bluuebunny/crossref_metadata_2025 huggingface dataset:
Baseline serum extracellular domain HER2 expression in hormone receptor-positive metastatic breast cancer: correlation with known tissue HER2 status.
Authors: Johnston S , O'Rouke L , Wang W , Pegram M , Press MF , Maltzman J
Published: December 2010

Abstract #3147

Background: The extracellular domain (ECD) of the HER2 protein is cleaved by metalloproteases and shed into the serum. Serum ECD (sECD) HER2 can be detected by ELISA and may have prognostic/predictive associations in patients (pts) with breast cancer. Although use of sECD HER2 as a surrogate for HER2 overexpression in hormone receptor-positive (HR+) metastatic breast cancer (MBC) is controversial, seroconversion can occur at disease relapse and may reflect a change in tumor HER2 status that is associated with a poorer prognosis. EGF30008 is a double-blind, placebo-controlled, first-line, phase III trial of letrozole with/without lapatinib in 1,286 postmenopausal women with HR+ MBC. We report baseline sECD HER2 at study entry on all pts and the association with original tumor HER2 status.  Methods: Serum samples were collected at study entry and every 4 weeks on study, including at disease progression. Patients were defined as sECD HER2+ if baseline sECD HER2 was ≥15 ng/mL. HER2 status was evaluated in tumor tissue by both immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), using conventional cutoffs. To assess the correlation between baseline sECD HER2 and tumor tissue HER2 status, odds ratios (OR) with 95% confidence intervals (CI) and sensitivity/specificity (tumor tissue HER2 status as standard) were calculated. Data were from a blinded cutoff on 12May08. These analyses will be repeated after the database is finalized and unblinded.  Results: Mean age was 63 ± 9.8 years. All pts had a HR+ original tumor, and 217 (17%) pts were confirmed as HER2+ by IHC or FISH. Median time from primary diagnosis to MBC was  3.3 years (range 0 - 33.9 yrs). Baseline sECD HER2 levels ranged from 2.5 to > 560 ng/mL (mean 21 ± 60 ng/mL) with a bimodal distribution consistent with previously published data. The mean was 62 ng/mL (range 2.8 to > 560 ng/mL) for HER2+ pts and 12 ng/mL (range 2.5 to 113.1 ng/mL) for HER2-negative pts. The OR between sECD HER2 at study entry and HER2 status of the original tumor was 4.5 (95% CI: 3.2, 6.2) with 42% sensitivity and 86% specificity.  Conclusions: This OR suggests some correlation exists between baseline sECD HER2 and original tumor HER2 status. We cannot assess the rate of seroconversion that may have occurred from primary diagnosis until MBC at study entry. The bimodal distribution suggests that a clear cohort of pts exists at the time of relapse/study entry who are positive for sECD HER2. Analyses are evaluating whether subsequent changes in sECD HER2 levels occur over time during therapy, whether seroconversion predicts for a shorter time to relapse during letrozole monotherapy, and whether any differences exist in sECD HER2 levels over time for pts treated with letrozole plus lapatinib are ongoing.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3147.
Trastuzumab 6 mg/kg and 4 mg/kg can be infused safely over 30 minutes.
Authors: Chan AS , Freeswick S , Sklarin NT
Published: December 2010

Abstract #3150

Background: Trastuzumab (T) is a humanized monoclonal antibody used in the treatment of breast cancers which overexpress the HER2 protein. Infusion-related hypersensitivity reactions (HSRs) have been reported in patients receiving T. Since T became commercially available in 1998, Memorial Sloan-Kettering Cancer Center (MSKCC) guidelines recommended that 4 and 6 mg/kg doses be infused over 90 minutes, as outlined in the product monograph. Based on more recent pharmacokinetic data of T and the experience at other institutions, it was postulated that a more rapid infusion of T would be well tolerated, even at doses greater than 2 mg/kg. As a result, in June 2007, the guideline at MSKCC was revised to infuse initial loading doses (8, 6 or 4 mg/kg) over 90 minutes and, if tolerated, all subsequent maintenance doses of 2, 4, and 6 mg/kg over 30 minutes. In this review, we sought to evaluate the safety and tolerability of T administered as a 30 minutes infusion.  Methods: Our institutional adverse drug reaction (ADR) reporting program was used to identify HSRs possibly related to T after implementation of the new infusion time guidelines. Computerized pharmacy records were used to retrospectively identify all patients who received T at MSKCC 1 year prior to implementation of new guideline (6/06 – 5/07), as well as the period of 10 months after the implementation of the revised guideline (7/07 - 4/08). The ADRs reported before and after implementation were reviewed and compared. Additionally, patient medication administration records were reviewed to confirm reactions reported via the ADR reporting program.    Results: Of the 2,633 4 and 6 mg/kg maintenance doses administered over 30 minutes, 2451 were given without concurrent administration of diphenhydramine, dexamethasone, or acetaminophen. 165 doses were escalated from 2 to 4 or 6 mg/kg and the infusion rate was kept at 30 minutes. The 2 patients with loading dose-associated HSRs, that occurred after the change in the guideline, were able to tolerate subsequent doses of T (4 and 6 mg/kg) infused over 30 minutes when rechallenged.  Conclusion: Trastuzumab can be safely infused over 30 minutes for 4 and 6 mg/kg maintenance doses and this is the current practice at our institution. This change has resulted in improved efficiency and patient convenience, and decreased cost associated with the longer duration infusions.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3150.
Multicenter international phase II study of oral vinorelbine (NVBo), capecitabine (X) and trastuzumab (H) triple combination in HER2-positive metastatic breast cancer (MBC): updated results with a longer follow-up.
Authors: Chan A , Ganju V , Becquart D , Conte P , Petruzelka L , Gil-Gil M , Morand M , Vaissiere N , Villanova G , Tubiana-Mathieu N
Published: December 2010

