bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase II study of pegylated liposomal doxorubicin (PLD) and carboplatin (Cb) can be administered with trastuzumab (H) in patients with metastatic breast cancer.
Authors: Collea RP , Kruter FW , Cantrell JE , George TK , Kruger S , Favret AM , Lindquist DL , Melnyk Jr. AM , Pluenneke RE , Shao SH , Crockett MW , Asmar L , O'Shaughnessy JA
Published: December 2010

Abstract #6118

Background: PLD and Cb are active in metastatic breast cancer (MBC) but no data exist regarding the antitumor activity of the combination. Both agents are synergistic with H in preclinical studies. The primary objective of this study was to determine the objective response rates (ORR) produced by PLD+Cb ± H.  Patients and Methods: 133 patients (pts) were registered to the study; 125 pts were treated and were stratified by HER2 status; 124 pts are currently evaluable for response. Pts had measurable disease per RECIST criteria and had received no more than 1 prior chemotherapy regimen for MBC; HER2+ pts received therapy first-line therapy for metastatic and 4% received prior adjuvant H. All pts received PLD 30 mg/m2 IV followed by Cb, AUC=5 IV on Day 1 of 28-day cycles. In addition to PLD+Cb, HER2+ pts received H on Day 1 and Day 15 (8 mg/kg IV first dose; 4 mg/kg IV subsequent doses).  Results: 79 pts and 46 pts received at least 1 dose of study drug on PLD+Cb (Arm 1) and PLD+Cb+H (Arm 2), respectively. Median age was 56 years. Estrogen receptor (ER) or progesterone receptor (PR) + pts and ER and PR- pts in Arm 1/Arm 2 were 63%/55% and 36%/45%, respectively, 49%/43%; pts were treated with prior doxorubicin in Arm 1/Arm 2 and 51%/30%. With prior taxane in Arm 1/Arm 2, of 79 pts on Arm 1 evaluable for response, 27% had an objective response compared with 53% of the 45 pts currently evaluable on Arm 2. Median overall survival was 17 months in Arm 1 and as not been reached in Arm 2. Median PFS is 5 and 10 months for Arm 1 and 2, respectively. The most common Grade 3-4 treatment-related toxicities for Arm 1/Arm 2 were: neutropenia 23%/35%, leukopenia 13%/22%, thrombocytopenia 20%/17%, fatigue 6%/13%, and anemia 11%/9%.  Conclusion: PLD+Cb in combination have moderate activity in MBC; also, the addition of H to PLD+Cb in HER2+ pts enhanced its activity. Preliminary toxicity results suggest that PLD can be safely combined with H with minimal cardiac toxicity. Final data analyses from this fully enrolled study will be reported at SABCS 2008.  This research was supported, in part, by a research grant from Ortho Biotech Clinical Affairs, LLC, Bridgewater, NJ.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6118.
Efficacy of palliative chemotherapy for metastatic breast cancer according to HER2-status and basal cytokeratin expression.
Authors: Kahlert S , Mainka P , Knall E , Bauer K , Mayr D
Published: December 2010

Abstract #6123

Introduction: The majority of patients (pts.) with metastatic breast cancer (MBC) will receive cytotoxic therapy (CT) at one time. Predictive factors for the choice of the optimal regimen are not available with the exception of the Her2-status. Triple-negative tumors, especially basal-like tumors are associated with impaired prognosis and sensitivity to CT in several studies without the option of endocrine or anti-her2 targeted treatment. Usually identification of these cases is done by gene expression assays. We tried to identify effective CT regimens in a retrospective trial for this subgroup.  Methods: We reviewed all patient files of women receiving at least one line of palliative CT in our institution from 1991 to 2005 and searched the archive of the institute of pathology for evaluable paraffin embedded tissue. In available material estrogen receptor (ER), progesterone receptor (PgR), Her2 Status and basal cytokeratins CK 5/6 and CK14 were determined by IHC and/or FISH (Her2). A tumor was defined as basal-like, if CK5/6 or CK14 were expressed in more than 10% off all tumor cells. The tumors were divided into four subgroups: ER/PgR positive and HER2 negative (ER/PgR+), Her2 positive (HER+), triple negative and no expression of CK5/6 or CK 14 (non-basal) and triple negative basal-like tumors (basal).  Results: We identified 240 pts. receiving 455 lines of palliative CT (240 1st line, 114 2nd line, 53 3rd line and 48 4th – 7th line). Regimens contained anthracyclines (44%), taxanes (27%), vinca alkaloids (15%), capecitabine (8%), platinum salts (4%) and trastuzumab (15%). 43% of the regimens were combination therapies.  The subgroups were ER/PgR+ (46%), HER+ (28%), non-basal (10%) and basal (16%). Survival of basal tumors was significantly shorter (10.7 months (mo.)) than the other groups (non-basal 23.7, HER+ 22.0 and ER/PgR+ 28.1 mo., p=0.001). Mean time to treatment failure (TTF) in the four groups was 2.1 (basal), 4.0 (non-basal), 5.5 (HER+) and 5.7 mo. (ER/PgR+).  Although anthracycline based therapies showed longer TTF in all four groups, the difference reached significance only in ER/PgR+ pts. (5.0 vs. 7.2 mo., p=0.004). Taxanes showed significantly lower TTF in ER/PgR+ pts. (6.3 vs. 4.3 mo., p=0.03). Use of combination therapy showed significant benefit for ER/PgR+ pts. (6.0 vs. 9.4 mo., p=0.008 (1st line only)).  Capecitabine, vinca alkaloids and platinum salts were used too seldom to draw conclusions.  Conclusions: Use of IHC for CK5/6 and CK14 helped to identify a subgroup of pts. with adverse prognosis of MBC compared to the other groups. This finding is consistent for all types of CT. We were not able to detect regimens of superior efficacy for this subgroup. The availability of IHC can ease additional studies in larger cohorts.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6123.
Results of the German fulvestrant in practice evaluation programme to evaluate the efficacy, safety, tolerability and acceptance of fulvestrant under daily routine conditions.
Authors: Warm M , Kates R , Overkamp F , Zaun SG , Harbeck N
Published: December 2010

