 pts), anemia (2), lymphopenia (2), hyponatraemia (2) and dyspnoea (1). 14 pts have progressed. Median TTP was 1.8 months (95% CI: 1.5-3.5 mos). There have been 6 deaths. Median OS has not been reached. Conclusions: AZD0530 has insufficient activity as a single agent in pts with advanced gastric adenocarcinoma to warrant further investigation. Further development in gastric cancer would require rational drug combinations or identification of a tumor phenotype sensitive to Src inhibiton. The study has closed to accrual. No significant financial relationships to disclose.

Efficacy of capecitabine (C)-based therapy in patients with first-line metastatic breast cancer (MBC) previously treated with adjuvant anthracyclines and taxanes.

665 Background: Anthracyclines and taxanes are used increasingly in neoadjuvant and adjuvant chemotherapy (CT) in breast cancer. Consequently, MBC is frequently diagnosed in anthracycline- and/or taxane-pretreated pts. Retreatment with these agents is commonly compromised by resistance and/or cumulative toxicity. C is effective in the management of first-line MBC; the current analysis was undertaken to determine the first-line clinical efficacy of C in pts pretreated with adjuvant CT. Methods: 3 studies of C 1000 mg/m2, bid, d1-14 q3w, were included: a retrospective study of single-agent C (n=226; Debled et al 2009); a phase II study of single-agent C (n=161; Kaufmann et al 2009); a phase III, randomized study (RIBBON-1) of C ± bevacizumab (A; 15mg/kg, d1 q3w; n=615). Results: Prior exposure to neoadjuvant and adjuvant CT was reported in around 50-75% of pts. Of these, around 60-75% and 40-45% received anthracyclines or taxanes, respectively. Overall response rate (ORR) and CBR (CR+PR+SD) were around 25% and 60%, respectively (Table). In Debled et al, univariate analysis demonstrated similar time to treatment failure (TTF) in chemotherapy-naive and -pretreated pts (8.9 vs. 8.3 months; p=0.46). A similar analysis in RIBBON-1 supports a substantial benefit with C in chemotherapy-naïve and -pretreated pts (median PFS: 6.7 and 4.4 months, respectively), with consistent effects in taxane- (6.1 and 4.2 months) and anthracycline- pretreated pts (6.4 and 4.4 months). Notably, the addition of A appeared to overcome the effect of prior taxane exposure: CA median PFS 8.7 and 8.3 months in taxane-pretreated and -naïve pts, respectively. Conclusions: These data demonstrate that C consistently achieves improved clinical outcome in pts who have received prior neoadjuvant or adjuvant CT. Debled et al 2009 Kaufmann et al 2009 RIBBON-1 Study C (n=226) C (n=161) C (n=206) CA (n=409) Neoadjuvant or adjuvant CT, % 48 54 75.7 70.4 Anthracycline, % 39 35.8 69.4 60.4 Taxane, % 5 24.5 40.8 39.4 ORR, % 56 26.1 23.6 35.4 CBR, % 76 64 60.2 72.9 TTF, months 8.8 NR NR NR PFS, months NR 7.3* 5.7 8.6 * TTP Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Roche Roche Roche

False positive endoscopic ultrasound fine needle aspiration cytology: incidence and risk factors

ObjectiveIt is broadly accepted that the false positive (FP) rate for endoscopic ultrasound fine needle aspiration (EUS FNA) is 0–1%. It was hypothesised that the FP and false suspicious (FS)...

Invited Commentary

The authors retrospectively analyzed a case series of 159 sleeve resections for non-small cell cancer (NSCLC) performed in a single institution during a 21-year time period [1]. The report includes patients that underwent sleeve lobectomy with and without prior neoadjuvant (induction) chemotherapy. Their findings indicate that induction chemotherapy does not affect postoperative complications, and that good long-term outcomes were obtained after bronchial sleeve resection for lung cancer.

Hypoxia-inducible factor-1α and -2α are expressed in most rectal cancers but only hypoxia-inducible factor-1α is associated with prognosis