Abstract #3151

Background: CT plus H is the standard treatment for HER2-positive MBC. Combination therapy of H plus vinorelbine is an active and safe regimen in this setting. The all-oral combination of NVBo and X has been reported as an active and safe regimen in many different trials in MBC. We report efficacy and safety information from an updated analysis of all 50 patients (pts) included in this trial, with a median follow-up of 28.5 months.  Methods: Main eligibility criteria included: HER2-positive disease (defined as IHC 3+ or FISH+), documented measurable metastatic disease previously untreated by CT, relapse ≥ 6 months after the end of neoadjuvant or adjuvant CT, Karnofsky PS ≥ 70. NVBo was given as at a dose of 80 mg/m2 (after a first cycle at 60) D1 and D8 every 3 weeks, X at 1000 (750 if ≥ 65 years) mg/m2 bid D1-D14 every 3 weeks, H at 4 mg/kg on D1 as a loading dose then 2 mg/kg i.v. weekly starting on D8. Treatment was continued until progression.  Results: Median age: 53.5years (18% ≥ 65); prior (neo)adjuvant CT 27 pts (54%); visceral involvement 41 pts (82%), > 2 metastatic sites 17 pts (34%); Median number of cycles: 10 (range 1-56); Median relative dose intensity: NVBo 75%, X 77%, H 96%; NVBo escalated to the recommended dose of 80 mg/m2 in 84% of pts; G3/4 NCI CTC v2 adverse events per pt: (n=49) neutropenia 69%, (n=50) febrile neutropenia 8%, infection without neutropenia 4%, stomatitis 4%, nausea 4%, vomiting 12%, diarrhea 16%, hand-foot syndrome 20%, asthenia 8%, LVEF decline 6%, alopecia (grade 2) 14%; Efficacy (n=44 evaluable patients): objective response rate (RECIST) 77% (95% CI [62-89]), CR 18%, PR 59%, SD 18%, PD 5%, disease control (CR+PR+ SD ≥6 months) 93% (95% CI [81-99]), median duration of response was 14.3 months (95% CI [9.8-16.8]), median progression-free survival was 12.8 months (95% CI [10.8-16.9]), overall survival results are not mature yet. Treatment is ongoing in 5 pts.  Conclusion: The combination of NVBo and X + H has shown high antitumoral efficacy in pts with HER2-positive MBC. Toxicity profile was acceptable with, in particular, a very low rate of alopecia. An efficacy and safety analysis in pts aged < vs ≥ 65 years will be performed and presented.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3151.
HER2 and HER3 cooperatively regulate tumor cell growth and determine sensitivity to the HER kinase inhibitor TAK-285.
Authors: Takagi S , Hayashi A , Ohta Y
Published: December 2010

Abstract #3155

Background: The HER (ErbB) receptor family plays a major role in the proliferation of tumor cells. Overexpression of these receptors occurs in breast and a variety of cancers and correlates with poor prognosis. We have identified TAK-285, a potent, selective and orally bioavailable small molecule inhibitor of HER kinases. TAK-285, which is currently in clinical trials for the treatment of solid tumors, inhibits EGFR (also known as ErbB1 or HER1) and HER2 (also known as ErbB2) and exerts clear anti-proliferative activity in in vitro and in vivo tumor models. Here, we elucidated the determinants of TAK-285 anti-tumor activity in vitro in a panel of human cancer cell lines.  Methods: Cell growth inhibition assay was performed using sulforodamine B staining method or CellTiter-GloTM assay (Promega). Candidate gene expressions were measured by quantitative PCR. Associations between the IC50 values and the candidate gene expressions were statistically analysed.  Results: TAK-285 exerted anti-proliferative effects in all of cell lines tested in a dose dependent manner but the effects ranged widely (IC50: 0.011-over 10 µmol/L). Statistical analysis showed an inverse correlation between sensitivity to TAK-285 (IC50 values) and HER2 or HER3 (also known as ErbB3) gene expression. PTEN or IGF-1R gene expression, reported to be involved in trastuzumab resistance, was not correlated with TAK-285 sensitivity. Immunoblot analysis revealed that HER2 and HER3 are coexpressed in most TAK-285 sensitive cells and TAK-285 inhibited phosphorylation of HER3. Because HER3 does not possess kinase activity, this suggests that HER3 is trans-phosphorylated by HER2. Knockdown of HER3 using siRNA inhibited tumor cell growth in TAK-285 sensitive cells but not in TAK-285 insensitive cells.  Conclusion: These results suggest that HER2 and HER3 mainly regulate tumor cell growth in TAK-285 sensitive cells and could be used as a molecular marker to select patients who are likely to respond to TAK-285.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3155.
A multicenter phase II study of non-pegylated liposomal doxorubicin (MYOCET®) in combination with trastuzumab and docetaxel as first line therapy in metastatic breast cancer.
Authors: Vanturini M , Bighin C , Puglisi F , Contu A , Aitini E , Colucci G , Merlano MC , Paccagnella A , Marini G , Crinò L , Djazouli K , Barbato A
Published: December 2010

