bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P2-03-02: Differential mutation pattern between neoadjuvant and metastatic settings in breast cancer patients
Authors: Xu B , Williams C , De P , Dey N , Klein J , Williams K , McMillan A , Leyland-Jones B 
Published: March 2017

Abstract
Background: Dysregulated signaling pathways occur in human cancers including breast cancer, making it a rational target for novel genome guided combinatorial personalized therapies. The aim of the present study was to investigate the different genetic mutation pattern between neoadjuvant and metastatic settings in breast cancer patients to guide research and clinical treatment.
Material and Methods: 150 breast cancer patients were involved in this study. 38 patients were receiving neoadjuvant treatment and 112 patients were in the metastatic setting. Tumor specimens obtained from the 150 patients were subjected to genetic mutation testing by FoundationOne. Genetic alterations detected by FoundationOne test were collected and analyzed.
Results: 96 and 149 different genes where reported by FoundationOne in neoadjuvant and metastatic setting respectively. The average number of non-synonymous mutation was five per case in the neoadjuvant setting and six per case in the metastatic setting. TP53 (58%), MYC (32%), PIK3CA (29%), PTEN (16%), CDH1 (13%), CCND1 (11%), EMSY (11%), LYN (11%) and ZNF703 (11%) were the most seen mutations in neoadjuvant setting. TP53 (40%), PIK3CA (39%), MYC (22%), CCND1 (21%), FGF19 (21%), FGF4 (21%), CDH1 (20%), FGF3 (19%), ERBB2 (17%), ESR1 (14%), FGFR1 (14%), ZNF703 (14%), GATA3 (13%), MYST3 (11%), PTEN (11%), EMSY (10%), NF1 (10%) and ZNF217 (10%) were the most seen mutations in metastatic setting. ESR1 and GATA3, which are seen in 14% and 13% of metastatic breast cancer patients, were not reported in neoadjuvant breast patients. Moreover, among the 16 metastatic breast cancer patients who has ESR1 mutation, 9 (56%) of them presented with PIK3CA or other genetic mutations which are directly involved in the phosphoinositide 3-kinase (PI3K)/AKT pathway.
Conclusion: A significantly more mutation in Receptor Tyrosine Kinases (RTKs)/ Growth Factor Signaling ( especially ERBB and FGFR pathways) was reported in the metastatic setting compare to the neoadjuvant setting, suggesting a critical role of the RTKs in metastatic breast cancer patients. The coexisting of ESR1 and PI3K/AKT pathway alteration and the absence of ESR1 in neoadjuvant setting also suggested that in early stage breast cancer patients who have a PI3K pathway alterations; there is a higher chance to develop ESR1 mutation with disease progression.
Citation Format: Xu B, Williams C, De P, Dey N, Klein J, Williams K, McMillan A, Leyland-Jones B. Differential mutation pattern between neoadjuvant and metastatic settings in breast cancer patients [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-03-02.
Abstract P2-05-15: The lymph node ratio as an independent prognostic factor for node-positive triple-negative breast cancer
Authors: He M , Jiang Y-Z , Tang L-C , Chen Y-L , Shao Z-M , Di G-H 
Published: March 2017

Abstract
Purpose: To evaluate the prognostic value of the lymph node ratio (LNR) in patients with axillary lymph node-positive triple-negative breast cancer (TNBC).
Patients and methods: Based on X-tile plots, we classified women into low-, medium-, and high-risk LNR groups. Univariate and multivariate Cox proportional hazards regression analyses for overall survival (OS), breast cancer-specific survival (BCSS) and disease-free survival (DFS) were performed. The prognostic efficacy of the LNR was investigated in the first cohort from the Surveillance, Epidemiology, and End Results (SEER) database (n=4114) and was further validated in an independent cohort from Fudan University Shanghai Cancer Center (n=417).
Results: The patients were classified into low- (≤0.30), medium- (0.30 to 0.70) and high-risk (&gt;0.70) LNR groups. Multivariate analysis revealed that the LNR was an independent predictor of OS (hazard ratio (HR) for high-risk LNR: 3.24; 95% confidence interval (CI): 2.56 to 4.09) and BCSS (HR for high-risk LNR: 3.57; 95% CI: 2.76 to 4.62) in the SEER population and also for DFS (HR for high-risk LNR: 4.29; 95% CI: 2.24-8.21) in the validation population. Subgroup analysis revealed that patient classification according to the LNR could discriminate among groups of patients with different survival rates based on pN staging.
