bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P5-09-13: HDAC inhibition re-sensitizes acquired hormone resistant cells to the cytotoxic effect of tamoxifen
Authors: Raha P , Thomas S , Thurn KT , Chen S , Munster PN
Published: August 2014

Breast cancer still continues to be a major cause of cancer related deaths in women, second only to lung cancer. Administering anti-estrogens and aromatase inhibitors, both in the adjuvant and metastatic settings, in estrogen receptor (ER) positive disease, is one of the most effective treatment strategies. However, prolonged exposure to these drugs leads to the emergence of resistance in about 40% of those who initially respond. Hence, the emphasis of a multitude of studies is to understand the underlying mechanisms of this acquired resistance and implementing means to overcome it.

Recent studies have implicated epigenetic modulation of gene expression in the development of resistance to the anti-estrogen tamoxifen. A clinical trial conducted by our group has demonstrated the efficacy of combining the HDAC inhibitor vorinostat with tamoxifen in patients who had progressed on prior anti-estrogen therapies and showed a total 40% clinical benefit (19% objective response and 21% stable disease for more than 6 months). In an effort to identify patients most likely to benefit from this novel therapy, we sought to elucidate the mechanism behind the clinical efficacy of this combination.

To this end, we have generated an in vitro tamoxifen resistant cell line (TAMR) by long-term exposure of MCF7 cells to 4-hydroxy tamoxifen. Significantly reduced anti-proliferative effect of tamoxifen and other anti-estrogens in TAMR compared to the sensitive MCF7 cells demonstrates the establishment of resistance to anti-estrogens in this cell line. In TAMR cells, addition of an HDAC inhibitor reverts resistance to tamoxifen. Although estrogen receptor (ER) expression in TAMR cells appears unaltered, the classical genomic signaling of ER in these resistant cells is suppressed and unresponsive to ligands, as deduced from transcription of ER response genes and luciferase assay of an ERE-luciferase construct. However, the ER remains important, since siRNA mediated depletion of ER inhibits cell growth in TAMR cells. Treatment with the dual EGFR/Her2 kinase inhibitor or an AKT inhibitor significantly inhibits the growth of these cells only when combined with tamoxifen, indicating the importance of crosstalk between pathways. Furthermore, Akt and mTOR protein and activities are down regulated by HDAC inhibition, which are further reduced when combined with tamoxifen. SiRNA mediated depletion of ER leads to reduced Akt and mTOR activities which suggests that ER may act as a driver, possibly through its non-genomic function at the plasma membrane activating members of the growth factor signaling pathways.

Studies are ongoing to further characterize the interaction of HDAC and ER inhibition on these signaling pathways and to determine their significance to resistance.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-09-13.
Abstract P5-09-14: Plant-derived estrogen receptorb agonists alone or in combination with aromatase inhibitors restore sensitivity in endocrine therapy resistant breast tumors
Authors: Samayoa C , Krishnegowda NK , Vadlamudi RK , Tekmal RR
Published: August 2014

Estrogen receptors (ER) play an important role in breast cancer. Over two-thirds of all breast cancers express ERa, and current endocrine therapies target its signaling. Antiestrogens (AE) block the binding of estrogen to ERα, while aromatase inhibitors (AI) inhibit local and systemic estrogen production. Both treatments improve outcomes for about 50% of patients with early or advanced ERα positive breast cancer. Unfortunately, therapeutic resistance frequently arises. There is a critical need to develop effective alternate strategies to prevent or delay the development of resistance to endocrine therapy and the resulting tumor progression. Both normal and tumor tissue express ERβ which has anti-proliferative activity and recent studies have identified several natural compounds that have the potential to function as ERβ agonists. Plant-derived ERβ-agonists, Liquiritigenin (Liq), from the plant Glycyrrhizae uralensis and S-equol, from the soy isoflavone daidzein, are currently in clinical trials for the treatment of vasomotor hot flashes associated with menopause. In this study we sought to determine if ERβ agonists alone or in combination with AI could resensitize Letrozole-resistant breast cancer cells in vivo. Xenografts were established using cells which model post-menopausal breast cancer. Endocrine therapy sensitive (MCF-7aro) and Letrozole resistant (LTLT-Ca) tumors were treated with either ERβ agonists or in combination with AI and progression was measured. In MCF-7aro tumors, ERβ agonist treatment reduced tumor volume and prolonged sensitivity to AI. In the therapy resistant tumors (LTLT-Ca), ERβ agonist treatment blocked tumor growth and restored sensitivity to AI therapy. To determine the molecular mechanism by which ERβ agonists inhibit tumor growth and prolong and restore sensitivity, qRT-PCR and western blot analysis was performed. Our results show changes in the levels of p53, NFkB, cyclin D1, and KLF5 in addition to other genes. To determine the role of ERβ agonists on the activation of these genes specific gene promoter-luciferase reporter constructs were used and the specificity of ERβ-mediated actions was confirmed using a siRNA approach. This study suggests that ERβ acts as a tumor suppressor by suppressing cell growth through the inhibition of cell cycle genes and by inducing apoptosis through the regulation of p53. In conclusion, this study demonstrates the potential role for ERβ agonists to improve adjuvant endocrine therapy to treat both hormone-responsive and hormone-resistant breast cancers.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-09-14.
Abstract P5-09-15: Polymorphism of the CYP2D6 gene in Brazilian women with breast cancer treated with tamoxifen
Authors: da Silva BB , de Vasconcelos-Valença RJ , Lopes-Costa PV , Gebrim LH
Published: August 2014

