bluuebunny/crossref_metadata_2025 huggingface dataset:
A novel capecitabine dosing schedule combined with bevacizumab is safe and active in patients with metastatic breast cancer: a phase II study.
Authors: Traina TA , Theodoulou M , Dugan U , Feigin K , Patil S , Geneus S , Godfrey L , Norton L , Hudis C
Published: December 2010

Abstract #6121

Background  Capecitabine (Xeloda®,C) has activity in breast cancer when dosed for 14 days (d) followed by a 7d rest (14 - 7). Using mathematical methods, we predict the optimal dosing schedule of C to be 7d followed by a 7d rest (7 - 7) (Norton et al, AACR 2005). Xenograft studies show this schedule improves tolerability and survival. The MTD of C(7 - 7) is higher than that for conventional dosing (Traina et al, JCO 2008). Bevacizumab (B), an anti-VEGF antibody, improves response when added to capecitabine in pts previously treated for metastatic disease (Miller et al, JCO) and improves PFS when added to taxanes in the 1st-line treatment of advanced disease (Miller et al, NEJM 2007; Miles ASCO 2008). B + conventionally-dosed capecitabine modestly increased TTP when used as 1st-line therapy (Sledge, ASCO 2007). This study tests C(7 - 7) with bevacizumab (B) in a Phase II trial.  Methods  Eligible patients (pts) have measurable, metastatic breast cancer (MBC), ECOG performance status (PS) ≤2 and normal organ function. Any number of prior chemotherapy (CRx) regimens is permitted. Pts with prior fluoropyrimidine or bevacizumab are excluded. Therapy (tx) consists of C (2,000mg BID, 7 - 7) and B (10mg/kg IV q2 weeks(wk)). Pts are evaluated for toxicity q2wk and for response q12wk. Cycle length: 4 wks. Primary endpoint: response rate (RR). Secondary endpoints: clinical benefit, TTP, PFS, toxicity. Using a mini-max, two-stage design, up to 40 patients will be enrolled. If >6/40 pts respond, then C(7 - 7) + B will be considered worthy of further study. If >11 pts experience Grade 3/4 capecitabine-related toxicity the trial will be stopped.  Results  Twenty-seven pts are enrolled. Median (med) age 57 yrs (29-71), med ECOG performance status 0 (0-2), ER/PR(+) 13, HER2(+) 1, sites of MBC: bone(13), liver/lung(13), soft tissue(12). Prior tx: Adjuvant: CRx (20), hormone tx (14); MBC: CRx (2), hormone tx (16). 27 pts are evaluable for toxicity. After a med of 6 (1-12) cycles: Twenty-three pts evaluable for response: PR=7 (confirmed=5), stable disease (SD) >6 mo =6, SD<6 mo=7, PD=3.Tx-related toxicity (# Gr 3/Gr 2): hand foot syndrome (HFS) (6/9); diarrhea (0/1); hypertension (2/1), proteinuria (0/0). 1 pt had grade 4 pulmonary embolism requiring discontinuation of B. Conclusions  Combination capecitabine (7 - 7) and bevacizumab appears well tolerated and active. Additional safety and efficacy data is anticipated prior to this meeting. Supported in part by Roche and Genentech.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6121.
All-oral combination of oral vinorelbine (NVBo) and capecitabine (X) in HER2-negative metastatic breast cancer (MBC): latest results of a multicenter, international phase II trial with a median follow-up of 37.7 months.
Authors: Tubiana-Mathieu N , Bougnoux P , Becquart D , Chan A , Majois F , Espie M , Morand M , Vaissiere N , Villanova G , Conte P
Published: December 2010

Abstract #6125

Background: Combination chemotherapy regimens are widely considered among the standards in the management of MBC. Oral therapy is an attractive option for many patients. The all-oral regimen of NVBo and X is active with good tolerability in MBC. We report an updated analysis of efficacy and safety from an international phase II study of NVBo plus X.  Methods: Main eligibility criteria included: measurable HER2-negative, CT-naive MBC, relapse ≥ 6 months after completing (neo)adjuvant CT, Karnofsky PS ≥ 70%, age ≥ 18 years. Study treatment: 3-weekly cycles of NVBo 80 mg/m2 (after a first cycle at 60) d1 and d8, plus X 1000 (750 if ≥ 65 years) mg/m2 twice-daily d1-14. Treatment was continued until progression or unacceptable toxicity.  Results: 55 pts were enrolled and 54 were treated: median age: 58.5 years (41% ≥ 65); prior (neo)adjuvant CT in 63%; type of CT: anthracycline 67%, anthracycline + taxane 18%, CMF 15%; visceral involvement in 78%; > 2 metastatic sites in 46%. Median 7 cycles (range 1-58); median relative dose intensity: NVBo 87%, X 87%; NVBo escalated to the recommended dose of 80 mg/m2 in 91% of pts. G3/4 NCI CTC v2 adverse events: (n=53) neutropenia 49% of pts, (n=54) vomiting 9%, stomatitis 7%, asthenia 7%, febrile neutropenia 6%, infection with G3/4 neutropenia 6%, nausea 4%, diarrhoea 4%, hand-foot syndrome 4%, thrombosis/embolism 4%. Efficacy (n=46 evaluable pts): objective response rate (RECIST) 52% (95% CI [37-67]), CR 2%, PR 50%, SD 28%, PD 20%, disease control (CR+PR+ SD ≥ 6 months) 63% (95% CI [48-77]). Median duration of response was 7.2 months (95% CI [6.0-11.7]). With a median follow-up of 37.7 months, median progression-free survival was 8.4 months (95% CI [5.8-9.7]) and median overall survival was 30.1 months (95% CI [18.2- 40.1]). 21 of the 54 pts treated in the study are still alive.  Conclusion: These results show that the all-oral combination of NVBo and X is an effective and well-tolerated first-line poly-chemotherapy regimen for MBC. A retrospective analysis has been made between pts with < or ≥ 65 years (efficacy and safety) and results will be presented during the meeting.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6125.
A comparison of high-dose (HD, 500 mg) fulvestrant vs anastrozole (1 mg) as first-line treatments for advanced breast cancer: results from FIRST.
Authors: Ellis MJ , Llombart A , Rolski J , Feltl D , Macpherson E , Lindemann J , Robertson JF
Published: December 2010

