bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P5-12-08: Survival differences by stage and race/ethnicity using the Nottingham prognostic index
Authors: Parise C , Caggiano V
Published: August 2014

Background

It is well documented that race/ethic disparities in breast cancer survival exist. The Nottingham Prognostic Index (NPI), based on tumor size, lymph node status, and histologic grade, is a well established method of predicting survival of operable breast cancer. The purpose of this investigation is to determine if race/ethnic disparities also exist among the NPI categories.

Method

We identified 157, 865 cases of stages 1-3 first primary female invasive breast cancer from the California Cancer Registry diagnosed between January 1, 2000 and December 31, 2010. The NPI was computed and cases were stratified as having good (NPI <3.4), moderate (3.4-5.4) and poor (> 5.4) prognosis. Kaplan Meier Survival analysis (95% CIs) was used to compare survival at eight years for patients who were white, black, Hispanic, or Asian/Pacific Islander (API) within each AJCC stage and NPI category.

Results

The distribution of cases by stage, race/ethnicity and good, moderate, and poor NPI categories is seen in the table.

Distribution of cases by stage, race/ethnicity and NPI categories WhiteBlackHispanicAPITotalStage 1     Good15,8287442,4432,16921,184Moderate28,9841,8025,1954,20040,181Poor9,7701,0152,4351,85515,075Stage 2     Good237234842350Moderate4,0872567315155,589Poor37,1094,00710,8937,18659,195Stage 3     Good803112Moderate56216983Poor9,4511,2793,7021,76416,196Total    157,865

Stage 1: There were no significant differences in survival within the good category. In the moderate category, APIs (95.5; 94.5, 96.6) had better survival than whites (93.6; 93.2, 94.0) whereas blacks (90.1; 87.8; 92.3) had worse survival. In the poor NPI category, APIs (92.6; 90.8, 94.4) also had better survival than whites (88.7; 87.8, 89.6).

Stage 2: In the moderate NPI category, blacks (92.8; 89.0, 96.7) had worse survival than whites (94.0; 93.0, 95.1) and in the poor category, blacks (73.8; 71.9, 75.8) and Hispanics (80.7; 79.5, 81.8) both had worse survival than whites (81.8; 81.2, 82.3) while APIs had better survival (84.6; 83.3, 85.8).

Stage 3: There were too few patients in the good and moderate NPI categories. In the poor category, blacks (47.8, 43.4, 52.1) had worse survival than whites (60.1; 58.4, 61.8) while APIs (64.2; 60.2, 68.2) had better survival.

Conclusion

The NPI provides further refinement of the disparities in survival among race/ethnicity. It appears that APIs have better survival than whites in all stages of disease.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-12-08.
Abstract P5-12-10: Pathological characteristics and patterns of recurrence and mortality among young Mexican breast cancer patients
Authors: Villarreal-Garza CM , Hoyos CM , Meza-Herrera V , Palacios VA , Hernandez-Vega MB , Aguila C , Lara-Medina F , Meneses A , Mohar A
Published: August 2014

Background: In Mexico, it is recognized that breast cancer (BC) is diagnosed at younger ages than that reported in the US and other populations. Although national data is not available regarding BC age of diagnosis distribution, data from the INCAN, the main referral center in Mexico, showed that 17% of the total 893 newly diagnosed BC patients seen in 2012 were younger than 40 years old (which is more than twice that -7%- reported for US BC patients). We conducted a retrospective study in order to describe the frequency of BC among young Mexican BC patients, as well as their pathological characteristics at diagnosis and patters of recurrence.

Methods: Clinical and pathologic data from young pts (≤42 years old) who were newly diagnosed with invasive BC between January 2007 and December 2010 at the INCAN in Mexico and were followed for at least 2 years were identified. Clinical stage at diagnosis was recorded and estrogen receptor, progesterone receptor and HER2 expression were determined by immunohistochemistry and/or FISH. Proportion differences were tested using the Chi-square test.

Results: 445 young patients were identified from a total of 2919 BC patients (15%). A total of 320 patients met the inclusion criteria for analysis. Median age of diagnosis was 36 years (19-42). 49% of patients were very young patients (≤ 35 years). 19% were diagnosed as early disease, 67.5% as locally advanced BC and 13.5% as metastatic. 32% of patients had triple negative BC disease, while 27% were HER2 positive. From the non-metastatic patients at diagnosis, 31% developed recurrence (65% systemic, 21% loco regional and 14% both). After a median follow-up of 26 months, 18% of the 320 patients died secondary to BC disease progression.

