bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P2-07-06: Multi-omics characterization of claudin-low breast tumors
Authors: Pommier RM , Morel A-P , Tissier A , Thomas E , Kielbassa J , Tonon L , Sohier E , Viari A , Saintigny P , Puisieux A
Published: February 2018

Breast tumors display highly heterogeneous characteristics both at transcriptional level and in term of genomic landscape. We recently reported that the differentiation status of the cell-of-origin influences the genetic route toward tumorigenesis1. Indeed, mammary stem cells exhibit the intrinsic property to tolerate the oxidative stress inherent to the oncogenic transformation through the expression of a preemptive program driven by ZEB1, an epithelial-to-mesenchymal transition (EMT)-related transcription factor, and MSRB3, a methionine sulfoxide reductase. Thereby, ZEB1-expressing tumors exhibit low level of DNA damage associated with few genomic alterations and low level of TP53 mutations. Importantly, these tumors share several transcriptional characteristics and features with normal stem cells, and with Claudin-Low (CL) molecular subtype of breast cancers. In the present work, we attempt to decipher molecular traits of CL breast tumors through multi-omics analyses of publicly available databases. This global approach allows us to highlight various CL breast tumors features as clinical attributes, gene expression, copy number alterations (CNA), somatic mutations or drug responses by differential analyses of breast tumors and cancer cell lines. Preliminary results indicate that, independently of tumor purity, CL breast tumors are mostly diploids, present a paucity of genomic rearrangements and a lower mutation rate compared to other breast tumors. They mainly, but not exclusively, show basal features and belong to the integrative cluster 4 (CNA-devoid) described by Christina Curtis and colleagues2. Concerning gene expression, CL breast tumors exhibit a frequent activation of RAS signaling pathway, an observation consistent with their sensitivity to MAPK inhibitors. Other analyses are currently ongoing and aim to better understand the biology of CL breast tumors in order to improve both the diagnosis and the therapeutic strategy used.

1. Morel A-P et al. A stemness-related ZEB1-MSRB3 axis governs cellular pliancy and breast cancer genome stability. Nature Medicine. 2017 Apr 10.

2. Curtis C et al. The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature. 2012 Apr 18.

Citation Format: Pommier RM, Morel A-P, Tissier A, Thomas E, Kielbassa J, Tonon L, Sohier E, Viari A, Saintigny P, Puisieux A. Multi-omics characterization of claudin-low breast tumors [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-07-06.
Abstract P2-09-24: Combination treatment with bromodomain and extra-terminal motif inhibitors in triple-negative breast cancer
Authors: Schafer JM , Lehmann BD , Redman LN , Liu P , Stubbs M , Ruggeri B , Scherle P , Pietenpol JA
Published: February 2018

Triple-negative breast cancer (TNBC) is one of the most aggressive subtypes of breast cancer. TNBC affects younger women and is characterized by earlier rates of relapse, higher frequency of visceral metastases, and shorter survival outcomes when compared to ER+ or HER2+ disease. Although the disease only represents ˜15% of all breast cancer cases, it accounts for 25% of all breast cancer deaths – with treatment options currently limited to chemotherapy. Development of targeted therapies for TNBC is challenging due to molecular heterogeneity and lack of high-frequency “driver” alterations amenable to therapeutic intervention. Recent studies have demonstrated increased sensitivity of TNBC to the anti-proliferative effects of Bromodomain and Extra-Terminal motif inhibitor (BETi) compared to the other breast cancer subtypes. To determine mechanisms of sensitivity to BETi, we analyzed the effect of a BETi across a panel of TNBC cell line models and identified cell lines that were both sensitive and insensitive to BETi. With the intent of identifying biomarkers of sensitivity, we performed RNA-seq and precision nuclear run-on and sequencing (PRO-seq) on both sensitive and insensitive cell line models and data generated identified significant differences in key growth regulatory and apoptotic signaling pathways, including notable differences in Myc-dependent signaling. Our data suggest potential biomarkers of BETi-sensitivity that may be of value in further pre-clinical studies. Further, our results provide mechanistic rationale for combinations of BETi with select, targeted therapies in a disease that is in need of new therapeutic intervention.

