bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract PD06-04: St. Gallen 2011 clinicopathological subtyping of breast cancer: impact of different proliferation assessment methods
Authors: Focke CM , Gläser D , Finsterbusch K , Decker T 
Published: August 2014

Abstract
Rationale: The St Gallen Consensus 2011 strongly recommends subtyping of breast cancer (BC). However, because there is no data from phase III trials to substanciate adjuvant therapy benefit gene expression arrays were not generally accepted to guide systemic therapy decisions. Instead, the consensus introduced clinicopathological BC subtypes (cpBCST) defined as sets of risk and predictive biomarkers which are established worlwide (Table 1).

To discriminate Luminal A vs. Her2 negative Luminal B BCs the St Gallen Consensus recommends Ki67 for defining proliferation. Although, because no standardized methodology or cut-off definition for Ki67 is available so far ‘some alternative measure of proliferation’ was suggested. We analyzed the influence of different proliferation assessment methods on BC subtype distribution.
Methods: cpBCST assessment including proliferation measurement by different variants of Ki67-Labeling-Index (KI67LI) was performed on 225 BCs. For comparison we used the Mitotic Activity Index (MAI) as the only prospectively evaluated and best reproducible proliferation measurement (Baak et al 2008). The Ki67-LI was based on counting any nuclear staining of distinctly defined target areas: (1) 100 tumor cells within the hot spot (Ki67-100), (2) 1020 tumor cells in 3 HPF in the tumor periphery including the hot spot (Ki67-1020periphery), and (3) 1020 tumor cells in 3 HPF including hot spot, cold spot, and an intermediate area (Ki67-1020spectrum). Staining quality and counting accuracy was tested as excellent by the 2011 circulation of the German Quality Initiative in Pathology. According to St Gallen, a cut-off &lt;14% was used. The MAI was measured in 10 HPFs with a total area of 1.59 mm2 using a cut-off ≥10 as evaluated by Baak et al. 2008.
Results:

Conclusions: The delimination of Luminal A and Luminal B Her2 negative BCs according to the St. Gallen Consensus 2011 is highly influenced by the method of proliferation assessment. Using the recommended cut-off &lt;14% all estimations of Ki67LI came out with Luminal A/Luminal B ratios (10–34% vs. 45–69%) which are much lower than those published (44–53% vs. 9–29%). As a consequence, this could lead to more cytotoxic treatment. Therefore, the biological relevance of KI67LI seems to be not unequivocal. Unlike this, proliferation measurement by MAI resulting in a Luminal A/Luminal B ratio of 52% vs. 29% seems more reliable. The differences may be due to the fact that mitotic figures reflect only the M phase, whereas Ki67 stains cells in nearly all phases of the cell cycle.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD06-04.
Abstract PD06-07: Evaluation of an optimal cut-off point for the Ki-67 index as a prognostic factor in primary breast cancer.
Authors: Tashima R , Nishimur R 
Published: August 2014