Abstract #3156

The objective of the phase II study is to evaluate the cardiotoxicity, general safety, and efficacy of non-pegylated liposomal doxorubicin, in combination with docetaxel and trastuzumab, as first line treatment of metastatic breast cancer.  Patients and methods: Patients (n = 31) with metastatic HER2-overexpressing breast cancer, who had not previously received chemotherapy for metastatic disease, received non-pegylated liposomal doxorubicin (50 mg/m2), docetaxel (75 mg/m2) every 3 weeks and trastuzumab (2 mg/kg/week) for up to eight cycles, followed by trastuzumab alone for up to 52 weeks. Cardiotoxicity was defined as signs and/or symptoms of congestive heart failure (CHF) and/or an absolute decrease in left ventricular ejection fraction (LVEF) of ≥ 20 units or a decline to ≤ 45%. Patients were allowed to receive adjuvant doxorubicin or epirubicin to cumulative doses up to 240 mg/m2 or 450 mg/m2, respectively.  Results: The mean LVEF at baseline was 62.8 ± 7.1% and decreased to 60.2 ± 6.5% at cycle 2, but did not change significantly during the rest of the study; mean values at cycle 8 and at the end of the study were 58.7 ± 7.0% and 57.3 ± 9.5% respectively. One case of symptomatic CHF occurred during the study.  The most common adverse events were hematologic toxicities, alopecia, asthenia and fever. The Overall Response Rate was 65.5% (CR 31%, PR 34.5%).The median progression free survival was 15.5 months (95% CI 11-24 months). The average overall survival was 27.9 months.Conclusions: These results suggest that the combination of non-pegylated liposomal doxorubicin, docetaxel and trastuzumab has shown a good cardiac safety profile at a long term follow up, comparatively to recent published results data in HET study. A promising efficacy including CR and PFS has been noted in 1st line MBC.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3156.
HER2 positive early breast cancers: tumour demographics and trastuzumab therapy in the real-world.
Authors: Marla S , Roxburgh P , Burton P , Stallard S , Mallon E , Canney P , Cooke T
Published: December 2010

Abstract #3159

Background: Various trials have shown substantial benefits of addition of Trastuzumab (Herceptin®) to adjuvant chemotherapy in Early Breast Cancer (EBC). We analysed our breast cancer population to determine the incidence of HER2 positive Early Breast Cancers, the tumour demographics and the number of patients eligible for and receiving trastuzumab therapy in this group.  Methods: Data for all patients diagnosed with EBC in 2006 was recorded prospectively in a database. Case notes were consulted where the HER2 positive patients, determined by a combination of IHC and FISH, had not received trastuzumab, to ascertain the reasons.  Results: A total of 951 patients were diagnosed with Breast Cancer in 2006. 417 (43.9%) of these were screen-detected cancers.  There were 123 (12.9%) HER2 positive newly diagnosed Breast Cancers of whom 117 were EBCs. The HER2 positivity rate in the screen detected cancers (n=417) was 9% and 17% in the symptomatic cancers (n=433).  1. Demographics of the HER2 positive Early Breast Cancer Population:  The median age at diagnosis was 61 yrs (range: 30-92).    2. Fifty nine (50.4%) of the HER2 positive EBCs received trastuzumab therapy.    Conclusions: The HER2 positivity rate is lower than that previously reported suggestive of changing demographics secondary to a high screen detected cancer population. A third of the HER2 positive tumours are screen detected. The percentage of ER positive, node negative and low grade tumours was higher than anticipated.  Only 50% of HER 2 positive EBC patients received trastuzumab therapy. Of those who did not receive trastuzumab, the commonest reason was low risk status or age and co-morbidities precluded chemotherapy.  HER 2 positivity alone confers high risk irrespective of pathological stage. Further trials are required to evaluate whether the substantial number of patients who are at present not eligible for trastuzumab therapy might also benefit.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3159.
HER2 protein expression predicts response to trastuzumab in FISH-positive patients.
Authors: Lipton A , Ali SM , Leitzel K , Koestler W , Fuchs E , Weidler J , Wu E , Sperinde J , Chappey C , Huang W , Bates M
Published: December 2010

Abstract #32

BACKGROUND: Fluorescent in Situ Hybridization (FISH) is currently employed to select patients for trastuzumab or lapatinib therapy. However, only a portion of patients will respond to these HER2-directed therapies. Using a novel assay to quantitate total HER2 (H2T) and HER2 homodimer (H2D) levels, we examined the relationship between these measurements and clinical outcomes in a cohort of trastuzumab-treated metastatic breast cancer patients previously assessed as FISH positive by central testing.  METHODS: The VeraTag assay was used to measure H2T and H2D. A cutoff previously defined by positional scanning was used to classify patients as H2T high or low (Leitzel et al. ASCO abstract # 1002, 2008). FISH status was determined using the Vysis assay and was performed by a single pathologist under standardized conditions (central testing). FISH + was defined as HER2/CEP17 ratio greater than 2.2. Kaplan-Meier and Cox proportional hazards analyses (TTP and OS) were conducted.  RESULTS: 99 MBC patients previously scored as IHC 3+ or 2+, FISH+ and treated with first line trastuzumab-containing regimens were re-tested by central FISH. 22 patients were found to be FISH- and 77 were FISH+. 67 FISH+ patients had high H2T levels, and 19 FISH- patients were H2T low. 14% (3/22) of FISH- patients were H2T high, and 13% (10/77) of FISH+ patients were H2T low (overall discordance rate = 13%). In Kaplan Meier analyses, patients assessed as FISH+, H2T high had a significantly longer TTP (median TTP=11.3 mos.) compared to those who were FISH-, H2T low (median TTP=4.5 mos. HR=0.42, p=0.0006), and also compared to those who were FISH+, H2T low (median TTP=3.7 mos. HR=0.43, p=0.01). Those patients who had discordant results (FISH+, but H2T low) behaved similarly compared with FISH-, H2T low (HR=1, p=0.99). Similar results were observed using H2D. In analyses restricted to central FISH+ patients only (N=77), Cox proportional hazards multivariate regression identified H2T as an independent predictor of TTP (HR=0.29, p=0.0015) and OS (HR=0.37, p=0.02).  CONCLUSION: In metastatic breast cancer patients previously assessed as FISH-positive by central testing, we observed an approximate 55-fold distribution of HER2 protein expression. Patients with HER2 gene amplification by FISH but low HER2 total protein expression or homodimer levels as measured by the VeraTag assay respond poorly to trastuzumab-containing therapy.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 32.
PI3 kinase activation and response to trastuzumab or lapatinib in HER-2 overexpressing locally advanced breast cancer (LABC).
Authors: Migliaccio I , Gutierrez M , Wu M , Wong H , Pavlick A , Hilsenbeck SG , Horlings HM , Rimawi M , Berns K , Bernards R , Osborne C , Arteaga CL , Chang JC
Published: December 2010