The prodrug tamoxifen is the standard endocrine treatment for estrogen receptor-positive breast cancer. Its effect depends on activation by the CYP2D6 enzyme, which is encoded by a highly polymorphic gene that varies according to ethnicity. The most important polymorphic variants are *4 (abolished enzyme activity), *10 and *17 (decreased enzyme activity) found in 25%, 38-70% and 35% of Caucasians, Asians and Africans, respectively, resulting in low endoxifen levels (a major metabolite), a lack of response to tamoxifen and a poor prognosis. There is a widespread racial miscegenation in Brazil and the country's public health care system has made tamoxifen available and free of charge to all women with hormone-sensitive breast tumor despite the undetermined genetic profile of these patients.This study aims to evaluate polymorphism frequency of the CYP2D6*4, *10 and *17 alleles in Brazilian breast cancer patients under tamoxifen treatment and metabolism phenotype. Methods: The study was approved by the Internal Review Board of the Federal University of Piauí. All patients signed an informed consent term before study entry. Sixty-five women with estrogen and progesterone receptor-positive and Her-2 negative breast carcinomas were enrolled in the study. A 3-ml peripheral blood sample was collected from each patient, using specific polymerase chain reaction technique (PCR) to analyze haplotypes *1, *4, *10 and *17, determined by studies of different Single-Nucleotide Polymorphism (SNP). Microsoft Office Excel software 2010 was used to compile and analyze the data obtained. Results: The frequency of CYP2D6 alleles *4, *10 and *17 was 17%, 37% and 3%, respectively. Haplotype *1/*10 was present in 26%, while the phenotype of intermediate metabolism occurred in 12% of the women studied. Conclusion: The present study showed a polymorphism frequency of CYP2D6, mainly of allele *10 and a deficiency in tamoxifen metabolism, characterized by intermediate metabolism in 12% of the women studied. Nevertheless, further studies must be developed with a larger sample of women to study not only the presence of the polymorphic variant but also disease prognosis.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-09-15.
Abstract P5-11-01: Impact of CDK mediated Smad3 phosphorylation and Pin1 in triple negative breast cancer cell migration
Authors: Hamdan R , Jeruss JS
Published: August 2014

Introduction: Estrogen receptor (ER), progesterone receptor (PR), and Human Epidermal Growth Factor Receptor 2 (HER2) negative breast cancers, also known as triple negative breast cancers can overexpress cyclins, such as cyclin D and E, which have been linked to cancer progression and metastasis. Cyclin/CDK complexes can phosphorylate and regulate Smads, downstream signaling proteins in the transforming growth factor-beta (TGF-b) superfamily. CDKs phosphorylate Smad3, predominantly in the linker region, resulting in the decreased tumor suppressive role of this protein. The peptidyl-prolyl cis/trans isomerase Pin1 is also overexpressed in breast cancer. Pin1 can bind phosphorylated Smads contributing to TGF-β induced cell migration and invasion. Inhibition of CDK-mediated Smad3 phosphorylation has been shown to restore Smad3 activity and decrease tumor cell migration in vitro. Based on these findings, we hypothesized that inhibition of Pin1 or CDK-mediated Smad3 phosphorylation would result in decreased triple negative breast cancer cell migration.

Methods: Hs578T, MDA-MB-436, and MDA-MB-231 triple negative breast cancer cells (TN) were transfected with either an si control (siCN) or an siPin1 plasmid to knockdown Pin1 protein expression. Transwell migration assays were used to determine the effect of Pin1 knockdown on migration. TN cells were treated with CDK4 or CDK2 inhibitors alone or in combination. The study cells were also stably transduced with lentiviral empty vector, wild-type (WT) Smad3, or a Smad3 mutant (5M) resistant to CDK-mediated phosphorylation. The effect of pharmacologically or genetically inhibiting CDK-mediated Smad3 phosphorylation on Pin1 binding to phosphorylated Smad3 (p-Smad3) or total Smad3 was determined using a co-immunoprecipitation assay (Co-IP).

Results: Transfecting the study cells with siPin1 resulted in decreased cell migration when compared to the siCN transfected cells. Treatment with the CDK4 or CDK2 inhibitors alone or in combination did not affect Pin1 protein levels, but resulted in decreased Pin1 binding to p-Smad3 with the greatest decrease found after treatment with combination therapy. Similarly, transduction of the study cells with the WT or the 5M Smad3 constructs had no effect on Pin1 levels but resulted in decreased Pin1 binding to Smad3. The greatest decrease was observed in the 5M transduced cells.