Citation Format: Schafer JM, Lehmann BD, Redman LN, Liu P, Stubbs M, Ruggeri B, Scherle P, Pietenpol JA. Combination treatment with bromodomain and extra-terminal motif inhibitors in triple-negative breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-09-24.
Abstract P2-11-04: Not presented
Authors: Patel SA , Mahmood SS , Nguyen T , Yeap BY , Jimenez RB , Taghian AG , Meyersohn NM , Neilan TG , MacDonald SM
Published: February 2018

This abstract was not presented at the symposium.
Abstract P2-11-06: Analysis of cardiac events among node positive breast cancer (NPBC) patients treated with three-dimensional conformal radiation therapy (3D-CRT)
Authors: Bradley JA , Sparks I , Prior P , Bergom C , Walker A , Wilson JF , Li XA , White J
Published: February 2018

Background: Regional nodal irradiation (RNI) in addition to the chest wall and/or breast can maximize local regional control and improve overall survival, but has been associated with late cardiac morbidity. We examined NPBC patients treated with RNI using 3D-CT based radiation therapy (RT) to evaluate incidence and type of cardiac events.

Methods: Between 2000 and 2007, 156 NPBC patients were treated with RNI following lumpectomy or mastectomy using 3D-CRT. In all cases, treatment target and normal tissue volumes were delineated on treatment CT scans. The heart contour included the left ventricle and the atria. Prescription dose was typically 50Gy in 25 fractions (range 44-54 Gy) to the chest wall and/or breast PTVeval. 37% received a boost to the chest wall and 73% to the lumpectomy cavity. The mean prescription dose to the axilla and supraclavicular lymph nodes was 47.6 Gy (range 43.2 – 54 Gy) and 46.8 Gy to the IMN (range 35.3 – 50.4 Gy). The dose-volume cardiac data and incidence of cardiac events is reported.

Results: Median follow-up of surviving patients was 7 years (range, 0.3-10.6). Median patient age was 50 (range, 27-91), 52% were premenopausal, 76% estrogen receptor positive, and 18% were HER-2 positive. The IMN received > 40 Gy in 66%. Chemotherapy was used in 94% of patients, and it was anthracycline-based in 82.3%. At the time of RT, 12.5% smoked, 9% had diabetes, 33% with HTN, and 4.4% had a history of CAD.

Average mean heart dose for the cohort was 5.2 Gy (range, 0.2 - 25.3 Gy). Mean cardiac V25 was 5.4% (range, 0-20%), mean cardiac V45 was 1.7% (range, 0-13.3%), and mean maximum cardiac point dose was 45.4 Gy.

There was 1 (0.7% of cohort) right sided patient with cardiac events and 8 (5.1% of cohort) left experiencing cardiac events. A total of 18 cardiac diagnoses were experienced among the 9 patients: Coronary artery disease with or without myocardial infarction (4), congestive heart failure (6), cardiomyopathy (3), and arrhythmia (5).

Conclusions: The cardiac event rate among these NPBC patients treated with RNI and anthracycline-based chemotherapy was low, but more common in women with left-sided breast cancer compared to right. Additional analysis using 3DCRT volumes are important to validate these findings and better define the dose-volume parameters for cardiac toxicity.

Citation Format: Bradley JA, Sparks I, Prior P, Bergom C, Walker A, Wilson JF, Li XA, White J. Analysis of cardiac events among node positive breast cancer (NPBC) patients treated with three-dimensional conformal radiation therapy (3D-CRT) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-11-06.
Abstract P2-12-13: Withdrawn
Authors: Kotani H , Terada M , Mori M , Horisawa N , Sugino K , Iwase M , Oonishi S , Kataoka A , Adachi Y , Gondou N , Yoshimura A , Hattori M , Sawaki M , Iwata H
Published: February 2018

This abstract was withdrawn by the authors.
Abstract P2-13-02: Not presented
Authors: Kim J , Kwak MJ
Published: February 2018

This abstract was not presented at the symposium.
Abstract P2-13-03: Statin use and breast cancer survival – a Swedish nationwide study
Authors: Borgquist S , Broberg P , Olsson H
Published: February 2018

Background: A sizeable body of evidence shows that statins can cease proliferation of breast cancer and prevent breast cancer recurrence. Given the epidemiological findings from other Scandinavian populations, we hypothesized that statins may have anticancer effects and therefore reduce cancer-related mortality in a Swedish population. This study investigates the association between both pre- and post diagnostic statin use and breast cancer outcome.