Abstract #34

Background: Activating mutations of PI3 kinase (PIK3CA) and PTEN loss may be associated with trastuzumab resistance. Trastuzumab, a HER2 humanized monoclonal antibody, and lapatinib, an EGFR/HER2 tyrosine kinase inhibitor are both established treatments. Greater understanding of the cellular response to trastuzumab or lapatinib is needed to tailor targeted therapy for individual patients and identify those less likely to benefit. Material and Methods: We performed two sequential neoadjuvant clinical trials in HER-2 overexpressing LABC: 40 patients received weekly trastuzumab at standard doses given initially as a single agent for the first 3 weeks, then in combination with 3-weekly docetaxel for 12 weeks (T), while 49 patients received lapatinib as a single agent (1,500 mg daily, orally) for 6weeks then the combination of 3-weekly trastuzumab/docetaxel for 12 weeks, before primary surgery (L). Sequential core biopsies of the primary breast tumors were taken at initial, weeks 1 and 3 after the first dose of trastuzumab, and at initial, weeks 2, 4, and 6 after lapatinib. Apoptosis, Ki67 proliferation rate, and PTEN were assessed by immunohistochemistry. Low PTEN was defined as Allred score of <3. Genomic DNA (10-100ng) was sequenced using the BigDye Terminator Cycle Sequencing Kit (Applied Biosystems) and an ABI 3730 automated capillary sequencer. Two sample and paired sample comparisons were performed using nonparametric tests. Results: There was a significant decrease in clinical tumor size after three weeks of trastuzumab (n=35, median=-20%), and six weeks of lapatinib (n=49, median=-74%) compared to pre-therapy (p<0.001). At surgery, pathologic complete response was observed in 38% in patients on upfront T and 70% patient on L. There was a significant increase in apoptosis (median=3.5% to 4.7%, p=0.006) within one week after trastuzumab, with no significant change in Ki67 at any of the time point. Lapatinib was associated with a no significant increase in apoptosis but a significant decrease in Ki67 at week 2, 4, and 6 of therapy (p<0.001). Cases with low PTEN or PIK3CA mutations were significantly less likely to have a pathologic complete response to T (p<0.005). Howver, low PTEN or PIK3CA mutations was not significantly associated with pathologic resistance to L. Conclusions: Activation of PI3 kinase pathway is associated with trastuzumab but not lapatinib resistance. Lapatinib may affect signalling through the Ras/Raf/MAPK/ERK pathway, inhibiting cell division. Low PTEN expression was not associated with lapatinib resistance, and may explain the clinical efficacy of lapatinib in trastuzumab-resistant patients, supporting clinical trials for the combination of both agents.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 34.
Transforming growth factor beta engages TACE/ADAM17 and ErbB3 to activate PI3K/Akt in HER2-overexpressing breast cancer and desensitizes cells to trastuzumab.
Authors: Wang E , Xiang B , Olivares MG , Chung C , Arteaga CL
Published: December 2010

Abstract #35

TGFb signaling synergizes with HER2 in breast cancer progression. Exogenous TGFb or expression of an activated TGFb type I receptor (Alk5T204D) in MCF10A/HER2 and BT474 cells activated PI3K/Akt and enhanced survival and migration. In both cell types, TGFb stimulated P-EGFR and P-HER2 as well as the association of p85, the regulatory subunit of PI3K, with Y1289 P-ErbB3 which, in turn, activated PI3K/Akt. RNA interference of ErbB3 or treatment with pertuzumab, an antibody that blocks HER2-mediated activation of ErbB3, blocked TGFb-induced P-ErbB3, P-Akt, and cell motility. Treatment with TGFb or expression of Alk5TD increased protein levels of secreted TGFalpha, amphiregulin, and heregulin without a change in mRNA levels. The increase on secreted ErbB ligands without a change in mRNA levels suggested increased shedding of ErbB pro-ligands by tumor necrosis factor a-converting enzyme (TACE). Transfection of siRNA against human TACE but not control siRNA abrogated TGFb-stimulated ErbB receptor phosphorylation, P-Akt, and cell invasiveness. Transfection of full-length mouse TACE but not truncated TACE lacking the cytoplasmic domain reconstituted TGFb-induced ErbB phosphorylation in cells transfected with human TACE siRNA. TGF-b increased TACE phosphorylation in both serine and threonine as measured by P-Ser and P-Thr immunoblots of TACE pull downs. Incubation of TACE with Alk5TD in the presence of ATP in vitro resulted in both Ser and Thr phosphorylation in full-length but not truncated TACE. Further, addition of TGFb or expression of Alk5TD desensitized SKBR3 and BT474 cells to trastuzumab. Treatment with the type I TGFb receptor (Alk5) small molecule inhibitor LY2109761, the PI3K inhibitor LY294002, or siRNA against ErbB3 or TACE restored the inhibitory effect of trastuzumab. Finally, we generated an active Alk5 expression signature by selecting genes that were differentially expressed between BT474/Alk5TD and BT474/vector cells. Mapping of this signature to a previously published 295-breast tumor array (van de Vijver et al. and Chang et al.) revealed 90 of 271 genes in the Alk5TD signature with a >1.5-fold change from the median expression which correlated with HER2-positive and basal-like tumors and conferred a worse recurrence-free (RFS) and overall survival (OS) (RFS p=0.05, OS p=0.01). Hierarchical clustering analysis to an array data set reported by Harris et al. in 22 patients with HER2+ breast cancer treated with neoadjuvant trastuzumab and vinorelbine (Clin. Cancer Res. 2007) showed that the Alk5TD signature correlated with tumors that did not respond clinically. These data suggest that TGFb potentiates signaling downstream ErbB receptors via TACE, ErbB3, and PI3K, thus contributing to tumor progression and resistance to anti-HER2 therapies.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 35.
The role of real-time virtual sonography in the management of enhancing breast lesions on contrast-enhanced MRI.
Authors: Nakano S , Fujii K , Yorozuya K , Mouri Y , Fukutomi T , Ishiguchi T , Arai O , Mitake T
Published: December 2010

