bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P2-14-03: Development and evaluation of a prediction model based on routine clinicopathological variables for predicting underestimated invasive breast cancer in women with ductal carcinoma in situ at stereotactic large core needle biopsy
Authors: Diepstraten SCE , van de Ven SMWY , Pijnappel RM , Peeters PHM , van den Bosch MAAJ , Verkooijen HM , Elias SG
Published: August 2014

Purpose: To develop a multivariable model for prediction of underestimated invasiveness in women with ductal carcinoma in situ (DCIS) at stereotactic large core needle biopsy (LCNB), that can be used to select patients for sentinel node biopsy (SNB) at primary surgery.

Methods: From the literature, we selected potential preoperative predictors of underestimated invasive breast cancer. Data of patients with nonpalpable breast lesions who were diagnosed with DCIS at stereotactic LCNB, drawn from the COBRA (Core Biopsy after RAdiological localization) and COBRA2000 studies, were used to fit the multivariable model and assess its overall performance, discrimination, and calibration.

Results: 348 women with LCNB-proven DCIS were available for analysis. In 100 (28.7%) patients invasive carcinoma was found at subsequent surgery. Nine predictors were included in the model. In the multivariable analysis, the predictors with the strongest association were lesion size (OR 1.12 per cm, 95% CI 0.98-1.28), the number of cores retrieved at biopsy (OR per core 0.87, 95% CI 0.75-1.01), presence of lobular cancerization (OR 5.29, 95% CI 1.25-26.77), and microinvasion (OR 3.75, 95% CI 1.42-9.87). The overall performance of the multivariable model was poor with an explained variation of 9% (Nagelkerke's R2), mediocre discrimination with area under the receiver operating characteristic curve of 0.66 (95% confidence interval 0.58-0.73), and fairly good calibration.

Conclusion: The evaluation of our multivariable prediction model in a large, clinically representative study population, proves that routine clinical and pathological variables are not suitable to select patients with LCNB-proven DCIS for SNB during primary surgery.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-14-03.
Abstract P2-16-06: Influence of trastuzumab pre-exposure in non metastatic disease to first line metastatic treatment efficacy including trastuzumab: The University Cancer Center - University Pierre & Marie Curie (IUC-UPMC) experience
Authors: Gligorov J , Vignot S , Richard S , Lotz J-P , Khayat D , Spano J-P
Published: August 2014

Background: Trastuzumab (TZB), is approved in France in adjuvant setting since 2005 for patients with HER2-positive breast cancer. The effectiveness of this treatment is well established, but little is known about the impact of pre-exposure to this drug in non metastatic disease and its effectiveness during its reintroduction in the metastatic disease.

Methods: We extracted from the database of two Medical Oncology Departments from University Cancer Institute - University Pierre & Marie Curie (IUC-UPMC), clinical parameters of patients treated in first-line HER2 positive metastatic breast cancer with treatments including TZB as the only antiHER2 treatment, between 2005 and 2011. We analyzed the impact of this treatment in patients who received adjuvant TZB and also in patients who did not.

Results. During this period, 456 patients were treated with TZB for a non metastatic HER2 positive disease, and 103 patients for a metastatic HER2 positive disease. Among the 456 patients treated in the (neo)adjuvant setting, the relapse rate was 3% (n = 16). The remaining 87 patients treated with first-line metastatic TZB were not previously treated with TZB in the adjuvant setting (n = 68) or had HER2 positive metastatic disease at time of initial diagnosis (n = 19). For patients previously exposed to TZB (n = 16), response rate (RR) of first-line treatment including TZB was 57% (95% CI: 35-81%) and time to failure treatment (TTF) was 243 days (95% CI: 114 to 330 days). For patients who have not been previously exposed to TZB (n = 87), the RR of first-line treatment including TZB was 61% (95% CI: 49-74%) and TTF was 267 days (95% CI: 182-343 days).

Conclusions: Despite the lack of direct comparison, it does not appear that treatment including TZB in non metastatic disease, will influence the efficacy of first-line treatment of metastatic featuring TZB reexposure.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-16-06.
Abstract P2-16-08: LORHA: Efficacy and safety of 1st-line trastuzumab based treatment, administered for at least 3 years, in patients with HER2-positive metastatic or locally advanced breast cancer - Final results
Authors: Ferrero J-M , Levy C , Spano J-P , Beuzeboc P , Coeffic D , Arnould L , Lortholary A , André F , Mayer F
Published: August 2014

Background: A subset of patients with HER2-positive metastatic (mBC) or locally advanced breast cancer (aBC) respond to 1st line trastuzumab-based regimen and have no disease progression for several years. These long-term responders were evaluated in daily practice in the LORHA study. Patients and disease characteristics were presented earlier (ESMO 2012).

Material and Methods: Lorha is an ambispective, multicenter, non-interventional study conducted in 57 centers in France. Eligible patients were women aged more than 18 years with HER2-positive mBC or aBC treated with 1st line trastuzumab and progression-free for at least 3 years after starting trastuzumab. The primary objective was to describe clinical and tumor characteristics. Secondary objectives included Progression Free Survival (PFS), Overall Survival (OS), treatment administration and safety. Patients were followed-up for 12 months.

Final results are presented here.