Abstract #6126

Background: The estrogen-receptor (ER) antagonist fulvestrant (Faslodex™) at the approved dose (AD, 250mg) has confirmed efficacy in postmenopausal women with advanced breast cancer following recurrence or progression on an anti-estrogen. However, evidence suggests that higher doses may have greater biological and clinical activity. A recent neoadjuvant study in patients with ER+, locally advanced disease showed significantly greater reductions in Ki67 LI and ER expression for fulvestrant high dose (HD, 500 mg) compared with AD.  Methods: FIRST (Fulvestrant fIRst-line Study comparing endocrine Treatments) is a Phase II, randomized, open-label, multicentre study comparing fulvestrant HD (500 mg/month [2×250 mg im injections] plus 500 mg on Day 14 of Month 1) vs anastrozole (1 mg/day) as first-line treatments for postmenopausal women with advanced breast cancer. Eligible patients had no prior treatment for advanced disease and ER+, evaluable disease. Patients received treatment until disease progression or an event necessitating discontinuation. The primary endpoint was clinical benefit rate (CBR), ie the proportion of patients achieving a complete response, a partial response or stable disease for ≥24 weeks. Secondary endpoints included: objective response (OR), time to progression (TTP), duration of response (DoR), duration of clinical benefit (DoCB) and tolerability (adverse events [AEs] and laboratory tests).  Results: In total, 205 women (median age 67 years) were included (fulvestrant HD: n=102; anastrozole: n=103). Median follow-up was 6.5 months. CBR was similar between treatments: fulvestrant HD 72.5%, anastrozole 67.0% (odds ratio 1.3023, 95% confidence interval [CI] 0.7170, 2.3976, p=0.3860). OR rates were: fulvestrant HD 36%, anastrozole 35.5%. Median TTP for anastrozole: 12.5 months; fulvestrant HD: not yet reached, corresponding to a 60% longer TTP for fulvestrant HD (hazard ratio=0.6266, 95% CI 0.3929, 0.9991, p=0.0496). DoR and DoCB were also numerically longer for fulvestrant HD. Both treatments were well tolerated, with no significant differences in the incidence of pre-specified AEs or the small number of withdrawals due to AEs.  Discussion: Fulvestrant HD offers CB and OR rates similar to those obtained with anastrozole 1 mg, with a significantly longer TTP. Fulvestrant HD was well tolerated, with no unexpected AEs. The AE profile of fulvestrant HD appears consistent with the known toxicity profile of the AD. These results are encouraging and provide further support for the improved clinical activity anticipated with fulvestrant HD. Confirmation of these findings is awaited from an ongoing Phase III, double-blind comparison of fulvestrant HD and AD (CONFIRM).

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6126.
Decreased expression of EZH2 is associated with ESR1 upregulation and response to anti-estrogens.
Authors: Jansen M , Ruigrok-Ritstier K , van Staveren I , Helleman J , Reijm E , Look M , Meijer-van Gelder M , Sieuwerts A , Sleijfer S , Foekens J , Berns E
Published: December 2010

Abstract #6127

Background: In prostate and breast cancer high levels of Enhancer of Zeste Homolog 2 (EZH2) are associated with tumor progression. EZH2, a histone H3 methyl transferase, is part of the polycomb complex. Together with histone deacetylases (HDACs) EZH2 regulates “genome wide” gene transcription silencing. The aims of this study are a) to correlate EZH2 expression with endocrine therapy response in patients with recurrent disease treated with first-line tamoxifen monotherapy and b) to determine the role of EZH2 in endocrine therapy response using in vitro cell line models.  Material and Methods: EZH2 mRNA levels were measured with quantitative real-time PCR (qRT-PCR) in 297 retrospectively collected hormone receptor positive (HR+) primary breast tumor specimens of patients with recurrent disease who did respond (N=110) or were resistant (N=187) to first-line tamoxifen monotherapy. In vitro, EZH2 and estrogen receptor (ESR1) expression was downregulated with siRNAs in the human breast cancer cell line MCF7 and assessed for their sensitivity to the selective estrogen receptor degrader ICI164.384 after 96hrs treatment (N=3). To establish therapy response in vitro, cell number counts were determined. All p-values are two-sided and significant if P<0.05.  Results: In 297 HR+ breast tumors, EZH2 as continuous variable, associated significantly with poor response (OR= 0.67 [0.49-0.91]; P=0.001) and a shorter progression-free survival (PFS) (HR=1.28 [1.11-1.47], P<0.001). In the multivariate model with traditional predictive factors, the tertile with highest EZH2 levels was independently related with response (OR= 0.50 [0.26-0.98]; P=0.045) and PFS (HR=1.82 [1.33-2.49], P<0.001).  In vitro, EZH2 downregulation in MCF7 with siRNAs showed a significant decrease in cell number compared to the mock silenced cell line (40%). Moreover, ICI treatment of EZH2 silenced MCF7 cells resulted in a 70% cell number decrease versus 23% decrease in the controls (P<0.001). In addition, EZH2 downregulation is associated with a twofold upregulation with ESR1 (P<0.001). Conversely, silencing of ESR1 in MCF7 resulted did not alter EZH2 levels but, as expected, increases HER2 protein levels.  Conclusion: In primary breast tumors, high EZH2 mRNA levels are associated with poor outcomes after tamoxifen therapy. These results suggest that EZH2 may identify patients at risk for tamoxifen therapy failure. In vitro studies show that downregulation of EZH2 inhibits cell proliferation and on the other hand results in upregulation of ESR1 levels. The latter may explain the increased sensitivity to ICI164.384 of EZH2 silenced cells.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6127.
Fracture risk in women with breast cancer: can baseline assessment of risk be used to guide treatment?.
Authors: Hadji P , Kalder M , Ziller M , Ziller V , Albert U
Published: December 2010

