bluuebunny/crossref_metadata_2025 huggingface dataset:
Neoadjuvant trastuzumab in patients with HER2-positive locally advanced breast cancer: primary efficacy analysis of the NOAH trial.
Authors: Gianni L , Eiermann W , Semiglazov V , Manikhas G , Lluch A , Tjulandin S , Feyereislova A , Valagussa P , Baselga J
Published: December 2010

Abstract #31

Background: Trastuzumab (Herceptin®; H) improves survival in HER2-positive early and metastatic breast cancer. The Phase III NOAH trial is the largest neoadjuvant study that evaluated the addition of H to an anthracyclines- and taxanes-based chemotherapy (CT) for patients (pts) with HER2-positive locally advanced breast cancer (LABC).  Methods: In this multicentre, randomised, open-label trial, women aged ≥18 years with HER2-positive (IHC 3+ or FISH+) LABC (T3N1 or T4; any T + N2 or N3 or + ipsilateral supraclavicular node involvement) were randomised to receive 3 cycles of doxorubicin (60 mg/m²) and paclitaxel (150 mg/m²) q3w, 4 cycles of paclitaxel (175 mg/m² q3w) and 3 cycles of CMF (cyclophosphamide 600 mg/m², methotrexate 40 mg/m², 5-fluorouracil 600 mg/m² q4w) on Days 1 and 8, with or without concomitant H (8 mg/kg loading dose then 6 mg/kg q3w for 1 year) before surgery. In parallel, LABC pts screened as HER2-negative (IHC 0/1+) received the same CT regimen. The primary end point was event-free survival (EFS), defined as the time between randomisation and disease recurrence or progression, or death from any cause. Secondary end points were pathological complete response (pCR), overall response rate (ORR), overall survival (OS) and safety. We report for the first time here the study's primary endpoint.  Results: 327 pts were enrolled. Baseline characteristics were balanced for randomised pts. Inflammatory breast cancer was present in 27% of HER2-positive vs 14% of HER2-negative tumours, while 35% vs 64%, respectively, were hormone-receptor positive. EFS was analyzed after 88 events in the HER2-positive group (n=228). EFS rate at 3 years was significantly better in the H + CT arm compared with CT alone: 70.1% vs 53.3%, respectively (HR 0.56; p=0.007). EFS rate in the HER2-negative arm was 67.4%. OS data were immature at this stage. Trastuzumab treatment was the only variable significantly associated with EFS outcome in multivariate analysis which included disease stage and hormonal receptor status. Both ORR and pCR were significantly higher in the H + CT arm compared to CT alone: 89% vs 77% for ORR, respectively (p=0.02); 39% vs 20% for pCR, respectively (p=0.002). Similar results for ORR and pCR were observed between the HER2-positive CT-alone arm and the HER2-negative arm. The addition of H to CT in the neoadjuvant setting was well tolerated with acceptable cardiac safety.  Conclusion: Neoadjuvant H significantly increased EFS in pts with HER2-positive LABC. This analysis of the NOAH study establishes neoadjuvant H with CT as a standard treatment option in women with HER2-positive LABC.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 31.
A breast international group survey of young breast cancer patients' attitudes towards the risk of loss of fertility related to adjuvant therapies. EORTC protocol 10002 – BIG 3-98.
Authors: Neskovic-Konstantinovic Z , Gomez H , Senkus-Konefka E , Dirix L , Jerusalem G , Murray E , Bottomley A , Rampion J , Duez N , Demonty G , Di Leo A
Published: December 2010

Abstract #3106

Objectives: Under the auspices of the Breast International Group (BIG), the European Organization for Research and Treatment of Cancer (EORTC) conducted a survey with the International Breast Cancer Study Group (IBCSG) and German Breast Group (GBG) of breast cancer (BC) patients (pts) aged 35 years or less at the moment of BC diagnosis. The primary objective of our survey was to evaluate the attitude of BC pts towards the risk of sterility related to anti-cancer treatments.  Patients and methods: Four hundred premenopausal, early stage BC pts participated in this survey after signing the informed consent, and 389 were evaluable. Patients completed a short, previously pilot-tested questionnaire, translated into 15 languages broadly following EORTC translation procedures.  Results: 228 pts (59%) wanted to have children in the future, but 158 (41%) did not, with 57 (36%) of these women stating they were afraid the cancer would return, and as such they would not like to have children. The wish to have children in the future was more frequently expressed by those women who had no children (84% of these pts against 43% of patients with children). Thirty-two (8%) women stated they would not undergo chemotherapy, and this was dependent on whether they already had children or not. Of the 355 pts (91%) who agreed they would have chemotherapy even knowing that this may reduce their chance of having children in the future, 113 (32%) would accept treatment even if there were only 1-5% extra chance of being cured. However, 169 (48%) would accept chemotherapy only if the extra chance of being cured exceeded 20%. Ninety-one (26%) women who would undergo chemotherapy would accept only the minimal risk of sterility of 0-25%, while 171 (48%) would accept as high as 76-100% risk of sterility. The maximum risk of sterility that would be accepted by BC patients is clearly influenced by their already having children.  Conclusion: Our international survey provides key evidence of young, early breast cancer patients' attitudes towards infertility related to breast cancer treatments. While obviously women are primarily interested in being cured, they are also highly concerned about the loss of fertility.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3106.
Extended follow-up results from a prospective multi-center study of the impact of the 21-gene recurrence score assay on medical oncologist and patient adjuvant breast cancer treatment selection, satisfaction, and anxiety.
Authors: Lo SS , Mumby PB , Rychlik K , Smerage J , Kash J , Chew HK , Hayes D , Albain KS
Published: December 2010