Conclusions: Although this series corresponds to patients treated at a reference national center, the data reported in this study suggests that BC among young women is very prevalent in Mexico compared to other populations. The causes underlying the striking difference in age at diagnosis in Mexican BC patients are unknown and have not been investigated, including the genetic contributing factors. As reported in non-Hispanic population studies, BC among young women is diagnosed in more advanced stages, and triple-negative and HER2 positive diseases are more frequent. It is associated with a high proportion of systemic and loco regional recurrence, with a dismal prognosis. Due to the substantial number of BC cases among young women in Mexico, its prospective study is more than justified. In order to meet with this goal, our group is preparing the establishment of the Mexican Young Women's Breast Cancer Cohort Program at the INCAN in Mexico and to launch the related scientific projects related to this plan.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-12-10.
Abstract P5-13-12: Risk of hepatitis B virus (HBV) reactivation in hepatitis B surface antigen negative/ hepatitis B core antibody positive and/or hepatitis B surface antibody positive breast cancer patients who receive chemotherapy
Authors: Hattori M , Ito Y , Takahashi S , Fukada I , Iwase T , Iwata H , Hatake K
Published: August 2014

Background: Recently, chemotherapy-induced reactivation of hepatitis B virus (HBV) has been reported not only in patients positive for hepatitis B surface antigen (HBsAg), but also in patients negative for it. Although HBV reactivation is associated with substantial morbidity and mortality in patients undergoing cancer chemotherapy, the exact frequency and risk for HBV reactivation in HBsAg-negative breast cancer patients who receive chemotherapy remains unclear. In this study, we examined the frequency and risk for HBV reactivation in Japanese breast cancer patients who have received chemotherapy.

Methods: A total of 562 HBsAg-negative breast cancer patients received chemotherapy from June 2008 to May 2009 at the Cancer Institute Hospital of JFCR in Japan. Antibody to hepatitis B core antigen (anti-HBc) and antibody to hepatitis B surface antigen (anti-HBs) were screened for before chemotherapy in all patients. In patients who were positive for anti-HBc and/or anti-HBs, serum HBV-DNA levels were measured and monitored during and after chemotherapy.

Results: 93 (17.4%) HBsAg-negative breast cancer patients were found to have resolved hepatitis B (HBsAg-negative, anti-HBc-positive and/or anti-HBs-positive). One patient was found to be positive for HBV DNA before the initiation of chemotherapy and received adjuvant chemotherapy with Entecavir prophylaxis. 65 patients received chemotherapy in adjuvant or neoadjuvant setting, 28 patients received it for metastatic disease. In our monitoring period (median 15.3 months), no HBsAg-negative/ anti-HBc-positive and/or anti-HBs-positive breast cancer patients developed HBV reactivation during and after their chemotherapy.

Conclusions: A number of HBsAg-negative breast cancer patients have received chemotherapy with a risk for HBV reactivation; however, it has been determined that conventional chemotherapy regimens for breast cancer are unlikely to increase the risk of developing HBV reactivation in these patients.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-13-12.
Abstract P5-14-12: Cosmetic outcome is better after intraoperative radiotherapy compared with external beam radiotherapy: An objective assessment of patients from a randomized controlled trial
Authors: Keshtgar M , Williams NR , Corica T , Bulsara M , Saunders C , Flyger H , Bentzon N , Cardoso JS , Michalopoulos N , Joseph DJ
Published: August 2014

The randomised controlled TARGeted Intraoperative radioTherapy (TARGIT) Trial has demonstrated non-inferiority between the novel technique of TARGIT (intra-operative radiotherapy with Intrabeam ®) and conventional whole-breast external beam radiotherapy (EBRT) in women with early breast cancer, in terms of the primary outcome measure of risk of local relapse within the treated breast. As there are very low recurrence rates, cosmesis becomes an increasingly important outcome of breast conserving treatment with both surgery and radiotherapy. This study was performed to determine if the single high dose of TARGIT compared with EBRT leads to impaired cosmesis.

A validated, objective assessment software tool for evaluation of cosmetic outcome was used. Frontal digital photographs were taken at baseline (before radiotherapy) and annually thereafter for up to five years. The photographs were analysed by BCCT.core which produces a composite score based on symmetry, colour and scar.

A total of 342 patients were assessed, all over 50 years old with a median age at baseline of 64 years (IQR 59 to 68). The BCCT.core scores were dichotomised into Excellent and Good (EG), and Fair and Poor (FP). There were statistically significant increases in the odds of having an outcome of EG for patients in the TARGIT group compared with the EBRT group at year 1 (OR = 2.07, 95%CI 1.12 to 3.85, p = 0.021) and year 2 (OR = 2.11, 95%CI 1.0 to 4.45, p = 0.05).

This objective assessment of aesthetic outcome in patients from a randomised setting demonstrates that those treated with targeted intraoperative radiotherapy have a superior cosmetic result compared with those patients who received conventional whole-breast external beam radiotherapy.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-14-12.
Abstract P6-02-01: Elucidating the change of TRAIL sensitivity in basal like TNBC cell lines by lapatinib, and further therapeutic implication
Authors: Lim B , Dolloff NG , Allen JE , Dicker DT , El-Deiry WS
Published: August 2014