Results: Overall 160 patients were enrolled; 128 were eligible for efficacy analysis and 154 for safety analysis. Median age was 61 years [34-95]. Tumor characteristics were: invasive ductal carcinoma for 112 patients (88%), positive hormonal receptors in 72 patients (58%). At initial diagnosis, 91 patients (71%) had stage I - II tumors and 37 patients (29%) had de novo mBC or aBC. The main metastatic localizations were bone, liver, lymph nodes and lung in 54 (43%), 44 (35%), 25 (20%) and 24 (19%) patients, respectively. Median 1st line trastuzumab treatment duration was 4.5 years [0.8 - 12.1]. Trastuzumab 1st line was associated with a taxane-based chemotherapy in 104/128 patients (81%). Median PFS was 6.4 years [5.7; - Not reached] and median overall survival was not reached. At 1-year follow-up, 23 deaths (15% of patients) were reported, mainly due to disease progression (21 patients - 91%). No toxic death related to trastuzumab was observed. Grade 3-4 adverse events reported prospectively occurred in 14 patients (10%) and included two patients (1.2%) with grade 3-4 cardiac events related to trastuzumab (congestive cardiac failure and left ventricular dysfunction), both events resolved, one with sequelae.

Conclusions: Final results of the LORHA study show that long responding patients receiving first-line trastuzumab-based treatment for aBC or mBC in daily practice, can reach a median PFS of more than 6 years, combined with an acceptable safety profile. Median overall survival is still not reached.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-16-08.
Abstract P2-16-13: Phase I dose escalation clinical trial of the PI3K inhibitor BKM120 and capecitabine (C) in metastatic breast cancer (MBC)
Authors: Dees EC , Marcom PK , Snavely A , Noe J , Anders CK , Blackwell K , Kimmick G , Reeder-Hayes K , Rosenstein D , Perou CM , Carey LA
Published: August 2014

Background: PIK3CA is one of the most frequently mutated genes in human breast cancer, and the high expression of a PIK3CA-pathway signature is associated with the poor prognosis Luminal B and Basal-like expression subtypes. BKM120 is an oral pan-class I phosphatidylinositol-3-kinase (PI3K) inhibitor, which has shown activity in preclinical and early clinical testing, and synergy with both endocrine and chemotherapy. In this trial we sought to evaluate the safety and estimate the maximum tolerated dose (MTD) of the combination of BKM120 and C in patients (pts) with MBC.

Methods: In a 3+3 dose escalation design, we evaluated four cohorts of BKM 120 daily plus C BID x 14 days in 21 day cycles. Standard definitions for DLT and MTD were used and evaluated on the first cycle. Toxicity was graded by CTCAE version 4. Response was evaluated after 2 cycles by RECIST criteria. Pts with MBC appropriate for treatment with C who had <4 prior chemotherapy regimens and normal organ, bone marrow and cardiac parameters were eligible.

Results: 21 pts (11 hormone receptor (HR)+, 3 HER2+, 9 HR/HER2-negative) were enrolled and treated. All were evaluable for toxicity and 14 for response to date. Median age was 54 (range 35-65). Median prior chemotherapy regimens for MBC was 2 (range 1-4). The following dose levels (DL) were evaluated: BKM120 50 mg/d + C 1000 mg/m2/BID x 14(DL 1-4 pts), BKM120 80 mg/d + C 1000 mg/m2/BID x 14 (DL2-3 pts), BKM120 100 mg/d + C 1000 mg/m2/BID x 14 (DL3-9 pts), BKM120 100 mg/d + C 1250 mg/m2/BID x 14 (DL4-5 pts). Most frequent adverse events (all grades) included: Nausea (12), mood disorders (11), PPE (9), diarrhea (8), fatigue (7), vomiting (5) mucositis (4), rash (4), photosensitivity (3), hyperglycemia (3). Grade 3 or higher AEs in any cycle were transaminitis (3) diarrhea (2) mood disorder (2), hyperglycemia, fatigue, photosensitivity, PPE (1 pt each). DLTs: grade 3 hyperglycemia (1/6 pts at DL3), and grade 3 mood disorder in 1/5 pts DL 4. Additionally 4 of 5 patients at DL 4 required dose reduction or delay prior to C3D1. Thus DL 4 exceeded the MTD and DL 3 was expanded for further safety evaluation. Antitumor activity was seen with best responses of 1 CR (at DL 3), 3 PR (DL1 and 4) and 7 SD.

PK analysis, assessment of tumor PIK3CA mutation status and intrinsic subtype by PAM50 is ongoing.

Conclusions: The combination of BKM120 100 mg po q day and C 1000 mg/m2 / BID x 14 d in 21 day cycles is tolerable and appears active. PK and biomarker analysis are ongoing. A phase II trial is planned.

Acknowledgements: This study was funded by Novartis Pharmaceuticals and by a grant from Susan G. Komen for the Cure (SAC 110044).

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-16-13.
Abstract P2-16-24: Folate targeted SMDC’s: A possible new treatment alternative for folate receptor expressing TNBC patients
Authors: Leamon CP , Reddy JA , Nelson M , Bloomfield A , Dorton R , Vetzel M
Published: August 2014

Triple negative breast cancer (TNBC) is a subtype characterized by lack of gene expression for the estrogen receptor, progesterone receptor and the Her2/neu protein. Hence, the lack of hormonal or Her2 targeted therapy options makes TNBC difficult to treat, resulting in a death rate which is disproportionately higher than for other breast cancer subtypes. Recently, the folate receptor (FR) was shown to be highly expressed in TNBC, and expression significantly correlated with the higher grades of malignancy as well as poor outcomes. These observations suggest that TNBC patients may benefit from treatment with an FR-targeted therapy. To address this question, an established FR-positive subcutaneous TNBC pre-clinical model (MDA-MB-231) was chosen to evaluate a panel of FR-targeted small molecule drug conjugates (SMDC) with high potencies and varying mechanisms of action. Thus, EC1456 (folate-tubulysin B; IC50 ∼ 1 nM) and EC1744 (a folate-DNA cross-linking agent; IC50 ∼0.1 nM) were dosed intravenously at 2 μmol/kg following a three times per week, two week schedule in tumor-bearing mice. Both FR-targeted agents were found to be highly active against the MDA-MB-231 tumors, with 80-100% cure rates. In all cases, the observed anti-tumor activity was not accompanied by any significant weight loss in the test animals. These findings suggest that folate-targeted SMDCs may be active against TNBC and that further preclinical studies are warranted.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-16-24.
Abstract P2-19-02: Do older women benefit from post-mastectomy breast reconstruction?
Authors: Sisco M , Johnson DB , Wang CE , Yao KA
Published: August 2014