Abstract #6130

Background: Breast cancer (BC) therapies have been associated with decreases in bone health. Recent studies have shown that BC survivors have a 31% increased fracture risk compared with their peers, elevating the importance of monitoring bone health in women diagnosed with BC. Bone mineral density (BMD) has been the standard used by clinical guidelines (WHO, ASCO) to direct therapeutic decisions. However, emerging guidelines place BMD in the context of several other clinical risk factors that have been correlated with overall fracture risk. This retrospective, case-controlled study uses current and emerging guidelines to estimate the percentage of patients with newly diagnosed breast cancer who may be at increased risk for fracture and who require preventive therapy. Methods: Baseline data from 88 pre- and 402 postmenopausal women (PMW) with BC were compared with data from an equal number of healthy age- and body mass index-matched women. BMD was assessed by 2 methods; dual-energy x-ray absorptiometry (DXA) at the lumbar spine (LS) and total hip, and quantitative ultrasonometry (QUS) at the os calcaneus and phalanges. Baseline BMD measurements were collected at a mean duration of 15 and 242 days after diagnosis of cancer in pre- and PMW, respectively. Results: Baseline LS and total hip BMD was similar between the healthy control groups and patients with BC. Among estrogen receptor-positive (ER+) BC patients, 18.8% of premenopausal women and 36.9% of PMW were osteopenic, and 8.9% of PMW were osteoporotic (according to LS BMD). Among ER+ PMW with BC, 15.9% of patients > 65 years of age, 8.3% of patients 55 to 65 years of age, and 1.4% of patients < 55 years of age had osteoporosis. Only 9% of ER+ PMW with BC would have received bone-protective therapy using the BMD limits (T-score ≤ –2.5) set by ASCO treatment guidelines. Based solely on clinical risk factors (eg, if DXA were not available), 6.5% of patients would have been identified for bone-protective therapy. When clinical risk factors and BMD were both used in the fracture-risk assessment, 28.6% of women would have been eligible for bone-protective therapy. Overall, therapy based on ASCO guidelines was estimated to prevent 18% of fractures, whereas combining risk factors and BMD would prevent more than 45% of fractures. Conclusions: Current treatment thresholds seem to inadequately identify patients who would benefit from bone-protective therapy. The results presented here support the use of overall fracture risk assessment in PMW with breast cancer. Using both BMD and clinical risk factors may more effectively identify patients at risk for fracture, although further studies are needed.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6130.
Pooled cardiac safety analysis of patients with HER2-positive metastatic breast cancer receiving trastuzumab.
Authors: Muehlbauer S , Revil C , Leyland-Jones B , Bell R , Baselga J , Marty M , Jones A , Feyereislova A
Published: December 2010

Abstract #6136

Background: The outlook for women with human epidermal growth factor receptor 2 (HER2)-positive early and advanced breast cancer has been significantly improved by the incorporation of trastuzumab (Herceptin®; H) into therapeutic regimens. H has a proven safety profile observed over 10 years of clinical experience in >500,000 patients (pts); however some concerns remain over cardiac dysfunction. This retrospective study reports detailed new analyses of pooled cardiac safety data from 6 metastatic breast cancer (MBC) trials.  Methods: Reports of selected adverse events of symptomatic congestive heart failure (CHF) and cardiac rhythm disturbances (CRDs) as well as left ventricular ejection fraction (LVEF) declines were analysed. As definitions of CHF differed between trials, a detailed manual review of original data was performed, including serious adverse event reports. CRDs were identified based on Medical Dictionary for Regulatory Activities terms. LVEF declines were defined as decreases of ≥15 percentage points (pp) from baseline (BL) or ≥10 pp from BL to an LVEF of ≤50%.  Results: In total, 882 MBC pts from 6 trials were evaluable for the pooled analysis: in 2 of the trials H was given as monotherapy (WO16229, MO16982) and in others H was combined with paclitaxel (BO15935), docetaxel (M77001), docetaxel and capecitabine (MO16419), and anastrozole (BO16216). There were 683 pts in the H group and 199 in the control group. Pt characteristics were well balanced between treatment groups. Symptomatic CHF was identified in 11 pts (1.6%) in the H group (including 1 death) and none in the control group. Of the 11 pts with CHF, 9 had received prior anthracyclines. Fifty-five CRDs (6.6%) were reported in 45 pts in the H group, with tachycardia (3.2%), palpitations (2.6%) and arrhythmias (0.6%) being the most frequent. With the exception of a single grade 3 event in each group, all CRDs were grade 1 or 2. Nearly all CRDs resolved with no sequelae (50/55 events; 91%). In the control group 2 pts (0.1%) experienced a CRD. The total number of pts evaluable for LVEF decline was 673 in the H group and 194 in the control group; 74 (11.0%) and 7 pts (3.6%), respectively, experienced a drop of ≥10 pp from BL to ≤50%. Eighty-nine (13.2%) and 9 pts (4.6%), respectively, had an LVEF decline of ≥15 pp from BL.  Discussion: This pooled analysis of pts from 6 MBC trials demonstrates that H-based treatment in MBC is associated with a low incidence of symptomatic CHF (1.6%) and LVEF declines (11-13% of pts). Although CRDs were observed with H, the majority were of limited clinical significance.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6136.
First step in management of weight gain induced by chemotherapy for early breast cancer.
Authors: Meunier A , Roux P , Bachelot T , Gargi T , Perol D , Bachmann P
Published: December 2010