Concusions: Inhibition of CDK-mediated Smad3 phosphorylation and knock down of Pin1 resulted in decreased migration of TN breast cancer cells. Inhibition of CDK-mediated Smad3 phosphorylation by mutation of the CDK phosphorylation sites or by treatment with CDK4 and CDK2 inhibitors negatively impacted Pin1 binding to Smad3. Together, these findings indicate that CDK-mediated Smad3 phosphorylation enhances Pin1 binding to Smad3 and promotes tumor cell migration in triple negative breast cancer cells.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-11-01.
Abstract P5-11-02: Radiation instigates EMT, CSC self renewal and pluripotency signal transduction in non-targeted (bystander) ERa+ and triple-negative breast cancer cells
Authors: Khan FH , Natarajan M , Aravindan S , Herman TS , Aravindan N
Published: August 2014

Ascertaining radiation-induced bystander response in non-targeted tumor cells, particularly on variables pertaining to resistance, relapse and tumor progression, may escort significant clinical implications. Accordingly, in this study, we investigated the radiation induced alterations in factors that drive the epithelial-to-mesenchymal transition (EMT), cancer stem cells (CSCs) self-renewal capacity and pluripotency maintenance in non-targeted breast (ERa+ MCF-7 and triple-negative MDA-MB-468) adenocarcinoma cells. Co-cultures of non-targeted breast cancer cells with irradiated (5Gy) counterparts for 24h were assessed for transcriptional regulation of 93 stem cell related molecules using QPCR profiling. Radiation-induced alterations in the expression of ABCG2, E-Cadherin, N-Cadherin, MYC, Nanog and SOX2 in bystander MCF-7 and MDA-MB-468 were assessed using western blot analysis. Radiation profoundly increased the transcriptional activation of stem-cell related molecules in distant bystander ERα+ MCF-7 (70 genes) and in triple-negative MDA-MB-468 (82 genes) cells. Interestingly, 62 of 70 genes activated in MCF-7 and 81 of 82 genes in MDA-MB-468 showed significant (>2 fold) upregulation. Evidently, radiation induced 66 genes (>2 fold, 58 genes) in bystander breast cancer cells independent of their hormone status. Consistently, immunoblotting revealed increase in the expression of ABCG2, N-Cadherin, MYC, Nanog and SOX2 in both MCF7 and MDA-MB-468. Together, these data demonstrates that radiation activates the EMT, CSCs self-renewal and pluripotency maintaining factors in non-targeted bystander cells and could thus play an instrumental role in breast cancer relapse and progression.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-11-02.
Abstract P5-11-03: Deciphering the role of HER3-DJ-1 interaction in breast cancer
Authors: Mukherjee S , Huang Z , Fa M , Dhupkar P , Mujoo K , Zhang N , An Z
Published: August 2014

Advanced breast cancer is notorious for its aggressive nature and poor prognosis. An ablated regulation in the EGFR family receptor signaling has been linked to the development of numerous tumor types, including breast cancer. HER3 is a unique member of the EGFR family that lacks intrinsic tyrosine kinase activity. However, HER3 can initiate signaling when dimerized with other family members such as HER2. HER3 overexpression is correlated with poor survival in breast cancer patients. HER3 also plays an important role in drug resistance mechanism such as in trastuzumab resistant breast cancer cell lines where it dimerize with EGFR to initiate signaling via the PI3K/Akt pathway. The identification of interaction partners of HER3's C-tail is critical to understand the signaling mechanism underpinning HER3's role in drug resistance and in progression of breast cancer. Our laboratory has identified a panel of novel HER3-interacting proteins by a combined immunoprecipitation and mass-spectrometry approach. One of the novel HER3 interacting proteins is DJ-1 which is a chaperone protein that plays an important role in the development of many cancers, including breast cancer. DJ-1 knockdown in high HER3 expressing breast cancer cell lines such as MCF-7 and MDA- MB-453 resulted in the reduction in HER3 levels as well as proteins downstream of the HER3 signaling pathway such as MAPK. We have also demonstrated that DJ-1 knockdown led to decrease in cancer cell proliferation. Studies are now in progress to determine the mechanism of regulation of HER3 by DJ-1 and the impact of DJ-1 KD in in vivo breast cancer xenograft models. These studies will help us to decipher key molecules which regulate HER3 mediated signaling and their role in breast cancer development and progression.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-11-03.
Abstract P5-11-08: SRA/SRAP contributes to TGF-b1 induced cell motility in cancer cells
Authors: Cooper CM , Yan Y , Xu W , Tsuyuki D , Hamedani MK , Davie JR , Leygue E
Published: August 2014

The steroid receptor RNA activator gene (SRA1) is a particularly intriguing genetic system in that both the corresponding RNA (SRA) and protein (SRAP) have been proven to be functional. Accumulated evidence overall suggests that both molecules act as distinct co-regulators of transcription, housed in ribonucleo-protein complexes able to positively or negatively regulate the activity of multiple transcription factors including -but not limited to- several nuclear receptors, MyoD and DAX-1.

A role for SRA/SRAP deregulation during breast tumorigenesis has been suggested. Indeed, not only do these molecules regulate the activity of both Estrogen Receptors, these major players in breast cancer etiology, but it has also been shown that SRA RNA is more highly expressed in breast tumors than in normal tissue, and that high levels of SRAP correlated to poorer survival in specific subsets of breast cancer patients.

In order to identify the genes and pathways regulated by SRA/SRAP, we performed deep sequencing of transcriptomes from MDA-MB-231 cells depleted of these molecules following RNA interference. The expression of 149 genes was consistently and significantly altered in four independent experiments comparing control RNAi vs SRA RNAi. Interestingly, cluster analysis using Ingenuity software defined a subset of genes (23 out of 149) directly associated with cell movement. Among them figured TGFBR1 (ALK5), a cell surface receptor-kinase mediating TGF-b signalling and a known promoter of cell motility in breast cancer cells.