The hypoxia-mediated response of tumours is a major determining factor in growth and metastasis. Understanding tumour biology under hypoxic conditions is crucial for the development of antiangiogenic therapy. Using one of the largest cohorts of rectal adenocarcinomas to date, this study investigated hypoxia-inducible factor-1α (HIF-1α) and HIF-2α protein expression in relation to rectal cancer recurrence and cancer-specific survival. Patients (n=90) who had undergone surgery for rectal adenocarcinoma, with no prior neoadjuvant therapy or metastatic disease, and for whom adequate follow-up data were available were selected. Microvessel density (MVD), HIF-1α and HIF-2α expressions were assessed immunohistologically with the CD34 antibody for vessel identification and the NB100-131B and NB100-132D3 antibodies for HIF-1α and HIF-2α, respectively. In a multifactorial analysis, results were correlated with tumour stage, recurrence rate and long-term survival. Microvessel density was higher across T and N stages (P<0.001) and associated with poor survival (hazard ratio (HR)=8.7, P<0.005) and decreased disease-free survival (HR=4.7, P<0.005). hypoxia-inducible factor-1α and -2α were expressed in >50% of rectal cancers (HIF-1α, 54%, 48/90; HIF-2α, 64%, 58/90). HIF-1α positivity was associated with both TNM stage (P<0.05) and vascular invasion (P<0.005). In contrast, no associations were shown between HIF-2α expression and any pathological features, and HIF-1α positivity had no effect on outcome. The study showed an independent association between HIF-1α expression and advanced TNM stage with poor outcome. Our results indicate that HIF-1α, but not HIF-2α, might be used as a marker of prognosis, in addition to methods currently used, to enhance patient management.

A phase I-II trial of Ispinesib, a kinesin spindle protein inhibitor, dosed every two weeks in patients with locally advanced or metastatic breast cancer previously untreated with chemotherapy for metastatic disease or recurrence.

Abstract Abstract #2148 Kinesin Spindle Protein (KSP) is a mitotic kinesin essential for cell cycle progression. Ispinesib, a selective KSP inhibitor, blocks mitotic spindle assembly with cell cycle arrest in mitosis and subsequent cell death. When dosed on a q21d schedule, the maximum tolerated dose (MTD) was 18mg/m2 and neutropenia was the dose-limiting toxicity (DLT), with nadir at 7-10 d and recovery by d15. Activity was observed in a Phase II trial of ispinesib dosed at 18 mg/m2 q21d in patients (pts) with locally-advanced (LA) or metastatic breast cancer (MBC) after anthracycline and taxane failure (response rate 4/45 [9%]). This trial evaluates safety and efficacy of ispinesib in LA or MBC, given on d1 and d15 q28d, thus increasing dose density.&amp;#x2028; Methods: This is a multicenter Phase I-II trial. In Phase I, DLT and MTD of ispinesib given d1 and d15 q28d will be determined. Eligibility criteria: LA or MBC; no prior chemotherapy (CT) except neoadjuvant or adjuvant and ≥ 1 year elapsed since CT; no CNS or leptomeningeal metastases; ECOG 0-1. This is a standard 3+3 dose escalation trial design, starting at 10 mg/m2 and escalating based on tolerability in Cycle 1. Pharmacokinetic data are collected on d1 and d15 of Cycle 1. Phase II of this trial will evaluate efficacy (response rate by RECIST) of ispinesib at the MTD.&amp;#x2028; Results: Phase I of the trial is ongoing. To date, 13 pts have been treated at 3 dose levels: 10 (n=2; 2 cycles, n=1; 6 cycles), 12 (n=1; 1 cycle, n=2; 3 cycles) and 14 mg/m2 (n=7; Cycle 1 ongoing). Among the first 6 pts, 4 were Stage IV, 3 had prior neoadjuvant and 2 adjuvant CT; 2 were chemo-naïve. Four had prior anthracycline and 3 prior taxane. Biomarker status was ER+, PR+, HER2- (n=3), ER+, PR-, HER2- (n=1), ER-, PR-, HER2+ (n=3), ER-, PR-, HER2- (n=4), and unknown (n=2). Mean age was 55 yr; for the first 2 dose levels (n=6 pts), the most frequent toxicity was neutropenia (n=4). Other events included mild GI toxicity. No neuropathy or alopecia has been reported. The only grade 3 or 4 toxicity was neutropenia (n=2). At the 14 mg/m2 dose level, one DLT has been reported: a grade 3 transaminase (AST) elevation in a patient with liver metastases which resolved with a dose delay of 4 days. As a result, this cohort was expanded to include 6 evaluable pts. One additional patient at the 14mg/m2 dose had a dose delay of 5 days due to non-DLT neutropenia.&amp;#x2028; Conclusions: Ispinesib appears to be well tolerated on a q2w dosing schedule at doses tested to date. A dose-density equal to that administered in the prior Phase II trial (0.86 mg/m2/day) was tolerated with the new q2w schedule. Dose escalation is ongoing. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2148.