Purpose: Despite evidence that post-mastectomy breast reconstruction (PMBR) decreases psychological morbidity and improves body image, older women (aged 65 and above) receive it six times less often than younger women. It is unclear whether this difference represents a disparity or reflects informed patient choices since the outcomes of PMBR in older women have never been rigorously studied. We hypothesized that in older women, the use of PMBR is associated with greater psychosocial well-being and breast satisfaction than mastectomy alone.

Patients and Methods: The Dillman method was used to survey 299 older women with stage 0-III breast cancer who underwent a mastectomy from 2006-2011. The response rate was 75.3%. The survey incorporated demographic questions and measured satisfaction and health-related quality of life outcomes using the Duke health profile and the BREAST-Q mastectomy module. Patients who underwent PMBR were compared to those who did not (no-PMBR) to determine differences in patient characteristics, satisfaction, and quality-of-life outcomes between groups. Satisfaction and outcome results were risk adjusted using multivariable logistic regression to account for differences between PMBR and no-PMBR groups.

Results: The median age of respondents was 72. Of these, 77/214 (36%) elected to undergo PMBR. Marital status, education level, race, and tumor stage were similar in PMBR and no-PMBR groups. Those in the PMBR group were generally younger and more affluent than those in the no-PMBR group (p<0.001 and p<0.05, respectively). There were no significant differences in age-adjusted physical health, anxiety, or depression scores between PMBR and no-PMBR groups. Both groups reported high levels of decisional satisfaction. However, after adjusting for age and income, PMBR was associated with greater breast satisfaction (BREAST-Q score 69 vs. 57, p<0.001) and greater psychosocial well-being (BREAST-Q score 83 vs. 76, p<0.001). These differences in scores compared favorably to those seen in younger women.

Conclusions: This is the first study to compare psychosocial outcomes and breast satisfaction between older women who undergo PMBR and those who do not. These findings show that older women have the potential to benefit from PMBR at least as much as younger women do. PMBR can be performed in a significant proportion of older women with high levels of satisfaction. Older women who are appropriate candidates should be encouraged to consider breast reconstruction, and efforts should be made to narrow the disparity in the delivery of PMBR between older and younger women.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-19-02.
Abstract P2-19-04: Latissimus dorsi muscle onlay patch alternative to acellular dermal matrix is useful for implant-based breast reconstruction
Authors: Lee J , Bae Y , Lee S
Published: August 2014

Introduction: The implants-based breast reconstruction is very useful method for breast conserving surgery in breast cancer. Recently, acellular dermal matrix (ADM) is applied to release the inferior pectoralis muscle for maintaining breast contour and to prevent burst out from the implant pocket. Authors applied latissimus dorsi (LD) muscle onlay patch instead of ADM for implant-based breast reconstruction.

Patients and methods: From January to December 2012, a total of 20 patients with breast tumor underwent 22 cases of implant-based breast reconstruction with ADM or LD muscle onlay patch. The cosmetic outcome is assessed with 4-point scoring system at 4 weeks after from chemotherapy or radiotherapy. And the statistical analysis was evaluated between 2 groups.

 After conventional breast conserving surgery was done, the origin of the pectoralis major muscle are released and the window is checked pectoralis major muscle medially, rectus sheath inferiorly, and serratus anterior muscle laterally. Then, LD flap is sutured to cover this window with avoiding the vessel injury. The implant is inserted in the subpectoral pocket and breast reconstruction is finished with LD flap.

Results: Mean operation time of ADM group and LD muscle onlay patch group was 153.9 and 299.7 minutes, respectively. (p = 0.054).

Demographic characteristicsCharacteristicsADM (n = 10)LD muscle onlay patch (n = 12)p-valueAge (years)36.8±10.145.8±12.50.820BMI (kg/m2)19.0±2.023.4±3.430.065Volume loss (g)153.9±120.29299.7±116.030.030OP time (minutes)198±86.06342.5±54.70.054Hospital stay (days)6.9±1.528.7±1.560.059Follow-up period (Mo)6.2±2.668.7±1.560.232Interval period (days)19.9±6.2427.9±7.580.516Chenotherapy5110.056Radiotherapy590.378Complication  0.571Inflammation10 Seroma11 Cosmetic outcome  1.000Excellent34 Good55 Fair23 

There were no significant differences between 2 groups; postoperative complication, cosmetic outcomes, and tumor characteristics.