We have now confirmed by quantitative PCR analysis a 40% decrease, upon SRA/SRAP depletion, of TGFBR1 mRNA expression in MDA-MB-231 cells as well as in other breast (MCF7, T5) and non-breast (Hela) cancer cell lines. Consistent with this decrease a drop to 60% of the basal TGFBR1 protein expression is seen by Western blot when MDA-MB-231 cells are depleted of SRA/SRAP. Western blot analyses also revealed that phosphorylation of several SMAD molecules, downstream effectors of TGFBR1 activation by TGF-β1, is impaired in the absence of SRA/SRAP in both MDA-MB-231 and Hela cells. This suggests that SRA/SRAP could potentially regulate TGF beta induced cell motility.

Using migration cell assays, we have now confirmed that upon TGF-β1 treatment for 6 hours, SRA/SRAP depleted cells had a significant decrease in migration as compared to control cells. Accordingly, live cell migration assays generated by a time-lapse videomicroscopy system, showed an increased track length and speed in both Hela and 231 cells over-expressed SRAP upon 10 h TGF-β1 treatment.

Taken together, these data suggest a cross-talk between SRA/SRAP and TGF-β signalling and induced cell motility.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-11-08.
Abstract P5-12-01: A comparison of hormone receptor status in black women born in the U.S., West Africa, East Africa and the Caribbean - A SEER analysis
Authors: Haynes BM , Ruterbusch JJ , Simon MA , Cote ML
Published: August 2014

Background: Breast cancer is the leading cancer diagnosed among women in the United States (U.S.) and is second only to lung for cancer-related deaths in women. Although white women have a higher incidence of breast cancer, African American (AA) women with breast cancer have higher breast cancer related mortality and have a lower five year survival (73.8%) compared to their white counterparts (81.6%). AA women are also diagnosed at a younger age, with 30-40% of AA women diagnosed under 50, compared to 20% of whites, and are more likely to present with more estrogen receptor negative/progesterone receptor negative (ER-/PR-) tumors than whites (42% vs. 29% respectively). Other studies suggest these disparities extend to black African women and white European women. The aim of this study is to determine whether breast cancer characteristics seen in U.S. born black women are comparable to African born black women and to provide additional insight on the role of race and genetic ancestry in breast cancer.

Methods: Surveillance, Epidemiology, and End Results (SEER) data (SEER 18 Registries) was used to examine hormone receptor (HR) status among 30,003 black women, born in the U.S. (28,838), West Africa (167), East Africa (183), or the Caribbean (815), diagnosed with a first primary breast cancer from 2000 through 2009. Chi-square tests were used to determine whether clinical variables differed by ethnic group. Proportional incidence ratios (PIR) and 95% confidences intervals (CI) were calculated to estimate excess risk of ER-/PR- tumors between the populations.

Results: There were no statistically significant differences in axillary lymph node, stage, histologic type, or surgical treatment at presentation by ethnic group. There was no statistically significant difference in the proportion of ER-/PR- receptor status comparing US blacks to black women born in West Africa (p-value = 0.16, PIR = 0.77, 95% CI: 0.56-1.05), however women from East Africa and the Caribbean were less likely to have ER-/PR- breast cancers compared with US born blacks. (PIR = 0.52, 95% CI: 0.35-0.74, p < 0.0001 PIR = 0.84, 95% CI: 0.73-0.97, p< 0.01 respectively). The crude overall 5-year survival rate of West African, East African and Caribbean born black women was significantly higher than those born in the U.S. (75.7%, p = 0.023, 85.9% p <0.0001, 84.0% p<0.0001, 65.3% respectively).

Discussion: Our results agree with historical data showing that many AA women have ancestral origins in West Africa and provides additional evidence supporting the role of ancestral genetics in breast cancer susceptability.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-12-01.
Abstract P5-12-03: Racial differences in breast cancer survival in a large urban integrated health system
Authors: Simon MS , Ruterbusch JJ , Pressler ME , Lamerato L , Krajenta R , Booza JC , Schwartz K
Published: August 2014

Background: Despite improvements in breast cancer outcomes, there continues to be a large gap in survival between African American (AA) and White women with breast cancer, which may be due at least in part to racial differences in access to care. In order to better understand breast cancer survival disparities, we evaluated factors that predict racial differences in survival among women treated at a large integrated health care system in Southeastern Michigan. Materials and Methods: The study population included 2,387 women (34% AA) with stage I through III breast cancer treated at the Henry Ford Health System (HFHS) from 1996 through 2005. Linked datasets from the HFHS, the Metropolitan Detroit Cancer Surveillance System (MDCSS) and the U.S. Census Bureau were used to obtain socio-demographic and clinical information. Co-morbidity was assessed by the Charlson co-morbidity index (CCI), and economic deprivation was categorized into 5 quintiles of increasingly worse socioeconomic deprivation, using a census tract deprivation index (DI). Results: AA women were significantly more likely than Whites to have larger (41% vs. 32% > 2 cm) and hormone receptor (HR) negative tumors (30% vs 19%), to have a higher CCI (15% vs 9% > 2) and to reside in a more economically deprived area (46% vs. 5% residing in quintile 5). Unadjusted analysis showed that AA had a significantly higher risk of death than White women (hazards ratio [HR], 1.36, 95% confidence interval [CI], 1.16-1.59). After multivariable adjustment for clinical (age, stage, HR and CCI), and societal factors (insurance, DI), race was no longer significantly associated with overall survival, HR, 1.12, 95% CI, 0.94-1.33, p = 0.22, and 1.02, 95% CI 0.83-1.24, p = 0.88, respectively. Stratified analyses by DI showed no racial difference in survival for each of 5 levels of DI. Discussion: In a large urban integrated health care system, racial differences in breast cancer survival appear to be related to clinical and socioeconomic characteristics.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-12-03.
Abstract P5-12-07: Triple-negative breast cancer in African American women - How women in New Orleans compare to the rest of Louisiana and the Nation
Authors: Loch M , Li X , Estrada J , Reske T , Chen V , Wu X-C
Published: August 2014

Background: For years clinicians have made the empirical observation that there is an unusually high number of African American women (AAW) with triple-negative (Tneg) breast cancer (BC) in New Orleans (NO). Knowing the rate of Tneg BC in AAW is higher than white women (WW), we explored the hypothesis that AAW in NO have a higher rate of Tneg BC when compared to AAW in the rest of Louisiana (LA) and the US.