Abstract #6132

Material and Methods: Fulvestrant is an estrogen receptor (ER) antagonist with a distinct mode of action used in the treatment of postmenopausal women with advanced breast cancer progressing or recurring on an antiestrogen. 848 postmenopausal women with ER+ advanced mamma carcinoma, relapsed during or after adjuvant anti-estrogene treatment, or with a disease progression under an anti-estrogene therapy, were enrolled in this Fulvestrant In Practice Evaluation Programme (IPEP). Under daily routine conditions and without intervention by the sponsor regarding selection of subjects, diagnostic procedures or therapeutic decisions relevant data of the fulvestrant therapy was documented over a period of 9 months. Results: The median patient age was 64 years, 52 % of patients had a co-morbidity, 78 % one or more prior palliative therapies. Efficacy: Clinical benefit was observed in 627/848 patients, including 62 complete and 177 partial remissions. Best response was delayed in 115 patients (not seen at 3 months but at 6 months). Estimated 9-month overall survival (OS) was 89%; 9-month event-free survival (EFS) was 71%. Safety: 244 non-serious adverse events by patient were recorded, most commonly General disorders and administration site conditions, gastrointestinal and musculo-sceletal symptoms. Excluding deaths, 7 serious adverse events were recorded (none attributed to fulvestrant); no new or unexpected safety issues arose. 20 patients died during observation. Tolerability: Tolerability was judged as good to very good by the majority of both specialists and patients with stable values at 3, 6 and 9 months. Acceptance of injection: The vast majority of both doctors and patients found the application via injection to be acceptable or very acceptable, the handling was judged by the doctors as mostly good to very good. Conclusion: Fulvestrant treatment was well tolerated and well accepted in this palliative patient collective, no new safety findings occurred. The treatment showed good efficacy with any patient, who had achieved disease stabilization or better after three months being likely to gain survival benefit from prolonged Fulvestrant therapy. Best response often occured delayed.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6132.
Results of randomized phase II trial combining Iressa® (gefitinib) and arimidex in women with advanced breast cancer (ABC). EORTC protocol 10021.
Authors: Mauriac L , Cameron D , Dirix L , Blot E , Piccart M , Marreaud S , Tjan-Heijnen V , Cufer T , Bogaerts J , Atalay Basaran G
Published: December 2010

Abstract #6133

Background: Preclinical data suggest that EGFR inhibitors could overcome endocrine resistance in breast cancer. This European multicenter, double-blind, placebo-controlled trial was designed to test the hypothesis that Gefitinib (G), as inhibitor of the EGFR pathway, can delay the onset of endocrine resistance in ABC. Methods: Postmenopausal patients (pts) previously treated for ABC (including locally recurrent or metastatic or elderly with locally ABC or bone metastases only) were randomly assigned in a 1:1 ratio to G 250 mg/day plus anastrozole (A, 1 mg/day) or to placebo plus A. Prior treatment with an aromatase inhibitor in metastatic setting or trastuzumab or anti EGF or anti VEGF was not allowed. Treatment was given until progression of the disease, unacceptable toxicity or patient refusal and the progression free rate was assessed at one year with disease evaluations according to RECIST performed every 8 weeks.  Results: The trial was prematurely closed in August 2007 due to slow recruitment. Seventy one out of a planned 108 pts were entered with a median age of 64 (range 42-84). 26 pts had prior chemotherapy and 43 prior endocrine therapy (adjuvant tamoxifen 60% and metastatic 16%). Median PS was 0 and 41 pts had visceral disease. To date, 326 months of treatment have been fully documented, for a median duration of 6 months. For 36 pts end of treatment has been reported: 26 due to progression and 6 due to toxicity (including one SAE: diarrhea gr 3 and spastic dyspnea gr 2). The most common adverse events were fatigue (49%), arthralgia/myalgia (39%), nausea (37%), diarrhea (35%), rash (35%), bone pain (29%), and hot flushes (26%).To date, the estimated progression free rate at one year is 42%. Conclusion: All patients will reach one year of follow up in August 2008. The database has not been unblinded yet. By the time of the conference unblinded final results will be available. A late breaking abstract will be sent in September.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6133.
A prospective characterization of the resolution of ixabepilone induced peripheral neuropathy: data from a large registrational program in patients with metastatic breast cancer.
Authors: Perez E , Pivot X , Vrdoljak E , Sparano JA , Vogel C , Peck R , Mukhopadhyay P , Vahdat L
Published: December 2010