Abstract #3113

Background: The 21-gene Recurrence Score (RS) assay has been validated to quantify the risk of distant recurrence in tamoxifen treated patients (pts) in node negative, estrogen receptor positive breast cancer (BC) and predict magnitude of chemotherapy benefit. We previously showed that the RS impacted medical oncologists (MOs) and pts adjuvant treatment decision making, decreased situational anxiety and decisional conflict, and improved pt satisfaction regarding adjuvant treatment decisions. Herein, we present the 12 month post-RS data for MOs and pts.  Material and Methods: MOs stated their treatment recommendation and confidence in it pre- and post-RS assay, and completed a 12 month questionnaire. Pts completed 4 questionnaires pre- and immediately post-RS, and 12 months later: 1) Patient Treatment Decision Making Questionnaire; 2) Decisional Conflict Scale (DCS); 3) State-Trait Anxiety Inventory; and 4) Functional Assessment of Cancer Therapy-Breast. Frequency distributions, means and standard deviations summarized data. Paired samples t-tests and repeated measures ANOVA assessed quality of life, decisional conflict and anxiety.  Results: Accrual goal was met with 89 evaluable pts. 16/17 (94%) MOs and 67 pts (75%) completed the 12 month assessment. There were no breast cancer recurrences recorded at 12 months. The majority of MOs reported increase confidence in their treatment recommendation (n=15, 93.8%), felt the RS provided additional information (n=15, 93.8%), and influenced treatment recommendation (n=14, 87.6%). Results from the DCS immediately post-RS indicate reduced conflict over treatment (p <.0001), greater pt satisfaction, and increased confidence with choice of adjuvant therapy (p <.0001). Pts reported they were glad they took the test 12 months later (n=62, 92.5%), found results easy to understand (n=60, 89.6%), and the test influenced treatment decision (n=54, 80.6%). Sixty four (95.5%) were satisfied with their adjuvant decision. State anxiety decreased over the year (mean 38.9 to 34.0, p. = 007), the most significant decline occurred pre- to immediately post-RS. Quality of life remained constant.  Conclusions: The RS assay has an immediate and enduring impact on MOs and pts adjuvant decision making. MOs and pts report continued confidence and satisfaction with the assay. Pts had a decrease in decisional conflict right after the test, situational anxiety declined over the next 12 months and quality of life remained stable.  Investigator initiated trial supported by an unrestricted clinical trials grant from Genomic Health Inc.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3113.
Sequencing of type I IGF receptor (IGF1R) inhibition affects chemotherapy response in vitro and in vivo.
Authors: Zeng X , Sachdev D , Zhang H , Yee D
Published: December 2010

Abstract #3122

Purpose: To determine the optimal sequence of combining anti-IGF1R antibodies with chemotherapeutic drugs in cancer cells in vitro and in vivo.  Experimental design: MCF-7 and LCC6 cells were treated with sub-cytotoxic concentrations of doxorubicin (DOX) with or without anti-IGF1R antibodies (scFv-Fc or EM164 and its humanized version AVE1642). Treatments were given simultaneously, DOX followed by anti-IGF1R antibody, or anti-IGF1R antibody followed by DOX, with measurement of in vitro proliferation, apoptosis, and anchorage-independent growth. Effects of sequencing on LCC6 xenograft growth and metastasis were studied.  Results: DOX followed by anti-IGF1R antibody (scFv-Fc or EM164) was the most effective combination strategy to inhibit cell monolayer growth and anchorage-independent growth. This sequential combination triggered increased Poly (ADP-ribose) polymerase (PARP) cleavage compared to other treatment sequences. The reverse sequence, antibody followed by DOX treatment, protected cells from chemotherapy by decreasing apoptosis, arresting cells in S phase, and inhibiting the level and activity of topoisomerase IIα . Finally, our in vivo data show that recovery of IGF1R prior to DOX therapy resulted in the best therapeutic responses. Low doses of AVE1642 that allowed IGF1R expression to recover at one week were more effective in combination with DOX than higher antibody doses.  Conclusion: The timing of IGF1R inhibition affects responses to chemotherapy. The optimal sequence was DOX followed by anti-IGF1R antibody, while the opposite sequence inhibited DOX effects. Thus, short course suppression in combination with DOX might be the optimal combination and provides a rationale for the design of future clinical trials.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3122.
Depression-anxiety and quality of life and the use of complementary and alternative medicine among breast cancer patients in Turkey.
Authors: Kalender ME , Dirier A , Sevinc A , Camci C
Published: December 2010

Abstract #3130

Purpose: Breast cancer is the most common cancer type among women. The aim of this study was to examine the association between the use of complementary and alternative medicine (CAM) and quality of life, and anxiety and depression, and demographic characteristics of Anatolian women with breast cancer.  Methods: Quality of life was measured with European Organization for Treatment and Research of Cancer (EORTC) quality of life core questionnaire (QLQ-C30, version 3.0) and anxiety and depression was measured with Hospital Anxiety and Depression Scale (HADS). The demographic characteristics of patients were filled by patient to a standard form.  Results: Totally 122 patients with breast cancer were enrolled, and 50% (n=61) of patients reported that they were using CAM. The most commonly used CAM methods were stinging nettle (57%) and prayer and spiritual healing (49%). The statistical analysis showed that, there was a meaningful correlation between CAM usage and education level (p=0.031) and radiotherapy (p=0.002). There was no relationship between use of CAM and patients age, time since diagnosis, stage of cancer, chemotherapy using, smoking and residence. Analysis of patients showed a positive correlation between CAM and RF2 (Role Functioning) (p=0.014) and FI (Financial Difficulties) (p=0.011) and negative correlation between CAM and EF (Emotional Functioning) (p=0.033). There was no correlation between use of CAM and anxiety and depression scale. The RF2 (p=0.02), EF (p=0.047), FA (Fatigue) (p=0.038), PA (Pain) (p=0.043) and depression results (p=0.008) were better at patients with high education level. We analysed CAM using in patients living in rural or urban area, and the EF (p=0.006), CF (Cognitive Functioning) (p=0.027), PA (p=0.025), DY (Dyspnoea) (p=0.045) and DI (Diarrhoea) (p=0.000) results were better in urban area.  Conclusions: According to the various studies in the literature, 20-83.3% of breast cancer patients were using CAM and the CAM methods are different in different countries and cultures. Our results suggest that the use of CAM among Anatolian women with breast cancer is popular. This study findings showed no correlation between anxiety and depression and CAM usage. There is a tendency to CAM usage in patients with financial problems. Emotional functioning was also worse in those patients. The study results showed that the use of CAM is more common among breast patients with bad emotional status and poor financial status.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3130.
Molecular marker correlates of clinical outcome in a phase II study of gefitinib or placebo in combination with anastrozole in postmenopausal women with hormone receptor-positive metastatic breast cancer.
Authors: Valero V , Bacus S , Mangalik A , Rabinowitz I , Arena F , Kroener J , Curcio E , Watkins C , Magill P , Cristofanilli M
Published: December 2010