Effect of Lymph Node Ratio and pN Classification on Survival Among Patients from SEERVariableOSBCSS HR a(95% CI)PHR a(95% CI)PLymph node ratio Low,≤0.301-1-Medium, &gt;0.30 and ≤0.702.05(1.63-2.59)&lt;0.0012.26(1.75-2.92)&lt;0.001High,&gt;0.703.24(2.56-4.09)&lt;0.0013.57(2.76-4.62)&lt;0.001pN N11-1-N21.53(1.21-1.93)&lt;0.0011.63(1.27-2.10)0.001N32.72(2.14-3.46)&lt;0.0012.97(2.29-3.85)&lt;0.001a Cox proportional hazards model. Hazard ratios are adjusted for age, race, histologic grade, tumor size, surgery type and radiotherapy.
Conclusion: The LNR shows potential for use as an additional prognostic factor for TNBC patients with positive lymph node involvement. Considering the heterogeneity of TNBC, use of the LNR might allow for optimization of the pN staging system, and this ratio should be considered when making treatment decisions.
Citation Format: He M, Jiang Y-Z, Tang L-C, Chen Y-L, Shao Z-M, Di G-H. The lymph node ratio as an independent prognostic factor for node-positive triple-negative breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-05-15.
Abstract P2-05-38: Spectral CT based radiomics signature: A potential biomarker for preoperative prediction of lymph node metastasis in breast cancer
Authors: Dong D , Zhang X , Fang M , Shen J , Tian J 
Published: March 2017

Abstract
Purpose:
To investigate the usefulness of radiomics signature based on computed tomographic (CT) spectral imaging, during the late arterial phase (AP) and portal venous phase (PVP), in preoperative predicting the lymph node (LN) metastasis in breast cancer (BC).
patients and methods:
This retrospective study was institutional review board approved, and written informed consent was obtained from all patients. We examined 60 female patients (LN metastasis positivity was 50%) with CT spectral imaging during the AP and the PVP and data was gathered from 2014 to 2016. Excised lymph nodes were located and labeled during surgery according to location on preoperative CT images and were evaluated histopathologically. For each patient, two 3D Hounsfeld Unit (HU) gradient maps which revealed the HU change of each voxel were built by quadratic fitting the spectral HU curves during the two phases respectively. Then the radiomics features were then extracted from the regions of BC and a suspicious LN judged manually in these maps. The potential association of the four groups of radiomics features with LN status was assessed by using a Mann-Whitney U test. The area under curves (AUC) of the receiver operating characteristic curves (ROC) were compared with data obtained from the conventional CT image.
results:
The 3D HU gradient map showed a great power of distinguishing among different components and was considered as a more effective tool for revealing the intratumour heterogeneity than the conventional CT image since the slope of spectral HU curves were significantly higher in malignant tumor. More than 500 radiomics features extracted from the regions of LN during the AP and the PVP exhibited significant differences (P &lt;0.05). Moreover, the numbers of this kind of features extracted from the regions of BC were more than 200. The highest AUC of single feature was 0.70, which was higher than those from the conventional CT image.
Conclusion:
Quantitative radiomics features based on 3D HU gradient maps have the potential to be exploited as an effective biomarker for preoperative prediction of lymph node metastasis in breast cancer.
Citation Format: Dong D, Zhang X, Fang M, Shen J, Tian J. Spectral CT based radiomics signature: A potential biomarker for preoperative prediction of lymph node metastasis in breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-05-38.
Abstract P2-06-04: Breast cancer after Hodgkin lymphoma: Influence of endogenous and exogenous gonadal hormones on the radiation dose-response relationship
Authors: Krul IM , Opstal - van Winden AWJ , Aleman BMP , Janus CPM , van Eggermond AM , de Bruin ML , Hauptmann M , Krol ADG , Schaapveld M , Broeks A , Kooijman KR , Fase S , Lybeert ML , Zijlstra JM , van der Maazen RWM , Kesminiene A , Diallo I , de Vathaire F , Russell NS , van Leeuwen FE 
Published: March 2017

Abstract
Background
After chest radiotherapy (RT) for Hodgkin lymphoma (HL), women experience a dose-dependent increased breast cancer (BC) risk. It is unknown whether endogenous and exogenous gonadal hormones affect the radiation dose-response relationship.