Methods: A Swedish nation-wide retrospective cohort study of 20,559 Swedish women diagnosed with breast cancer (July 1st, 2005 through 2008). Dispensed statin medication was identified through the Swedish Prescription Registry. Breast cancer-specific death information was obtained from the national cause-of-death registry until December 31st, 2012. Cox regression models yielded hazard ratios (HR) and 95% confidence intervals (CI) regarding associations between statin use and breast cancer-specific and overall mortality.

Results: During follow-up, a total of 4,678 patients died, whereof 2,669 were considered breast cancer-specific deaths. Compared to non- or irregular use, regular pre-diagnostic statin use was associated with lower risk of breast cancer-specific death (HR=0.77 (95%CI 0.63-0.95), P=0.014). When evaluating diabetes patients only (N=545), this association was strengthened (HR=0.63 (95%CI 0.40-0.98), P=0.044). Post diagnostic statin use was in similarity associated with lower risk of breast cancer–related death compared to non-use (HR=0.83 (95%CI 0.75-0.93), P=0.001).

Conclusion: This study supports the notion that statin use is protective regarding breast cancer-specific mortality in agreement with previous Scandinavian studies, although less so with British studies. These disparities should be investigated further.

Citation Format: Borgquist S, Broberg P, Olsson H. Statin use and breast cancer survival – a Swedish nationwide study [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-13-03.
Abstract P3-03-04: Not presented
Authors: Jiang Z , Xu F , Fu P , Fan Z , Jin F , Liu H , Wang X , Zhang H , Wang H , Zhang J
Published: February 2018

This abstract was not presented at the symposium.
Abstract P3-05-11: Immune and basal signature correlation to targeted therapies and race in QNBC patients
Authors: Hughley RW , Colomb WD , Shweta T , Yates C
Published: February 2018

Background: African American women have worse prognosis and poor survival rates due to lack of Androgen Receptor expression. These subtypes, the Quadruple Negative Breast Cancers (QNBC), currently have no treatments. Previously, we found that AA TNBC have 28% more chance of being QNBC and have 25% higher rate of progression vs the Caucasian Americans (CA). Also, these QNBC patients have a unique immune and basal signature. Here, we explore individual genes and their correlation to race and immune therapies. Methods: We analyzed AR mRNA expression in 925 tumors from CA or AA women from The Cancer Genome Atlas and independently validated AR protein levels by immunohistochemistry in 197 primary tumors. Samples were dichotomized as AR positive or negative using mean gene expression cutoff. Gene expression comparisons among groups were determined using standard t-tests, ANOVA, and odds ratios with a significance threshold alpha of 0.05. a of 0.05. Therapy targets were selected from the list of significantly differentiated genes. Boxplots and heatmaps were made using R packages. Cumulative Incidence plots for time to progression were constructed using XLStats and Grays test for significance. Results: QNBC CA have higher expression of PDCD4 (p <.001), CD46 (p <.001), CD3EAP (p =.04) and CD84 (p =.07) compared to QNBC AA. CD47 (p = .63) and PD1 (p =.96) express no significant differences in race[CY1]. QNBC AA show higher expression of NFKB (p <.001), CCL2 (p <.001), and IL12 (p <.001) compared to QNBC CAs. Interestingly, QNBCs with high expressions of CD47 (p = .04) have poor prognosis[L2]. Thus, QNBC patients with low expression of CD46 (p =.025), PDCD4 (p < .001), and CD3EAP (p < .001) have poor prognosis and overall survival. Conclusions: Current immune targeted therapies like CD47 and PD1 looks favorable for treatment in some QNBC patients. Race appears to effect other major therapy target gene expressions in the QNBC immune basal signature as well. This may imply that QNBC AA and CA have different immune response which may explain racial progression differences. Assessment of immune markers may contribute to more accurate prognosis.