Abstract #3131

Background: Preclinical data suggest that crosstalk between growth factor receptor pathways and estrogen receptor (ER) is involved in the development of endocrine resistance. Therefore, inhibition of epidermal growth factor receptor (EGFR) is a potential target in this setting. This phase II randomized, double-blind, multicenter study evaluated the efficacy and tolerability of gefitinib (Iressa) or placebo in combination with anastrozole (Arimidex) in postmenopausal women with newly diagnosed hormone receptor-positive (HR+) metastatic breast cancer (MBC).  Methods: Patients were randomized (1:1) to anastrozole 1 mg/day and either gefitinib 250 mg/day or placebo. The primary objective was progression-free survival (PFS); and secondary objectives included clinical benefit rate (CBR; defined as objective response plus stable disease ≥24 weeks), objective response rate (ORR) by RECIST, overall survival, safety and correlative biological markers. Biomarkers in tumor tissue (ErbB family receptors including EGFR, or other downstream related effectors and other markers of proliferation and apoptosis) by immunohistochemistry were assessed to explore potential correlations with outcome. Enrollment closed early due to slow recruitment and formal statistical testing was not performed.  Results: 94 women were randomized to gefitinib plus anastrozole, and 43 to placebo plus anastrozole, 50 from 30 centers in 4 countries. PFS was significantly longer for gefitinib plus anastrozole over placebo plus anastrozole (HR [gefitinib:placebo] 0.55, 95% CI 0.32-0.94; median PFS 14.5 vs 8.2 months). A numerical advantage in CBR was seen for gefitinib plus anastrozole over placebo plus anastrozole (49% [21/43; 95% CI 35-65] vs 34% [17/50; 95% CI 21-49]). ORR was 2% (1/43) with gefitinib plus anastrozole and 12% (6/50) with placebo plus anastrozole. Too few patients died before data cut-off to allow conclusions on overall survival to be drawn. Safety and tolerability profiles showed no unexpected findings. Correlative biological markers data will be available later in the year after which the abstract will be updated and resubmitted.  Discussion: This clinical trial demonstrated that EGFR inhibition and estrogen deprivation with gefitinib in combination with anastrozole was associated with a marked advantage in PFS and CBR vs placebo plus anastrozole in ER+ MBC. These data suggest that EGFR inhibition in combination with anastrozole warrants further investigation.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3131.
Decrease in serum extracellular domain of HER2 at 4 and 8 weeks is associated with prolonged progression-free survival on lapatinib monotherapy.
Authors: Lipton A , Leitzel K , Ali S , Carney W , Platek G , O'Rourke L , Martin A , Maltzman J
Published: December 2010

Abstract #3140

Background: The extracellular domain of the HER2 oncoprotein (ECD HER2) is shed into the serum and can be detected by ELISA. This study investigated whether baseline serum ECD HER2 level is associated with prolonged progression-free survival (PFS) on lapatinib monotherapy. Additionally, we analyzed whether change in serum ECD HER2 at week 4 and 8 after start of lapatinib therapy is associated with prolonged PFS.  Methods: Study EGF20009 investigated lapatinib monotherapy in 138 HER2-positive patients with metastatic breast cancer who had not previously received chemotherapy or trastuzumab. Serum was collected at baseline and every 4 weeks after initiation of oral lapatinib (1,500 mg daily or 500 mg twice daily). Disease assessment was performed at week 8, 12 and every 12 weeks thereafter. Disease status was assessed by an independent radiology committee, and response was measured using RECIST. Serum ECD HER2 was measured using the ELISA from Siemens HealthCare DX/Oncogene Science. A serum ECD HER2 decrease or increase ≥ 20% from baseline was defined as a significant change.  Results: Baseline ECD HER2 was not associated with PFS; however, a ≥ 20% decrease from baseline serum ECD HER2 was associated with prolonged PFS, and a ≥ 20% increase from baseline was associated with shorter PFS. Patients who experienced a ≥ 20% decrease from baseline serum ECD HER2 at week 4 had a median PFS of 199 days (95% confidence interval [CI] = 145, 253) compared with 135 days (95% CI = 104, 171) for patients who did not (p = 0.016). Similarly, patients who experienced a ≥ 20% increase from baseline serum ECD HER2 at week 4 had a median PFS of 113 days (95% CI = 59, 135) compared with 199 days (95% CI = 142, 253) for patients who did not (p < 0.001). Similar associations were observed for the week-8 changes in serum ECD HER2 levels.  Conclusions: Baseline ECD HER2 was not associated with PFS, whereas a ≥ 20% decrease from baseline serum ECD HER2 at week 4 and 8 was associated with prolonged PFS on lapatinib monotherapy. Single-agent lapatinib could be considered for the subset of patients whose ECD HER2 declines in the first 8 weeks of therapy, whereas a combination of chemotherapy with anti-HER2 therapy may be more appropriate for the patients whose ECD increases by ≥ 20%. Identification of a subgroup of patients who may be able to avoid cytotoxic chemotherapy in the MBC setting is an attractive prospect in our quest to find suitable therapies for appropriate patients.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3140.
Lapatinib (L) with weekly paclitaxel (P) as first-line therapy for patients (pts) with HER2+ metastatic breast cancer (MBC).
Authors: Jagiello-Gruszfeld A , Tjulandin Sergei S , Dobrovolskaya N , Manikhas A , Pienkowski T , Knott A , DeSilvio M , Oliva C
Published: December 2010