Tumor characteristicsCharacteristicsADM (n = 10)LD muscle onlay patch (n = 12)p-valueTumor type  0.088Atypical ductal hyperplasia20 Carcinoma in situ31 Invasive carcinoma511 Dermal invasion011.00Tumor size2.0±1.453.8±2.270.586Multicentricity310.293Stage  0.440031 I21 IIA24 IIB13 IIIA01 IIIB02 Microcalcification230.594Differentiation  0.038Well20 Moderate35 Poor06 Perineural invasion  0.706Positive01 Negative1011 Lymphovascular invasion  0.261Positive04 Negative108 Estrogen receptor  0.770Positive87 Negative05 Progesterone receptor  0.013Positive85 Negative07 c-erbB2 protein  0.074Positive04 Negative88 

However, ADM was found to be much more expensive than LD muscle onlay patch.(p<0.001)

Conclusion: Implant-based breast reconstruction with LD muscle onlay patch would be a feasible surgical technique alternative to ADM, when LD flap is planned for breast reconstruction.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-19-04.
Abstract P3-02-02: Cyclin D1 overexpression increases the risk for breast cancer death 4-fold in hormone receptor positive and node negative breast cancer
Authors: Ahlin C , Grönberg M , Valachis A , Zhou W , Amini R-M , Blomqvist C , Fjällskog M-L
Published: August 2014

Background: Cyclin D1 has a central role in cell cycle control, but also directly affects the estrogen receptor. It has been shown that cyclin D can activate the estrogen receptor in a ligand-independent way and studies are implying that cyclin D overexpression may be linked to tamoxifen resistance. We wanted to explore the prognostic value of cyclin D overexpression in node negative breast cancer.

Patients and methods: We examined the expression of cyclin D1 using immunohistochemistry on tissue micro array (TMA) sections from a case control study (1:1) consisting of 380 patients with T1-2N0M0 breast cancer. Adjuvant radiotherapy and endocrine treatment was allowed, but not chemotherapy. Event was defined as breast cancer death. Breast cancer specific survival was analyzed in univariate and multivariate models using conditional logistic regression.

Results: Cyclin D1 was inversely correlated to Elston grade (rho = 0.2; p = 0.000); moderately correlated to PgR status (rho = 0.3, p = 0.000) and strongly correlated to ER status (rho = 0.4, p = 0.000). Cyclin D1 overexpression did not increase the risk for breast cancer death analyzing the whole patient population. However, subgroup analyses of hormone receptor positive patients showed an increased risk for breast cancer death (OR 4.2; 95% CI 1.4-12.6) and (OR 3.9; 95% CI 1.3-12) when adjusted for tumor size and age at diagnosis.Conclusion: Cyclin D1 is an independant prognostic factor of outcome in hormone receptor positive and node negative breast cancer with overexpression increasing the risk for breast cancer death 4-fold.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-02-02.
Abstract P3-02-03: The phosphatase function of the eyes absent (EYA) homolog is required for the induction of breast cancer cellular proliferation via cyclin D1
Authors: Pestell RG , Wu K , Li Z , Tian L , Chen K , Wang J , Hu J , Sun Y , Li X , Ertel A
Published: August 2014

The Drosophila Eyes Absent Homologue 1 (EYA1) is a component of the retinal determination gene network (RDGN) and serves as an H2AX phosphatase. The cell fate determination gene network includes the dachshund (dac), twin-of-eyeless (toy), eye absent (eya), teashirt (tsh) and sine oculis (So). In Drosophila, mutations of the RDGN leads to failure of eye formation, whereas, forced expression induces ectopic eye formation. EYA functions as a transcriptional co-activator being recruited in the context of local chromatin, but lacking intrinsic DNA binding activity. EYA family members EYA 1-4 are defined by a 275 amino acid carboxyl-terminal motif that is conserved between species, referred to as the EYA domain (ED). The human homologs EYA 1-4 are highly conserved in their EYA domain and amino termini, with the exception of a small tyrosine rich residue region named EYA domain II.

Altered expression or functional activity of the RDGN has been documented in a variety of malignancies. DACH1 expression is reduced in breast, prostate, endometrial and brain cancer. EYA2 is up regulated in ovarian cancer, promoting tumor growth. EYA1 and EYA2 enhanced survival in response to DNA damage producing agents in HEK293 cells. Eya2 was required for Six1/TGFb signals that govern a prometastatic phenotype and epithelial mesenchymal transition (EMT). Although EYA proteins are expressed in human breast cancer, the relationship to molecular genetic subtype, prognosis and the molecular mechanisms governing contact-independent growth are not known.

The cyclin D1 gene encodes the regulatory subunits of a holoenzyme that phosphorylates and inactivates the pRb protein. Herein, comparison with normal breast demonstrated EYA1 is overexpressed with cyclin D1 in luminal B breast cancer subtype. EYA1 enhanced breast tumor growth in mice in vivo requiring the phosphatase domain. EYA1 enhanced cellular proliferation, inhibited apoptosis, and induced contact-independent growth and cyclin D1 abundance. The induction of cellular proliferation and cyclin D1 abundance, but not apoptosis, was dependent upon the EYA1 phosphatase domain. The EYA1-mediated transcriptional induction of cyclin D1 occurred via the AP-1 binding site at -953 and required the EYA1 phosphatase function. The AP-1 mutation did not affect SIX1-dependent activation of cyclin D1. EYA1 was recruited in the context of local chromatin to the cyclin D1 AP-1 site. The EYA1 phosphatase function determined the recruitment of CBP, RNA polymerase II and acetylation of H3K9 at the cyclin D1 gene AP-1 site regulatory region in the context of local chromatin. The EYA1 phosphatase regulates cell cycle control via transcriptional complex formation at the cyclin D1 promoter.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-02-03.
Abstract P3-02-04: QM-FISH analysis of the genes involved in the G1/S checkpoint signaling pathway in triple-negative breast cancer
Authors: Zhang J , Zhang S , Hou G , Shao Y , Zhang X
Published: August 2014

OBJECTIVES: To analyze copy number alterations(CNAs) of the genes involved in the G1/S checkpoint signaling pathway of triple-negative breast cancer (TNBC) and non- triple-negative breast cancer(non-TNBC) and in order to find specific CNAs associated with overall survive for TNBC.In all,to provide an effective target for future treatment.