Triple negative breast cancer (TNBC) comprises 15-20% of breast cancer, and carries a poor prognosis. Recently, efforts to understand this heterogeneous group of cancers have led to recognition of different subtypes of TNBC by Dr. Pietenpol et al based on genetic and functional signature. So far, the only targeting agent for TNBC still remains as androgen receptor inhibitor for LAR group. Thus, other strategies in therapeutic development for TNBCs are necessary. TRAIL (Tumor Necrosis Factor-related apoptosis inducing ligand), a member of the TNF-alpha family of death receptor ligands, induces apoptosis by binding death receptors (DR4 and DR5), could be a good strategy in therapeutic development in TNBC. Unfortunately, majority of breast cancer cell lines are resistant to TRAIL targeted therapy especially basal like group of cells, as previously shown in the work of Lipkowitz at the NCI. Lapatinib, a well known as erbB 1 and 2 inhibitor had been found to have off target activity inducing JNK, an important activator of nuclear transcription of death receptor, and mitochondrial mediated intrinsic apoptosis pathway. Interestingly, study of combination therapy with lapatinib and TRAIL not only confirmed baseline poor sensitivity to TRAIL induced apoptosis in “basal like” HCC 1937 and MDA-MB-468 cell lines, but also revealed an unexpected difference in sensitization to TRAIL induced apoptosis by Lapatinib pre-treatment between these two cell lines. When treated with 48hrs Lapatinib high–dose treatment, HCC 1937 showed increased sensitization whereas MDA-MB-468 did not. Both HCC 1937 and MDA-MB-468 are in the same basal like 1(BL1) group by Dr. Pietenpol's analysis, and their baseline sensitivity to TRAIL inducing apoptosis are the same. In terms of apoptosis - there are two big categories of cells. Type I cells are independent of mitochondria for the induction of Fas death receptor mediated apoptosis, where as type II cells are mitochrondria-dependent. Thus we hypothesized that this difference in lapatinib induced TRAIL sensitization between two cell lines is due to difference in one being type I vs the other being type II cell, and this type of apoptosis is not likely equal in same subgroup of TNBC. If this hypothesis is correct, targeting apoptosis pathway in TNBC should incorporate the recognition of apoptosis cell types rather than functional/genetic based subtypes. We will further elucidate our hypothesis by studying JNK, caspase 3 and 9 activity and downstream of both intrinsic, extrinsic apoptosis pathway.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-02-01.
Abstract P6-04-13: Preclinical testing using a novel CT20p peptide-nanoparticle combination in breast cancer
Authors: Vishnubhotla PS , Boohaker RJ , Lee MW , Nemec KN , Santra S , Khaled AS , Perez M , Khaled AR
Published: August 2014

BACKGROUND: The marked difference in metabolism observed between tumor and normal cells could contribute to the development of invasive and metastatic forms of breast cancer. The problem is that while patients diagnosed with invasive forms of breast cancer may be initially responsive to treatment, a significant number develop relapsing and even metastatic disease. There is a critical unmet need to develop new therapeutic approaches for patients diagnosed with invasive forms of breast cancer that are effective given the unique metabolism of tumor cells. METHODS: We examined the cytotoxic properties of a novel peptide, CT20p, derived from the C-terminus of Bax. For delivery to cells, the amphipathic nature of CT20p allowed it to be encapsulated in polymeric nanoparticles (NPs). NPs were made using aliphatic hyperbranched polyester (HBPE) that incorporated surface carboxylic groups and interior hydrophobic cavities for encapsulation of CT20p. To examine the cytotoxic potential and targeting capacity of CT20p-HBPE-NPs, we treated MDA-MB-231 breast cancer cells and MCF-10A breast epithelial cells with the peptide-nanoparticle combination and measured changes in mitochondrial function, cell metabolism and induction of apoptotic and non-apoptotic cell death. The ability of CT20p-NP-HBPE to cause tumor regression was examined by subcutaneously implanting MDA-MB-231 cells in nude mice. RESULTS: Initial studies showed that CT20p caused the release of calcein from mitochondrial-like lipid vesicles, without disrupting vesicle integrity, and, when expressed as a fusion protein in cells, localized to mitochondria. While the peptide alone had little effect upon intact cells, likely not penetrating the plasma membrane, when encapsulated and delivered by nanoparticles, CT20p-HBPE-NPs proved an effective killer of breast cancer cells. CT20p-HBPE-NPs initiated non-apoptotic cell death within 3 hours of treatment by targeting mitochondria and deregulating cellular metabolism. Nanoparticles alone or nanoparticles encapsulating a control peptide had minimal effects. The cytotoxicity of CT20p-HPBE-NPs was most pronounced in breast cancer cells, sparing normal, epithelial cells. In implanted breast tumors, CT20p-HBPE-NPs accumulated in tumors within 24 hours and reduced tumor burden by 50-80%. CONCLUSION: These results reveal the innovative features of CT20p that allow nanoparticle-mediated delivery to tumors and the potential application in combination therapies that target the unique metabolism of cancer cells.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-04-13.
Abstract P6-04-14: mRNA expressions of lamin B1 and lamin B receptor: Clinical correlations with human breast cancer
Authors: Wazir U , Ahmad MH , Bridger JM , Harvey A , Jiang WG , Sharma AK , Mokbel K
Published: August 2014

BACKGROUND: Lamin B (LMNB) and lamin B receptor (LBR) are key components of the nuclear envelope, with roles in chromosomal stability, DNA repair, and cell differentiation. Lamins provide structural support to the nuclear envelope, while LBR is believed to anchor lamin B to the envelope. In addition, LBR also has a number of downstream mediators which affect cell cycle and cell differentiation.

Classically, they have been implicated in a spectrum of largely congenital ailments including certain forms of muscle dystrophy and progeria. These conditions are collectively referred to as “laminopathies”.

More recently, defects in the expression of lamins have been implicated in neoplasias of the colon, prostate, liver and ovaries.

In this study, we have endeavoured to elucidate the relationships between the mRNA expressions of LMNB1 and LBR and the clinicopathological parameters of human breast cancer.