Methods
We conducted a nested case-control study among female 5-year HL survivors treated before 41 years between 1965-2000. Data were collected through medical records and questionnaires for 174 BC cases and 466 matched controls. RT charts, simulation films and mammography reports were used to estimate the radiation dose to the location of the breast tumor.
Results
The median interval between HL and BC diagnosis was 21.9 years. 98% of BC cases had received chest RT, compared to 92% of controls. We observed a linear radiation dose-response curve with an adjusted excess odd ratio (EOR) of 5.4%/Gray (95%CI:1.8%-13.37%). Women with menopause &lt;30 years (caused by high-dose procarbazine or pelvic RT) had a lower BC risk (OR:0.13, 95%CI:0.03-0.54) than women with menopause ≥50 years. BC risk increased with 7.4% for each additional year of intact ovarian function after RT (P&lt;0.001). Among women with an early menopause (&lt;45 years), the use of hormone replacement therapy (HRT) for ≥2 years did not increase BC risk (OR:0.81, 95%CI:0.30-2.21). Endogenous and exogenous hormones did not statistically significantly modify the slope of the radiation dose-response relationship.
Conclusion
HRT use did not appear to increase BC risk in female HL survivors with a therapy-induced early menopause. Moreover, there was no evidence for interaction between RT dose and years with intact ovarian function or HRT use.
Citation Format: Krul IM, Opstal - van Winden AWJ, Aleman BMP, Janus CPM, van Eggermond AM, de Bruin ML, Hauptmann M, Krol ADG, Schaapveld M, Broeks A, Kooijman KR, Fase S, Lybeert ML, Zijlstra JM, van der Maazen RWM, Kesminiene A, Diallo I, de Vathaire F, Russell NS, van Leeuwen FE. Breast cancer after Hodgkin lymphoma: Influence of endogenous and exogenous gonadal hormones on the radiation dose-response relationship [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-06-04.
Abstract P2-07-12: The association between patient comorbidity and breast cancer survival
Authors: Han J , Lee H-B , Lee E-S , Kang YJ , Kim Y , Choi J , Rhu J , Han W , Noh D-Y , Moon H-G 
Published: March 2017

Abstract
Background
There are studies suggesting significant association between the patient's comorbidity and perioperative outcomes. In breast cancer, patient comorbidity can also influence the oncologic outcome by affecting the decisions regarding adjuvant treatments. In this study, we examined the long-term oncologic outcome in breast cancer patients who underwent curative surgery according to their pre-existing comorbid conditions.
Methods
The medical records of 2,501 patients who underwent surgery for primary breast cancer from June 2006 to June 2010 were reviewed retrospectively. The patients were classified into three groups (ASA 1, 2, 3) according to preoperative ASA status determined by the anesthesiologists. Clinico-pathologic characteristics and survival outcomes of the patients were compared among the different co-morbidity groups.
Result
There were 1,792 (71.6%), 665 (26.6%), and 44 (1.8%) patients in ASA 1, 2, and 3, respectively. Total 95 (3.8%) deaths and 269 (10.8%) recurrences (loco-regional and distant) occurred during the median follow-up period of 71 months. Patients with high comorbidity showed significantly higher rate of death (51 (2.8%), 38 (5.7%) and 6 (13.6%) deaths in ASA 1, 2 and 3 group, respectively, p&lt;0.001). The ASA 3 patients also showed significantly higher rate of breast cancer recurrence when compared to other groups (180 (10.0%), 80 (12.0%) and 9 (20.5%) in ASA 1, 2 and 3, respectively, p=0.041). Cox multivariate analysis demonstrated that high ASA score (ASA 3) was an independent prognostic factor in DFS, OS and BCSS (95% confidence interval [CI], 1.661-6.780; p=0.001, 1.753-11.321; p=0.002 and 2.222-18.429; p=0.001). Fewer patients in the high co-morbidity group received adjuvant therapies (77 (4.3%), 44 (6.6%) and 8 (18.2%) in ASA 1, 2 and 3, p&lt;0.001). The increased recurrence of breast cancer in the high morbidity group was most seen in patients who did not receive adjuvant therapies. The incidence of serious adverse effect during the adjuvant therapy did not differ according to the co-morbidity conditions.