Abstract
Background: The proliferation biomarker Ki-67 is considered to be a prognostic factor for breast cancer and has been investigated in several studies. However, there is no standard cut-off point for the Ki-67 index. Therefore, we retrospectively investigated an optimal cut-off point in terms of the prognostic factor in primary breast cancer.
Patients&Methods: Immunohistochemical (IHC) analysis of the proliferation marker Ki-67 index was performed on 4338 patients with primary breast cancer until March 2012 at Kumamoto City Hospital. Out of these patients, there were 2375 consecutive cases with ER and/or PgR positive and HER2 negative tumors since 1997. Items examined were ER, PgR, HER2, tumor size, nodal status, nuclear grade, and p53 overexpression. The Kaplan-Meier test was used to calculate prognosis (cumulative disease-free survival (DFS) and overall survival (OS)) and tested with the log-rank procedure. Cox's proportional hazard model was used to perform a univariate and multivariate analyses of the factors related to DFS. In addition, an analysis was conducted to determine various cut-off values for the Ki-67 index.
Results: The median Ki-67 value was 21%, with a mean of 26.2%. Univariate and multivariate analysis revealed that the Ki-67 index was an independent prognostic factor for DFS and OS. A multivariate analysis revealed the following hazard ratio (HR) and cut-off values for the Ki-67 index; HR was 1.92 in cases with a cut-off value of 20%, 1.91 in 35%, 1.87 in 40%, 1.89 in 45% and 1.79 in 50%, respectively. These findings suggested that the optimal cut-off point was 20%. In the cases with luminal type (ER and/or PgR positive and HER2 negative) breast cancer, a higher Ki-67 value (20% ≤) correlated with larger tumor size, positive nodes, higher grade, and overexpression of p53. Moreover, patients with a higher Ki-67 value showed significantly lower DFS/OS rates. A multivariate analysis also revealed that the Ki-67 index is a significant prognostic factor in luminal type breast cancer.
Conclusion: The optimal cut-off value for the Ki-67 index is 20%. Moreover, this proliferation marker is a significant prognostic factor in evaluating primary breast cancer.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD06-07.
Abstract PD07-03: INCREASED PATHOLOGIC COMPLETE RESPONSE RATE AFTER A LONG TERM NEOADJUVANT LETROZOLE TREATMENT IN POSTMENOPAUSAL ESTROGEN AND/OR PROGESTERONE RECEPTOR-POSITIVE BREAST CANCER
Authors: Allevi G , Strina C , Andreis D , Zanoni V , Bazzola L , Bonardi S , Foroni C , Milani M , Cappelletti MR , Generali D , Berruti A , Bottini A 
Published: August 2014

Abstract
Background: Neoadjuvant endocrine therapy has been increasingly employed in clinical practice to improve surgical options for postmenopausal women with bulky hormone receptor-positive breast cancer. Recent studies indicate that tumor response and in particular the pathologic complete response (CR) in this setting may predict long-term outcome. The letrozole approval in neoadjuvant setting is based on a study that included 4 months of letrozole treatment only. Prospective studies have not investigated treatment duration beyond 6 months, and retrospective studies suggest that useful responses can occur after this period. The purpose of this study was to determine the clinical and pathologic response of 2.5 mg daily letrozole used with different schedule in breast cancer patients (pts) unfit for chemotherapy.
Patients and Methods: This single Institution retrospective study comprised 102 postmenopausal women with primary breast cancer (clinical stage ≥T2, N0-1), who were divided into 3 subgroups (34 each in single subgroup) according to the different duration of neoadjuvant letrozole treatment: 4 months (subgroup A), 8 months (subgroup B) or 12 months (subgroup C) of treatment. The subgroups were comparable in terms of baseline characteristics.
Results: Pts and tumor characteristics included: median age 77.3 years (range 53.9–95.4); 100% estrogen receptor-positive, 81.4% progesterone receptor-positive; median Ki67 13.5% (range 2–90%). All pts were evaluable for clinical and pathologic response. A total of 77 pts (75.5%) achieved an objective response at individual end: 40 (39.2%) clinical CR and 37 (36.3%) partial responses (PR). The clinical CR were significantly confined to subgroups C (20/34 pts, 58.8%) and B (16/34 pts, 47.1%) than to subgroup A (4/34 pts, 11.8%) (p for trend = 0.00001). Objective response rate was 46.1% (47/102 pts) at month 4, 83.8% (57/68 pts) at month 8, and 94.1% (32/34 pts) at month 12 compared with baseline. As expected, letrozole induced a significant reduction of Ki67 expression after treatment in any single subgroup, without significant differences between them. With very interest, the pathologic CR rate was significantly higher in subgroup C (7/34 pts, 20.6%) than in subgroups A (1/34 pt, 2.9%) and B (1/34 pt, 2.9%) (p for trend &lt;0.02).
Conclusions: One-year neoadjuvant letrozole therapy can lead to a high pathologic CR rate. This observation suggests that pathologic CR may be a reliable endpoint after endocrine therapy, but a long-term drug exposure is needed. The optimal letrozole treatment duration in neoadjuvant setting is a matter of future research.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD07-03.
Abstract PD08-05: Spanning the Continuum to assess, serve and navigate Latinas with breast cancer: A Tale of Six Projects
Authors: Ramirez AG , Holden AE , Gallion K , SanMiguel SA , Munoz E , Penedo FJ , Perez-Stable EJ , Talavera GG , Carrillo JE , Fernandez ME 
Published: August 2014