METHODS: Breast cancer tissues (n = 115) and associated non-cancerous tissue (ANCT) (n = 30) underwent reverse transcription and quantitative PCR. Transcript levels were correlated with clinicopathological data.

RESULTS: LMNB1 mRNA expression was higher in ANCT as compared to cancerous tissue (ANCT vs. cancerous tissue: 0.12 vs. 0.00; p = <0.0001). This difference remained highly significant in all patient categories by tumour grade and clinical stage.

In addition, the expression of LMNB1 declined with worsening clinical outcome. This association was statistically significant when comparing patient with disease-free survival with disease related mortalities (Disease-free vs. mortalities: 0.0011 vs. 0.000; p = 0.0177).

LBR mRNA expression was found to be directly associated with tumour grade (grade 1 vs.3: 0.00 vs. 0.00; p = 0.0479) and the Nottingham Prognostic Index (NPI1 vs. 3: 0.00 vs. 0.00; p = 0.0551).

CONCLUSIONS: To our knowledge, this is the first study to suggest such a role for LMNB1 and LBR in human breast cancer.

The contrasting relationships of LMNB1 and LBR expressions with the clinicopathological parameters of human breast cancer may suggest that disruptions in the physiologically normal interactions between these molecules in the nuclear envelope may serve as pathway leading towards the pathogenesis of human breast cancer. Potentially this may be a significant pathway requiring further investigation to be better understood, in order to identify further potential areas for therapeutic intervention.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-04-14.
Abstract P6-05-12: Comprehensive molecular analysis of estrogen receptor positive breast cancer to determine clinically actionable alterations
Authors: O'Brien C , Savage H , Huw L , Fumagalli D , Salgado R , Criscitello C , Pugliano L , Laios I , Piccart M , Michiels S , Sotiriou C , Loi S , Lackner MR , Wilson TR
Published: August 2014

Introduction.

Understanding the genetic landscape of estrogen receptor positive breast caner is critical for defining clinically actionable alleles that may be targeted using next generation biologics. PIK3CA mutations have previously been reported to be the most common mutation within estrogen receptor positive breast cancer, however the overlap and mutual exclusivity with other key driving alleles is poorly understood, especially how these biomarkers change following treatment failure. We custom designed a mutation, copy number variation and RNA expression panels to profile biomarkers from low quality formalin fixed paraffin embedded extracted material. Data relating to key pathways, such as PI3K and immune modulatory pathways, and overlap with other biomarkers will be presented.

Methods.

Formalin fixed paraffin embedded material was available from 195 primary cases and 95 paired metastatic estrogen receptor positive breast cancer patients. Samples were assayed for the expression of PTEN by IHC, hotspot mutations in 11 oncogenic driving genes using Q-PCR based technology, copy number alterations in 42 genes using Q-PCR based technology and RNA expression using a custom designed 400 breast cancer specific NanoString gene panel.

Results.

PTEN loss, as defined by H-score of 0, was found in 4.5% of primary samples and in 4.3% of metastatic samples. PIK3CA mutations were found in 43% of primary samples and in 38% of metastatic samples and were largely found to be mutually exclusive with PTEN loss. AKT1 mutations were found in 5.4% of primary samples and in 4.1% of metastatic samples. Less frequent mutations in KRAS (7.0%) and BRAF (1.7%) were found in the primary sample, and some were co-existing with PIK3CA mutations. Copy number gains were found in CCND1 (23.5%), ZNF703 (19.5%), FGFR1 (16.8%) and PAK1 (11.4%) and were largely concordant with the paired metastatic sample. Analysis with clinical outcome is ongoing.

Conclusions.

PIK3CA was the most frequently altered gene detected and was mutually exclusive with other key driving mutations within the PI3K pathway (AKT1 and PTEN). A strong concordance was observed between genetic alterations found in the primary sample and the paired metastatic sample. Mutations and expression gains within clinically actionable targets were found less frequently, but may provide alternative treatment strategies for these patients following failure of endocrine therapy.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-05-12.
Abstract P6-05-18: A53, cell cycle phenotype and Cdc7 kinase: Identifying patients likely to benefit from targeted Cdc7 therapy
Authors: Ian P , Leigh E , Fizza M , Kai S , Gareth WH , Richard S
Published: August 2014

We previously reported multiparameter analysis of cell cycle regulatory proteins in breast cancer and identified three prognostic ‘cell cycle phenotypes’. Phenotype iii represents cells traversing through the mitotic cell division cycle and is associated with poor prognosis and high Cdc7 levels1. Cdc7 kinase initiates DNA synthesis at chromosomal replication origins and is rate-limiting for S phase entry. In cell-based studies we discovered a new, p53-dependent cell cycle checkpoint which reversible arrests normal cells in G1 phase if DNA replication initiation is perturbed. In cancer cells treated with Cdc7 inhibitors this checkpoint function is lost, resulting in aberrant S phase entry and subsequent apoptotic cell death2,3. Cdc7 kinase is therefore emerging as a novel therapeutic target in cancers bearing mutant p53.

In this study we investigated whether the inclusion of p53 mutation status adds further prognostic power to the cell cycle phenotype. We also questioned whether p53 mutant breast cancers express high Cdc7 levels and are thus more likely to be of cell cycle phenotype iii (susceptible to Cdc7-targeted therapy).