Abstract #4001

[Purpose]  The aim of this study was to evaluate the role of real-time virtual sonography (RVS) in the management of enhancing breast lesions visualized with contrast-enhanced MRI.  [Materials]  Between April 2006 and May 2008, 92 women underwent breast MRI at our hospital. Of these 92 patients, 55 underwent MRI for staging of known breast cancer, and the remaining 37 underwent MRI for problem solving, including abnormal findings at physical examination or on conventional images. All patients were examined using mammography, sonography, MRI and RVS. The RVS system is capable of superimposing a sonography image with the MRI image of the same section in real time using a position tracking system with a magnetic sensor. Breast MR images were obtained on a 1.5-T imager using a flexible body surface coil, with the patient in the supine position.  [Results]  Overall sensitivity for detecting primary breast cancer was 74% (43/58) for mammography, 93% (54/58) for sonography, 97% (56/58) for MRI, and 97% (56/58) for RVS. Incidental enhancing / suspicious lesions (IELs) which were not predicted by the previous conventional imaging techniques were found in 55% of the patients (51/92),. Of these, 59% (24/41) of IELs could be identified only on repeated sonography, but 85% (35/41) of them were identified easily using the RVS system (p<0.05). The RVS system was able to project enhanced MRI information onto a body surface correctly while checking sonography form images without the use of large-scale equipment. Histologically, 10% (4/41) of the IELs were invasive ductal carcinoma.  [Conclusions]  The present results suggest that the RVS system offers excellent accuracy for identification of enhancing breast lesions. RVS can accurately select the cases in which MR guided biopsies are required.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4001.
Accuracy of MRI in selecting patients for breast conserving therapy after neoadjuvant chemotherapy.
Authors: Straver ME , Loo CE , Vrancken-Peeters MT , Rutgers EJ , Gilhuijs K
Published: December 2010

Abstract #4006

Introduction: Accurate assessment of the extent of residual breast cancer is crucial for the surgical planning after neoadjuvant chemotherapy (NAC). Compared to conventional imaging, MRI shows superior ability to monitor tumor response. Nonetheless, controversy exists about the precision of MRI to visualize disease extent after NAC. The aim of this study was to determine which variables influence the accuracy of MRI.  Methods: Retrospective analysis of 130 patients treated with NAC. Contrast-enhanced MRI studies were performed on a 1.5-T scanner with a dedicated breast coil before, during and after NAC. The outcome parameters were the accuracy of the estimation of tumor size on final MRI and the accuracy in predicting the ability to perform breast conserving therapy (BCT). Tumor size on the final MRI was therefore compared to residual tumor size on pathology. Discrepancy <10 mm between MRI and pathology was defined as correct prediction. Patients with a tumor size <30 mm on MRI were considered indicative for BCT. The MRI indication for BCT was compared with the surgical treatment feasible based on size on pathology.  Results: In 61/130 patients (47%) the difference between size on MRI and size on pathology was >10 mm. In 50% (n=32) this discrepancy between pathology and MRI would lead to different surgical treatment. Based on the MRI indication for BCT, 19 patients would have unjustly undergone BCT (disease extent at MRI <30 mm and disease extent at pathology >30 mm). In 13 patients MRI alone would have led to mastectomy (extent >30 mm) while the actual extent at pathology was <30 mm. Thus, MRI accurately indicated selection of surgical treatment in 98 patients (75%). Inaccurate indication (25%) was caused by underestimation as well as overestimation of disease extent. Variables significantly influencing the accuracy of MRI were type of lesion on baseline MRI, pattern of tumor decline, histological and molecular subtype.    Conclusions: The results show the strengths and limitations in monitoring tumor response with MRI. For preoperative assessment the final MRI should be evaluated with the knowledge of the baseline MRI and the molecular and histological subtype.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4006.
Comparative analysis of high resolution synchrotron radiation images of fibrocystic change and breast cancer.
Authors: Park SH , Lee JH , Bong JG , Kim JG , Kim KH , Sang HJ , Youn HS
Published: December 2010