Abstract
Background Breast cancer is the most commonly diagnosed cancer among Latinas: 14,200 diagnosed in 2009. Groundbreaking work has shown that patient navigation may assist minority patients to negotiate the Cancer Care Continuum. Here we report the efforts of Redes En Acción: The National Latino Cancer Research Network at the Institute for Health Promotion Research in San Antonio, Texas in applying these findings to Latinas.
Methods We conducted six studies to assess and address the needs and self-reported barriers to care of Latina breast cancer patients, leading to the development and controlled trial of a theory-driven, culturally appropriate patient navigation model and program. We currently are evaluating health-related quality of life and barriers to genetic testing in Latina breast cancer survivors.
Results Latinas with breast cancer face significant obstacles across the cancer care continuum, originating from multiple domains, including traditional values, timely access to care and cultural orientation. These have a direct influence on interaction with the system or indirectly via influences on existing barriers including socioeconomic marginalization and affective response to the stress of any of these.

Conclusion Although not considered as such, the Cancer Care Continuum implicitly demands consideration of the cultural underpinnings of behavior that govern interaction with it. Further research is required to understand these underpinnings. Simultaneously, culturally-sensitive services must be incorporated into the medical care system in order to ensure its successful function.
Acknowledgement This research was enabled by grants from the San Antonio Cancer Institute/Cancer Therapy and Research Center, San Antonio, Texas (P30-CA054174), Susan G. Komen for the Cure (POP 2000 704), and the National Cancer Institute via Redes En Acción (U01-CA86117 and U54 CA153511-01).
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD08-05.
Abstract PD09-05: Single nucleotide polymorphism of XRCC1 which participates in DNA repair mechanism predicts clinical outcome in relapsed or metastatic breast cancer patients treated with S1 and oxaliplatin chemotherapy: Results from multicenter prospective study (TORCH_KCSG BR07-03)
Authors: Im S-A , Oh D-Y , Keam B , Lee KS , Ahn J-H , Sohn J , Ahn JS , Kim JH , Lee MH , Lee KE , Kim HJ , Lee K-H , Han SW , Kim S-Y , Kim SB , Im Y-H , Ro J , Park H-S 
Published: August 2014

Abstract
Background: S1 and oxaliplatin (SOX) combination chemotherapy is an effective regimen in anthracycline and taxane pretreated metastatic breast cancer (MBC) patients with manageable toxicities (KCSG BR07-03, SABCS 2011 #Abst P3-16-06). The aim of this study was to investigate the association of the single nucleotide polymorphisms (SNPs) and clinical outcome in MBC treated with SOX chemotherapy.
Patients and Methods: A total of 87 MBC patients previously treated with or resistant to anthracycline and taxane chemotherapy were enrolled in this prospective multicenter trial. The patients received S-1 80mg/m2/day (day 1–14) and oxaliplatin 130 mg/m2 (day 1) every 3 weeks till progression. Among the 87 patients, 77 patients were available for SNP analysis. Germline DNA from peripheral blood (PB) mononuclear cells was extracted. SNPs in 4 genes from pathways that may influence cellular sensitivity to S1 and oxaliplatin (TS, ERCC, XPD, and XRCC) were genotyped from PB sample using PCR-restriction fragment length polymorphism.
Results: Overall response rate (RR) was 38.5% (95% CI: 27.7–49.3) and disease control rate was 67.9% (95% CI:57.5–78.3) to SOX. Median time-to-progression (TTP) and overall survival (OS) were 6.0 mo (95% CI: 5.1–6.9 mo) and 19.4 mo (95% CI: not estimated), respectively. XRCC1 Arg194Trp SNP which participates in DNA repair mechanism showed correlation with the clinical outcome. RR was tend to higher in XRCC1 Arg194Trp CC genotype compared with CT or TT genotype (50.0 % vs 35.1% or 12.5%, P = 0.121). TTP of patients with CC genotype in XRCC1 Arg194Trp was significantly longer than the TTP of patients with CT or TT genotype (median TTP: 6.4 mo in CC, 5.9 mo in CT, 3.0 mo in TT, P = 0.007) as well as overall survival (OS) (median OS: not reached in CC, 13.9 mo in CT, 7.1 mo in TT, P = 0.006). After adjusting for hormone receptor status, performance status, and visceral involvement, prognostic value of XRCC1 Arg194Trp SNP remained significant (Hazard Ratio=1.322 and 4.484, P = 0.016). Other SNPs were not significantly associated with survival or toxicities.
Conclusion: XRCC1 Arg194Trp SNP is associated with clinical outcome of MBC patients treated with SOX chemotherapy. Further studies of the relationship between germline polymorphisms in XRCC1 and functional mechanism researches are warranted.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD09-05.
Abstract PD09-08: The potential role of TLK2 as a therapeutic target in breast cancer.
Authors: Kim J-A , Cao X , Tan Y , Schiff R , Wang X 
Published: August 2014