Abstract #6140

Background:  Ixabepilone (ixa), the first in a new class of antineoplastic agents, showed clinical benefit in combination with capecitabine (C) in 2 large clinical trials in metastatic breast cancer (MBC) pts whose tumors were resistant to (study 046, JCO, 2007) or pretreated with anthracycline (A) and taxanes (T) (study 048). In 048, ixa + C, compared to C alone, demonstrated significant increases in PFS (HR 0.79 [0.69-0.90]) and ORR (43% vs 29%). A trend toward increased OS was seen both in 048 (HR 0.90 [0.78-1.03]) and in 046 (HR 0.90 [0.77-1.05]), which did not reach statistical significance. Similar to taxanes, dose-limiting peripheral neuropathy (PN) is a side effect associated with ixa treatment. Here we present the incidence rates, management of ixa-induced PN from 3 registrational studies in pts with MBC and an analysis of resolution time. Also, data on potential risk factors for PN are presented.  Methods:  Incidence of PN is summarized from a 2000 pt program from 3 multi-center clinical trials. In this program, almost 1100 pts with MBC received ixa either as a monotherapy (40 mg/m2 IV over 3h Q3w, N=126) in a phase II study, or in combination with C (1000 mg/m2 PO BID x14d Q3w) in 2 large phase III studies (N = 369 and N = 595). PN was evaluated every 4 weeks after completion of treatment until toxicity was resolved. Resolution of PN was defined as the time from onset of worst grade to baseline or grade 1. A Cox regression analysis was also performed on a dataset of 945 pts with different tumor types across multiple studies, receiving ixa as a monotherapy or in combination with C, to identify the potential risk factors for grade 3/4 PN.  Results:  Incidence rates of grade 3/4 PN and resolution time observed in 1 phase III study (046) and the phase II (081) have been published before (081: JCO, 25; 3407). Here we present the data from the final confirmatory phase III study (048).    PN was effectively managed with dose reduction. After dose reduction, symptoms improved or did not worsen in the majority of pts, and a median of 2-3 additional treatment cycles were delivered. Pts with diabetes were at a higher risk of grade 3/4 PN (HR: 1.67 [1.00-2.78], p-value = 0.049).  Conclusions:  Incidence of ixa-associated PN was similar to that observed in trials of other T based regiments. Ixa-induced PN has a predictable median time to resolution of 5-6 weeks over 3 large studies.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6140.
The need for DXA assessment of breast cancer patients following 5 years tamoxifen prior to starting an aromatase inhibitor.
Authors: Brown L , Whannel KJ , McLennan A , Wilson CR , Doughty JC
Published: December 2010

Abstract #6141

Introduction: Aromatase inhibitors are increasingly being used in the adjuvant treatment of post-menopausal women with breast cancer. They are more effective than tamoxifen in terms of disease free survival and have a different side effect profile, all causing loss of bone mineral density. They can be introduced at different points in the adjuvant pathway. It has been postulated that if given in the extended setting, letrozole after 5 yrs tamoxifen, bone health may be less important. Tamoxifen is reported to increase bone mineral density so should make subsequent bone mineral density reduction with letrozole less significant. The aim of this study was to determine whether DXA scanning should be undertaken in women following 5 yrs of tamoxifen prior to starting letrozole.  Method: 166 women who had completed 5 years of tamoxifen underwent DXA with assessment of vertebral morphometry and risk factors associated with osteoporosis and fracture rate.  Results: Mean age was 63yrs (standard deviation [S.D] 10yrs); 154 women were post menopausal being at least 2 years after their last menstrual period; 12 women were unable to recall when they menopaused. Mean t-score and S.D was calculated at each site; spine -1.26(1.3); femoral neck -1.16(1.1) and total hip -0.91(1.1). Results were categorised by lowest t-score.    Conclusion: We have demonstrated that of 166 women following completion of 5 yrs tamoxifen 26.5% have osteoporosis and 35.5% osteopenia. 28% required treatment with bisphosphonates. It cannot be assumed that Tamoxifen will cause a sufficient increase in BMD to render DXA scanning unnecessary. All patients should have DXA scanning following completion of 5 yrs tamoxifen prior to commencing letrozole.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6141.
A pilot study of vascular endothelial growth factor inhibition with bevacizumab in patients with lymphedema following breast cancer treatment.
Authors: Miller KD , Christmon D , Schneider BP , Storniolo A , Clare SE , Sledge GW
Published: December 2010