Citation Format: Hughley RW, Colomb WD, Shweta T, Yates C. Immune and basal signature correlation to targeted therapies and race in QNBC patients [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-05-11.
Abstract P3-05-12: VISTA expression on tumor-infiltrating lymphocytes in breast cancer: Clinical correlates and association with PD-1
Authors: Burugu S , Gao D , Nielsen TO
Published: February 2018

Background: The V-domain containing Ig Suppressor of T Cell Activation (VISTA) is a recently discovered immune checkpoint receptor with homology to PD-1. VISTA expression on tumor-infiltrating lymphocytes (TILs) blocks their proliferation and effector functions. Recent pre-clinical data in cancer mouse models treated with anti-VISTA and anti-PD-L1 combinations showed promising results and non-redundant functions of VISTA and PD-L1 blockade. However, the expression and prognostic value of VISTA+ TILs in primary breast tumors has not been investigated in detail. Here we assess expression, prognostic value, and associations of VISTA+TILs with other immune checkpoint markers (PD-1/PD-L1, LAG-3, and IDO-1) and with H&E TIL counts.

Methods: A tissue microarray consisting of breast carcinoma primary excision specimens (n=330) from the University of British Columbia hospital, linked to detailed clinicopathological data and outcomes, was used in this study. Patients from this cohort did not receive neoadjuvant treatment. A VISTA antibody (Clone D1L2G) was applied on a 4μm section of the tissue microarray by immunohistochemistry using a Ventana automated stainer. VISTA+TILs in direct contact with tumor nest were scored and reported as absolute count per 0.6mm core. Positive cases were defined as cases with VISTA+TILs≥1. All descriptive and survival analyses were conducted using SPSS software.

Results: VISTA+TILs were present in 30% of cases and were significantly (p<0.05) associated with younger age (<50 years old), larger tumors (>2cm), hormone receptor negativity (ER/PR) and high Ki67proliferation index (≥13.25%). Almost half (48%) of basal-like breast cancers were positive for VISTA expressing TILs. No significant prognostic associations were observed in this cohort. Among the immune checkpoint receptors analyzed, VISTA+TILs were highly associated with PD-1+ TILs: 79% of cases positive for PD-1+TILs were also infiltrated by VISTA+TILs. Interestingly, we found that VISTA+TILs and PD-1+TILs were enriched in cases with otherwise low levels (<10%) of H&E TILs.

Conclusions: Our study identifies the presence of VISTA+TILs in breast cancer patients and its strong association with PD-1+TILs. These results suggest that VISTA blockade could be a good candidate for combination therapy with other immune checkpoint inhibitors, a concept being tested in early phase clinical trials. Validation of these findings in a larger independent cohort powered for multivariate analysis is currently ongoing.

Citation Format: Burugu S, Gao D, Nielsen TO. VISTA expression on tumor-infiltrating lymphocytes in breast cancer: Clinical correlates and association with PD-1 [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-05-12.
Abstract P3-05-18: The complex landscape of breast cancer immune evasion and its implications to personalized and combined immunotherapy
Authors: Bou-Dargham MJ , Liu Y , Sang Q-XA , Zhang J
Published: February 2018