Our results show that Cdc7 levels are inversely correlated with p53 mutation status (n = 173) and are highest in cell cycle phenotype iii and harder to treat Her-2 and triple negative breast cancer subgroups. Cell cycle phenotype is the strongest predictor of early relapse compared to p53, Ki67 and Cdc7 on univariate analysis and remains so on multivariate analysis after adjusting for p53 status (HR = 3.80, p = 0.002).

These findings support the supposition that p53 negatively regulates Cdc7 expression. Combined testing for p53 status, cell cycle phenotype and Cdc7 expression identifies those patients with breast cancer most likely to benefit from targeted therapy with Cdc7 inhibitors.

1 Br J Cancer. 2009 Mar 24;100(6):959-70

2 EMBO J. 2010 Oct 6;29(19):3381-94

3 Am J Pathol. 2010 Oct;177(4):2034-45.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-05-18.
Abstract P6-05-22: Young-onset breast cancer exhibits a more aggressive tumor biology
Authors: Cabioglu N , Bozdogan A , Eren-Boler D , Kara H , Karayagiz H , Uras C
Published: August 2014

Objective: Previous studies demonstrated poorer survival in patients with young-onset breast cancer. Therefore, we investigated the distinguishing molecular characteristics associated with young onset breast cancer.

Material and Methods: Between September and February 2013, 506 patients with breast cancer, who underwent surgery at our institution, were retrospectively analyzed tailored by age ≤40 (n = 94; 18.6%) and >40 to determine clinicopathological and biological differences. Therefore, molecular subtypes were determined by immunohistochemistry for ER, PR, Ki67, and HER2-neu.

Results: The median age was 50 (27-87). Patients aged ≤40 presented with more advanced disease (stage III/IV; 34% for ≤40 vs 20% for >40, p = 0.003). Among patients, who underwent surgery as initial treatment (n = 411), patients ≤40 were more likely to have or tumors with invasive ductal carcinoma type (p = 0.049), or tumors >20 mm (p = 0.033), or axillary positivity (p = 0.003), or with multifocality/multicentricity (p<0.001), or with high nuclear grade (p = 0.019), or with histological grade (p = 0.023), or lymphovascular invasion (p = <0.001), higher Ki-67 expression (%15≤) rates (p = 0.014), or lower luminal A rates (luminal-A vs other; p = 0.04) compared with patients aged >40. Furthermore, logistic regression analyses revealed presence of multifocality/multicentricity (OR:2.6; 95% CI: 1.4-4.5; p = 0.001), lymphovascular invasion (OR:2.1; 95% CI: 1.2-3.6; p = 0.008), and molecular subtype other than luminal A (OR:2.4; 95% CI: 1.1-5.1; p<0.001) were significant features that were associated with breast cancer aged ≤40.

Conclusion: Our results suggest that tumors of patients with younger age exhibit a more aggressive biology compared to patients older than 40 as shown by molecular subtype analyses that could result in poor prognosis.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-05-22.
Abstract P6-06-42: Impact of molecular subtype on overall survival according to age in Korean women
Authors: Lee A , Woo J , Yun C , Min SY , Kim Y , Yu S , Lim W , Paik N-S , Moon B-I
Published: August 2014

Introduction: Breast cancer is a heterogeneous diseases, which is based on expression of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Using these factors, molecular subtype can be determined as luminal A, luminal B, HER2+, and TNBC. This is considered as an important prognostic factor. In breast cancer, age is the one of the important prognostic factors and prognosis is varied according to patients’ age. We performed this study to analyze the impact of molecular subtypes on prognosis of breast cancer according to patients’ age.

Patients and methods: We performed this study by using Korean Breast Cancer Society Registration Program data. Total 15,286 patients are included into this study, and they underwent surgery during the period Jan. 2001 to Dec. 2006. All patients were divided into two groups according to age (younger: age≤34, older: age≥35) and molecular subtypes were classified into four groups as follows: luminal A (ER+ and/or PR+, HER2-), luminal B (ER+ and/or PR+ HER2+), HER2+ (ER-, PR-, HER2+), and triple-negative (ER-, PR-, HER2-). We determined prognostic impact of molecular subtype on overall survivals (OS). Clinicopathologic results and OS were compared by chi-square test, Kaplan Meier test, and Cox's hazards model.

Results: Younger group more frequently had tumors with negative hormone receptor (ER-/PR-), worse prognostic factors and diagnosed with more advanced stage compared to older group. In univariate analysis, molecular subtype was not related with OS in younger group (p = 0.069), but not in older group (p<0.001). In multivariate analysis, molecular subtype was an independent prognostic factor for OS only in older group (p = 0.690 vs p<0.001).

Conclusion: In young breast cancer patients, less than 35 years, the impact of molecular subtypes on overall survival was not significant compared to other age group.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-06-42.
Abstract P6-06-53: Ki67 labelling index (Ki67LI) can subdivide homogeneous HER2 negative luminal grading groups (HNL-GG) in distinct biological entities
Authors: Ferro A , Russo LM , Eccher C , Triolo R , Barbareschi M , Caldara A , Dipasquale M , Galligioni E
Published: August 2014

Background: Several studies have emphasized Ki67LI biologic and prognostic value and its potential application of its assessment in routine practice, particularly to define prognostic subgroups of luminal/hormone receptor-positive (HR+) tumors.