Methods: We analyzed data from the Louisiana Tumor Registry, one of the NCI funded SEER registries, for the tumor characteristics of invasive female BC diagnosed in 2010, focusing on racial disparities; HER2 status was not available prior to 2010. We explored the association of HER2 status with age, race, ER, PR, T, N and M status to determine crude and adjusted odds ratios and rate distribution of subtypes using SEER*Stat and SAS programs. With the recent release of SEER 18 data including HER2 status in cases diagnosed in 2010 we also looked at national rates of Tneg BC in WW compared to AAW and compared these findings to NO and LA.

Results: Overall age-adjusted incidence rate of Tneg BC in AAW was 34.0 per 100,000 in NO, 27.2 per 100,000 in AAW in the rest of LA and 20.4 per 100,000 in SEER 18. This translates into a statistically significant increase in incidence rates of Tneg BC in AAW in NO by 67% (p = < 0.05) compared to SEER 18. The rates in WW were 11.3 per 100,000 in all 3 locations. AAW with Tneg BC in NO were more likely to have more aggressive BC. Young age, black race, large tumor size, higher grade and TNM stage were significantly associated with the high risk of Tneg BC. After adjusting for age, geographic area, and other tumor characteristics, the higher risk of Tneg BC in AAW remained in NO compared with the rest of LA and locations of the SEER 18 registries.

Table 1: 2010 Tneg rates per 100,000 in NO, LA and SEER 18  RateCountRate RatioRate Lower CIRate Upper CIWhiteSEER 1811.33884154    LA11.30512000.99700.85731.1543 NO11.2441320.99160.66501.4340BlackSEER 1820.39961094    LA27.18622041.33271.13841.5534 NO34.0092611.66721.25822.1711

Conclusions: The incidence rates of Tneg BC in AAW in NO and LA are significantly higher than in SEER 18, with rates in NO being the highest. Rates of Tneg BC in WW in all data sets were similar. SEER 18 analysis also confirms a higher incidence of Tneg BC in AAW compared with WW as previously reported in smaller case series. AAW in NO are more likely to have poorly differentiated and Tneg BC compared to AAW in the rest of LA. This newly identified disparity in the AAW population in NO has clinical implications and translational research potential as it enables us to broaden the understanding and treatment of this aggressive disease.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-12-07.
Abstract P5-12-09: Clinical stage, not race, predicts receipt of sentinel lymph node biopsy in medically-underserved patients
Authors: Wiatrek RL , Kao LS , Robinson EK , Rieber AG , Ko TC , Wray CJ
Published: August 2014

Background: Sentinel lymph node biopsy (SLNB) has replaced axillary node dissection for staging clinically node negative breast cancer patients. Previously, other investigators have found disparities in the rate of SLNB in African Americans. Therefore, we hypothesized that African Americans and Hispanics are offered SLNB less frequently than Caucasians in a large safety-net hospital.

Methods: A retrospective review of female patients who underwent breast cancer surgery from 2002-2011 at a safety-net hospital was completed. Data was collected from the institutional cancer registry and medical record for: age at diagnosis, patient demographics, pathologic and clinical stage at presentation, and receipt of SLNB. Patients with clinically negative nodes (N0) were determined to be appropriate for SLNB. Patients with clinically positive nodes, biopsy proven nodal involvement, or stages IIIC or IV were deemed not appropriate for SLNB.

Results: Of 566 patients, the mean age at diagnosis was 53 years (range: 28-79); 46% (n = 269) were Hispanic, 31% African American (n = 174), 17% Caucasian (n = 95) and 5% Asian/Other (n = 28). Based on clinical stage, which was available for 561 patients, 64% were eligible for SLNB. Of those, 95% received appropriate SLNB. Race was not a predictor of eligibility for or receipt of appropriate SLNB.

 TotalCaucasianAfrican AmericanHispanicOtherp-value %(n = 566)%(n = 95)%(n = 95)%(n = 269)%(n = 28) Clinical Stage     0.70010.4 (59)7.4 (7)10.9 (19)11.2 (30)10.7 (3) 123.5 (133)25.3 (24)24.7 (43)22.7 (61)17.9 (5) 2A28.3 (160)29.5 (28)24.7 (43)11.5 (31)35.7 (10) 2B15.4 (87)18.9 (18)19.0 (33)7.1 (19)17.9 (5) 3A6.0 (34)5.3 (5)5.7 (10)7.8 (21)0 3B7.6 (43)8.4 (8)6.9 (12)7.8 (21)7.1 (2) 3C3.4 (19)1.1 (1)1.7 (3)5.2 (14)3.6 (1) 44.6 (26)3.2 (3)5.7 (10)4.5 (12)3.6 (1) Unknown0.9 (5)1.1 (1)5.7 (10)0.7 (2)3.6 (1)        Appropriate for SLNB64.0 (362)67.4 (64)61.5 (107)63.2 (170)75.0 (21)0.48Received appropriate SLNB94.7 (343)93.8 (60)92.5 (99)95.9 (163)100.0 (21)0.28