Abstract #6142

Purpose: Lymphedema is a significant long-term complication of primary therapy for breast cancer but little is known regarding its etiology and persistence other than relation to the number of lymph nodes (LN) removed. We suggest the following model: Mechanical disruption of normal lymphatic drainage leads to increased back pressure on lymphatic vessels producing an increase in interstitial fluid pressure (IFP). The increased in IFP triggers local production of VEGF-C to stimulate compensatory lymphangiogenesis. As VEGF-A (and to a lesser extent –C) also increases vascular permeability, the consequent increase in interstitial fluid and edema predominate. Anecdotally, several patients (pts) with metastatic disease treated with bevacizumab monotherapy noted improvement in long-standing lymphedema. This pilot study was conducted to explore these observations prospectively.  Methods: We used an existing biospecimen bank to conduct a case-control study to compare VEGF-A, -C, -D and VEGFR-3 serum concentrations in breast cancer pts with and without lymphedema (matched for age and LN status). In a separate pilot trial, pts with significant unilateral lymphedema receive bevacizumab, 15 mg/kg every 3 weeks. Baseline assessments include arm volume, interstitial fluid pressure (IFP), extracellular fluid volume by lymphometer (ECF), quality of life (QOL) and plasma VEGF-C, -D, and R-3. IFP is measured serially for 24 hours after the first treatment; arm volume, ECF, QOL, and plasma VEGF-C/D/R-3 are assessed at 3 and 6 weeks.  Results: Samples were available for 16 pts with chronic lymphedema and 24 matched controls. Median VEGF-C levels were significantly increased in pts with lymphedema (6895 pg/ml vs. 5349 pg/ml, p=0.001). Median VEGF-A levels were slightly higher in pts with lymphedema (375 pg/ml vs.250 pg/ml, p=NS). Eight pts have been enrolled in the pilot trial thus far. Median duration of lymphedema was 4.4 years (2.2-16.6) Median time since surgery was 7.1 years (3.4-17.6); median time since radiation (n=7) was 4.4 years (2.3-7.9). Complete IFP data is available in 5 pts. Baseline IFP was significantly higher in the affected compared to unaffected arm (9.04 vs. -2.07 mmHg; p=0.0017). Median IFP in the affected arm decreased an average of 42.6% 24 hours after bevacizumab infusion (11.1 vs. 6.9 mmHg; p=0.09). Total arm circumference decreased by an average of 2.8 cm three weeks after initial treatment.  Conclusions: Preliminary data supports the hypothesis that VEGF plays a central role in the development and persistence of lymphedema after local therapy for breast cancer. Inhibiting VEGF acutely decreases IFP and may be an effective treatment. Treatment and accrual to the pilot trial continues; full data will be available by December 2008.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6142.
Liposomal doxorubicin is less cardiotoxic than epirubicin in patients with breast cancer: evidence from a randomized clinical trial employing biological, tissue Doppler and standard echocardiographic endpoints.
Authors: Lotrionte M , Palazzoni G , Comerci G , Abbate A , Biondi-Zoccai G
Published: December 2010

Abstract #6145

PURPOSE: Cardiomyopathy following anthracycline chemotherapy may have ominous clinical implications in cancer patients treated with this effective yet potentially toxic therapy. Liposomal anthracyclines (such as liposomal doxorubicin) have the potential for more selective uptake by cancer cells and reduced cardiac toxicity, but early detection at subclinical stage by means of non-invasive tests is pivotal to disclose treatment differences. We thus designed a randomized clinical trial, the Liposomal doxorubicin-Investigational chemotherapy-Tissue Doppler imaging Evaluation (LITE) pilot study to compare the safety of liposomal doxorubicin vs standard epirubicin in terms of clinical and subclinical cardiotoxicity.  METHODS: Women with breast cancer and indication to anthracycline chemotherapy were randomized to liposomal doxorubicin or standard epirubicin. Multimodality non-invasive tests, including serial troponin, NT-pro-B-type natriuretic peptide (NT-pro-BNP), standard and tissue Doppler echocardiography were used at baseline and then during follow-up visits to identify subclinical cardiotoxicity.  RESULTS: A total of 46 females were enrolled, with a follow-up of 11.0±1.4 months. Use of liposomal doxorubicin instead of epirubicin was associated, at follow-up, with significantly higher left ventricular systolic lateral wall velocities (9.89±2.00 cm/s vs 9.79±2.67 cm/s, P=0.011), and significantly smaller decreases in left ventricular ejection fraction (follow-up LVEF 60.8±4.8% vs 57.1±4.3%, P=0.038). In addition, we found significant correlations between peak NT-pro-BNP values and left ventricular ejection fraction (R=-0.451; P=0.021), and that early changes in diastolic and systolic tissue Doppler parameters could significantly predict much later changes in standard echocardiographic parameters, such as left ventricular ejection fraction (R=0.399; P=0.0035), end-diastolic diameter (R=-0.445; P=0.020), end-systolic diameter (R=-0.427; P=0.010), and deceleration time (R=-0.565; P=0.002).  CONCLUSIONS: The present randomized clinical trial, by exploiting tissue Doppler imaging parameters, suggests that a chemotherapy regimen based on liposomal doxorubicin is less cardiotoxic than one based on standard epirubicin in the treatment of patients with breast cancer. Moreover, prolonged follow-up from the overall study cohort shows that NT-pro-BNP values and early changes in tissue Doppler parameters can significantly predict later alterations in standard echocardiographic parameters, thus providing a potential tool for early detection of subclinical cardiotoxicity.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6145.
A comparative analysis of the attitudes of doctors and patients towards adherence behaviour and information provision.
Authors: Gavin J , Ung O , Neck P , Everingham S
Published: December 2010

Abstract #6150

Background: Research into adherence to breast cancer therapies has primarily focused upon quantifying adherence rates of patients with an absence of research into the factors affecting adherence behaviour, however, the practitioner-patient relationship is the medium within which the importance of adherence may be discussed and extra support provided. This study is the first to directly compare the attitudes of clinicians and patients towards adherence and information provision using Fishbein's validated model of attitude measurement. Methods: Separate studies completed in 2008 measured attitudes towards adherence and patient information for Australian breast cancer specialists (n=41) and breast cancer patients enrolled in Verve, the Arimidex patient support programme (n=125). These studies were approved by the Southern Cross University Human Research Ethics Committee and survey response rates of 58% for patients and 68% for specialists were achieved. Independent sample t-tests were used to measure differences between clinicians and patients importance and belief strength ratings on the composite variables of disease, product information, lifestyle information, support materials and adherence behaviour. Differences between low and high-risk patient groups were a particular focus of data analysis. Results: Specialists significantly underestimated the importance low and high-risk patients place on many aspects of adherence and patient information. Specialists believe low-risk patients are less likely than high-risk patients to adhere to treatment and understand their condition, product information or lifestyle factors. This view is not supported by the patient data which showed there was no significant difference between patient risk categories in terms of the importance patients placed upon adherence behaviour and the provision of information. Conclusions: There are significant discrepancies between the importance Australian breast cancer specialists and breast cancer patients place on some aspects of their disease management. SpecialistsÂ attitudes towards high-risk patients are more aligned than they are for low-risk patients. Conversely, these data show that a patientÂs breast cancer risk category does not correlate with the importance that patients place upon adherence behaviour and the provision of information. These data suggest that the provision of information should be extended equally to all early breast cancer patients regardless of their risk of recurrence.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6150.
Hormone therapy use before diagnosis and breast cancer survival in the California teachers study.
Authors: Marshall SF , Chang E , Clarke CA , Cress R , Deapen D , Horn-Ross PL , Largent J , Neuhausen S , Reynolds P , Templeman C , Bernstein L
Published: December 2010