Methods: Ki67LI was identified by immunohistochemical staining in 3760 EBC pts treated from 1995 to 2008. Median age was 61 y. The relationship with clinic-pathological parameters and the prognostic significance of KI67LI were investigated in all EBCs and in HER2 negative luminal (2380 HNL) cases stratified on homogeneous grading (594 G1, 1282 G2, 504 G3).

Results: Median Ki67LI values were 22% in all cases, 20% in HNL and 10, 20 and 35% in different HNL grading group (HNL-GG).

Ki67LI > 22% (1873 pts) was significantly (p<0.001) associated with younger age, ductal type, greater size, positive N, poor G, absent or low ER /PR expression, positive HER-2, triple negative subtypes.

Local and Distant Relapses were 138 (7.3%) and 355 (18.9%) in < or > 22% Ki67LI respectively. Median time to first event was 31.7 ms in > 22% vs 50.1 ms in < 22% Ki67. At median f-up of 77 months EFS and OS were 91.9 and 92.1% in < 22% vs 78.9% and 81% in > 22% Ki67 respectively (p <0.001).

Prognosis in term of DFS and OS was consistently worse for > 22% compared to < 22% Ki 67 in all clinical-pathological subsets, except in negative ER group. In multivariate analysis, KI 67mantained an independent prognostic significance for DFS and OS.

In HNL, EFS and OS were 93.7 and 92% in < 20% vs 81.7 and 83.3% in >20% Ki67(p <0.001). Using median ki67LI value for different homogenous HNL-GG as cutoffs, we stratified these populations in low and high risk. The results are shown in the following table.

Stratification in high and low risk subgroups of homogeneous HNL-GGSubgroupsEFSpOSpG1 high91.7%0.04392.7%0.114G1 low96.0% 96.0% G2 high84.2%<0.00187.5%0.012G2 low93.7% 90.6% G3 high70.9%0.05376.4%0.036G3 low83.2% 80.7% 

Conclusions: Our study confirms prognostic value of Ki67LI in EBC, associated with other clinical-pathological characteristics. Cutoffs are different into HNL-GG. They can cathegorize at least two biological entities in every grading group providing additional prognostic information in planning therapies and outcome prediction.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-06-53.
Abstract P6-07-11: Health economic impact of breast cancer index (BCI) for late disease management in patients with estrogen receptor-positive, node-negative breast cancer
Authors: Gustavsen G , Schroeder BE , Kennedy P , Pothier K , Erlander MG , Schnabel CA
Published: August 2014

Background

Several recent randomized, prospective clinical trials (MA.17, ATLAS, aTTom) have demonstrated the clinical benefit of extending endocrine therapy beyond 5 years to address the persistent risk of recurrence in patients with ER+ breast cancer. Breast Cancer Index (BCI) is a gene expression-based test that predicts overall (10y) risk of recurrence in patients with ER+, LN- breast cancer, and also informs late (post-5 year) disease management by providing information on risk of late (≥5y) recurrence, and likelihood of benefit from extended (≥5y) endocrine therapy. Previously, BCI was shown to be cost saving across a 10-year disease horizon. The current study specifically assessed the health economic benefit of BCI for late disease management, evaluating the impact of identifying patients at risk of late recurrence and those that may benefit from extended endocrine therapy.

Methods

A fact-based economic model was developed which projected the cost and effectiveness of BCI from a US third-party payer perspective in a hypothetical population of patients with ER+, LN- breast cancer who are disease free at 5 years post-diagnosis compared to standard clinical practice. Patients flowed through the model based on patterns of care and BCI data. Costs associated with endocrine therapy, toxicity, follow-up, and recurrence were modeled over 5 yrs. Model inputs were based primarily on published literature, and supplemented by interviews with disease experts and payers. Sensitivity analyses were performed around key inputs to estimate effects on the model.

Results

Use of BCI is projected to be cost saving in this population of patients that are disease-free at 5 years post-diagnosis, with a net cost savings of $691 per patient tested after accounting for BCI cost. Gross cost savings were projected to be achieved through reduced recurrence in patients receiving extended endocrine therapy based on BCI ($4,102), and reduced recurrence in previously non-compliant patients ($39). BCI was cost saving for both pre- and post-menopausal women. Sensitivity analyses demonstrated that results were most sensitive to current use of extended endocrine therapy in postmenopausal patients, future use of extended endocrine therapy in BCI (H/I) high patients, and the percentage of patients characterized as BCI (H/I) high.

Conclusions

BCI is projected to be cost saving in a population of ER+, LN-, breast cancer patients who are recurrence free at 5 years post-diagnosis. Cost savings are achieved through projected impact on extended endocrine therapy use and endocrine therapy compliance, and provide additional cost savings beyond impact on chemotherapy utilization. These findings require validation in additional cohorts, including studies of real-world clinical practice.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-07-11.
Abstract P6-08-06: Sexual function, sexual activity and quality of life in women with breast cancer
Authors: Beutel B , Schrof I , Rita H , Lehmann K , Kullmann V , Alexander T , Herbert S , Andreas DB
Published: August 2014

Background: Breast cancer (BC) is generally assumed to have an impact on sexual function and activity. Although there are several studies addressing the issue, case control studies are currently limited.