Cancer immunotherapy activates the patient's immune system to recognize and kill cancer cells. The efficacy of immunotherapy in human breast cancer (BRCA) is hindered by the poor understanding of the immune system's anti-tumor response and tumor evasive mechanisms, and the lack of optimized treatment regimens for each BRCA patient. There are 6 known evasion mechanisms (M) by which tumors can escape immune surveillance. M1: immunosuppression via interleukin 10 (IL-10) and tumor growth factor beta (TGF-β); M2: induction of tolerance by cytotoxic T-lymphocyte associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1) and its ligands (PD-L1/PD-L2), and interferon gamma (IFN-γ); M3: apoptosis resistance via the expression of anti-apoptotic molecules, namely baculoviral IAP repeat-containing protein 3 (BIRC3), TNF receptor associated factor 1 (TRAF1), and TNF alpha induced protein 3 (TNFAIP3); M4: counterattack via decoy death receptors; M5: impaired antigen presentation by decreasing beta 2 microglobulin (B2M) and human leukocyte antigens A and B expression (HLA-A and HLA-B); and M6: ignorance caused by the absence of a danger signal or an antigen. Yet, which mechanisms or combination of mechanisms BRCA tumors utilize is unknown. Moreover, the currently used biomarkers for the choice of immunotherapy are not ideal, as for example, not all PD-L1+ patients respond to anti-PD-L1 treatment, and certain PD-L1- patients respond. Thus, there is a need for more precise biomarkers. Using the sequential biclustering method on the RNA-sequenced data of BRCA from The Cancer Genome Atlas (TCGA), eighty-one percent of BRCA patients were grouped into 7 different clusters (CL) of immune evasion subtypes. We found that the majority of breast cancer tumors utilize multiple immune evasion mechanisms. Tumors may use from 1 up to 4 combinatorial mechanisms simultaneously. We also identified classifier genes that would help sort patients based on their evasion mechanisms, and guide the choice of immunotherapy. This is especially important since the immune evasion molecules may not be the ideal biomarkers for the best choice of immunotherapy. Moreover, we showed that triple negative breast cancer (TNBC) patients were significantly associated with CL2 (M5).

Citation Format: Bou-Dargham MJ, Liu Y, Sang Q-XA, Zhang J. The complex landscape of breast cancer immune evasion and its implications to personalized and combined immunotherapy [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-05-18.
Abstract P3-06-01: Not presented
Authors: Klauber-DeMore N , Bonilla I , Nassar P , Hilliard E , Molano I , Spruill L
Published: February 2018

This abstract was not presented at the symposium.
Abstract P3-09-03: Not presented
Authors: Eriksson M , Li J , Leifland K , Czene K , Hall P
Published: February 2018

This abstract was not presented at the symposium.
Abstract P3-10-09: The association age-related parity and HER2 over-expression in breast cancer
Authors: Bae SY , Kim J , You JY , Jung SP , Bae JW
Published: February 2018

Backgrounds

Reproductive factors, such as age at menarche, parity, age at first birth, and breast feeding, are known to be associated with risk of breast cancer. Recent studies show the association between the reproductive factors and the molecular subtypes of breast cancer, especially in luminal-like subtypes. Nulliparity is known a risk factor of breast cancer, multiparity is considered a protective factor. However, pregnancy associated breast cancers show the high expression of HER2, Therefore, we hypothesized the number of birth (multiparity) is correlated with the over-expression of HER2.

Methods

We reviewed the database of 2,594 breast cancer patients were over 20 years of age, diagnosed between January 2000 and April 2017 at Korea University of Anam Hospital, Seoul, Korea. According the number of birth, nulliparous (the number of birth = 0; 271 patients), primiparous (the number of birth = 1; 420 patients) and multiparous (the number of birth≥2; 1,903 patients) groups were classified.

Results

The median age (range) of nulliparous, primiparous and multiparous groups was 43 (22-77), 48 (27-87) and 51 (26-86) years (P<0.001). In univariate analysis, the number of birth was associated with the expression of ER and HER2, nulliparous patients showed higher ER positivity (P=0.013) and multiparous patients showed higher HER2 overexpression (P=0.048). There was no association with PR and Ki-67 level. In logistic regression with age, the parity was negative correlation with ER positivity (OR 0.83, 95% CI 0.72-0.95, P=0.010) and positive correlation with HER2 overexpression (OR1.18, 95% CI 1.02-1.36, P=0.021) P=0.009) and multiparity was higher HER2 overexpression (OR 1.41, 95% CI 1.02-1.94, P=0.033). By subgroup analysis with menopausal status, there was statistically significance in only premenopausal women, not in postmenopausal women. In premenopausal women, the parity was negatively associated with ER positivity (OR 0.78, 95%CI 0.64-0.94, P=0.010) and multiparity was associated with HER2 overexpression (OR 1.72, 95%CI 1.12-2.63, P=0.013), there was no difference in HER2 overexpression between nulliparous and primiparous patients.