Abstract #6139

Adjuvant therapies for breast cancer are often associated with weight gain (WG). Overweight, obesity and WG have deleterious consequences for quality of life and probably for breast cancer evolution.  This french monocentric prospective study aimed to determine the incidence of overweight, obesity and WG during and one year after adjuvant chemotherapy (CT) for early breast cancer. Secondary goals were to examine the observance of national nutritional recommendations for healthy living, to observe their effects on WG prevention and to estimate patients needs for dietetic management.  Method : Patients younger than 66 years candidates for adjuvant CT for early breast cancer underwent dietary evaluation at the beginning of CT and were informed of the benefits of WG prevention, healthy diet and living habits. Written recommendations are given. A dietetic follow-up was systematically proposed. Weight, Body Mass Index (BMI) and nutritional habits over the last year before diagnosis, and at 6 and 12 months after chemotherapy were recorded. Statistical analysis is performed to test the association between WG and initial parameters (alpha level 5%).  Results: Of 272 consecutive patients recruited from Oct 2004 to Oct 2006, 242 are evaluated at 6 months and 233 after 1 year. The mean age was 51 years ; 44.1% were not menopausal before chemotherapy. TNM classification was as follows: T0: 15%, T1: 41%, T2: 32%, T3: 9%, T4: 3% and N+: 68%. Chemotherapy regimes were based on doxorubicin for 40% of cases, on taxanes for 1.5% and both for 58.5% . Hormonal therapy was provided to 74.85% of the patients. The average weight before chemotherapy was 65.9 kg (44-117); 25.7% of patients were overweight (25<BMI<30) and 15.1% obese (BMI>30). A third experienced WG during the year before diagnosis. Six months after CT, 52.1% patients had gained weight (<5% body weight for 59%, but >10% for 7.1%) and 29.8 % had lost weight. At one year, WG affected 59.7% of the patients. The average of WG is 5.88% of body weight and 14.4% of the patients gained more than 10%. WG before diagnosis seems to be the only factor associated with post CT absence of weight gain (OR 0.542, IC 95% [0.308-0.954], p= 0.0338). Only 43 women (16%) asked for dietetic follow-up, which induced weight loss for 57%. Health recommendations of the national program of nutrition and health (PNNS in France) were observed by 36.1% of the patients at the beginning of treatment, versus 43.5% at 6 months and 52.1% at one year.  Discussion and conclusions :  This study confirms the high rate of patients gaining weight after chemotherapy. Nutritional information alone is not sufficient, and appropriate healthy program (nutritional follow up and physical activities) must be proposed to limit weight gain and avoid possible consequences on disease free survival and further co morbidities.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6139.
Multi-disciplinary pre-therapeutic consultation significantly improves management of breast cancer patients.
Authors: Ciobotariu N , Fioretta G , Rapiti E , Neyroud I , Balmer-Majno S , Sappino A , Schaefer P , Bouchardy C , Vlastos G
Published: December 2010

Abstract #6151

Introduction  Modern therapeutic management of breast cancer requires a multidisciplinary approach. Since 2001, the Geneva University Hospitals has set up a pre-therapeutic consultation (COSP) involving gynaecologists, medical oncologists, radiation therapists, as well as radiologists, pathologists, plastic surgeons, and nurses. The COSP team discusses and provides therapeutic recommendations for newly diagnosed breast cancer patients seen in our institution. This study evaluates the impact of COSP on patient's management.  Patients and methods  Between 2001-2005, 1771 patients had breast cancer diagnosis among the resident population: 750 patients were referred to the COSP and 1021 were not. We compared patients and tumours characteristics between these two groups by logistic regression. We compared concordance between initial proposed therapeutic option and final COSP treatment recommendation by heterogeneity test. Changes in treatment were considered as major if they concerned type of surgery, or the addition of systemic neo-adjuvant treatments. Other changes were coded as minor. Trend tests were calculated to evaluate management changes over time.  Results  Patients referred to the COSP were significantly younger, more often of low socio-economic status, foreigners, divorced, and treated in public sector. They were less frequently diagnosed through screening, and had more advanced stage at diagnosis. Complete initial treatment recommendation was available for 654 patients. For 109 (17%) patients, COSP dramatically changed the initial therapeutic propositions. For 169 (26%) patients, COSP proposed only minor changes. Among patients referred to the COSP, we observed a significant increase of immediate reconstructive surgery (p<0.001) and an increase of standard treatment options for women aged 80 years or more (p<0.001). Similar changes were absent among patients not referred to the COSP.  Conclusion  The multi-disciplinary pre-therapeutic consultation provides important changes in initial treatment options in routine health care practice. In particular it improves reconstruction and generalisation of good practices in elderly patients. This approach should become a gold-standard in the management of all breast cancer patients.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6151.
Significant increased recurrence rates among breast cancer patients with HER2-positive, T1a,bN0M0 tumors.
Authors: Rakkhit R , Broglio K , Peintinger F , Cardoso F , Hanrahan EO , Litton JK , Sahin A , Larsimont D , Meric-Bernstam F , Buchholz TA , Valero V , Theriault RL , Piccart M , Ravdin P , Hortobagyi GN , Gonzalez-Angulo AM
Published: December 2010