Abstract #4009

Background: Synchrotron radiation imaging enables us to observe detailed microscopic structures of a biologic sample without staining. If synchrotron imaging can reveal microstructures of breast tissues with various pathologic conditions effectively, this may be used for clinical purposes related to diagnosis and treatment of breast diseases. We attempted to get high resolution x-ray microscopic images of human breast tissues of fibrocystic change and breast cancer using zone plates and phase contrast technique, and compared distinctive features of breast tissues of these conditions seen in synchrotron images.  Material and Methods: X-ray microscopic images were obtained from the Beam line 1B2 of Pohang Light Source, the third generation synchrotron radiation facility with operating energy of 2.5 GeV at Pohang, South Korea. The x-ray was set at 11.1 KeV, and the beam was monochromatized by W/B4C monochromator. The condenser and microscopic objective zone plates were used as x-ray lenses. Formalin-fixed 10 μm thick human breast tissues were attached on Kapton film, and positioned 25 m away from the beam source. Zernike phase plate next to the condenser zone plate was applied for phase contrast imaging. The magnified x-ray image was converted into a visual image on the CsI(TI) scintillation crystal and captured by a full frame CCD camera. The obtained synchrotron images of fibrocystic change and breast cancer tissues were analyzed and compared to one another.  Results: High resolution x-ray microscopic images of fibrocystic change and breast cancer tissues with a spatial resolution of 60 nm were obtained. The synchrotron images of fibrocystic change showed a harmonious framework of breast tissues with profuse glandular structures and various collagen strands. However, the synchrotron images of breast cancer tissues revealed altered breast parenchyma with architectural distortion and extensive fibrosis. The collagen strands were thickened, interrupted and irregularly oriented. The glandular elements and ductal structures were atrophic or lost.  Discussion: The synchrotron images of breast cancer reveal severe alteration of breast parenchyma, collagen strands and glandular structures, compared to those of fibrocystic change. These changes are important features of breast cancer seen in high resolution synchrotron images.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4009.
Invasive and non-invasive breast cancer can be distinguished from normal mammary gland or benign breast tumor by apparent diffusion coefficient in magnetic resonance imaging.
Authors: Ishii M , Kimijima I , Suzuki M
Published: December 2010

Abstract #4011

Introduction: MRI (magnetic resonance imaging) has become increasingly important in the diagnosis of breast cancer and evaluation of the area to be resected. However, large amounts of information are buried in plain MRI, including apparent diffusion coefficient (ADC). This study measured ADC for normal breast tissue, benign breast tumor and malignant breast tumor, and tested the ability to differentiate malignant lesions from benign breast tumor or normal mammary gland.  Patients and Methods: ADC was measured for 122 consecutive patients who visited our institute with breast abnormality from January 2007. Malignant breast tumor was diagnosed in 101 patients (invasive breast cancer, n=81; non-invasive cancer, n=20) and 21 patients displayed benign breast tumor (n=11) or normal mammary gland (n=10). A 3.0-T MRI system was used in this study and the motion-providing gradient added was 0 and 1000 s/mm2.  Results: Mean ADC for the 101 breast cancer patients was 0.939±0.225 10-3 mm2/s, lower than that of the 26 benign or normal patients, at 1.247±0.269 10-3 mm2/s (p>0.0001, t test). Among breast cancers, mean ADC was 0.892±0.021 10-3 mm2/s for invasive lesions and 1.081±0.247 10-3 mm2/s for ductal carcinoma in situ. Each showed significantly lower ADC than benign or normal breast tissues (p>0.0001 each). Three cases of micro-papillary cancer were identified, and this type of cancer is known to display a worse prognosis. Mean ADC for these cases was 0.660±0.089 10-3 mm2/s, lower than the average for breast cancer. Furthermore, mean ADC in 46 cancer cases with histological grade II III was 0.857 10-3 mm2/s, lower than that of the 23cases with grade I tumor, at 1.023 10-3 mm2/s (p=0.0029).  Conclusion: This study revealed that even non-invasive breast cancer can be distinguished from benign lesions by ADC. As ADC can be obtained rapidly without use of contrast enhancers, this approach has potential for application in breast screening. Furthermore, as aggressive cancers such as invasive micropapillary cancer or high-grade cancer show low ADC, use of ADC values as potential prognostic markers should be investigated.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4011.
Correlation between kinetic features on breast MRI computer-aided detection (CAD) and prognostic factors of breast cancer.
Authors: Kim H , Kim H , Shin H , Lee J , Ko M , Moon J
Published: December 2010

Abstract #4015

The purpose of this study was to correlate the kinetic features of breast MR computer-aided detection (CAD) with the prognostic factors of breast cancer.  A total of 65 patients were included in our study from December 2007 to March 2008. We reviewed kinetic features of MR CAD such as proportion of initial rapid rise enhancement, percentage of washout, and enhancement patterns. We also recorded prognostic factors such as tumor size, estrogen receptor, progesterone receptor, HER-2/neu status, lymphovascular invasion, and histologic grade on pathology. We correlated the kinetic features on MR CAD with prognostic factors. Pearson and Spearman correlation test were used to evaluate correlation between kinetic features and tumor size. Fisher exact test also used for the statistical analysis between kinetic features and other prognostic factors.  In 65 cases, 59 cases showed rapid washout enhancement patterns, 5 cases showed rapid plateau pattern and only one case showed medium plateau. Tumor size showed correlation with the initial rapid rise enhancement (p=0.03) on Pearson correlation test and the delayed washout percentage (p=0.05) on Spearman correlation test.  Positive progesterone receptor status was significantly associated with rapid early enhancement (p=0.023) and delayed washout (p=0.05), respectively. HER-2/neu status showed trend with the early enhancement (p=0.063). Other prognostic factors such as estrogen receptor, lymphovascular invasion and histologic grade showed no significant correlation with the kinetic features on MR CAD.  Several kinetic features on MR CAD were correlated with the specific prognostic factors of breast cancer. Recognition of several kinetic features correlated with prognostic factors might help to predict of patients' prognosis and to decide the treatment plan.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4015.
The ability of preoperative magnetic resonance imaging to predict actual pathologic tumor size in women with newly diagnosed breast cancer.
Authors: Vallow L , Mclaughlin S , Hines S , McDonough M , Geiger X , Christopher S
Published: December 2010