METHODS: We selected the samples randomly form Tianjin Cancer Hospital between August, 2006 and August, 2007,which contained one hundred TNBC cases and one hundred non-TNBC cases. Quantitative mμlti-gene fluorescence in situ hybridization (QM-FISH) was used to study CNAs of the genes involved in the G1/S checkpoint signaling pathway, including CCND1,c-Myc,p21, CHEK2, p16, Rb1, Mdm2and p53.

RESULTS: The amplification rates of c-Myc and the deletion rates of p53 in TNBC tended to be higher than those in non-TNBC, whereas the amplification rates of CCND1 and Mdm2 in non-TNBC tended to be higher than those in TNBC. In Kaplan-Meier analysis, the amplification of CCND1 (P = 0.02) and c-Myc (P = 0.02) as well as the deletion of p53 (P = 0.01) predicted worse survival in the TNBC group. While in the non-TNBC group, the amplification of CCND1 (P = 0.01) and Mdm2 (P = 0.04) as well as the deletion of p53 (P = 0.049) were associated with worse survival. The amplification of c-Myc and the deletion of p53 in TNBC were associated with higher mortality risk (HR,2.87;95%CI,1.14-7.21[P = 0.03]; HR, 3.34;95%CI, 1.22-9.09 [P = 0.02]), whereas the mortality risk tended to be higher in the patients with amplification of CCND1 (HR, 4.35;95%CI,1.23-15.39 [P = 0.02])in non-TNBC.

CONCLUSIONS: The amplification rates of c-Myc and deletion rates of p53 in TNBC tended to be higher than those in non-TNBC, whereas the amplification rate of CCND1 and Mdm2 tended to be higher in non-TNBC. c-Myc and p53 were independent prognostic factors for TNBC, while CCND1 was the independent prognostic factors for non-TNBC.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-02-04.
Abstract P3-05-03: HER2-CONNECT® pathologist-assisted image analysis algorithm for HER2 IHC interpretation improves correlation with HER2 FISH results
Authors: Miller DV , Stender H , Kristensen T , Min RK , Isaac J , Hansen J , Seaman J , Grunkin M , Vyberg M
Published: August 2014

Background: HER2 testing by immunohistochemistry (IHC) is prone to inter-observer variability and subjective interpretation. Pathologist-assisted digital image analysis is recommended in the CAP/ASCO guidelines to improve interpretive consistency. As a quality benchmark, HER2 IHC results should correlate with HER2 fluorescence in-situ hybridization (FISH) in >95% of positive and negative cases. HER2-CONNECT® (Visiopharm, Hoersholm Denmark) is a digital analysis algorithm that scores stained membrane interconnectivity rather than relying solely on staining of individual cells. As such, it can be thought of as a surrogate for the so-called “chickenwire” pattern characteristic of true HER2 positive tumors. In this study we applied HER2-CONNECT® analysis with pathologist quantitative interpretation (HC+PQI) to a set of breast tumors with known HER2 FISH status to assess concordance.

Design: Breast carcinoma tissue sections previously stained with HER2 IHC (HercepTest) and interpreted manually were retrospectively re-submitted for HC+PQI. These included core and excisional biopsies from primary and metastatic sites. Fixation times were documented within recommended guidelines. HER2 FISH (PathVysion) was performed on all cases. Using connectivity scores on a scale of 0 - 1.0 from the analyzed regions, a pathologist determined the overall% of HER2 positive tumor cells in the sample (since HER2-CONNECT reports connectivity, but not tumor cell quantitation) and reported a final score per CAP/ASCO guidelines (<10% = 1+, 10-30% = 2+, >30% = 3+).

Results: 190 cases comprised the analysis set, including 77 3+, 73 2+, and 40 0/1+ as scored in the original reports. 66 cases were HER2 FISH amplified (64/77, 83% of the original 3+ cases and 2/73, 2.7% of 2+ cases) and 6 cases were FISH equivocal. None of the 0/1+ cases were HER2 FISH amplified. Using HC+PQI, the new scores were 67 3+, 68 2+, and 55 1+. Correlation between HC+PQI and HER2 FISH was 95.5% (64/67) for 3+/amplified and 100% (55/55) for <2+/nonamplified (overall concordance 97.5%). Using FISH as the gold standard, the HC+PQI interpretation reduced the false positive rate from 13% (15/108) to 3% (4/108). 17 of 63 HER2 nonamplified samples originally scored 2+ were changed to 1+ on HC+PQI (i.e. reduction of FISH testing by 27% (17/63)).

Conclusions: Relative to the original report scores, HC+PQI improved correlation with HER2 FISH and reduced the overall number of 2+ results (potentially reducing the number of FISH tests required). These data also objectively highlight the importance of the “chickenwire” pattern in positive result interpretation for HER2.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-05-03.
Abstract P3-07-08: Breast cancer in China reveals transcriptomic likeness to Caucasian breast cancer
Authors: Huang X , Dugo M , Callari M , Sandri M , DeCecco L , Carcangiu ML , Iorio M , Xue J , Daidone MG , Ménard S , Tagliabue E , Wu J , Orlandi R
Published: August 2014