Abstract #701

Background: Controversy surrounds the prognosis of breast cancer patients with T1a,bN0M0 tumors following locoregional therapy and the need for adjuvant systemic therapy, especially for HER2+ disease. The purposes of the study were to determine the recurrence-free survival (RFS), and distant recurrence-free survival (DRFS) in small HER2+ tumors compared with hormone receptor ( HR)+ and triple receptor- (TN) tumors.  Methods: Stage T1a,bN0M0 breast cancers diagnosed between 1973-2003 were reviewed by dedicated breast pathologists. HER2+ tumors were defined as 3+ by IHC or gene amplification. Patients were categorized into 3 groups:TN (ER-, PR-and HER2-), HER2+ (regardless of HR status) and HR+ (HER2-). RFS and DRFS were estimated by the Kaplan-Meier method and compared with the log-rank test. Cox proportional hazards models were fit to determine the association of each group with the risk of recurrence after adjustment for other characteristics.  Results: Of the 1796 patients, 427 were excluded from the analysis due to being male (2), lack of receptor information (249), and adjuvant chemotherapy (176) leaving 1369 pts for analysis. Median age was 57 years,(range, 26-88). There were 381(28%) T1a and 988(72%) T1b tumors; HR+ 68%, TN 23%, HER2+ 9%. Patients who had HER2+ breast cancer tended to be younger,(p=0.001); have more T1a tumors, (p=0.001); and have higher nuclear grade,(p<0.001). At a median follow-up of 74 months(range 1-350), there were 160 recurrences and 77 distant metastases. Five and 10-year RFS and DRFS are summarized in the table. After adjustment for other characteristics, patients with HER2+ breast cancer had a significantly worse RFS (HR: 5.19, 95% CI: 3.21-8.39, p<0.0001) and DRFS (HR: 4.66, 95% CI: 2.47-8.80, p<0.0001) compared to patients with HR-positive breast cancer.  Conclusions: Breast cancer patients with HER2+ T1a,bN0M0 tumors have a significant risk of relapse and should be considered candidates for adjuvant systemic therapy including anti-HER2 agents.   

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 701.
Poor survival outcomes in HER2 positive breast cancer patients with low grade, node negative tumours. Implications for trastuzumab therapy?.
Authors: Tovey SM , Marla S , Brown S , Burton P , Canney P , Stallard S , Mallon E , Edwards J , Cooke T
Published: December 2010

Abstract #702

HER2 status is established as a poor prognostic marker for survival in breast cancer and has been validated as a predictive marker for response to trastuzumab following chemotherapy.We determined the number of patients both eligible for and actually receiving trastuzumab therapy for early breast cancer (EBC) in 2006 in a tertiary breast oncology unit. We also performed a retrospective analysis of the impact of HER2 status on survival in a large cohort of low grade, node negative patients who would currently be deemed ineligible for trastuzumab treatment.  Methods  1. Data for all patients diagnosed with EBC in 2006 was recorded prospectively in a database. Case notes were consulted where the HER2positive patients had not received trastuzumab, to ascertain the reasons.  2. A retrospective cohort of 367, grade 1 or 2, node negative patients diagnosed between 1980-2002 (median followup 6.2yrs) was analysed to assess the impact of HER2 status (Herceptest 3+/FISHpos) on survival.  Results  1. A total of 951 patients were diagnosed with Breast Cancer in 2006. 417(43.9%) of these were screen-detected. 123(12.9%) were HER2positive (117 were EBC) and 59 (50.4%) of the HER2 positive EBCs received trastuzumab therapy. Of the 58 (49.6%) patients who did not receive trastuzumab, 25 (43%) were patients considered low risk due to small, node negative, low grade tumours.  2. Retrospective cohort. The overall hazard ratio for HER2 positivity was 6.78 with 5yr breast cancer specific survival rates of 96% (HER2 neg) and 68% (HER2 pos). The reduction in survival in HER2 positive cases persisted when patients were split into subgroups by ER status, tumour size and age.    Conclusions  Only 50% of our HER2 positive EBC patients received trastuzumab therapy in 2006. The commonest reason for not receiving trastuzumab was low risk status precluding chemotherapy.  However, the substantial reduction in survival shown in our retrospective cohort provides support for the use of trastuzumab in these 'low risk' HER2 positive patients who typically are classified as very good prognosis, are not routinely offered standard chemotherapy, and as such do not fit current prescribing guidelines for trastuzumab. A clinical trial to assess the benefit of adjuvant trastuzumab alone in this group of patients is suggested. Our results are in keeping with the HERA trial where the best prognosis tumours (node negative and size 1-2cm) had benefit similar to the overall cohort.  The persistence of poor outcomes in our ER positive subgroup despite endocrine therapy confirms the recent trans-ATAC analysis based on HER2 status and suggests that we cannot not rely solely on adjuvant endocrine therapy in these largely ER positive patients.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 702.
Combination antiHER therapeutics — efficacy of alternative dosing regimens in ER+/HER2+ breast cancer xenografts.
Authors: Wiechmann LS , Soliz R , Hilsenbeck S , Rimawi M , Osborne CK , Schiff R
Published: December 2010