Abstract
Invasive breast cancer (IBC) is a heterogeneous disease with distinct molecular and histological features as well as diverse biological behaviors. It is thus critical to find specific gene aberrations that can drive breast cancer initiation and progression as potential therapeutic targets. Our lab has established bioinformatics workflows to identify therapeutic oncogene targets. We have nominated Tousled-Like Kinase 2 (TLK2) as a candidate therapeutic target from 44,932 human genes based on integrative copy number data from The Cancer Genome Atlas (TCGA). TLK2 is a nuclear serine/threonine kinase that serves as a cell cycle checkpoint regulating chromosome assembly, and is inactivated by phosphorylation through the ATM dependent manner in the response to the double strand breaks during the S-phase. Interestingly, we observed 12–14% of focal TLK2 gene amplifications and translocations in invasive breast cancers, which are more frequent in luminal B tumors. Chromosomal aberrations may leads the deregulation of TLK2 kinase activity and results in overcoming the cell cycle checkpoint upon DNA damage such as IR or chemotherapeutic drugs treatments in breast cancer, thus destabilizing the cancer genome. Indeed, our preliminary data show that TLK2 knockdown substantially inhibits cell proliferation in breast cancer cells overexpressing TLK2. Further, this response is sustained in their derivative strains resistant to hormone or anti-Her2 therapies, suggesting the potential of TLK2 inhibition to sensitize these therapies as well. Overall, I expect that this study will provide compelling evidence regarding the role of TLK2 in breast cancer tumorigenesis and genomic instability, and establish its potential as a therapeutic target. The possibility of developing specific TLK2 inhibitors can be well demonstrated by the previous success of drugs against other cell cycle checkpoint kinases that are currently under clinical trials. In addition, molecular assays detecting TLK2 derangements may be applied in the clinics to identify patients who might benefit from future TLK2 inhibitor. If TLK2 endows resistance or sensitivity to other therapies, assays detecting TLK2 aberrations may also have important predictive value for personalization of these treatments.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD09-08.
Abstract PD10-06: CXCL13 mRNA predicts Docetaxel benefit in Triple Negative tumors
Authors: Wirtz RM , Leinonen M , Bono P , Isola J , Kellokumpu-Lehtinen P-L , Kataja V , Turpeenniemi-Hujanen T , Jyrkkiö S , Eidt S , Schmidt M , Joensuu H 
Published: August 2014