The incidence of breast cancer among Chinese women has been historically much lower than that of Caucasian women but has increased dramatically over the past 30 years in urban areas of China, an increase likely to continue in the next decades across China with progressive urbanization and economic development. However, it is still unclear whether differences in breast cancer incidence between Chinese and Caucasian women reflect differences in disease biology in addition to environmental factors. To address this question, we compared consecutive cohorts of Chinese and Italian breast cancer patients who underwent surgical resection in the years 2005-2007 at Fudan Cancer Center of Shanghai (China) and Fondazione IRCCS Istituto Tumori of Milan (Italy), respectively, two comprehensive cancer centers with similar inpatients and outpatients recruited in a large area. Analyses of clinico-pathological characteristics of 1563 Chinese and 1052 Italian consecutive breast cancer patients revealed that 50% of patients in the Chinese cohort were younger than 50 years versus 29% of Italian patients, indicating that Chinese women develop breast cancer earlier than Italian patients, with a peak of frequency at 50-60 years. Among Chinese breast tumors, 63% were estrogen receptor (ER)-positive versus 85% of the Italians, and the prevalence of ER-positive tumors was equivalent in pre- and postmenopausal Chinese cases, suggesting the same hormonal features in tumors of younger and older patients, consistent with findings in the Italian cohort.

Microarray-based gene and miRNA expression profiling was then conducted on 80 Chinese and 97 Italian samples using Illumina Gene and MicroRNA expression technologies. To minimize potential bias and artifact due to variability in specimen collection, storage, processing and analysis of high-throughput results, samples initially collected in the Chinese and Italian hospitals were all stored, randomly processed and analyzed in the Italian center. Analysis revealed a comparable pattern of gene and miRNA expression in the 2 cohorts with unsupervised hierarchical clustering of 12,338 genes and 858 miRNAs, and similar expression of intrinsic and extracellular matrix (ECM) genes led to a similar partition in intrinsic and ECM subtypes, indicating molecular similarity among Chinese and Caucasian breast cancers.

Supported by Ministero Affari Esteri (Italy-China significant bilateral project).

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-07-08.
Abstract P3-07-09: Breast cancer susceptibility associated single nucleotide polymorphisms (SNPs) and prognosis: GG genotype of a SNP rs3803662 (TOX3/TNRC9) associated with better survival
Authors: Lee JW , Moon H-G , Han W , Noh D-Y
Published: August 2014

Backgrounds: After completion of human genome project, some genetic variants are discovered and highlighted by genome-wide association studies (GWAS). Single nucleotide polymorphisms (SNP) are considered to be the key variations leading to the various breast cancer susceptibility between each individuals. In 2011, our group has validated 5 SNPs as significant risk factor of breast cancer in Korean women for the first time. Recently, there has been some attempts to find clinical meaning of SNPs in each breast cancer patient. But it was not successful.

Methods: Consecutive patients with histologically confirmed primary breast cancer subjected to operative procedures between 2002 and 2009 in Seoul National University Hospital were included for analysis. Patients diagnosed with noninvasive breast cancer (ductal carcinoma in situ and lobular carcinoma in situ) or stage IV breast cancer were excluded. Peripheral venous blood samples were obtained and stored at the time of operation. The SNPs genotyped included rs2046210 (6q25.1), rs2981582 (FGFR2), rs889312 (MAP3K1), rs3803662 (TOX3/TNRC9), and rs4973768 (SLC4A7). SNP genotyping was carried out on an Applied Biosystems 7900HT realtime PCR system (Applied Biosystems). We made collaboration with the Korean Central Cancer Registry (KCCR) to improve the validity of the mortality data. Total of 3,209 patients were included for survival and recurrence analysis.

Results: 492 (15.33%) patients had recurrence. And there were 277 (8.63%) mortalities overall. The median follow-up was for 85.59 month (±29.979). The GG genotype of SNP rs3803662 showed better survival than other AA, AG genotypes (Cumulative survival was 89% vs 84% at 120 months f/u). And it is validated at multivariate analysis (p = 0.024).

Conclusion: This study showed strong association between a certain genotype of single SNP and survival of breast cancer patients for the first time. Further lab investigation including functional study or studies on other races should be performed to find a novel or alternative hidden pathways of cancer progression.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-07-09.
Abstract P3-09-15: Permanent chemotherapy induced alopecia in early breast cancer patients after (neo)adjuvant chemotherapy: Long term follow up
Authors: Bertrand M , Mailliez A , Vercambre S , Kotecki N , Mortier L , Bonneterre J
Published: August 2014

Background:

Chemotherapy-induced alopecia (CIA) persisting for more than six months after the end of chemotherapy is defined as permanent alopecia. Scalp cooling is proposed to reduce this distressing side-effect.We evaluated the prevalence and the risk factors of permanent CIA in breast cancer patients receiving (neo)adjuvant chemotherapy.

Patients and methods:

79 patients (pts) treated with (neo)adjuvant chemotherapy (fluorouracil, epirubicin, cyclophosphamide (FEC-100) and docetaxel) for early breast cancer at the Oscar Lambret Center between July 2005 and December 2007 were included in our study. Scalp cooling was used to all pts during chemotherapy. All patients underwent a clinical examination and photographs of the scalp five years after the end of chemotherapy. These images were analysed by two different physicians and patients were divided into two groups: alopecia (regardless of severity) and control. They were asked for the impact on their quality of life. Potential risk factors were collected.

Results:

26 pts (32.9%) had alopecia: minimal (21 pts), moderate (2 pts) or severe (3 pts). In alopecia group, pts were significantly older and more often postmenopausal than in the control group (p 0.0073 and 0.005, respectively). In multivariate analysis (age and menopause), menopause was identified as a significant risk factor for developing alopecia (OR = 4.136, 95% CI (1.482-11.54)). The presence of impaired quality of life was significantly higher in the group alopecia than in the control group (p = 0.00006). There was no significant difference on personal history, potentially alopeciant drug intake (include hormonotherapy) and depilation of the eyebrows between the two groups. Main hypotheses are irreversible toxicity on stem cells follicles hairs, endocrine disorders and earlier onset of androgenetic alopecia in genetically predisposed subjects.