Conclusion
In this study, high comorbidity was related to increased risk of death and recurrence in breast cancer. The increased risk of recurrence in high co-morbidity group was mostly seen in patients who did not receive adjuvant therapies. In patients who underwent the adjuvant therapies, the incidence of serious adverse effects did not differ according to the co-morbidity status.
Citation Format: Han J, Lee H-B, Lee E-S, Kang YJ, Kim Y, Choi J, Rhu J, Han W, Noh D-Y, Moon H-G. The association between patient comorbidity and breast cancer survival [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-07-12.
Abstract P3-03-08: A large-scale functional screen to identify resistance mechanisms to selective estrogen receptor degraders fulvestrant and GDC-810 in ER+ breast cancer
Authors: Mao P , Quartey Q , Cohen O , Piccioni F , Wagle N 
Published: March 2017

Abstract
Therapies that target the estrogen receptor provide clinical benefit and improved survival for patients with estrogen receptor-positive (ER+) breast cancer, yet drug resistance remains a challenging problem, leading to disease relapse and mortality. In recent years, the selective estrogen receptor degrader (SERD) fulvestrant has become an important therapeutic option for patients with resistant ER+ metastatic breast cancer, and newer oral SERDs such as GDC-810 are currently being tested in clinical trials. The mechanisms of intrinsic and acquired resistance to SERDs remain to be fully elucidated.
We conducted a large-scale lentiviral open reading frame (ORF) screen to identify genes whose overexpression confers drug resistance to either fulvestrant or GDC-810 in the ER+ breast cancer cell line T47D. The lentivral ORF expression library used in this study consists of 16,544 barcoded ORFs, including 2,767 ORFs with mutations. The initial screen yielded 72 genes resulting in resistance to fulvestrant and 85 genes resulting in resistance to GDC-0810, with 44 genes overlapping. The top ranked-genes included multiple genes belonging to the PI3K/Akt, ERbB/HER, and FGF/FGFR pathways as well as genes involved in cell cycle progression.
Fibroblast growth factor receptor 1 (FGFR1) amplifications are frequently observed in patients with ER+ breast cancer, and have previously been implicated in resistance to endocrine therapies. Several FGFs (FGF3, FGF6, FGF10, and FGF22) were among the top-ranked resistance genes for both fulvestrant and GDC-0810, suggesting that activation of the FGFR signaling pathway may render cells resistant to fulvestrant and GDC-810. In the presence of FGF2, overexpression of FGFR1 in ER+ breast cancer cells resulted in resistance to both fulvestrant and GDC-0810. The ability of an FGFR inhibitor to overcome FGFR-mediated resistance to SERDs is being tested. Additional potential resistance genes identified in the ORF screen are also being validated.
In summary, a whole-genome functional resistance screen has identified several candidate genes and pathways that may cause resistance to fulvestrant and GDC-810. Several of these candidates, such as FGFR1, are also found in patients who develop resistance to SERDs, suggesting rational combination therapies to overcome or preempt SERD resistance.
Citation Format: Mao P, Quartey Q, Cohen O, Piccioni F, Wagle N. A large-scale functional screen to identify resistance mechanisms to selective estrogen receptor degraders fulvestrant and GDC-810 in ER+ breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-03-08.
Abstract P3-04-03: S100β as a predictive biomarker and monitoring tool in endocrine resistant breast cancer
Authors: Charmsaz S , Hughes É , Byrne C , Bane F , Tibbitts P , McIlroy M , Hill AD , Young LS 
Published: March 2017

Abstract
In estrogen receptor positive breast cancer, endocrine therapy is the standard line of treatment and even though it results in reduced recurrence and mortality, a significant number of patients will eventually relapse. Early detection of metastatic disease would significantly enhance management of endocrine resistant breast cancer. Here we investigate the potential of the calcium-binding protein S100β as a predictive biomarker and monitoring tool in endocrine treated patients. Furthermore, the efficacy of S100β inhibition as therapy in patients that fail first line endocrine therapy was examined.