Abstract
Background: Presence of immune cell infiltrates in tumor may influence outcome of patients with node negative breast cancer (BC) (Schmidt et al 2008). High expression of CXCL13 (B lymphocyte chemoattractant chemokine) was strongly associated with favorable survival in one recent series consisting of BC patients treated with adjuvant chemotherapy (Razis et al. 2012). Here we examined the clinical significance of breast tumor CXCL13 mRNA levels within the context of the FinHer trial, where patients were randomly assigned to receive 3 cycles of either docetaxel or vinorelbine followed by 3 cycles of FEC. Patients with HER2-positive BC had a second randomization for trastuzumab vs. control. Since intratumoral B cells are of particular importance for obtaining response to chemotherapy in triple negative BC (TNBC) and of limited value in luminal BC (Schmidt et al. 2012), and trastuzumab treatment is a confounding factor in HER2+ BC, we focused on TNBC.
Methods: RNA was extracted from FFPE tumor tissue of 917 (90.8%) out of the 1010 patients who participated in the FinHer trial. CXCL13 mRNA expression was measured using RT-qPCR. The molecular subtypes (luminal, HER2-enriched and triple-negative) were determined using IHC and central chromogenic in situ hybridization (CISH) testing. Prognostic significance of factors was assessed using univariate and multivariate analyses. Distant disease-free survival (DDFS) between groups was compared using the log-rank test.
Results: Tumor CXCL13 mRNA expression showed a bimodal distribution and correlated negatively with tumor ESR1 mRNA levels (r = −0,31; p &lt; 0.0001). 146 (15.9%) out of the 917cancers were classified as TNBC. High tumor CXCL13 mRNA levels above the median were strongly associated with favorable 5-yr DDFS in TNBC compared to low levels (85% vs. 60%; p &lt; 0.0001). The prognostic value of tumor CXCL13 was evident in the subset of women with TNBC treated with vinorelbine (5-year DDFS 90% vs. 40%; p &lt; 0.0001), whereas no significant association was found in the docetaxel arm (5-year DDFS 80% vs. 80%; p = 0.76). When only patients with TNBC and low CXCL13 mRNA levels were assessed, patients treated with docetaxel had better DDFS compared to those treated with vinorelbine (5-year DDFS 80% versus 40%; p &lt; 0.0064). There was no DDFS difference between treatment arms in patients exhibiting high CXCL13 expression.
Conclusions: Tumor CXCL13 mRNA expression is a favorable prognostic factor for women with TNBC treated with adjuvant chemotherapy providing further evidence that the host immune response may influence outcome of patients with early BC. The clinical significance of the host B cell immune response may vary substantially pending on the type of chemotherapy administered.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD10-06.
Abstract PD10-09: CYP2D6 and adjuvant tamoxifen: Impact on outcome in pre- but not postmenopausal breast cancer patients
Authors: Margolin S , Lindh J , Thorén L , Xie H , Koukel L , Dahl M-L , Eliasson E 
Published: August 2014

Abstract
Background: The therapeutic effect of tamoxifen in adjuvant treatment of hormone receptor positive breast cancer might be impaired in patients with cytochrome P450 2D6 (CYP2D6) genotypes that predispose to decreased formation of potent anti-estrogenic tamoxifen metabolites. However, previous studies have shown inconsistent findings in this regard. In light of two recent studies failing to show an impact of CYP2D6 genotype on outcome in postmenopausal patients, we hypothesized that deficient CYP2D6 might be of greater importance in premenopausal patients with high levels of circulating estrogen. We therefore aimed to study the effect of CYP2D6 activity in both pre- and postmenopausal patients who were adherent to tamoxifen treatment for at least one year.
Methods: 382 patients, from a population-based cohort of unselected breast cancer patients that were prescribed adjuvant tamoxifen for five years, constituted the base of the study. Information on menopausal status, tumor characteristics, treatment data including compliance and outcome was retrieved from medical records. Comprehensive CYP2D6 genotyping was performed and functionally translated into constitutive, metabolic activity.
Results: In patients adherent to tamoxifen for at least one year (n = 313) there was an association of reduced CYP2D6 activity (≤50% of normal) to both recurrence (p = 0.02) and breast cancer-specific mortality (p = 0.03). In a multivariable analysis including CYP2D6 activity, age at diagnosis, tumor size, lymph node status, grade, adjuvant chemotherapy and concomitant use of CYP2D6 inhibitors, CYP2D6 remained an independent predictor of recurrence (HR = 0.39, 95% CI: 0.18–0.85, p = 0.02) and breast cancer specific survival (HR = 0.33, 95% CI 0.12–0.90, p = 0.03). Gradually decreasing CYP2D6 activity paralleled increasing risk of recurrence and breast cancer related mortality. The effect of CYP2D6 derived mainly from premenopausal patients with an association to both recurrence (p = 0.01) and breast cancer specific survival (p = 0.04). There was no such association in the postmenopausal group.
Conclusion: In a prospectively collected cohort of tamoxifen-treated breast cancer patients, an association between CYP2D6 genotype and outcome was evident in patients that were adherent to tamoxifen treatment for at least a year. Importantly, this effect derived from premenopausal patients only.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD10-09.