Abstract #65

Background: Breast cancer survival appears to be improved by pre-diagnostic use of hormone therapy (HT), but it is unclear from existing studies whether this is attributable to a direct beneficial effect of HT or because HT use encourages the development of certain tumor types with better prognosis. It is therefore important to examine whether the association between HT use and survival still remains after adequate adjustment for tumor characteristics.  Methods: The California Teachers Study is an ongoing prospective study of female public school teachers and administrators. These analyses included 2,783 postmenopausal women whose use of HT was known and who were diagnosed with an incident primary invasive breast cancer after joining the cohort in 1995-96 and followed until death or the end of 2005. Incident cancers and tumor characteristics were ascertained through annual linkage with the statewide California Cancer Registry. Deaths were ascertained through annual linkage with the California state mortality files, the Social Security Administration Death Master File and the National Death Index. HT and other covariates were self-reported on the baseline questionnaire. We estimated the relative risk (RR) of breast cancer death stratifying by age in years, and using age in days from breast cancer diagnosis as the time scale (censoring deaths from other causes).  Results: During the follow-up period, 159 (5.7%) women died of breast cancer. In unadjusted analysis, former and current HT use, specifically current estrogen-progestin (EP) use (RR=0.37; 0.24-0.57) but also current unopposed estrogen (E) use (RR=0.64; 0.43-0.95), was significantly associated with reduced breast cancer mortality, compared with no HT use. In multivariable analysis, taking into account race, body mass index, smoking history, lifetime physical activity, and co-morbidities, the risk estimates were somewhat attenuated (EP RR=0.40; 0.26-0.63 and E RR=0.67; 0.44-1.00). After additional adjustment for tumor characteristics (stage at diagnosis, estrogen receptor status, number of positive lymph nodes, grade and tumor size) and treatment received (surgery type and radiation) the risk estimates were considerably attenuated (EP RR=0.53; 0.33-0.84 and E RR=0.82; 0.53-1.27).  Conclusion: Use of EP before diagnosis was associated with a reduced risk of death due to breast cancer. Use of E was also associated with reduced breast cancer mortality, although the association was not statistically significant after adjustment for indicators of general health, characteristics of the tumor and treatment.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 65.
Influence of anthracycline- and taxane-based neoadjuvant chemotherapy on tumor HER2 protein expression in locally advanced breast cancers: results from the I-SPY TRIAL (CALGB 150007/150012 & ACRIN 6657).
Authors: Livasy C , Carey L , DeMichele A , Cowan D , Markey J , Little D , Investigators I-SPY Clinical , Dressler L
Published: December 2010

Abstract #703

Background: The I-SPY trial is a multi-institutional study of locally advanced breast cancers in which serial biopsies of breast tumors are performed at multiple timepoints, allowing comparison of tumor biomarker status before, during, and after therapy. Tumor HER2 status has an important role in predicting response to chemotherapy and targeted therapy in breast cancer. The aim of this study was to determine if the administration of neoadjuvant chemotherapy was associated with changes in tumor HER2 protein expression.  Methods: Eligible patients had biopsy-confirmed primary breast cancer measuring at least 3 cm. Required initial treatment was an anthracycline based neoadjuvant chemotherapy regimen: AC followed by T (91%), AC without T (6%), and chemotherapy beyond AC +/- T 2%. Serial core biopsies were performed at baseline (T1), after one cycle of AC (T2), intra-regimen (T3), and pre-surgery (T4). Immunohistochemistry (IHC) for HER2 was performed centrally on core samples at T1 and T2 and on post-surgery (PS) excision/mastectomy specimens (for patients with residual tumor). HER2 results were classified as negative, indeterminate, or overexpressed using conventional scoring criteria. Tumor HER2 status was compared between timepoints T1 and T2, T2 and PS, and T1 and PS. Patients receiving Herceptin therapy were excluded from this analysis. Additional molecular analysis is being performed and the IHC results will be compared with gene expression and phospho-HER2 results.  Results: 221 patients were enrolled and completed therapy. The median age was 49 years, with a range of 27-69. Median tumor size was 6 cm; 58% had clinically positive nodes. HER2 results were obtained centrally at baseline on 178 (80%) patients. 41 of 178 (23%) tumors were positive for HER2 overexpression. The overall pCR rate in HER2 positive patients was 52% compared to 19% for HER2 negative patients (p<0.001). Patient HER2 results were compared at T1 and T2 (n=154), T2 and PS (n=81), and T1 and PS (n=89). Nine of the 32 (28%) HER2 positive patients with multiple timepoint HER2 results were excluded due to receiving Herceptin therapy. The tumor HER2 status between timepoints is summarized in the table below.    Conclusions: Tumor HER2 protein expression levels appear stable in patients undergoing neoadjuvant chemotherapy with anthracycline- and taxane-based regimens. Rare tumors (2-3%) showed a change from a HER2 positive result to a HER2 negative result during chemotherapy; these findings may be related to tumor heterogeneity rather than a true treatment-induced change in HER2 status.  Support: CALGB CA31964 and CA33601, ACRIN U01 CA079778 and CA080098, NCI SPORE CA58207.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 703.
Multiplexed AQUA-based assessment of SWOG 9313 shows prognostic value of continuous ER, PR and HER2 assessment.
Authors: Rimm DL , Barlow WE , Harigopal M , Tedeschi G , Peggy PL , Yeh I , Haskell C , Livingston R , Hortobagyi GN , Hayes DF
Published: December 2010