Methods: We performed a cross-sectional investigation of sexual function and activity utilizing the sexual activity questionnaire, the female sexual function index, and parts of the EORTC QLQ C30. Patients with breast cancer (BC) were compared with a control group (C) of non-cancer patients. Inclusion of BC was only allowed if treatment was completed ≥ 12 months previously and patients were disease-free. This study was approved by the ethical committee of the Landesärztekammer Hessen. All consecutive patients with breast cancer who were treated at our hospital were prospectively documented in a clinical tumor registry since 2001. All patients’ records are updated annually. The control sample without any oncologic disease of 392 age-matched females was recruited in the Department of Prosthodontics, University Hospital Mainz.

Results: Between December 2009 and May 2010 the questionnaires were sent out to 790 women (398 x BC and 392 x C), 21.6% of which responded. Response rates in both groups were equivalent (84 patients with BC [21.2%] and 87 control subjects [22.2%]). Median age was 57 years (C) and 62 years (BC), respectively (p = 0.005). 51.5% (C) and 60% (BC) were not sexually active, mainly owing to lack of a partner (39%) or lack of interest (21%) in controls and lack of interest (48%, p<0.05), self-reported physical problems (34%, p<0.05), and physical problems of the partner (22%, p<0.05) in breast cancer patients. There were significant differences between both groups in the SAQ discomfort score (p<0.05). We did not observe significant differences in quality of life or other scores regarding sexuality.

Conclusions: About half of the women in both groups were not sexually active. However, reasons for non-activity differ. Quality of sexuality tends to be impaired in BC patients, but this seems not to influence quality of life. A shift of priority caused by substantial anxiety regarding cancer specific survival might explain our findings.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-08-06.
Abstract P6-09-05: Neem leaf extract, rich in nimbolide and azadirachtin targets radiation-induced stemness in surviving breast cancer cells
Authors: Pandian V , Natarajan M , Aravindan S , Herman TS , Aravindan N
Published: August 2014

Recently, we have shown that the neem leaf extract (NLE) rich in Nimbolide and Azadirachtin exerted radiosensitization and alleviates tumor progression in varied solid tumor models. Accordingly, in this study, we investigated its potential in the regulation of radiation (IR)-induced stemness in surviving breast cancer (BCa) cells. Human breast adenocarcinoma (MCF-7) cells either mock-irradiated or exposed to IR (2Gy) with or without NLE (1, 10 or 100μg) pre-treatment (for 3h) and analyzed at 3h or 24h post-IR. Transcriptional alterations of 93 molecules that drive EMT, CSCs self-renewal capacity and pluripotency maintenance were analyzed using QPCR profiling. NANOG, SOX2, ABCG2, N-cadherin, E-cadherin and GSK3β expression was examined by immunoblotting. Radiation profoundly increased 67 stem-cell related molecules in surviving BCa cells. NLE exerted a dose-dependent (1μg, 23; 10μg, 51; 100μg, 64 genes) inhibition of IR-induced stem-cell related molecules. Second-phase observations at 24h post-IR revealed no recovery of NLE-inhibited transcription with complete inhibition of 12, 66 and 64 genes after 1, 10 and 100μg. Gene comparison analysis revealed both ‘dose-independent’ (20genes at 3h and 12genes at 24h) and ‘time-independent’ (6, 50 and 61 genes at 1μg, 10μg and 100μg respectively) inhibition. Interestingly, six genes (BMP4, CDH1, EGF3, FOXA2, GSK3β and HDAC2) showed both ‘time-and-dose-independent’ inhibition. Coherently, immunoblotting revealed a consistent regulation of IR-induced NANOG, SOX2, ABCG2, N-cadherin in the surviving BCa cells. Together these data demonstrate that NLE targets IR-induced stemness in surviving BCa cells and may thus serve as a potential “deliverable” to negate breast cancer relapse and progression.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-09-05.
Abstract PD4-1: Comparison of mutations and protein expression in potentially actionable targets in 5500 triple negative vs. non-triple negative breast cancers
Authors: O'Shaughnessy JA , Gatalica Z , Kimbrough JM , Millis SZ
Published: August 2014

Introduction

Triple negative breast cancer is a heterogeneous disease with no established targeted treatment options for patients with metastatic disease.

Methods

A cohort of 5500 patient samples was evaluated for differences and similarities in gene mutation (Sanger or Illumina Truseq), protein expression (immunohistochemistry), and/or amplification/rearrangement (CISH or FISH) between triple negative and non-triple negative breast cancers, with 16% of those patients identified as triple negative by IHC testing.

Results

PIK3CA and P53 gene mutations, PIK3CA, TOP2A, and EGFR amplification (measured as ≥ 4 copies in 40% or more tumor cells by FISH), and AR, EGFR, SPARC, and TS protein expression were shown to differ between the triple negative and non-triple negative breast cancer patients. The rate of mutation of the P53 tumor suppressor gene, measured by sequencing was twice as high in TNBC patients as in non-TNBC patients (60% versus 30%), while PIK3CA was mutated in half as many TNBC patients (12% versus 31% of non-TNBC patients). Amplification of Her2, PIK3CA, cMYC, and TOP2A was significantly greater in the non-TNBC patient population, while amplification of EGFR was significantly higher in the TNBC patient population (24% versus 13% of non-TNBC patients). Androgen receptor was expressed in 56% of the non-TNBC cohort but in only 15% of the TNBC cohort.