Conclusions: There was no difference in the rate of SLNB between racial and ethnic minority patients at a large safety-net hospital. The previously reported disparity likely resulted from more advanced presentation of disease rather than lack of appropriate care. Efforts to improve disparities seen in medically underserved patients should be focused on earlier detection and treatment of breast cancer.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-12-09.
Abstract P5-13-09: Evaluation on the risk factors and prognosis for patients with synchronous bilateral breast cancer in a Chinese cohort
Authors: Chen J-J , Wang Y , Xue J-Y , Yang B-L , Huang S , Chen Y , Chen J-Y , Yang W-T , Shao Z-M , Wu J
Published: August 2014

Background: There has been an increasing rate of synchronous bilateral breast cancers, mainly because of the increased morbidity, improved detection abilities, better prognosis and higher life expectancy of breast cancer patients. However, evidences in the literature regarding the risk factors of bilateral breast cancers are scare, and the survival of synchronous bilateral breast cancers still remain controversies. The purpose of the present study is to investigate the risk factors and prognosis of bilateral breast cancers in a Chinese cohort.

Methods: The present study included 181 patients with synchronous bilateral breast cancer and 10,831 patients with unilateral breast cancer treated in Fudan University Shanghai Cancer Center between Jan 2007 and Dec 2012. Patients with metastases or inflammatory diseases, or metachronous bilateral breast cancer (after 6 months of first cancer) were excluded. Age of the cases, family history, menopausal status, histology types, pathological stages, types of accompanied benign lesions, and patterns of surgeries and adjuvant therapies were examined to investigate the risk factors of bilateral breast cancers.

Results: Patients with synchronous bilateral breast cancer were significantly elder than those with unilateral breast cancer (mean age 53 yrs vs. 51yrs, p<0.001). Presence of sclerosing adenoma and lobular carcinoma component were the two independent risk factors of early-stage synchronous bilateral breast cancer, with the relative risk rate at 5.52 (95% CI: 3.04-10.01) and 5.00 (95% CI: 2.64-9,47), respectively. The rate of in situ carcinoma with or without microinvasion was significantly higher in patients with sclerosing adenoma associated synchronous bilateral breast cancers at 64.3%. With a median follow-up of 35 months, the disease free survival for synchronous bilateral breast cancer was 95.0%, similar to that of unilateral breast cancer. However, for synchronous bilateral breast cancer patients with N3 disease or previously received neoadjuvant therapy (20 cases), the 1.5 year-disease free survival was merely 50%, significantly worse than that of unilateral breast cancer with N3 disease or previous neoadjuvant therapy.

Conclusion: The rate of synchronous bilateral breast cancer was higher in patients with sclerosing adenosis or lobular carcinoma component. The prognosis for early-stage synchronous bilateral breast cancer was similar to those with early-stage unilateral breast cancer. However, among patients with N3 disease or previously received neoadjuvant therapy, synchronous bilateral cohort was associated to worse survival compared with unilateral cohort.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-13-09.
Abstract P5-14-18: Indication of post-mastectomy radiation associated with risk of local recurrence in breast cancer patients with 1-3 lymph node metastasis
Authors: Saruwatari A , Ishida M , Koi Y , Akiyoshi S , Igawa A , Oikawa M , Koga C , Nishimura S , Nakamura Y , Ohno S
Published: August 2014

Objective: Post-mastectomy radiotherapy (PMRT) is strongly recommended for breast cancer patients with 1 to 3 axillary lymph node metastasis (N1-3) in NCCN guidelines Version 3.2013 (category 1), whereas the indication of that treatment should be considered individually according to the risk of local recurrence (St Gallen Consensus Meeting 2013). In order to support decision making of PMRT, we evaluated the risk factors of local recurrence after mastectomy.

Patients and methods: We reviewed retrospectively 2422 cases with Stage I – III primary breast cancer receiving surgery at National Kyushu Cancer Center between 2000 and 2009. Seven hundred seventy six of them underwent mastectomy, and 547 of them received no PMRT. We analyzed the risk of local recurrence in relation to clinicopathologial factors, the status of hormone receptor and HER2, especially in cases with N1-3.

Results: Among 547 cases with no PMRT, there were 364 cases with no LN metastasis (N0), 146 N1-3, and 37 N≥4, and 5-year local disease free survival (DFS) rates were 97.0%, 91.2%, and 73.4%, respectively. In N1-3 (146) cases who underwent no post-operative regional radiotherapies, the 5-year DFS in extent of lymph vessel infiltration (ly) were: ly0 was 97.9% (50) and ly1-3 was 87.9% (92) (ly unknown were 4). In the ly0 cases, the 5-year local DFSs were 100% in grade 2 and 85.7% in grade 3; 100% in ER positive and 90.0% in ER negative; 90.9% in HER2 positive and 100% in HER2 negative. Those in the cases of ly1-3 were 94.5% and 73.4%, 88.7% and 76.6%, and 91.0% and 64.3%, respectively.