Abstract #3145

L, an oral tyrosine kinase inhibitor of EGFR/HER2, is active as monotherapy and in combination with chemotherapy for HER2+ MBC. In a planned subgroup analysis of a Ph III trial, EGF30001, L (1500mg QD) + P (175mg/m2 q3w), significantly improved overall response rate (ORR) and progression free survival (PFS) compared with P alone as initial therapy for HER2+ MBC. Here we report final results of a phase II, single-arm multicenter trial, EGF105764, assessing activity of L with weekly P in first line MBC.  Methods: Safety and efficacy of L (1500 mg QD)+P (80 mg/m2/wk x 3q wk) was evaluated in 57 pts with newly diagnosed, HER2 FISH+, Stage IV MBC. Primary endpoint was ORR.  Results and Discussion: All pts had ECOG PS ≤1, no pt received previous trastuzumab but 61% received prior adjuvant/neo-adjuvant chemo- or anti-hormonal therapy. Median time from prior chemotherapy was 63 weeks. No patient had suspected baseline CNS disease. At time of data cut-off, 41 (72%) pts progressed or withdrawn. The median duration of L treatment was 45 (range 2-87) wks, and 26 (range 0 to 80) wks for P. The investigator-assessed ORR was 77% (44/57), with 3 CR and 41 PR, (95% CI: 64.2, 87.3) with a median duration of response (DoR) of 42.3 wks (95% CI: 37.7, 64.1). The independently confirmed ORR was 51% (29/57), with 0 CR and 29 PR, (95% CI: 37.3, 64.4) with a median DoR of 39.7 wk (95% CI: 26.9, 50.0). CNS relapse was reported in 4/41 pts (10%). Most common AEs were diarrhoea (56%, ≥gr3: 5%), neutropenia (44%, ≥gr3: 26%), rash (40%, ≥gr3: 3%), fatigue (25%, ≥gr3: 0%), and neurological (25%, ≥gr3: 0%). Four pts had 1 dose reduction of L (2 due to diarrhoea) and 19 pts had ≥1 dose delay (6 due to diarrhoea). Dose reductions for P occurred in 7 pts; 45 pts had ≥1 dose delay (63% due to toxicity). There were no protocol defined LVEF decreases.  In the 86pt subset with HER2+ tumors in EGF30001, the investigator reported ORR was 63% in the L+q3w P and 38% for P+placebo. The safety profile of L+P used qw or q3w is comparable: diarrhoea all grades (56% vs 58%), rash all grades (40% vs 43%), and neurological events all grades (25% vs 26%). Neutropenia (all grades) was more common in the qw schedule of P (44% vs 26%), but the incidence of ≥gr3 was comparable (26% vs 21%, for qw vs 3qw respectively).  Conclusions: L + weekly P as first-line therapy for HER2+ MBC was well tolerated and produced a high, investigator assessed ORR of 77%. These data suggest that the combination of L and P (at any schedule) may be an option for newly diagnosed patients with HER2+ MBC.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3145.
Phase II study of liposomal doxorubicin (Myocet®), docetaxel and trastuzumab combination as first line treatment of patients with her-2/neu positive locally advanced or metastatic breast cancer.
Authors: Amadori D , Gasparini G , Ardizzoni A , Comella G , Saracchini S , Barone C , Bordonaro R , Djazouli K , Barbato A
Published: December 2010