Conclusion:

The risk of permanent alopecia induced by anthracyclins and taxans based chemotherapy should not be underestimated. Early breast cancer pts, especially if they are postmenopausal, have to be aware of this toxicity with major aesthetic and psychosocial consequences.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-09-15.
Abstract P3-09-16: Improved quality of life for early stage breast cancer survivors on a low carbohydrate, calorie restricted dietary intervention
Authors: Krie AK , Demuth HM , Hu Y , Ageton C , Bohlen KN , Norfolk D , Thomes R , Muth J , Fahrendorf A , Kittelsrud J , Rojas-Espaillat LA , Davies GE
Published: August 2014

Background: It is well known that obesity and weight gain are significant issues in breast cancer survivorship. Weight gain frequently occurs after a breast cancer diagnosis, often attributed to adjuvant chemotherapy and the onset of menopause. Weight loss in the general population has been widely studied and shown to improve overall quality of life. The effect of weight loss on functional health and well being in breast cancer survivors is not well studied. The purpose of our study was to evaluate quality of life measures in overweight breast cancer survivors on a low carbohydrate, calorie restricted dietary intervention.

Methods: Overweight estrogen-receptor positive postmenopausal breast cancer survivors who completed radiation and chemotherapy were eligible for the dietary intervention. There were 23 women enrolled on the study, 14 completed the dietary intervention and were used for analysis. The dietary intervention utilizes 0.5g protein/pound (actual body weight), less than 40 grams of carbohydrates, and 800-1200 calories per day. Patients stayed on the dietary intervention for an average of 23 weeks (7-59) depending on their weight loss goal. Quality of life was measured by a short-form health survey, SF-36, measuring functional status, wellbeing and overall evaluation of health (Brazier, 1992). Patients completed the quality of life questionnaire at baseline and every two months until the end of year 2. The student's t-test was used to analyze mental and physical health scores at baseline and intervals thereafter, p-value ≤0.05 was considered statistically significant.

Results: The average total body weight reduction after dietary intervention was 19.9% equivalent to 43.7 pounds. Changes in the physical health scores from baseline were significant when compared to 2-months after diet start (p = 0.001) and diet termination (p = 0.00001). These changes remained significant at the 2-month follow-up visit (p = 0.0001). The changes to mental health scores were not statistically significant when compared to baseline.

Conclusion: Overall physical health quality of life scores were improved as a result of the low carbohydrate, calorie restricted dietary intervention in estrogen-receptor positive postmenopausal breast cancer survivors. Over half of the patients started with mental health scores above the general population norm, which could have contributed to the lack of statistical significance. Additional research with a larger sample size may confirm the positive influence of weight loss through a low carbohydrate dietary intervention.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-09-16.
Abstract P3-14-06: Residual tumor autophagy marker LC3B is a prognostic marker in local advanced breast cancer underwent neoadjuvant chemotherapy
Authors: Chen S , Jiang Y-Z , Huang L , Liu Y , Yu K-D
Published: August 2014

Purpose

A membrane-bound microtubule-associated protein chain 3B(LC3B) is known as one of the most specific biomarker for autophagy. The goal of this study is to investigate the prognostic value of autophagy marker LC3B in patients with residual tumors after neoadjuvant chemotherapy(NCT) for local advanced breast cancer(LABC)

Patients and Methods

Expression of LC3B in residual breast cancer cells were assessed by immunohistochemistry in surgical specimens from 229 patients who were diagnosed with histological proven invasive breast cancer. All patients had undergone neoadjuvant chemotherapy followed by mastectomy, and were considered as non pathological complete responders(non-pCR)after pathological evaluation. The density of positive staining of LC3B was measured with the use of a computerized image system. Prognostic value of various clinicopathologic factors was combined and evaluated by using Cox regression model.

Results

LC3B density was similar in the peripheral and central area of tumor(P = 0.328), however, it was siginifcantly lower in the extratumoral area(P<0.001 and P<0.001, respectively). High LC3B density was more likely to be observed in patients with PR-negative at diagnosis(P = 0.033), Beclin-1-positive(P<0.001) at surgery and higher Ki-67 index at surgery(P = 0.029). Breast cancer subtype was also correlated to LC3B expression(P = 0.003), an obvious lower proportion of LC3B-high density was detected in luminal-A patients than in other subtypes(32.4% in luminal-A, 59.4% in luminal-B, 65.4% in HER-2+, and 46.7% in TNBC). In survival analysis, only LC3B and residual nodal status after NCT resulted significant predictors of both RFS(HR = 1.180,P = 0.012 and HR = 3.067, 6.103, P<0.001, respectively) and overall survival(HR = 2.428, P = 0.008 and HR = 1.809,4.283, P = 0.003, respectively). Ki-67 was also an indepentent predictor for RFS(HR = 1.122, P = 0.019). The prognostic value of LC3B was most significant in triple-negative patients than in other subtypes. With a combination of LC3B expression and status of residual involved lymph nodes, patients were classified into four groups with different risk of relapse and death(P<0.001 for RFS and P = 0.003 for OS). Patients with no positive node residual and low LC3B expression were at low risk of relapse and death, with 5-year RFS and OS of 97% and 97%, respectively. However, the 5-year RFS and OS for patients with a positive node satus and high LC3B were only 52% and 66%, respectively.