Conclusion: In patients with N1-3 breast cancer, the risk of local recurrence after mastectomy was significantly related to grade, extent of lymph vessel infiltration, ER and HER2. PMRT could be omitted in case with ly0,additionaly with grade 1-2, ER positive and HER2 negative. The remaining cases have the risk of local recurrence over 10%, if they don't receive PMRT, in which the indication of PMRT should be considered.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-14-18.
Abstract P5-15-03: Prediction of positive resection margins in patients with non-palpable breast cancer
Authors: Barentsz MW , Postma EL , van Dalen T , van den Bosch MA , Hui M , Gobardhan PD , Witkamp AJ , van Diest PJ , van Gorp J , van Hillegersberg R , Verkooijen HM
Published: August 2014

Background

Obtaining tumor free resection margins is essential in patients undergoing breast conserving surgery. Several risk factors associated with positive margins are described in literature. We developed a prediction model to predict positive resection margins in patients undergoing breast conserving surgery of non-palpable lesions.

Methods

A total of 576 patients with non-palpable invasive breast cancer underwent breast conserving surgery at five different hospitals in the Netherlands. A prediction model for positive resection margins was built using multivariate regression analysis and internally validated by bootstrapping.

Results

Positive resection margins were present in 69/576 (12%) patients. Factors associated with positive margins included microcalcifications on mammography (OR 1.8, 1.0-3.2), tumor not visible on ultrasound (OR 2.6, 1.2-5.6), presence of DCIS (OR 2.3, 1.3-4.0), multifocality (OR 3.5, 1.0-12.1), caudal location in the breast (OR 1.9, 1.1-3.5), and invasive tumor size (OR 1.83, 1.6-2.7). Together, these factors were able to moderately discriminate between patients with positive versus negative margins (area under the ROC 0.71, 95% CI 0.648 – 0.780). After internal validation the discrimination was slightly lower with an AUC of 0.694. Prevalence of positive margins was 5.2% in the highest risk quintile versus 26.3% in the lowest quintile.

Conclusion

A model predicting positive resection margins after breast conserving surgery in non-palpable breast cancer was built. This model is moderately able to differentiate between women with high versus low risk of positive margins, and may be useful for surgical planning (eg. preoperative MRI) and informing of patients.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-15-03.
Abstract P5-15-04: Clinical benefits of using nomogram for predicting positive resection margins in breast conserving surgery
Authors: Lee E , Han W , Moon H-G , Kim J , Lee JW , Kim MK , Yoo T-K , Kim J , Noh D-Y
Published: August 2014

Achieving a clear resection margin in breast conserving surgery (BCS) is an important factor in tumor recurrence in breast cancer. To obtain clear resection margins and reduce re-excision rates, some surgeons obtain intraoperative assessments of the margins of excised specimens, using intraoperative frozen biopsy. But intraoperative frozen biopsy has several problems such as low sensitivity or longer operation time. We have previously reported a nomogram for prediction of positive resection margin by integrating preoperatively available clinical and pathologic information. The factors were the presence of microcalcification, mammographic density, tumor size discrepancy between magnetic resonance imaging and ultrasonography, and the presence of ductal carcinoma in situ or lobular carcinoma in needle biopsy specimens.

We conducted a prospective trial to examine the accuracy and clinical benefits of the nomogram in 442 breast cancer patients (nomogram group) who underwent BCS between Dec 2011 and March 2013, and compared the clinical outcome with that of the 253 patients (control group) who underwent BCS between Jan 2011 and Oct 2011. For nomogram group, the intraoperative frozen section biopsy was omitted in patients with low nomogram scores.

Applying our nomogram did not increase the rate of reoperation due to resection margin positivity when compared to the control group (6.56% vs. 4.25%, respectively, p = 0.22). In the nomogram group, the reoperation rate in patients with low nomogram score who did not undergo intraoperative frozen biopsy was 3.2%, and this is lower than the reoperation rate in the control group. Additionally, we experienced a significant reduction in operation time by 15 minutes when compared to the control group (p<0.001).

In conclusion, our results show that out nomogram for predicting positive resection margin for patients who receive BCS can significantly reduce the operation time without increasing reoperation rate.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-15-04.
Abstract P5-15-05: The impact of a change in margin width policy on rates of re-operation for breast conserving surgery
Authors: Richardson CE , Arima Y , Wishart GC , Ambler GK , Benson JR
Published: August 2014

Background: The definition of a negative surgical margin in prospective randomized trials of breast conserving surgery (BCS) is ‘no tumour at ink’ with no conclusive evidence that wider margins of 1mm, 2mm or 5mm are essential for optimal outcomes in the era of modern radiotherapy techniques and systemic therapy. Our group have previously shown that residual tumour is present in only 6% of specimens when re-excision is prompted by a margin of 2 – 5mm compared with 40% for when primary tumour margins are ≤2mm. An audit was undertaken to determine the effect of a change in margin mandate from 5mm to 2mm on rates of re-excision and residual disease in re-excision specimens.

Methods: Data were collected retrospectively from 410 women undergoing BCS for symptomatic and screen-detected invasive and non-invasive disease between November 1st 2009 and October 31st 2011. Rates of re-excision and residual disease in re-excision specimens were compared for 215 patients in the 12 months immediately before (Group 1) and 195 patients in a similar time period after (Group 2) a change in margin policy. All impalpable lesions had conventional intra-operative specimen imaging. Statistical analysis was performed using Fisher's exact test.