Abstract #3149

Objective: the aims of the study are to assess activity and safety of liposomal doxorubicin (Myocet®) in combination with Docetaxel and Trastuzumab as first-line treatment of patients with HER-2/neu positive MBC.  Methods: forty-six (46) non treated patients with metastatic HER2-overexpressing BC were planned to receive Myocet 50 mg/m2 (d1) and Docetaxel 30 mg/m2 (d2 and d9) plus Trastuzumab (d2, 4 mg/kg followed by 2 mg/kg weekly) for at least 6 cycles (up to a maximum of 8 unless occurrence of unacceptable toxicity or PD). Cycles were repeated every 21 days. Objective response was assessed according to WHO criteria every 3 cycles. To evaluate the tolerability WHO grading toxicity events were assessed at each cycle. Cardiotoxicity was defined as signs and/or symptoms of CHF and/or a decrease in LVEF below normal limit (< 50%) or a decline ≥ 15% from baseline value. To evaluate LVEF an echocardiography was done at baseline and at cycles 3, 6 and 8.  Results: we reported preliminary results of 46 patients enrolled. 41 patients completed at least 3 cycles and at first response evaluation Complete Response was seen in 2 pts (CR=4,9%), Partial Response in 22 pts (PR=53,7%), Stable Disease in 15 pts (SD=36,6%) and Progression Disease in 2 pts (PD=4,9%). The Overall Response Rate (ORR) was 58,6%.  36 pts completed the planned chemotherapy (6 cycles): Complete Response was seen in 4 pts (CR=11,1%), Partial Response in 15 pts (PR=41,7%), Stable Disease in 9 (SD=25,0%) and Progression Disease in 8 pts (PD=22,2%). The Overall Response Rate (ORR) was 52,8%. 12 pts were entered in the follow up and for this subgroup median TTP was 13 months.  All 46 enrolled patients were included in the safety analysis. Most frequent toxicity events occurred during the study were: granulocytopenia Grade 4 in 16 pts (30.4%), leukocytopenia Grade 3 in 15 pts (32.6%), increase of transaminase levels Grade 1 in 14 pts (30.4%), alopecia Grade 4 in 16 pts (34.8%) and nausea Grade 2 in 13 pts (28.3%). In 2 patients LVEF dropped < 50% and other 2 pts registered a decrease of LVEF >15% with respect to baseline value. In the whole population LVEF mean value changed from 62.6 ± 4.9 at baseline to 61.0 ± 5.5 at cycle 3, to 62.9 ± 6.4 (cycle 6) and to 60.0 ± 8.1 (cycle 8).  Conclusion: these preliminary results suggest that the combination of non-pegylated liposomal doxorubicin, docetaxel and trastuzumab has shown a promising activity in first line MBC. The combination is safe with no significant change in LVEF values from baseline to the end of therapy.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3149.
Phase II trial of neoadjuvant 5-fluorouracil, epirubicin and cyclophosphamide (FEC100) followed by weekly paclitaxel and trastuzumab (PH) for HER2 positive breast cancer (Kinki Multidisciplinary Breast Oncology Group; KMBOG-0402).
Authors: Masuda N , Nakayama T , Matsunami N , Kashiwaba M , Kamigaki S , Yamamura J , Anami S , Takeda M , Yasumura Y , Taguchi T
Published: December 2010

Abstract #3160

Background: Achievement of pathological complete response (pCR) by primary systemic chemotherapy (PST) correlates with improved disease-free survival in operable breast cancer patients. Based on data of the higher pCR rate with concomitant chemotherapy and trastuzumab (H) presented by the randomized prospective trial (Buzdar AU, et al: JCO 23:3676-85; 2005), we performed a multi-center, prospective phase II study to assess the addition of H to primary systemic chemotherapy in HER2+ pts in Japan.  Methods: Generally, the concomitant combination therapy with anthracycline-containing regimens and H is not recommended because of the increasing rate of cardiac toxicity. This study was designed to evaluate the efficacy and safety of PST for the operable breast cancer with HER2+ phenotype. PST is the sequential chemotherapy with 4 cycles of FEC100 followed by 12 times in combination with weekly paclitaxel (P) 80mg/m2 and H 2mg/kg (PH x 12).. The inclusion criteria is pts with histopathologically confirmed invasive breast carcinoma, T1-3N+M0/T2-3N0M0, HER2 positive by FISH or immunohistochemistry (IHC) 3+, PS=0-1, adequate hematologic, renal, hepatic and cardiac function and a written informed consent. The study was designed to detect a pCR rate of >43% in at least 42 pts. The evaluation of pathological response was carried out on all the surgical specimens sliced every 5 mm interval.  Results: From Dec 2004 to Dec 2007, 43 pts were enrolled. Pre-reviewed data is now available for all pts: median age 56 [26-75 years]; 15 (35%) pre-menopausal; median clinical tumor size 40 mm [15-80]; 14 (33%) were ER-positive phenotype. All pts had a normal cardiac function before entry and after FEC→PH. No episodes of serious adverse events were reported. Febrile neutropenia was observed on 5 pts (12%). Grade 2 or 3 neuropathy was limited to 4 pts (9%). Other grade 3 non-hematological toxicities were not observed. Two pts requested to stop the treatment with P after 6 times of infusion because of neuropathy, edema and hyperpigmentation on the face, however, they had completed 12 times of H infusion. After PST, breast conservative surgery was done in 38 patients (88%) and mastectomy in 5 (12%). The overall pCR rate was 60% (26/43), and 6 of 26 pts had only component of DICS.  Conclusions: In HER2+ pts, PST with FEC100x4 followed by PHx12 was active and promising, achieving high pathological complete response without significant toxicity.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3160.
Diagnosis of mass forming lesions in combination with real-time tissue elastography.
Authors: Nishiyama Y , Kawagoe A , Sakaguchi U , Nishiyama R
Published: December 2010

Abstract #4013

[Purpose]  Although “hardness” is a characteristic of invasive carcinomas, it was not given much importance until now because of its poor quantitative nature and reproducibility. However, due to the development of real-time tissue elastography (EG), the objective measurement of “hardness” is now possible. Moreover, we examined whether mammography (MMG) + B-mode ultrasound (US) in combination with EG improves diagnosability.  [Subjects and methods]  One hundred and seventy-seven patients with mass-image-forming lesions (135 benign, 42 malignant) whose tissues were diagnosed by core and mammotome biopsies from Oct 2007 to May 2008 were included in the study. Instruments used were Hitachi EUB-8500 and HV-900. The hardness is scored on a scale 1 to 5. Score 1: Distortion appears in the image of the entire low echo tumors, Score 2: Image of most of tumors are distorted but no distortion is seen in certain areas, Score 3: Distortion appears only in the peripheral areas, Score 4: No distortion appears in the entire tumors, and Score 5: No distortion appears even in the peripheral areas. The cases over score 4 are assumed to be malignant. US of category 4 or more, and MMG of category 3 or more were evaluated as malignant.  [Results]  In 57 patients with lesions of less than 1.1 cm (50 benign, 7 malignant), US + MMG showed sensitivity and specificity of 71.4% and 88.0%, respectively, whereas US + MMG + EG showed sensitivity and specificity of 100% and 80.8%. Moreover, when EG was combined with conventional methods, sensitivity increased from 71.4% to 100%. On the other hand, in 120 patients with lesions of 1.1 cm or more (85 benign, 35 malignant), US + MMG showed sensitivity and specificity of 100% and 55.3%, respectively, whereas US + MMG + EG showed sensitivity and specificity of 100% and 61.2%. There were no significant differences in sensitivity and specificity between the 2 methods, and no additional advantages were observed when EG was used.  [Conclusions]  Thus, in this study sensitivity could be increased by EG for tumors with a diameter of less than 1.1 cm. Therefore, it was suggested that biopsy may be omissible for low EG scores.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4013.
Evaluation of response to neoadjuvant chemotherapy in primary breast cancer using PET.
Authors: Choi J , Kim K , Kim W , Lee S , Lim H , Cho E , Han B , Kim Y , Ahn J , Im Y , Lee J , Nam S , Yang J
Published: December 2010