Primary tumor tissue expression of S100β protein was assessed in a retrospective cohort of endocrine treated breast cancer patients. Expression of S100β indicated a significant reduction in time to disease recurrence (n=509, Wilcoxon p&lt;0.0001, hazard ratio 2.43, 95% C.I. is 1.607 to 3.69, p&lt;0.0001, Cox proportional hazard model).
S100β protein is also detectable in serum of breast cancer patients and elevated levels of serum S100β prior to removal of primary tumor is associated with poor disease free survival in endocrine treated patients (n=190, Wilcoxon p=0.0367, hazard ratio 2.68, 95% C.I. is 1.12 to 6.41, p=0.026, Cox proportional hazard model). Serum levels of S100β are significantly reduced after primary tumor resection (n=19, p=0.0003). In serial samples taken during the treatment period, elevated levels of S100β significantly associated with disease progression and with the emergence of metastatic disease (p=0.0031).
In an in-vivo model of endocrine resistant breast cancer, raised levels of S100β marked the emergence of disease progression. The oncogene steroid receptor co-activator 1 (SRC1) and its interaction with homeobox protein (HOXC11) regulates S100β production in a src-kinase dependent manner. Here, src-kinase inhibition reduced tumor burden with a concomitant reduction in serum S100β. We also observed a marked reduction in expression of proliferative marker Ki67 and S100β protein following the treatment of endocrine resistant patient tumor explants with src-kinase inhibitor.
Associations between elevated levels of serum S100β and subsequent disease progression in endocrine treated patients, suggests S100β as a monitoring tool for early detection of disease progression. Additionally high level of S100β can be used as a potential companion diagnostic tool for stratifying patients on endocrine therapy suitable for treatment with small molecule src-kinase inhibitor.
Citation Format: Charmsaz S, Hughes É, Byrne C, Bane F, Tibbitts P, McIlroy M, Hill AD, Young LS. S100β as a predictive biomarker and monitoring tool in endocrine resistant breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-04-03.
Abstract P3-04-08: The role of HER2 mutations in resistance to endocrine therapy in ER+ breast cancer
Authors: Nayar U , Cohen O , Oh C , Wagle N 
Published: March 2017

Abstract
Resistance to endocrine therapies in estrogen receptor positive (ER+) metastatic breast cancer is widespread, and understanding the mechanisms whereby these tumors acquire resistance is a critical need. Through whole-exome sequencing of metastatic tumor biopsies from patients with endocrine resistant ER+ metastatic breast cancer, we identified 13 different HER2 mutations, including five in the kinase domain, four in the signaling domain, three in the extracellular domain, and one in the transmembrane region of the protein. Two of the kinase domain mutations (L755S and V777L) have been previously described and shown to be activating and resistant to reversible anti-HER2 targeted therapies; the remaining mutations have not been reported. In several of these patients, whole exome sequencing of a pre-treatment primary tumor did not identify the HER2 mutations seen in the corresponding metastatic tumor, suggesting that they were acquired during therapy. To examine the role of HER2 mutations in endocrine resistance, we generated ER+ breast cancer cell lines (MCF7 and T47D) stably expressing the HER2 mutants observed in our clinical data. Several mutants promoted enhanced growth in charcoal dextran-stripped media, which lacks estradiol and mimics treatment with aromatase inhibitor. In addition, several mutants conferred varying degrees of resistance to fulvestrant and tamoxifen. Taken together, these results suggest that HER2 mutations are associated with acquired resistance to endocrine therapies in patients with ER+ breast cancer. The ability of irreversible anti-HER2 agents as well as other agents that target the HER2 pathway to overcome this resistance is being tested for individual HER2 mutations in vitro. The results from these studies may provide a clinical rationale for therapeutic combination strategies in patients with refractory tumors that have acquired endocrine resistance through HER2 mutations.
Citation Format: Nayar U, Cohen O, Oh C, Wagle N. The role of HER2 mutations in resistance to endocrine therapy in ER+ breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-04-08.