Pre-operative estimation of esophageal tumor metabolic length in FDG-PET images with surgical pathology confirmation

The aim of this study was to evaluate a 3D tumor segmentation method for fluorodeoxyglucose positron emission tomography (FDG-PET) in the context of noninvasive estimation of tumor metabolic length (Lm), as it correlates with surgical pathology and phantom results. Thirty-four patients (7 women, 27 men) with esophageal cancer were retrospectively evaluated. All patients underwent FDG-PET-computed tomography (CT) imaging following endoscopic ultrasound (EUS). Seventeen patients had esophagectomy after PET/CT, without prior neoadjuvant therapy. Tumor length was assessed by EUS (Le, n=31) and histopathology (Lp, n=17). Images were evaluated quantitatively with a 3D threshold-based region-growing program (Medical Image Processing Analysis and Visualization). Lm, total metabolic volume (Vm), maximum standardized uptake value (SUVmax), and average SUV (SUVa) over the entire tumor were obtained for several threshold values (mean activity in the liver plus 0-, 1-, 2-, 3-, and 4-SD of the activity in the liver). Lm showed a good correlation with Lp for all thresholds (best correlation for Lm(2-SD), r=0.74, P<0.001). A positive nonsignificant correlation was observed between Lp and Le (r=0.30, P=0.29). Lm(2-SD) correlated well with Le (r=0.71, P<0.001). Good correlations were also observed between Lm(2-SD) and Vm(2-SD) (r=0.89, P<0.001) and SUVa(2-SD) (r=0.38, P<0.05). Vm(2-SD) also had a significant correlation with Lp (r=0.61, P<0.05) and Le (r=0.57, P<0.001). FDG-PET-derived tumor metabolic length of untreated esophageal carcinomas correlates well with surgical pathology results, and provides preliminary evidence that noninvasive delineation of the superior and inferior extent of viable tumor involvement might be feasible using computer-generated metabolic length measurements.

Efficacy of Radical Retropubic Prostatectomy as the Primary Treatment for Patients with Clinically Localized Prostate Cancer and a Serum PSA Level ≥0ng/ml

Purpose: We retrospectively reviewed the clinicopathological characteristics ofpatients who underwent radical retropubic prostatectomy (RRP), and these patients had clinically localized prostate cancer and a preoperative serum prostate-specific antigen (PSA) level ≥20ng/ml. Materials and Methods: Among the 266 patients who underwent RRP without any prior neoadjuvant therapy between March 2004 and March 2006, 29 patients had clinically localized prostate cancer and a preoperative serum PSA level ≥20ng/ml. We analyzed several clinicopathologic factors that might predict organ-confined disease. Results: Of the 29 patients, 11 (37.9%) had organ-confined cancer. The level of serum PSA, the PSA density (PSAD), the Gleason score (3+4 or less), the prostate volume, tumor volume and the tumor percentage were significant factors for predicting organ-confined cancer (p<0.05). The number of the positive cores, the percentage of the core material that was positive, the sum of the tumor length of the positive core, tumor percent of the total core length and tumor percent of the positive core length were also significantly higher in the group with an extraprostatic extension of disease compared tothe organ-confined cancer group (p<0.05). Conclusions: For the patients with clinically localized prostate cancer and a serum PSA level ≥20ng/ml, radical prostatectomy can be considered as the primary treatment for some cases that have a relatively lower PSA and PSAD, a biopsy Gleason score of 3+4 or less and low predictive volume of the tumor from the biopsy results. (Korean J Urol 2007;48: 945-950)

Phase II Clinical Trial of Ixabepilone (BMS-247550), an Epothilone B Analog, in Metastatic and Locally Advanced Breast Cancer

Ixabepilone (BMS-247550) is an epothilone B analog that stabilizes microtubules and has antitumor activity in taxane-refractory patients in phase I studies. In a phase II trial, we evaluated the efficacy and safety of ixabepilone in women with metastatic and locally advanced breast cancer. Breast cancer patients with measurable disease who had paclitaxel and/or docetaxel as prior neoadjuvant, adjuvant, or metastatic therapy were treated with ixabepilone at 6 mg/m2/d intravenously on days 1 through 5 every 3 weeks. Levels of glutamate (glu) -terminated and acetylated alpha-tubulin, markers of microtubule stabilization, were detected by Western blot and by immunohistochemistry in a subset of matched pre- and post-treatment tumor biopsies. Thirty-seven patients received 153 cycles of ixabepilone. The best responses were a complete response in one patient (3%), partial responses in seven patients (19%), and stable disease in 13 patients (35%). Grade 3 and 4 toxicities included neutropenia (35%), febrile neutropenia (14%), fatigue (14%), diarrhea (11%), nausea/vomiting (5%), myalgia/arthralgia (3%), and sensory neuropathy (3%). Two patients were removed from study because of prolonged grade 2 or 3 neurotoxicity, and three patients were removed from study for other grade 3 and 4 nonhematologic toxicities. Compared with baseline levels, levels of both glu-terminated and acetylated alpha-tubulin were increased in tumor biopsies performed after ixabepilone therapy. An objective response was seen in 22% of the patients in a population who had been previously treated with a taxane. Sensory neuropathy was mild with grade 3 neurotoxicity rarely seen. Microtubule stabilization occurred in tumor biopsies after treatment with ixabepilone.