Abstract #4019

Purpose  To estimate the usefulness of PET scan to assess the response of neoadjuvant chemotherapy, PET scan results were compared with conventional imaging modalities(US and MRI).  Patients and Methods  Fourty-one patients undergoing neoadjuvant chemotherapy between December 2004 and March 2008 were included. PET scan was performed before and after chemotherapy. Pathologic results were classified into two groups; pathological complete response(pCR) and non-pCR. Clinical responses were assessed with the results of imaging modalities such as post-chemotherapy size or pSUV(postTx), size difference between treatment(delta) and reduction rate(RR) of size or pSUV, and they are compared with postoperative pathologic results.  Results  7 out of 41 patients (17.1%) had pCR. The results of US shows that postTx size (1.7±1.5cm) of pCR was not dfferent from those of non-pCR (3.6±3.0cm), and the delta (3.1±1.9cm) and RR (67.7±29.1%) of pCR were higher than those of non-pCR (1.3±1.3cm, 31.0±25.4%), respectively. As a result of MRI, postTx size, delta, RR of pCR was differ from those of non-pCR (1.0±1.7cm vs 2.8±1.7cm p<0.05; 4.5±1.0cm vs 2.3±1.8cm, p<0.05; 88.0±20.8% vs 44.6±24.7%, p<0.01). In PET scan, only postTx pSUV of pCR was differ from that of non-pCR (1.4±1.3 vs 5.3±8.3cm, p<0.05). As a result of receiver operating characteristic curve analyses for the prediction of pathological response of breast cancer, area under curve values (95% confidence interval) of US, MRI, PET for delta were 0.83(0.69∼0.98), 0.91(0.80∼1.01), 0.62(0.38∼0.86), and those of RR were 0.80(0.60∼0.99), 0.90(0.77∼1.02), 0.72(0.47∼0.96), respectively  Conclusions  We suggest that MRI is useful method to evaluate the response of neoadjuvant chemotherapy. Although PET scan shows less effective for evaluating the response of chemotherapy than MRI, PET scan with the ability to detect the distant metastatic lesions may be helpful to decide the proper management plans for advanced breast cancer.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4019.
Insulin-like growth factor binding protein-1 (IGFBP-1) targets both the insulin-like growth factor (IGF) and integrin pathways for the inhibition of breast cancer cell motility.
Authors: Ibrahim YH , Hartel J , La Parra K , Yee D
Published: December 2010

Abstract #402

The insulin-like growth factor (IGF) system is a relevant therapeutic target for the treatment of breast cancer. Besides receptor targeted therapies, inhibition of ligand-receptor interactions by IGF-sequestering agents such as IGF binding proteins has also proven efficacious. We have used IGF binding protein (IGFBP-1) to neutralize IGF action. This binding protein both binds IGF-I and binds integrins through a RGD sequence and blocks IGF-I induced proliferation and motility. To examine the functional motifs in IGFBP-1, we studied breast cancer cells and examined IGF-induced signaling and biology after exposure to native recombinant human IGFBP-1 (rhIGFBP-1), reduced rhIGFBP-1, and an RGD mutant (Trp-Gly-Asp, WGD) rhIGFBP-1. Native and WGD IGFBP-1 retained IGF-I binding affinity, whereas reduced IGFBP-1 lost ligand binding as confirmed by western ligand blot. Chronic (>3 hour) 80nM rhIGFBP-1 treatment abrogated paxillin phosphorylation and initiated MAPK activation in an IGF-independent manner, and inhibited basal motility and adhesion to fibronectin. While 80nM native rhIGFBP-1 abolished IGF-induced IRS, PKB/Akt and ERK phosphorylation, 80nM reduced rhIGFBP-1 only inhibited IGF-induced PKB/Akt phosphorylation. rhIGFBP-1 inhibited IGF-induced motility, adhesion to fibronectin and anchorage independent growth at IC50 40-80nM. In contrast, efficacy of reduced IGFBP-1 ranged between 80-160nM. Both the IGF-binding and the integrin-binding mechanisms of action of IGFBP-1 were inhibitory to IGF-induced integrin functions. In contrast, IGF-neutralization (but not integrin effects) was required for the inhibition of biology of breast cancer cells in monolayer. Therefore, this study demonstrates that IGFBP-1 has two distinct functional motifs that contribute to the inhibition of breast cancer basal and IGF-induced functions, and that the integrin and IGF-binding motifs of IGFBP-1 cooperatively inhibit IGF-action.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 402.
Accuracy of breast MRI in predicting tumor extent.
Authors: Yao K , Rachel D , Bova D , Hulvat M , Rychlik K
Published: December 2010