Conclusion

Parity was associated with ER and HER2 expression, multiparous patients were associated with ER negativity and HER2 overexpression, especially in premenopausal women. This suggests that pregnancy could affect risk of breast cancer, especially in HER2 positive breast cancer subtype (ER- HER2+ tumors), before menopause. We need further investigation and evaluation.

Citation Format: Bae SY, Kim J, You JY, Jung SP, Bae JW. The association age-related parity and HER2 over-expression in breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-10-09.
Abstract P3-10-13: Bilateral breast cancer in China: A 10-year single-center retrospective study
Authors: Li H , Jiang H , Zhang R , Shao B , Yan Y , Ran R , Di L
Published: February 2018

BACKGROUD: Women with unilateral breast cancer are at increased risk for developing contralateral disease. The objective of the single-center retrospective study was to evaluate the incidence of bilateral breast cancer (BBC) and to analyze the clinicopathological characteristics for BBC in China.

METHODS: We retrospectively reviewed the electronic medical records of 3924 female patients with breast cancer consecutively treated at the department of Breast Oncology in the Peking University Cancer Hospital between 2006 and 2016. BBC was categorized as synchronous (within 6 months) or metachronous bilateral breast cancer (after 6 months of a first tumor). Patients with BBC were identified according to the criteria described by Chaudary et al. Patients with stage IV first breast cancer, and those who were found to have distant metastases between the first and second primary breast cancer were excluded. Analyses of demographic, clinicopathologic, and treatment characteristics were done between sBBC and mBBC.

RESULTS: The incidence of BBC in our population was 3.2% (127 of 3924). Of those, 2.5 % ( 99 of 3924) were metachronous bilateral breast cancer ( mBBC ), and 0.71 % (28 of 3924) were synchronous bilateral breast cancer ( sBBC ). The overall median age of the patients at first diagnosis was 45 years (range, 27-81 years). The age of onset of the first mBBC was significantly younger than that of sBBC ( p = 0.027). In mBBC subgroups, the median time interval between first and second tumors was 68 months (range, 7-342 months), and 80.8% of the second tumor were diagnosed within 10 years of the diagnosis of the first tumor. A positive family history of breast cancer was found in 25% of sBBC and 9.1% of mBBC ( p = 0.025). In ER-negative first tumor of mBBC, 56.1% of the second tumor were ER-positive. Mastectomy was the commonest surgery performed in these patients.

CONCLUSIONS: Our results confirmed the necessity of screening contralateral breast at the diagnosis of unilateral breast cancer and following-up for Chinese patients with breast cancer.

Citation Format: Li H, Jiang H, Zhang R, Shao B, Yan Y, Ran R, Di L. Bilateral breast cancer in China: A 10-year single-center retrospective study [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-10-13.
Abstract P3-10-18: Factors associated with mammographic density in Japanese women
Authors: Uchida K , Ohashi H , Hiroko N , Mimoto R
Published: February 2018

Background: Increased mammographic breast density decreases the sensitivity and the specificity of mammography screening and is associated with a significant risk factor for breast cancer. No studies were identified that examined the impact of supplemental screening on breast cancer recurrence rates or mortality for women with dense breasts. The aim of this study is to examine factors associating with breast density in Japanese women.

Data sources and methods: We used mammography check-up participants (n=5159, women aged 40 years or older) between Apr 2014 and Mar 2017 as our baseline data. Using a self-administered questionnaire, data of life style were collected. Logistic regression was used to estimate the odds of having dense breasts by age, body mass index (BMI), alcohol consumption, smoking, parity, menopausal status, dysmenorrhea, hormone replacement therapy (HRT), family history of breast cancer, physical exercise, fried foods intake, brightly colored vegetables intake, coffee intake, tea intake and bone mineral density. Breast densities were divided into four categories based on BI-RADS classification. BI-RADS 3 and 4 were defined as dense breast. All statistical tests were two-sided.

Results: Dense breast accounted for 62.3% of mammography screening participants. Dense breast at an early age was more frequent as 78.0% in the 40's. Alcohol intake (20 g or more a day, OR=1.62, 0.026) in post-menopausal women showed statistically significant positive interaction with dense breast. Weak positive interaction was seen in bone mineral density>80% (OR=0.63, 0.086, n=775). On the other, age (OR=0.97, <0.001), BMI (OR=0.78, <0.001), number of live birth (one; OR=0.77, <0.030, two or more; OR=0.37, <0.001) and post-menopause (OR=0.60, <0.001) showed statistically significant negative interactions with dense breast.