Abstract #706

Background In preclinical studies of HER2 positive breast cancer, combination antiHER therapy with lapatinib (L) and trastuzumab (T), is more promising than monotherapy. To reduce side effects, cost and increase patient compliance, we investigated novel dosing and scheduling of the L and T combination to find alternative treatment approaches.  Methods Mice bearing xenograft tumors of BT474 (ER+/HER2-amplified) cells were treated with control estrogen supplementation, with estrogen withdrawal alone, or with estrogen withdrawal in combination with one or two HER inhibitors (T-10mg/Kg biweekly, L-100mg/Kg 5d/wk) continuously. Alternative dosing regimens included limited treatment duration (14, 42 days), intermittent administration (14 days on/ 14 days off L+T treatment), and dose adjustments (1/2L + 1/2T). Tumor volumes and weights were evaluated weekly. Results were analyzed with the Fisher's exact test or survival analysis methods (Kaplan-Meier estimates) and generalized Wilcoxon test. Group sizes were designed to rule out relatively large decrements in efficacy [i.e. 99% complete regression (CR) vs 65% CR]. All statistical tests were two-sided.  Results At day 140 of the experiment, BT474 xenografts demonstrate de novo resistance to estrogen deprivation (ED) and respond more rapidly to the drug combination (L+T) compared to L or T alone. CR rates for xenograft tumors treated for 14 or 42 days are similar to full therapy, although relapses occur earlier (47% relapses at day 140 for 14 day treatment, compared to 20% and 0% for 42 day or full treatment, respectively). Intermittent treatment is as effective as full dose (one mouse demonstrating small palpable growth following CR died before confirmation of relapse). Decreasing the dose did not substantially change the percentage of tumors that undergo complete regression (CR) and did not accelerate treatment failure [Progression Free Survival (PFS) at day 140], but was associated with longer time to complete tumor regression (TTR).    Conclusion Intermittent treatment with combined T and L is a promising strategy that warrants further investigation. Though 42 days of therapy led to complete tumor regression, our preliminary data suggest that a sustained response is more likely to be achieved by treatment >42 days. Longer follow up is needed to determine the effectiveness of decreased dose regimens.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 706.
Superiority of sequential docetaxel over standard FE100C in patients with intermediate risk breast cancer: survival results of the randomized intergroup phase III trial EC-Doc.
Authors: Nitz U , Huober J , Lisboa B , Harbeck N , Fischer H , Moebus V , Hoffmann G , Augustin D , Weiss E , Gluz O , Kuhn W
Published: December 2010

Abstract #78

Background: Taxane based adjuvant chemotherapy (CHT) is standard of care in node-positive breast cancer. Several pre-planned subgroup analyses detected the maximum benefit from taxanes in patients with 1-3 positive lymph nodes (LN).  According to the St. Gallen consensus CHT in endocrine responsive tumors is optional in these patients. Recently the ABCSG reported excellent survival data after endocrine therapy +/- bisphosphonates without CHT in low to intermediate risk breast cancer (Gnant et al., ASCO 2008). The EC-Doc trial compares a modern sequential taxane-based regimen with standard FE100C in patients with 1-3 positive LN.  Methods: Patients from 18 to 65 years with primary breast cancer and 1 to 3 positive LN were eligible if they had operable breast cancer with histologically confirmed free margins. M0 status was assessed by conventional staging. 2011 patients were randomized to a phase III trial comparing 4 cycles E90C600 q3w followed by 4 cycles of Docetaxel100 q3w (n=1008) (Arm A) versus 6 cycles of F500E100C500 q3w (n=828) or C600M40F600 d1, 8 q4w (n=175) (Arm B). The primary endpoint is EFS. Secondary endpoints are OS, toxicity and quality of life.  Results: Baseline characteristics were well balanced between both study arms. Arm A/B: mean age 51.5/51.5 years, median tumor size 2.0/2.0, HR positive 77.7% / 78.3%, G3 34.1% / 34.4%. Toxicity data from the EC-Doc trial were recently presented (Nitz et al. , ASCO 2008). After a median follow up of 41 months both estimated 5-year EFS (91% vs. 86%, p=0.005) and OS (95% vs. 90%, p=0.004) were significantly better in the EC-Doc arm.  For the comparison of EC-Doc vs. FE100C the respective values were: HR 0.58, p=0.004, estimated 5 year EFS 91% / 85% and 5 year estimated OS 95% / 91% (p =0.03). For the hormone receptor positive subpopulation the HR was 0.51 in favour of EC-Doc (p= 0.007).  Conclusions: Our study indicates a superiority of sequential taxane-based EC-Doc CHT in terms of EFS and OS over standard FE100C in an intermediate risk group. The addition of modern third generation taxane based CHT to conventional endocrine treatment is associated with excellent EFS and OS in patients with 1-3 positive LN.  As shown even for the subgroup of patients with HR positive disease the benefit from third generation taxane based CHT is substantial so that an endocrine only adjuvant strategy may result in undertreatment. With respect to the excellent survival rates prospective randomized trials testing the existing genetic tests are mandatory.  Updated survival and efficacy analysis in distinct molecular subtypes (Her-2/neu, triple-negative) will be presented.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 78.
Assessing the spatial extent of breast tumor intrinsic optical contrast using ultrasound and diffuse optical spectroscopic imaging.
Authors: Liu J , Cerussi AE , Li A , Tanamai W , Kwong R , Hsiang D , Tromberg BJ
Published: December 2010