Conclusion

LC3B is a prognostic marker in non-pCR patient after neoadjuvant chemotherapy for breast cancer, which highlighting the importance of autophagy in the biological behavior of chemo-resistence cancer cells. Evaluating and targeting autophagy in neoadjuvant setting may help in prevention of disease relapse in non-pCR patients.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-14-06.
Abstract P4-01-08: Assessing response in breast cancer with dynamic contrast enhanced magnetic resonance imaging: Are signal intensity time curves adequate?
Authors: Woolf DK , Padhani AR , Li SP , Beresford MJ , Jane Taylor N , Ah-See M-LW , Stirling J , Gogbashian A , Makris A
Published: August 2014

Introduction

Quantitative dynamic parameters including Ktrans can predict for both response and outcome in breast cancer patients treated with neoadjuvant chemotherapy (NAC). Quantitative methods are time-consuming to calculate in practice, requiring expensive additional software and expertise. For diagnostic purposes, signal intensity-time curves (SITC) are used for tissue characterisation. In this study we compared NAC-related changes in SITC with the quantitative DCE-MRI biomarker Ktrans (wash-in rate) and response and outcomes.

Methods

73 women with histologically-proven primary breast cancer underwent DCE-MRI studies before and after two cycles of NAC. Patients received anthracycline and/or docetaxel based chemotherapy. At completion of NAC, patients had surgery, radiotherapy and endocrine therapy / trastuzumab if ER/ HER2 positive. SITCs for each of the paired DCE-MRI studies were visually scored using a published pattern recognition schema consisting of 5 distinct patterns encompassing wash-in and wash-out phases and compared to the endpoints of OS, DFS and pathologic response.

Results

58 patients completed the study and were evaluable. Median age was 45 years (range 22 to 70), 41 patients were ER/ PR +ve, 12 Her-2 +ve and 13 triple negative. At baseline the majority of patients (n = 28, 48%) had a curve shape of 4 (Table 1). Linear regression analyses showed that curve shapes were significantly related to ktrans values both before (r2 = 0.465, p<0.0001) and after 2 cycles of NAC (r2 = 0.615, p<0.0001).

37 of 58 patients (64%) had changes in curve shape in response to NAC; 35 (95%) had decreases in curve shape and two (5%) had increases. Decreases in curve shape of 1 point were seen in 15 (43%), 12 patients had decreases in shape of 2 (34%), and eight had decreases of 3 (23%). Changes in curve shapes were significantly related to changes in ktrans (r2 = 0.576, p<0.0001).

Changes in curve shape were significantly correlated with clinical (p = 0.005) and pathologic response (p = 0.034).

Reduction in curve shape of ≥2 points was significant for overall survival using Kaplan-Meier analysis with a 5 year OS of 80.9% vs 68.6% (p = 0.048).

Table 1: Signal Intensity time curves (n = 58)Signal intensity time curve typeBaselinePost 2 cycles of NAC10 (0%)0 (0%)21 (1.7%)26 (44.8%)312 (20.7%)10 (17.2%)428 (48.3%)18 (31%)517 (29.3%4 (6.9%)

Conclusions

These data suggest that SITCs are closely related to the quantitative DCE-MRI biomarker Ktrans and that change in curve shape can be used to predict clinical and pathologic benefit as well as survival. In clinical practice, the use of SITC which needs no special software to generate, provides a useful method of assessing the effectiveness of NAC for primary breast cancer.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-01-08.
Abstract P4-03-01: Analysis of the impact of intraoperative margin assessment with adjunctive use of MARGINPROBE® vs. standard of care on margin status with different definitions of positive margin depth, results from a randomized prospective multi center study
Authors: Gittelman M
Published: August 2014

Background: The current practice of breast conserving surgery (BCS) involves intraoperative margin assessment according to the surgeon's gross assessment and judgment. This intraoperative assessment has been associated with a 20% to 40% reoperation rate to assure negative margins. MarginProbe (Dune Medical Devices, MA, USA) was developed to provide real-time assessment of lumpectomy specimens to evaluate for the presence of disease at the surgical margins. A 21-center international pivotal study was conducted to determine if adjunctive use of MarginProbe can enable surgeons to identify positive margins intraoperatively, resulting in fewer patients who are candidates for re-excision procedures. Results for a 1mm definition of positive margins have been reported previously. We sought to understand the benefit of device use at alternative thresholds.

Methods: 664 women with non-palpable lesions undergoing lumpectomy for DCIS and invasive cancer were enrolled and 596 randomized (1:1) in the operating room following standard of care (SOC) lumpectomy. In the device arm, MARGINPROBE was used to assess all surfaces of the lumpectomy specimen and positive readings required additional resections. The device was not used on additional resections. All specimens were examined to verify excision of the target lesion intraoperatively. Pathologists were blinded to study arm. Additional surgeries to re-excise involved margins were performed per each individual site criteria. Patients were followed for 2 months following surgery; additional procedures were documented. Distance from tumor to each margin face was recorded for each patient.

Results: Following lumpectomy, the number of patients having positive margins due to failed intraoperative assessment was significantly reduced in the device arm at each potential definition of positive margins.

Patients with positive margins after 1st surgeryDepthDevice (%) N = 298Control (%) N = 298p-value0mm6.413.40.00571mm15.438.3<0.00012mm22.549.7<0.00013mm30.957.0<0.00014mm36.661.7<0.00015mm39.966.4<0.0001*excludes positive margins on shavings, as device was only used on the main specimen

Conclusions: It has been shown previously that adjunctive use of MARGINPROBE significantly reduced the number of candidates for re-excision at a 1mm definition of positive margins. Based on this analysis, surgeons can expect a substantial reduction in the number of patients with positive margins at definitions from tumor on ink to 5mm.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-03-01.