Abstract #704

Introduction: HER2 is expressed at high levels due to gene amplification in about 15% of breast cancer cases and it has been shown to be a poor prognostic marker. However, HER2 is also expressed in normal breast duct tissue, albeit a much lower levels. We hypothesized that continuous analysis of expression using AQUA will provide prognostic information beyond that attainable with conventional methods.  Methods: A tissue microarray was made from 2123 cases of the 3122 patients accrued to SWOG 9313, in which sequential doxorubicin and cyclophosphamide (A-C) was compared to combination AC. A multiplexed assessment of HER2 and estrogen receptor (ER) was performed on the same slide using the immunofluoresence-based AQUA® method of automated quantitative analysis. Reproducibility and fidelity of multiplexing were determined for each marker by regression analysis.  Results: As expected, both ER and PR were significantly predictive of disease-free survival (DFS) when both are tested as continuous variables, both adjusted for node status, tumor size, treatment and menopausal status (p-values 0.005 and <0.001, respectively). HER2, measured as a continuous variable showed a bi-phasic effect. It has been previously reported (Camp et al, Cancer Research 2003, 63;1445) that both the high and low expressers of HER2 have worse outcome (low levels are equivalent to that seen in normal breast ducts). Splitting the SWOG cohort by deciles shows that both the top and bottom decile have worse DFS than the middle 80% (log rank p=0.012). Also, modeling the hazard ratio as a function of concentration shows a U-shape relationship showing both high and low HER2 expression is associated with poorer DFS.  Conclusions: The AQUA method provides a reproducible method of continuous measurement of ER, and HER2 on the same slide. In this cohort both ER and PR as continuous variable are highly prognostic, as expected, but multiplexing with HER2 did not affect outcome. Quantitative analysis demonstrated that both low and high levels of HER2 expression were associated with poor outcome. Studies are ongoing to determine the significance of this observation with respect to biological classifications of breast cancer and relationships with breast cancer therapies.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 704.
HER2 status and efficay of taxane-based adjuvant therapy of early breast cancer (EBC): a metanalysis of randomized trials involving 7,831 patients.
Authors: De Laurentiis M , Criscitiello C , Giordano A , Giuliano M , Lauria R , Forestieri V , Montanino A , De Placido S
Published: December 2010

Abstract #707

Background. Taxanes have recently been introduced in the adjuvant treatment of EBC yielding on average an improvement of disease-free-survival (DFS) and overall survival (OS) as compared to anthracycline-based regimens (De Laurentiis et al., JCO 2008). It has been questioned, however, that this average benefit may be driven largely by improved outcome in a restricted subset of patients. Particularly, it has been suggested that only patients with HER2+ tumors may derive benefits from taxane administration (Pritchard et al. JCO 2008). We performed a meta-analysis on the interaction between HER2 status and the efficacy of adjuvant taxane-based therapy by pooling subsets data of the available randomized trials.  Methods. We searched the Pubmed database to identify randomized trials that compared taxane-based with non-taxane-based adjuvant chemotherapy regimens for EBC and reported efficacy data according to HER2 status. We also searched the proceedings of major international conferences to identify relevant trials with subset analyses. Hazard Hatios (HRs) for DFS were pooled across the studies according to HER2 status by inverse variance weighting. A pooled test for treatment by HER2 status interaction was performed by weighted linear meta-regression. All statistical tests were two-sided.  Results. Six studies were eligible for this analysis, accounting for 11,631 patients, of whom 7,831 had HER2 status information available. Overall, taxanes were superior to non-taxane-based regimens in terms of DFS with a pooled HR = 0.85 (95%CI: 0.77-0.93). At pooled subgroup analysis taxanes yielded a statistically significant DFS improvement both in HER2+ disease (n = 1,730), with a pooled HR = 0.78 (95% CI: 0.67 to 0.92; p= 0.004), and in HER2- disease (n = 6,101), with a pooled HR = 0.88 (95% CI = 0.79 to 0.98; p= 0.02). A test for interaction showed that there is no statistically-significant difference in the efficacy of taxane-based chemotherapy according to HER2 status (p=0.27).    Discussion. There is no evidence of interaction between HER2 status and taxane efficacy in EBC. HER2 status should not be used to decide which patients are candidate to adjuvant taxane-based therapy.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 707.
Lapatinib is active in patients with HER2-amplified breast tumors expressing p95HER2.
Authors: Guix M , Aura CM , Jimenez J , Scaltriti M , Gomez HL , Doval DC , Ellis C , Gagnon R , Liu Y , Koehler M , Baselga J
Published: December 2010