Abstract #806

Background: Near infrared (NIR) light is sensitive to several important tissue components and has been used to detect, characterize, and monitor breast tumor functions. However, little is known about the relationship between anatomic and functional contrast derived from intrinsic optical signals. Diffuse Optical Spectroscopic Imaging (DOSI) is a non-invasive, bedside functional imaging technique that quantifies the concentrations and molecular states of tissue hemoglobin, water, and lipids. Pilot studies have shown that DOSI may be a useful tool for breast lesion detection/characterization and therapeutic monitoring.  Materials and Methods: DOSI data were compared with theoretical computer simulations to estimate the nature and extent of optical contrast with respect to standard ultrasound imaging. DOSI reflectance measurements were obtained from 10 breast tumor patients, with both malignant (N=5) and benign (N=5) lesions. Patient average ages: 35+/-7.8 years vs. 44.3+/-14.7 years, lesion depth 10.9+/-5.5 mm vs. 15.8+/-5.3 mm, and maximum size 13.0+/-6.0 mm vs. 14.8+/-4.9 mm for benign and malignant, respectively. Two trial tumor models were simulated to model actual tumor optical properties (hemoglobin): (a) a discrete target constrained to ultrasound dimensions, and (b) a distributed target that spatially extended beyond ultrasound dimensions.  Results: High optical contrast (i.e., the ratio target to background) was observed for both benign (1.53+/-0.17) and malignant (2.06+/-0.4) lesions, even for this younger population. While the discrete target model could not match experiment and simulation, a distributed model provided excellent agreement. The spatial extent of optical properties in breast tumor was significantly greater than anatomical dimensions reported by ultrasound imaging. The extent of the distribution was greater in the malignant lesions than in the benign ones. Further simulations also suggested that invasive breast tumors in this population with anatomical size 10 mm may still be detectable at depth 30 mm using DOSI in reflectance.  Discussion: The spatial extension of tumor optical contrast complicates co-registration of optical functional images with anatomic images. The true optical contrast is significantly higher in breast cancer tumors, likely 4-5x than the hemoglobin levels in normal tissues. Breast tumor optical contrast is more realistically modeled as a spatially distributed target, which facilities a fast 3D imaging scheme in reflectance geometry. Results from these topographic reconstructions will be discussed.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 806.
Targeting of chemotherapy to Tie-2-receptor positive angiogenic endothelial cells of tumor vasculature.
Authors: Li P , Liu Y , Maynard J , Tang Y , Deisseroth A
Published: December 2010

Abstract #902

Background: There are at least three types of cells in tumor tissue which express the Tie2 receptor (Tie2R): dividing vascular endothelial cells (TVECs), Tie2R-expressing monocytes (TEMs) and Tie2R-expressing mesenchymal progenitor cells (TMPCs).    We tested if the targeting of chemotherapy to these classes of Tie2R positive cells could suppress tumor cell growth.  Material and Methods: We constructed replication incompetent adenoviral vectors carrying the cytosine deaminase (CD) suicide gene driven by the mouse Tie2R transcriptional promoter and enhancer sequences. In these viruses, we inserted an RGD-4C peptide into the HI loop of the fiber knob domain of the vector to increase its transduction efficiency in TVECs. At the same time, we added two mutations (S408E and P409A) in the AB loop of the fiber, which ablated the CAR-binding ability of the vector. The resulting vector was named AdTie2RCD(MRGD).  Results: In vitro viral infection assays involving the human umbilical vein endothelial cells (HUVECs) showed that the RGD-modified vectors have a higher transduction efficiency as compared with their adenoviral vector counterparts which have a wild type fiber protein. Mice carrying the rat Her-2-Neu positive N202 mouse breast cancer cells and the mouse B16 melanoma cells were treated with intravenous injections of Hetastarch and the AdTie2RCD(MRGD) vector followed by intraperitoneal injections of 5-Fluorocytosine (5-FC). The Hetastarch was given before the intraveinous infusion of the adenoviral vector in order to reduce the uptake of the adenoviral vector by the reticuloendothelial cell system. The Tie2R targeted chemotherapy sensitization vectors induced greater degrees of suppression of tumor cell growth than did the control group, achieved the similar treatment effect to its CMV promoter counterpart, but with less side effect.    Histological analysis showed that these vectors specifically targeted the TVECs, TEMs and TMPCs through which they may have exerted cytotoxic effects in the presence of 5-FC on the tumor cells.  Discussion: Our results showed that N202 breast cancer cell line is more responsive to the Tie2R-targeting therapy compared to B16 mouse melanoma cell line and the Tie2R-directed anti-angiogenic therapy deserves further study, in combination with other types of therapy to pave the way for future clinic trails.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 902.
Bevacizumab (BV) maintenance therapy significantly delays disease progression (PD) or death compared with placebo (PL) in the AVADO trial (BV + docetaxel [D] vs D + PL in 1st-line HER2-negative locally recurrent [LR] or metastatic breast cancer [mBC]).
Authors: Fumoleau P , Greil R , Rayson D , Müller V , Barni S , Aleknavicius E , Tellez E , Wilson C , Miles DW
Published: December 2010