Abstract #4022

Introduction: The use of breast MRI to delineate tumor extent prior to surgical resection is becoming more commonplace. How well breast MRI predicts tumor size and extent compared to standard breast imaging is still under investigation.  Objective: To determine which imaging modality; mammogram (MGM), ultrasound (U/S), or MRI most accurately predicted tumor size and number of tumor foci.  Methods: This was a retrospective review of a prospectively collected database of all breast MRIs performed prior to surgical resection for invasive and noninvasive breast cancer. MGM, U/S, and MRI reports were reviewed and correlated with pathologic tumor size and number of foci.  Results: A total of 89 patients with breast cancer underwent bilateral breast MRI prior to surgical resection. Sixty (67%) of the tumors were ductal carcinomas, 21 (24%) were lobular carcinomas, 7 (7%) ductal carcinoma in situ and 2 (2%) were mixed ductal and lobular. The mean tumor size was 1.5cm (0.1-6.0cm) and 32 (38%) were node positive. Fifty three (60%) of the patients underwent lumpectomy and 36 (40%) underwent mastectomy. Of the three imaging modalities, MGM, U/S, and MRI; MRI predicted tumor size significantly more accurately then MGM or U/S (correlation coefficient 0.59 vs 0.78 vs 0.81 respectively). MRI also predicted the number of foci significantly more accurately then MGM or U/S (correlation coefficient 0.48 vs. 0.44 vs. 0.26 respectively). MRI overestimated tumor size by at least 1cm in 12 (14%) patients and the number of tumor foci in 11(16%) patients.    Thirteen (15%) of the patients benefitted from MRI while 14 (16%) did not.  Conclusions: MRI predicted tumor size and number of foci more accurately then MGM or U/S. Despite these findings, MRI overestimated tumor size and number of tumor foci in a greater percentage of patients then MGM or U/S. More studies are needed to determine the true value of MRI for preoperative surgical planning.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4022.
Magnetic resonance imaging and ultrasonography in predicting pathologic extent after preoperative chemotherapy in stage II-III breast cancer.
Authors: Guarneri V , Pecchi A , Torricelli P , Piacentini F , Frassoldati A , Mauri C , Battista R , Canossi B , D'Amico R , Conte P
Published: December 2010

Abstract #4024

Introduction and aims: the main advantage of preoperative chemotherapy (PCT) is tumor down-staging, that can allow either mastectomy in large, inoperable primaries, or breast conserving surgery (BCS) for patients initially candidate to mastectomy. Therefore, an accurate measurement of residual disease after PCT is critical in the optimal surgical planning. Aim of this study is to evaluate the accuracy of breast magnetic resonance imaging (MRI) and ultrasonography (USG) in predicting the extent of breast residual disease.  Patients and Methods: patients with stage II-III invasive breast tumor receiving PST and imaged with post-treatment MRI, USG or both were included; deltas were calculated as differences between the longest tumor diameter as measured by MRI and USG and the pathologic size of residual breast tumor. Differences between deltas were tested by using T test for paired data.  Results: 45 patients treated with PCT in our Institution were eligible. Patients characteristics were as follows: mean age 50 yrs (range 30-70 yrs); stage IIA 31%, IIB 49%, IIIA-B: 20%. Eighty-nine % of the cases had ductal histology, 69% had ER positivity, and 24% had HER2 over-expression. The mean T size at diagnosis was 3.8 cm (range 1.5-8 cm). PCT type was anthracycline-based (24%) or anthracycline-taxane combination (76%). Forty-four patients have been evaluated after PCT by MRI, 41 by USG, 40 patients by both MRI and USG. The mean T size (range) after PCT was 2 cm (0-6.5 cm) and 1.7 cm (0-5 cm) as measured by MRI and USG respectively. The mean interval between breast imaging and surgery was 20 days (range 1-63). Type of surgery was mastectomy in 45% and BCS in 55% of the cases; 6 patients (13%) achieved a pathologic complete response (pCR). The mean pathologic T size was 1.98 cm (range 0-6 cm). The mean of the deltas were 0.04 (SD 1.91) and -0.19 (SD 1.53) for MRI and USG respectively (p=0.22). A complete response by MRI was observed in 9 cases: 3 cases were confirmed as pCRs; 2 cases presented with scattered microscopic residual disease. An USG complete response was observed in 8 cases (4 confirmed pCRs).  Conclusion: in this series of patients, MRI and USG do not show significant differences in predicting the breast residual tumor after PCT. The major challenge for breast imaging after PCT is represented by scattered residual disease.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4024.
Apocrine carcinoma of the breast: clinical presentations, multimodality imaging findings and pathologic correlation.
Authors: Woo O , Kim A , Cho K , Seo B , Kang E
Published: December 2010

Abstract #4029

Background :   Apocrine carcinoma (AC) of the breast is a rare malignant tumor and is lack of standardized criteria for the diagnosis. Thus clinicopathological features and radiologic findings have not been determined. We retrospectively analyzed the clinical presentation and the multimodality imaging findings of mammography, ultrasography and MRI and correlated with pathologic results.  Materials and Methods :   We retrospectively examined data on 850 patients who had been surgically treated for primary breast carcinoma between 2003 and 2008. Among them, there were 10 cases with the diagnosis of apocrine carcinoma.  Ten patients underwent mammography and ultrasonography and six patients underwent MR imaging. Eight patients underwent pre-operative US-guided core needle biopsy. We analyzed the radiologic findings and pathologic results.  Results :   The present study showed that the frequency of apocrine carcinoma was 1.2%. Almost all patients were symptomatic and painless lump was the most common complaint. Patient ranged in age from 38 to 62 year (mean, 50.5 years). The mean lesion size was 1.9cm (range, 1.1-3.5cm).  Common imaging features were as follows: mass or focal asymmetry without microcalcifications (n=7), mass with microcalcifications (n=3) on mammography; a mass with an round to irregular shape (n=9), indistinct-margin(n=8) on ultrasonography. On six dynamic contrast-enhanced MRI, enhancing masses in 3, mass with spotty nodular enhancement adjacent to the tumor in 3, which showed rapid enhancement and delayed washout pattern in five cases and plateau enhancement pattern in one case. Specifically, 3 patients had unilateral multifocal cancer. Two patients showed ipsilateral axillary lymphadenopathy.  Pathologic examination revealed AC (n=3), AC with apocrine carcinoma in situ (n=3), apocrine carcinoma in situ (n=1) and, AC with intraductal component and EIC positivity (n=3). Mass with spotty nodular enhancement on MRI was correlated with intraductal component and EIC positivity.  Conclusion :   The radiologic findings of apocrine carcinoma of the breast are not specific. Occasionally, apocrine carcinoma shows mass with spotty nodular enhancement adjacent to the tumor on MRI and this finding is correlated with intraductal component and EIC positivity.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4029.
Notch-1 expression is not related to the percentage of CD326+ cells in bone marrow aspirates of patients with primary breast cancer.
Authors: Lee B , Li C , Lucci A , Cohen EN , Gao H , Krishnamurthy S , Ueno NT , Hortobagyi GN , Cristofanilli M , Woodward WA , Reuben JM
Published: December 2010