Conclusions

The gene mutation and protein expression differences in the triple negative subset of breast cancer patients, such as EGFR amplification, SPARC protein expression and P53 gene mutation, could inform new therapeutic possibilities for these difficult to treat, often more aggressive cancers.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr PD4-1.
Abstract PD5-3: Anti-metastatic activity, chemotherapeutic enhancement and therapeutic potential of targeting Hsp90 with ganetespib in triple negative breast cancer
Authors: Proia DA , Zhang C , Sequeira M , Jimenez J-P , He S , Nagai M , Acquaviva JL , Smith DL , Sang J , El-Hariry I
Published: August 2014

Background: While the incidence of triple negative breast cancer (TNBC) is only 10-20%, these tumors show a disproportionate mortality for breast cancer patients. Due to a lack of effective molecular targets in this disease, therapeutic options are largely limited to systemic chemotherapeutic approaches which have shown disappointing efficacy in the metastatic setting. Here we undertook a comprehensive evaluation of the activity of the drug candidate, ganetespib, a potent inhibitor of heat shock protein 90 (Hsp90), in this malignancy.

Methods: The sensitivity of TNBC cells to ganetespib was determined in viability assays using a panel of tumor lines. The effects of ganetespib exposure on client proteins and their effector pathways were examined by Western blot and reverse phase protein array analysis. The anti-metastatic activity of ganetespib was evaluated using a 4T1 metastasis model. Combinatorial drug analyses were performed with chemotherapeutic agents. DNA damage and cell cycle disruption were assessed using the comet assay, Western blotting and fluorescence microscopy. The in vivo efficacy of the compound, both as a single agent and in combination, was established using MDA-MB-231 xenograft models. Computed tomography scans were obtained for a metastatic TNBC patient undergoing ganetespib treatment.

Results: Ganetespib reduced cell viability in TNBC cell lines with low nanomolar potency. Ganetespib treatment induced robust destabilization of multiple client proteins and oncogenic signaling pathways and suppressed lung metastasis in the experimental model. Ganetespib potentiated the cytotoxic activity of doxorubicin via enhanced DNA damage and mitotic arrest, conferring superior efficacy to the doxorubicin + cyclophosphamide (AC) regimen in MDA-MB-231 xenograft models. Ganetespib also promoted mitotic catastrophe and apoptosis in combination with taxanes in vitro, and these effects translated to significantly improved combinatorial activity in vivo. Marked tumor shrinkage of metastatic lung lesions was seen in the patient while on ganetespib monotherapy.

Conclusion: The preclinical activity profile and clinical evidence of tumor regression suggest that ganetespib offers considerable promise as a new therapeutic candidate to target TNBC. In particular, the capacity of ganetespib to potentiate the activity of standard of care chemotherapeutics provides a rationale for the exploration of this agent in novel combinatorial treatment strategies for this disease.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr PD5-3.
Abstract PD6-1: Tumor spheres growing from peripherally circulating tumor cells exhibit stem cell features
Authors: Pachmann K , Zimon D , Pizon M , Pachmann U
Published: August 2014

Background: Among the cells that are disseminated from a malignant tumor only very few are capable to resettle in distant organs and grow into life-threatening metastases. Therefore, the question arises how and whether such cells which have the potential to grow into metastases can be detected. It has been shown that a subpopulation of cells from breast cancer tissue can form so-called mammospheres with stem cell features. Here we show that such tumor spheres can also be grown from peripherally circulating tumor cells from breast cancer patients in different stages of disease

Materials and Methods: Using a nondissipative approach with only one enrichment step of red blood cell lysis, the cells from the pellet, containing the white blood cells together with the putative tumor cells were cultured under conditions favoring the growth of epithelial cells. At 7, 14 and 21days the cell cultures were inspected for the appearance of spheroids staining with anti-EpCAM, anti-CD24 and anti-CD44 antibody and.expressing ALDH1.

Results: Peripherally circulating cells from patients with malignant tumors in different stages of disease were analyzed for the presence of circulating epithelial tumor suspect cells and the frequencies of tumorspheres. Tumorspheres could so far be grown from 79% of 36 patients in whom more than 1700/ml epithelial tumor suspect cells were detected. Numbers of tumorspheres varied from 1 to 29 /ml and correlated with the aggressiveness of the tumor. Surprsingly the numbers were highest in patients after surgery who had not yet received any systemic therapy. The size of the spheres increased from day 7 to day 21. The spheres were negative for CD24 and positive for CD44. They highly express ALDH1 and thus exhibite typical features of stem cells.

Conclusion: Here, we demonstrate that the circulating tumor cells, detected in our approach contain a subpopulation with stem cell-like properties capable of growing into tumorspheres. The frequency and growth potential of cells capable of forming spheres seems to be dependent from the properties of the primary tumor. The possibility to grow tumorspheres from peripherally circulating tumor cells may open up a new field, where the relevant cells with stem cell properties from individual patients can now be specifically analysed further for genetic endowment, transcriptional activity, heterogeneity and stem cell markers.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr PD6-1.