Abstract #708

Background: A subgroup of HER2 overexpressing tumors also express p95HER2, a truncated fragment of the HER2 receptor that lacks the extracellular domain and retains kinase activity. Tumors expressing p95HER2 have a worse clinical outcome and are resistant to trastuzumab therapy (Scaltriti M. et al, JNCI 2007). The hypothesis that lapatinib, a small molecule inhibitor that targets the intracellular kinase domain of EGFR and HER2, would be active in these tumors was tested by correlating p95HER2 expression with clinical response to lapatinib in EGF20009, a lapatinib monotherapy study  Methods: Archival tumor blocks were obtained from patients (pts) participating in study EGF20009. In this study, pts with untreated locally advanced or metastatic HER2 amplified breast tumors either received lapatinib 1500mg daily or 500mg BID (H.L. Gomez et al, J Clin Oncol 2008). Pre-treatment samples were analyzed for p95HER2 expression by immunofluorescence using 2 antibodies against HER2, binding to the intracellular and extracellular domain, respectively, plus a pan-cytokeratin antibody. Tumors were scored as p95HER2 positive (p95HER2+) [if any cytoplasmic staining was detected with the intracellular HER2 antibody and this staining co-localized with the pan-cytokeratin antibody], negative (p95HER2-) [no intracellular HER2 cytoplasmic staining) or non-evaluable (N/E) [no cytokeratin or HER2 staining by immunofluorescence]. The presence of p95HER2 was then correlated with response rate (RR), stable disease for over 100 days (SD) and progression-free survival (PFS) to lapatinib. A Cox-proportional hazards model was used to compare the groups. In order to correlate the presence of p95HER2 with HER2 extracellular domain in the serum, a quantitative determination of the 105 kD ECD level in serum (Oncogene Science HER2/neu Microtiter ELISA) has also been performed.  Results: 68/105 tumors were evaluable for p95HER2 expression. Fourteen were p95HER2+ (20.5%) and 54 were p95HER2- (79.5%). The observed percentage of p95HER2+ tumors is concordant with published reports. Among the 14 pts with p95HER2+ tumors, 7 responded (RR: 50%) and 1 had SD for > 100 days for an overall clinical benefit rate of 57% (RR+SD). In the p95HER2- population (N=54), 24 pts responded (RR: 44.4%) and 16 pts had SD >100 days for an overall clinical benefit rate of 56% (RR+SD). PFS was similar in both groups, with a median PFS of 24 wks in pts with p95HER2+ and p95HER2- tumors (p=0.97, HR 1.1). These findings compare with the median PFS of 20.7 wks for the entire population in the trial (N=138pts). Further correlation of p95 status and HER2 ECD status of the tumors will be presented.  Conclusion: These data demonstrate that lapatinib has similar activity in pts with p95HER2+ or p95HER2-, HER2 amplified breast tumors.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 708.
MCF-7 cells selected for acquired resistance to an anti IGF-IR antibody remain sensitive to fulvestrant and to an IGFIR tyrosine kinase inhibitor (TKI).
Authors: Zhang X , Seidel B , LaPara KS , Yee D
Published: December 2010

Abstract #72

Monoclonal antibodies and tyrosine kinase inhibitors (TKI) targeting the type-1 Insulin-like growth factor receptor (IGFIR) are currently in clinical trials. Resistance to several targeted therapies has been observed and is not well understood. Estrogen receptor (ER) has been shown to interact with IGFIR signaling to promote cell growth. To examine acquired resistance to IGF1R monoclonal antibodies, we selected ER positive MCF7L cells in increasing concentrations of an IGFIR inhibitory antibody (scFvFc, treated over 2 years). These cells (MCF7L-scFvFc) had downregulated IGFIR levels, increased basal phosphorylation of IRS-1 with constitutive activation of Akt. MCF7L-scFvFc cells had enhanced basal growth and were no longer responsive to IGF-I and estradiol (E2). To examine the relationship between IGF1R and ER function, we used the pure steroidal anti-estrogen fulvestrant to examine effects on growth of the parent and antibody-resistance cells. In parent MCF7L cells, fulvestrant inhibited growth responses to IGF-I and E2 treatment when each ligand was given individually, but when both ligands were given together, the growth inhibition was reversed. In MCF7L-scFvFc, fulvestrant inhibited growth response to IGF-I, but cells still responded to E2 even in the presence of fulvestrant. Fulvestrant inhibition of MCF7L-scFvFc basal growth was associated with downregulation of ER and IGFIR system components. Fulvestrant treatment induced PARP cleavage in MCF7L, but not in MCF7L-scFvFc cells. IGF-I partially protected cells against fulvestrant induced PARP cleavage, and E2 treatment has full protective effects on these cells. These data suggest that MCF7L-scFvFc cells were more resistant to cell apoptosis induced by fulvestrant. Other monoclonal antibodies directed against IGF1R were ineffective in reversing the resistance in MCF7L-scFvFc cells. To determine if activated IGF1R was responsible for the behavior of MCF7L-scFvFc cells, we used the IGF1R TKI AEW541. AEW541 inhibited growth of these antibody resistant cells and a combination of fulvestrant and AEW541 completely inhibited cell growth and IGF signaling in both MCF7L and MCF7L-scFvFc cells. Thus, activated IGFIR signaling was still required for the growth of MCF7L-scFvFc cells. In conclusion, MCF7L-scFvFc had low levels of IGF1R but retained activated IGF1R signaling that was inhibited by TKI (AEW541). In addition, the ER antagonist fulvestrant also inhibited growth of these cells. In these ER-positive cells, combined blockade of ER and IGF1R could provide a more prolonged inhibition of cell growth. Moreover, cells selected for resistance to an IGF1R antibody remain sensitive to IGF1R TKIs. Thus, concurrent or sequential targeting of IGF1R and ER function should be examined in breast cancer clinical trials of ER positive breast cancer.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 72.
NSABP B-30: definitive analysis of quality of life (QOL) and menstrual history (MH) outcomes from a randomized trial evaluating different schedules and combinations of adjuvant therapy containing doxorubicin, docetaxel and cyclophosphamide in women with operable, node-positive breast cancer.
Authors: Ganz PA , Land SR , Geyer CE , Costantino JP , Pajon ER , Fehrenbacher L , Atkins JN , Polikoff JA , Vogel VG , Erban JK , Livingston RB , Perez EA , Mamounas EP , Wolmark N , Swain SM
Published: December 2010