Abstract #4018

Background: Preoperative breast magnetic resonance imaging (MRI) has been shown to identify occult breast disease in women with newly diagnosed breast cancer. We sought to determine the accuracy of MRI in predicting the actual pathologic tumor size in women with newly diagnosed breast cancer.  Methods: Preoperative breast MRI was reviewed in 460 women with newly diagnosed breast cancer. The size in terms of maximum tumor dimension, of 476 incident breast cancers on MRI were recorded and correlated with the actual pathologic size upon surgical resection. The correlation of size from MRI to pathology was determined. The size discrepancy was analyzed in relation to tumor size and histology.  Results: MRI demonstrated 476 breast cancers (460 in the ipsilateral breast and 16 with concurrent contralateral breast cancer). Median age was 62 with a range of 25 to 91. The T stages of the population included T0 in 19% of the women, 60% had T1 lesions, 18% had T2 lesions and 3% were T3 or T4. The histology consisted of DCIS alone in 20%, infiltrating ductal in 74% and infiltrating lobular in 6%. Pre-operative MRI was unable to define an enhancing lesion usually due to hematoma following core needle biopsy in 9.8% (47/476). MRI described the size of the incident lesion in 90% (429/476). The mean difference in size between the preoperative MRI and the actual pathologic size for the entire group was 2.4 mm. MRI underestimated tumor size in only 3% of cases. The mean difference according to T stage and histology between MRI and actual pathologic size is listed in Table 1. The percentage of difference between MRI size and pathologic size for the entire group is presented in Table 2.        Discussion: The mean difference in tumor size estimated by preoperative MRI in women with newly diagnosed breast cancer was within 5 mm of the actual pathologic size in 68% of patients. MRI was accurate in predicting T stage with no significant difference in relation to histology or T stage. This analysis further clarifies the role of preoperative MRI in surgical and treatment planning.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4018.
The utility of preoperative breast magnetic resonance imaging in invasive breast cancer according to HER2 status.
Authors: McLaughlin SA , Vallow LA , Hines SL , Tan W
Published: December 2010

Abstract #4020

Background: HER2 positive (HER2+) breast cancer accounts for 20% of all breast cancer and is an independent adverse prognostic factor. Breast magnetic resonance imaging (MRI) has been shown to identify additional mammographically occult ipsilateral (I/L) and contralateral (C/L) disease, however indications for preoperative MRI in patients with newly diagnosed breast cancer are not standardized. While invasive lobular cancer, younger patient age, and increased breast density have been suggested as routine indications, the role of preoperative MRI according to HER2 status has not been evaluated.  Methods: All patients with invasive breast cancer who underwent preoperative MRI between January 2003 and December 2007 were reviewed. Retrospective chart review was performed to collect clinical, radiographic, and pathologic data. The incidence of additional I/L or C/L malignacy was calculated. Additionally, changes in surgical management because of MRI findings were recorded.  Results: Of the 401 women with invasive breast cancer undergoing preoperative breast MRI, 51 (13%) had HER2+ tumors. The average age at the time of MRI was similar in both groups. HER2+ patients were more likely to have nodal disease, and tumors with higher rates of lymphovascular invasion or extensive intraductal components.    When compared to HER2- patients, more HER2+ patients had additional ipsilateral MRI abnormalities. A second ipsilateral cancer was found in 31% of HER2+ patients compared to 25% of HER2- patients. When analyzed according to ER status, HER2+/ ER- patients were more likely to have an additional site of cancer compared to HER2+/ER+ patients (42% vs 23%). Conversely, among HER2- patients, rates of additional ipsilateral cancer were similar for HER2-/ER+ (26%) and HERr2-/ER- (23%) patients. Of the 216 patients (HER2+ and HER2-) with additional ipsilateral MRI findings (benign or malignant), 125/216 (58%) patients were deemed appropriate breast conservation (BCT) candidates after MRI. However, BCT was only chosen in 84/125 (67%) patients. Additional contralateral disease was documented in 8% of HER2+ versus 5% of HER2- patients.  Conclusions: HER2 positivity remains and important prognostic factor for women with breast cancer. Indications for routine preoperative MRI are unclear. In patients with newly diagnosed Her2+ invasive breast cancer routine preoperative MRI may be valuable in the subset of patients who are also ER-. Further study is needed to determine the influence of MRI on patient decisions for surgical therapy.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4020.
The role of FDG-PET for preoperative evaluation of regional lymph node metastases in locally advanced breast cancer.
Authors: Seo J , Son B , An S
Published: December 2010