Abstract #903

Background: BV (Avastin®) is a monoclonal antibody to VEGF that significantly improved PFS and response rate when combined with 1st-line taxane chemotherapy (CTx) in two randomised phase III studies in patients (pts) with LR or mBC: E2100 (weekly paclitaxel ± BV) and double-blind, PL-controlled study AVADO (D ± two different BV doses). Preclinical data suggest that BV inhibits tumour neovascularisation and can limit tumour vascular regrowth. Both above trial protocols recommended BV use until PD, even after discontinuation of concomitant CTx. In the NO16966 trial in metastatic colorectal cancer, PFS was longer for pts continuing BV following cessation of CTx than for those where BV and CTx were stopped at the same time. We report results of an exploratory analysis of time to PD or death after cessation of D in pts in AVADO.  Methods: AVADO compared BV 7.5 or 15mg/kg + D 100mg/m2 with PL + D in 736 pts with inoperable LR or mBC, ECOG PS 0–1 and adequate LVEF. D and BV/PL were administered q3w, with D given for up to 9 cycles and BV/PL continued until PD or unacceptable toxicity.  Results: The table presents median time from discontinuation of D until PD or death in different subgroups in the AVADO study. Approximately 70% of pts in each arm discontinuing D went on to receive at least one dose of BV or PL before PD.    Conclusions: Continuation of single-agent BV at either dose after discontinuation of D significantly delayed PD or death compared with single-agent PL. These results support the hypothesis that BV may inhibit tumour neovascularisation and progression following CTx and suggests that clinical benefit may be maximised by treatment with BV until progression.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 903.
Cancer clinical trials in the 21st century: the need for a paradigm shift in design, conduct, and support.
Authors: Piccart MJ , Philippe B
Published: December 2010

Abstract #ES-1

Over the last fifteen years, more than 45,000 women with early disease were randomized to taxane versus non-taxane regimens across 26 separate trials. Although collective results from 21 first-generation studies involving more than 36,000 women suggest that the addition of a taxane modestly improves anthracycline therapy, we are still uncertain of which subgroups of patients benefit from taxanes. The shortcomings of this enormous international effort provide many important lessons for the design, conduct, and support of clinical trials in the 21st century. Our growing understanding of the molecular heterogeneity of breast cancer dictates that this “one size fits all” approach to adjuvant therapy is now obsolete. Past efforts to investigate emerging therapies have suffered by the inclusion of women with endocrine responsive, luminal low proliferative disease, who enjoy a favourable long-term outcome in the absence of any adjuvant systemic therapy. Even when a clearly defined population has been defined, such as HER2 positive disease for adjuvant trastuzumab, there has been substantial duplication of efforts by individual co-operative groups. As a result, we remain uncertain of the optimal duration and schedule of adjuvant trastuzumab administration. Post-registration trials testing shorter duration trastuzumab regimens require greater numbers of participants to demonstrate non-inferiority and are now being conducted with considerable opportunity cost. Future registration studies will require careful upfront selection of secondary trials designed to address specific, non-overlapping questions of clinical importance. New-generation trials must mandate prospective collection of biospecimens and integrate cutting-edge technologies as early barometers of efficacy to accelerate the trajectory of novel agents to the clinic with the parallel development of therapeutic biomarkers that can be used to individually tailor treatment. Such a paradigm shift will require a new partnership between investigators, patients, and industry with a unified global commitment to reshape the framework of clinical trials, so that further progress can be made in the fight against breast cancer in the 21st century.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr ES-1.
Management of the contralateral breast in women with breast cancer.
Authors: Tuttle T
Published: December 2010

Abstract #MS1-2

Patients with unilateral breast cancer are at increased risk for developing a second cancer in the contralateral breast. The annual risk of clinically detected metachronous contralateral breast cancer is about 0.7% Some women choose contralateral prophylactic mastectomy (CPM) to prevent cancer in the contralateral breast. A recently published study found that the use of CPM increased by 150% from 1998 to 2003 in the United States. Several studies have demonstrated that CPM significantly decreases the occurrence of contralateral breast cancer; the risk reduction is about 97%. Since the risk of systemic metastases often exceeds the risk of contralateral breast cancer, most patients will not experience any survival benefit from CPM. Moreover, CPM is not risk free, and patients may need to undergo additional surgical procedures, especially if reconstruction is performed. Nevertheless, most patients are satisfied with their decision to undergo CPM. Alternatives to CPM include close surveillance with clinical breast examination, mammography, and possibly breast magnetic resonance imaging. Endocrine therapy with tamoxifen or aromatase inhibitors significantly reduces the risk of contralateral breast cancer and may be more acceptable than CPM for some patients. Ovarian ablation and cytotoxic chemotherapy also reduce the risk of contralateral breast cancer. For women with unilateral breast cancer, management of the normal contralateral breast is complex. Future prospective studies are critically needed to evaluate the decision-making processes leading to CPM.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr MS1-2.
Systems approach to personalized molecular medicine.
Authors: Mills G
Published: December 2010

Abstract #MS2-1

The realization of the promise of personalized molecular medicine will require the efficient development and implementation of novel targeted therapeutics. The overall likelihood of response to particular drugs represents the interaction between predictors of sensitivity with predictors of resistance. The phosphatidylinositol 3'kinase (PI3K) pathway is aberrant at multiple levels across a wide variety of tumors making it the most common activating aberration in cancer. This has led to the development and now early clinical testing of drugs targeting multiple components of the pathway. The efficient utilization of these drugs will require the ability to accurately determine mutation and activation status in tumors as well as determining the interaction between the PI3K pathway and other pathways in driving tumor pathophysiology. The PI3K pathway is critically important to cellular function and is thus under exquisite homeostatic control. The feedforward and feedback loops in the pathway determine the response to perturbation of the pathway by mutation or therapeutic intervention. Strikingly inhibition of the pathway at the level of mTOR or AKT results in the activation of potent feedback loops resulting in activation of multiple cell surface tyrosine kinases, PI3K itself and AKT. This may contribute to the observation that mTOR inhibitors appear to make some patient tumors grow more rapidly an unexpected and disappointing consequence. Our preliminary systems biology-based mathematical and experimental models of the PI3K signaling network accurately predict these consequences as well as the biochemical processes involved. Further, the models suggest combinations of targeted therapeutics likely to reverse the negative effects of the mTOR inhibitors converting the outcome from negative to positive in terms of tumor growth.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr MS2-1.