Abstract #4030

Background: The presence of epithelial cells (CD326+CD45dim) in the bone marrow (BM), i.e. disseminated tumor cells (DTC), are related to poor prognosis of primary breast cancer (PBC). Notch signaling pathway is involved in the development of the breast and aberrant activation of Notch signaling is an early event in breast cancer. Others have shown that breast cancer stem cells (BCSC) with the putative phenotype of CD44+CD24- can be identified within cell lines and primary tumor and have upregulated genes including Notch-1. However, it is unclear if Notch-1 is highly expressed by DTC and BCSC in BM of patients with PBC. We hypothesized that the Notch-1 expression is correlated with the level of BCSC within DTC. In this study, we enumerated BCSC in DTC-enriched populations in patients with PBC and assessed the expression of Notch-1 by RT-PCR.  Methods and Patients: As part of an ongoing prospective study, from September 2006 to May 2008, 121 BM aspirates were collected from as many patients with PBC. Thirty-seven patients, median age of 52 years (range, 30-76 years), provided BM aspirates under anesthesia at time of surgery. At the time of BM collection, 9 patients had received neoadjuvant therapy. BM mononuclear cells (BMC) were enriched for DTC using anti-CD326 antibody-coated magnetic beads, and isolated using the AutoMACS-Pro cell separator system. DTC and BCSC were identified by multi-color FACS analysis. Thereafter, DTC-enriched cell preparations were analyzed for expression of ER, PR, HER-2, Notch-1, and Numb by RT-PCR; level of each transcript was normalized to a ratio to the house keeping gene GAPDH.  Results: The mean ± SEM DTC in BMC was 1.05 % ± 0.09% and the majority was BCSC (79.7% ± 1.87%). The proportion of DTC-enriched fractions that expressed Notch-1, Numb, ER, PR, and HER-2 transcripts was 27/37 (73.0%), 33/37 (89.2%), 24/37 (64.9%), 15/37 (40.5%), and 20/37 (54.1%), respectively. The expression of Notch-1, Numb, ER, PR, and HER-2 transcripts did not correlate with the percentage of DTC. Contrary to our hypothesis, Notch-1 and Numb mRNA expression in DTC-enriched cells negatively correlated with the percentage of BCSC (Spearman's rho = -0.384, p= 0.027; and rho= -0.347, p= 0.048, respectively).  Conclusions: Our results show no correlation between the level of Notch-1 expression and the percentage of BCSC in DTC-enriched populations in BM of patients with PBC. Since these studies were conducted in CD326-enriched populations, it underscores the necessity to further purify the CD44+CD24- cells and conduct studies in isolated single cells to definitively delineate the gene expression of BCSC from patients with PBC.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4030.
The insulin-like growth factor receptor I status in luminal A breast carcinoma.
Authors: Ben Hamida A , Sircoulomb F , Beckhouche I , Chaffanet M , Bertucci F , Birnbaum D , Jacquemier J
Published: December 2010

Abstract #4034

Background: The IGF-IR overexpression is reported to be detectable in 43-50% of primary breast cancers, its clinical and prognostic significance remains undetermined. Insulin growth factor type I (IGF-IR) is induced by estrogens in estrogens receptor (ER) positive cells that could explain why the IGF-IR overexpression is strongly related to ER positive breast cancer. However a small proportion of ER/PR negative cases overexpressed IGF-IR. The aim of this study was to correlate IGF-IR status by three techniques on a series of breast carcinomas : DNA microarrays ,CGH arrays and Immunohistochemistry.  Material and Methods: Immunohistochemical phenotypes were studied in a series of 72 cases of breast carcinoma (40 basal and 32 luminal A). A series of 13 Markers was also studied IGF-IR, ER, PR, AR441, bcl2, FoxA1, Ki67, Gata3, P53, EGFR, ERBB2, CAV1 and MS110(BRCA1). Gene expression profiling with DNA microarrays (Affymetrix) and 244k CGH microarray was done on the same cases.  Results: The IGF-IR expression was observed in IHC in 61% of the cases, overexpression in 25% and Gain or amplification in 7% .The IHC IGF-IR positivity was strongly correlated to the IGF-IR expression ( R=0.28 p<0.016) and IGF-IR DNA status (R=0.53 p= 5.610-6 ). IGF-IR over-expression in DNA microarrays is the only one results to be strongly associated to the luminal A subtype : 15/18 of the over expressed cases p=1.56 e-7. However the IHC expression of the ER related biomarkers is significantly associated to the IGF-IR overexpression.    Discussion: The IGF-IR overexpression is representative of the Luminal A subtype, and to the ER regulated gene in IHC. Exploration of a panel of IGF-IR antibody is mandated before to best evaluate this target gene in IHC, who could contribute to the hormonal response.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4034.