Abstract #4021

Backgound: The aim of this study was to evaluate the role of FDG-PET in detecting regional lymph node metastases in locally advanced breast cancer.  Methods: FDG-PET was performed in 114 women with locally advanced breast cancer. Among them, 7 were with primary tumor larger than 5cm, 18 were with inflammatory breast cancer, and 89 were with clinically palpable axillary lymph node metastases. FDG uptakes of axillary, internal mammary, and supraclavicular lymph node were correlated by comparing pathologic and radiographic findings.  Results: The sensitivity, specificity, and positive predictive value of FDG-PET for detection of axillary lymph node metastases in 83 patients who did not receive neoadjuvant chemotherapy were 91%, 33.3 % and 94.7% respectively. Among the 83 patients, 4 were with false-negative and 6 were with false-positive. Those for detection of axillary lymph node metastases in 12 patients who received neoadjuvant chemotherapy were 55.6%, 100%, and 100% respectively, and 4 of them were with false-negative and no one was with false-positive results. The sensitivity and positive predictive value of combined assessment of clinical examination and ultrasound scan on axillary node metastases were 92.1% and 93.3% in 81 patients. Those of combined assessment of clinical examination, ultrasound scan, and PET were 100% and 95.7% in 69 patients. FDG uptake in internal mammary node was seen in 14 out of 114 patients (12.2%). The positive predictive value of FDG-PET for detection of internal mammary metastases in 9 patients with pathologic confirmation was 75%. 6 of them were with true-positive, 2 were with false-positive, and 1 was false-negative. Among the 6 true positive patients, 3 were not detected internal mammary metastases in ultrasound scan. FDG uptake in the supraclavicular node was seen in 22 out of 114 patients (19.2%). The positive predictive value of FDG-PET for detection of supraclavicular metastases in 12 patients with pathologic confirmation was 58.3%. 7 of them were with true –positive and 5 were with false-positive. 1 of 7 true-positive patients was not detected supraclavicular lymph node metastases in ultrasound scan.  Conclusions: The sensitivity of FDG-PET for detection of axillary lymph node metastases was higher than that of FDG-PET for detection of internal mammary or supraclavicular lymph node. The addition of FDG-PET to standard work-up of locally advanced breast cancer patients could provide a more precise evaluation of regional lymph node metastases. Positive combined assessment of clinical examination, ultrasound scan and PET on axillary node metastases also could be an indication for full ALND without SNB.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4021.
Tumor volume analysis in clinical oncology.
Authors: Gordon AB , Stebbing J , Coombes C
Published: December 2010

Abstract #4023

Background: RECIST 'Response Evaluation Criteria in Solid Tumors' uses the longest diameter to measure Partial Response (PR), Stable Disease (SD) and Progressive Disease (PD). When the diameter of a sphere doubles the volume increases eight times (Volume = 4/3 Π r3). We have previously proposed that data be expressed as volume in cubic centimetres rather than as longest diameter in centimetres. (Poster 2021 SABCS 2007) Ref 1.  Method: To investigate this further we assessed 56 patients from a primary breast cancer therapeutic trial. We then compared traditional RECIST measurements with our Tumor Volume Analysis TVA using a new device LCD calculator, (patent applied for number GB244189), which has three separate programs. (1) calculation of the volume of a mass in one or two or three diameters or dimensions. (2) volume comparison between a first and second mass shown as a difference in cubic centimetres or percentage. (3) diameter comparison as RECIST between a first and second mass shown as a difference in centimetres or percentage.  Results: When data are expressed as volume in cubic centimetres the response levels are higher in percentage terms. A RECIST PR of 30% becomes volume PR of 66% Table 1. Table 2 demonstrates data we have obtained using a previous study Ref 2. When the diameter is converted into volume the response levels are higher, which was statistically significant (p< 0.05).  Tumor Volume Analysis: A one dimensional sphere of 3cm in diameter has a volume of 14.14 cubic centimetres. A bidimensional ellipse of 3cm x 2cm has a volume of 6.28 cubic centimetres. A date shaped tri-dimensional mass 3cm x 2cm x 1cm has a volume of 3.14 cubic centimetres.  Conclusions: This demonstrates the importance of providing three dimensional measurements of a tumor. This is particularly the case in serial measurements when treatment effects are being monitored.  Ref 1 SABCS Breast Cancer Volume 106 Supplement 1 December 2007 PPS1-S302 S91  Ref 2 Polychronis et al. Lancet Oncology Volume 6, June 2005 383-391.       

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4023.
Evaluation of breast cancer using magnetic resonance imaging with diffusion sequence.
Authors: Pérez Carrión R , Salinas Hernández P , Martínez de la Vega V , Recio Rodríguez M
Published: December 2010

Abstract #4026

The diffusion is a physical property that describes the microscopic random movement of molecules in response to termal energy. The diffusion may be affect by biophysical properties of tissues: cellular density, tumor structure (necrosis, edema), and microcirculation.  We have made a quantitative analysis of the images of diffusion, calculating the coefficient of apparent diffusion (ADC) that reflects the capacity of specific diffusion of the tissue. The ADC is an objective parameter that can be used to characterize the tissues. It measures the displacement in unit of time (mm2/sec).  In malignant tumors the barriers to the diffusion are increased (high hypercellularity) and therefore, the diffusion is restricted, which is translated as low values of ADC.  We present 30 cases of infiltrating breast carcinoma, studied by sequence of diffusion SE EPI (TR 6500 msec; TE 85 msec; Matrix 128 x 80, NEX 6, Thickness 7 mm, GAP 3 mm, Value b 600 mm2/sec. AXIAL 38 courts 2 min 37 sec).  In malignant tumors the ADC is minor of 1,1 x 10-3 and is lower than that of benign injuries and normal tissue fibroglandular.  The apparent diffusion coefficient (ADC) are:  • Cancer: 1,03 ± 0,23 x 103 mm2/sec.  • Fibroadenoma: 1,74 ± 0,16 x 103 mm2/sec.  • Cyst: 2,17 ± 0,25 x 103 mm2/sec.  • Fibroglandular tissue: 1,83 ± 0,25 x 103 mm2/sec.  Also we present 10 patients in whom we have used the ADC in the follow-up of the chemotherapy treatment. We have confirmed that the early increase of the ADC shows correlation with good response.  We attach the example of a patient.  Breast MR difussion: evaluation of chemotherapy response.    Good evolution: rapid increse of ADC.  In the scientific meeting we will present the results.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4026.