Results: Amongst these 410 BCS patients, there were similar proportions of symptomatic and screen-detected cases in each group, but slightly more wire-localized procedures in group 2 (59.5% versus 48.4%; p = 0.029). Rates of patient re-excision were 21.9% (47/215) for group 1 and 25.6% (50/195) for group 2 with no significant difference between margin mandates of 5mm and 2mm respectively (p = 0.42). Eleven patients in each group had a completion mastectomy with 6 and 4 patients in Groups 1 and 2 respectively undergoing >1 re-excision. There was a trend for an increased proportion of residual disease following a change in margin policy (30.2% group 1, 40.7% Group2; p = 0.32) and the majority of re-excision cases had ductal carcinoma in situ alone or combined with invasive cancer in the primary specimen (>80%). There was no significant difference in the proportion of wire-localizations for all re-excisions (≥1) between Group 1 (31/42 = 74%) and Group 2 (25/43 = 58%) (p = 0.17).

Conclusion: A reduction in target surgical margin width from 5mm to 2mm has not decreased rates of re-excision but yields a trend towards an increase in proportion of specimens with residual disease. Longer follow up is required to assess rates of local control and further analyses will ascertain whether a less stringent margin policy is more appropriate for contemporary BCS where adjuvant treatments contribute to local control.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-15-05.
Abstract P5-16-03: Influence of radiotherapy boost in patients with ductal carcinoma in situ of breast cancer: A multicenter, retrospective study in Korea (KROG 11-04)
Authors: Kim JH , Choi DH , Park W , Ha SW , Kim K , Ye JW , Suh C-O , Shin KH , Kim DW , Lee JH
Published: August 2014

Purpose

We aimed to estimate the effect of boost radiotherapy on local relapse-free survival (LRFS) in patients with ductal carcinoma in situ (DCIS) of breast cancer.

Material and Methods

We included patients from 8 institutions who met the following inclusion criteria: having tumor status Tis, age 18 years or older at diagnosis, having had breast conserving surgery (BCS) and radiotherapy within 12 weeks after surgery. From January 1995 through December 2006, 594 patients with DCIS breast cancer treated with BCS and radiotherapy were analyzed retrospectively in a study by Korean Radiation Oncology Group (KROG). All patients received whole breast radiotherapy (median 5040 cGy) after BCS. Among them, 154 patients (25.9%) received boost radiotherapy (median 1000 cGy) after whole breast radiotherapy. Patients who received boost radiotherapy had higher tumor grade, more comedo pattern and less papillary pattern. Other patients’ or tumor characteristics were not statistically different between boost group and no boost group.

Results

After median follow-up of 89 months (range 26-200), 5 year and 10 year LRFS was 98.3% and 95.6%. There was no statistically significant difference of LRFS between boost group and no boost group.

Local relapse free survival according to boost radiotherpay 5-year LRFS* (%)10-year LRFS (%)p-value**Boost group98.196.20.626No boost group98.495.4 *Local relapse free survival, **Log-rank test

Nineteen (3.2%) patients had ipsilateral breast recurrences, of whom, 12 patients had invasive breast cancer and 7 had DCIS. Positive HER2 receptor was associated with higher invasive recurrences.

Ipsilateral breast recurrences according to HER2 receptor TotalHER2 receptor (+)HER2 receptor (-)p-value*Ipsilateral breast121110.017Invasive8800.023DCIS**4310.642*Fisher's exact test, **Ductal carcinoma in situ

Nine (1.5%) patients developed contralateral breast cancer, of whom, 6 were invasive breast cancer and 3 were DCIS. On multivariate analysis, only margin status was a significant prognostic factor for LRFS.

Conclusion

In the absence of randomized trials, boost radiotherapy could not decrease local recurrence in DCIS of breast cancer after BCS and radiotherapy. In addition, patients with positive HER2 receptor would need further treatment like target agent, trastuzumab. NSABP B-43 study result would answer the question.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-16-03.
Abstract P5-16-07: Intracystic papillary carcinoma of the breast: Implications for therapy from the surveillance epidimiology and end results database
Authors: Howard-McNatt M , Brown D , Levine E , Isom S
Published: August 2014

Intracystic papillary carcinoma is a rare breast neoplasm that has been classified as a variant of ductal carcinoma in situ. However, patients can develop metastatic disease. The indication for radiation and lumpectomy versus mastectomy as far as survival is unknown.

Methods: We identified 2,649 female patients with intracystic papillary carcinoma from the Surveillance, Epidemiology, and End Results (SEER) registry. Differences in demographics, clinical features and survival of patients were assessed using the Kaplan-Meier method and Cox regression.

Results: The median patient age was 66 years. The majority of patients were white and those who presented with Stage 0 disease. Most patients did not have their lymph nodes examined and only 34% received radiation therapy treatments. Using a log-rank test, survival was significantly different by race, with whites having a better survival than black patients (p<0.001). Furthermore, early stage disease (p<0.001) and those who received radiation (p<0.0001) had improved survival. In a Cox regression survival model adjusting for age, stage, and grade, patients who were black (hazard ratio [HR], 1.85) had a significantly higher risk of death than whites. Patients who received radiation therapy (HR, 0.49) had an improved survival over those who did not undergo radiation therapy treatments. There was no difference in survival in patients who received either a lumpectomy or mastectomy.

Conclusion: Intracystic carcinoma of the breast has a good overall survival. Survival is improved in white patients and in patients who receive radiation therapy. This suggests that radiation therapy should be offered to women with intracystic papillary cancer who undergo breast conserving surgery.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-16-07.