Conclusion: Dense breast accounted for 62.3% of all participants. Dense breast was more frequent at early age as 78.0% in their 40's. Alcohol consumption and bone mineral density in post-menopausal women were positive interaction with mammographic breast density. On the contrary, age, BMI, number of live birth and post-menopause were negative interaction with mammographic breast density.

Citation Format: Uchida K, Ohashi H, Hiroko N, Mimoto R. Factors associated with mammographic density in Japanese women [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-10-18.
Abstract P3-14-11: Comparative effectiveness of antiemetic regimens for highly emetogenic chemotherapy-induced nausea and vomiting: A systematic review and network meta-analysis
Authors: Yokoe T , Hayashida T , Nagayama A , Seki T , Takahashi M , Takano T , Abe T , Kitagawa Y
Published: February 2018

Background

The optimal choice of antiemetic therapy for chemotherapy-induced nausea and vomiting (CINV) needs to be clarified. This study assessed the efficacy and safety of antiemetic regimens for highly emetogenic chemotherapy (HEC).

Methods

Randomized trials that compared different antiemetic regimens were included from MEDLINE. Quality was assessed using the Cochrane risk-of-bias tool. We followed Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Data were pooled using random-effects models. We conducted indirect comparisons using network meta-analysis of a Bayesian model. The main outcomes were the odds ratio (OR) for overall complete response (CR [i.e., no emesis and no rescue]). Safety was assessed from the trial description. All statistical tests were two-sided.

Findings

We systematically reviewed 24 randomized control trials (12,104 participants), which compared 12 different antiemetic regimens. Palonosetron (PAL) 0·75 mg (PAL0·75) + dexamethasone (Dex); aprepitant (APR) + a serotonin-3 receptor antagonist (5HT3) + Dex; and APR + PAL (0·25 mg or 0·50 mg) + Dex were more favorable than the reference regimen (OR, 1·51; 95% credibility interval [95%CrI], 1·18-1·91; OR, 1·78; 95%CrI, 1·58-2·05; and OR, 2·28; 95%CrI, 1·66-3·18, respectively). The oral combination of netupitant and palonosetron (NEPA) was more effective than conventional regimens (OR, 2·39; CrI, 1·73-3·30). Olanzapine (OLZ)-containing regimens were apparently the most effective: the ORs of OLZ + 5HT3 + Dex, OLZ + PAL + Dex, and OLZ + APR + 5HT3 + Dex were 2·78, 2·58, and 4·98, respectively.

Interpretation

The regimens of PAL0·75 + Dex, APR + 5HT3 + Dex, and APR + PAL + Dex were more favorable in conventional regimens (i.e., regimens without NEPA or OLZ), which support the NCCN guideline strategy. NEPA could be a better choice than conventional regimens. OLZ-containing regimens could be an optimal choice; thus, more trials need to be accumulated.

Citation Format: Yokoe T, Hayashida T, Nagayama A, Seki T, Takahashi M, Takano T, Abe T, Kitagawa Y. Comparative effectiveness of antiemetic regimens for highly emetogenic chemotherapy-induced nausea and vomiting: A systematic review and network meta-analysis [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-14-11.
Abstract P3-15-03: Clinical benefit, toxicity, and cost of metastatic breast cancer drug therapies: Visualizing randomized and non-randomized evidence
Authors: Silberholz J , Vahdat L , Bertsimas D
Published: February 2018

Background: Given the rapidly expanding size of the clinical trial literature for metastatic breast cancer (MBC) clinical trials, oncologists need tools that enable them to efficiently review the settings and results of previous studies.