Abstract #76

Background: QOL and MH outcomes were integrated into the NSABP B-30 trial as secondary outcomes to the efficacy analyses which are being presented separately. Explicit secondary aims of the NSABP B-30 study were 1) to compare toxicities among the regimens, 2) to compare QOL, and 3) to examine differences in amenorrhea and its relationship to symptoms, QOL, and efficacy. Here we examine the secondary aims of the study as a companion to the efficacy results that are presented separately.  Materials and Methods: 5351 pts with cT1-3, N0-1, M0 were enrolled from 3/1/99 to 3/31/2004. 2170 were enrolled on the QOL study, and 2449 were enrolled on the MH study and were randomized to one of three treatment groups: Group 1 [doxorubicin (A) 60 mg/m2 and C 600 mg/m2 q 3 weeks (wks) x 4 followed by docetaxel (T) 100 mg/m2 q 3 wks x 4; Group 2 [A 50 mg/m2 and T 75 mg/m2 q 3 wks x 4]; Group 3 [A 50 mg/m2 T 75 mg/m2 and cyclophosphamide (C) 500 mg/m2 q 3 wks x 4]. All patients with ER-positive tumors received hormonal therapy after completing chemotherapy. Preliminary results from Group 1 have been reported previously (Swain, et al. Breast Cancer Res Treat, 2008).  Results: The protocol specifies that 800 deaths are required for the definitive analysis of treatment, QOL, and MH outcomes, which are expected to occur by fall 2008. For this final report, results from a comparison of the three arms will be analyzed and presented.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 76.
BCIRG 005 main efficacy analysis: a phase III randomized trial comparing docetaxel in combination with doxorubicin and cyclophosphamide (TAC) versus doxorubicin and cyclophosphamide followed by docetaxel (AC→T) in women with Her-2/neu negative axillary lymph node positive early breast cancer.
Authors: Eiermann W , Pienkowski T , Crown J , Chap L , Pawlicki M , Martin M , Saleh M , Sehdev S , Provencher L , Von Minckwitz G , Semiglazov V , Slamon D , Tabah-Fisch I , Buyse M , Riva A , Taupin H , Sauter G , Mackey J ,   on Behalf of the BCIRG005 Investigators
Published: December 2010

Abstract #77

Background: The relative benefits of adjuvant breast cancer chemotherapy with docetaxel in combination with anthracycline, or given sequentially after an anthracycline-based regimen, are unknown.  Material and Methods: We randomized women with axillary lymph node positive, central HER-2 nonamplified, breast cancer to either TAC (75/50/500 mg/m2 q3wk x 6 cycles) or AC (60/600 mg/m2 q3wk x 4 cycles) followed by T (100 mg/m2 q3wk x 4 cycles). Patients were prospectively stratified by number of positive nodes (1-3 vs. 4+) and hormone receptor status. Patients with ER and/or PR positive (HR+) tumors received hormonal therapy after chemotherapy. The primary endpoint was disease-free survival (DFS) with 80% power to detect an absolute difference of 5%. Secondary endpoints included overall survival and safety.  Results: A total of 3298 patients (1649 per arm) were recruited between August 2000 and February 2003. Baseline characteristics were well balanced: age<50 yrs 47%, 1-3 nodes 61%, HR+ 82%, T > 2 cm 58%. The planned 6 cycles of TAC were given to 93.5% of patients and 8 cycles of AC-T to 90.5%. Febrile neutropenia (17.9% vs. 8.5%) was more frequent with TAC, while grade 3 / 4 neutropenic infections were equivalent (8.7% with TAC vs. 8.0%). One septic death occurred in the TAC arm. Grade 3 / 4 non-hematological toxicity rates were fatigue (5.2% vs. 6.3%), nausea (4.5% vs. 4.1%), vomiting (4.2% vs. 4.1%), diarrhea (2.9% vs. 3.1%), stomatitis (2.6% vs. 3.0%), peripheral edema (1.3% vs. 2.6%), neuropathy-sensory (0.6% vs. 2.0%) and CHF (0.1% vs. 0.4%) in the TAC and AC-T arms, respectively. The other Garde 3 / 4 docetaxel specific toxicities (nail and skin toxicities were observed in less than 0.5% in both arms. The protocol specified main efficacy analysis triggered by 688 DFS events will be presented, with a median follow-up of 60 months.  Discussion: The safety profile of the two docetaxel-based adjuvant chemotherapy regimens is comparable with the exception of a higher incidence of febrile neutropenia with TAC. This analysis will define the relative efficacy of combination vs. sequential docetaxel-containing chemotherapy in the adjuvant treatment of women with node positive, HER-2 negative breast cancer.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 77.