Methods: We searched the Cochrane Central Register of Controlled Trials and PubMed to identify clinical trials testing MBC drug therapies. Key eligibility criteria included >90% of patients enrolled in trial having MBC, therapeutic clinical trials, and Phase II or III studies with at least 10 patients at a dosage level. From each study, we extracted information about clinical benefit and toxicity of drug therapies, and we further estimated the costs of all drug therapies. We built a web-based visualization tool that presents the results of all studies testing a given drug combination, stratified based on patients' receptor statuses and prior exposure to therapy. The tool presents both aggregate and study-level results, and reports both unadjusted study results and standardized results based on key patient characteristics in the study populations.

Results: We included 1,783 studies containing 2,549 treatment arms and 170,515 patients in the visualization tool. The tool reports information on 77 HER-2-directed therapies, 101 hormonal therapies, and 675 undirected therapies. The visualization tool has been made publicly accessible for patients and doctors to access at http://cancertrials.info.

Discussion: We believe this tool will make literature reviews significantly more efficient for oncologists, enabling them to better leverage insights from the clinical trial literature when making treatment decisions.

Citation Format: Silberholz J, Vahdat L, Bertsimas D. Clinical benefit, toxicity, and cost of metastatic breast cancer drug therapies: Visualizing randomized and non-randomized evidence [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-15-03.
Abstract P3-15-04: Signalling pathways targeted by the YangZheng Xiaoji extract and the therapeutic implications in human breast cancer
Authors: Jiang WG , Ye L , Owen S , Ruge F , Martin TA , Sanders AJ , Gao G , Wei C , Wu Y , Davies E
Published: February 2018

Background. Yangzheng Xiaoji is a formulation of Chinese medicine and has been used in the treatment of solid cancer as an adjuvant to chemotherapy by reducing the side effects to the patient. There has been evidence to show that the medicine has a direct biological role in cancer cells. In the present study, we sought to investigate the potential effects of the medicine on breast cancer cells and in particular aimed to identify the key targets and molecular pathways contributing to the anti-cancer effect of the medicine.

Methods. Human breast cancer cell lines (BT549, BT20, MDA MB-231, MCF-7 and ZR 75-1) with varying invasiveness and receptor status were used. The soluble extract of Yangzheng Xiaoji, namely DME25 was used in the study. The effects of DME25 on the growth, toxicity and cellular migration were assessed. Signalling kinase changes were screened using kinase antibody array based array technologies. Kinases were also validated using phosphorylation based protein blotting.

Results. Of the five breast cancer cell lines tested, Yangzheng Xiaoji extract DME25 showed little cytotoxicity over a broad range of concentrations. However, DME25 were able to markedly reduce the migration of the panel of breast cancer tested, without being toxic. Triple negative cells responded in a similar fashion with other cells. It was also noted that the adhesion of these cells were also inhibited by DME25. Using a protein kinase array, it was shown that a number of kinase complexes were inhibited by the medicine, notable ones including EGFR family kinases (reduced by 35%), Janus protein kinases (JAK) (by 57%), and Ras-related C3 botulinum toxin substrate (Rac1 or CDC42 GTPase) (by 49%) and Ribosomal protein S6 kinases (RSKs) (by 52%). Given the clinical significance of RSKs in human breast cancer, we further evaluated the role of RSK and RSK inhibitors in DME mediated cell functions and have demonstrated that both in triple negative breast cancer cells and receptor positive breast cancer cell lines, DME25 was able to synergistically enhance the effect of RSK2 inhibitor, SL1010-1, on the both the cellular migration and cell growth.

Conclusion. Yangzheng Xiaoji has a broad and direct effect on the migration of breast cancer, an effect unrelated to hormone receptor status and independent of cytotoxicity. The medicine appears to target kinase pathway, particularly for the RSK kinases, suggesting an important clinical implication in the treatment of breast cancer.

Citation Format: Jiang WG, Ye L, Owen S, Ruge F, Martin TA, Sanders AJ, Gao G, Wei C, Wu Y, Davies E. Signalling pathways targeted by the YangZheng Xiaoji extract and the therapeutic implications in human breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-15-04.
Abstract P3-15-05: Early breast cancer in the elderly: characteristics, therapy, and long-term outcome
Authors: Gal O , Ishai Y , Sulkes A , Shochat T , Yerushalmi R
Published: February 2018

Objective: The number of older adults diagnosed with breast cancer is increasing. However, data on breast cancer characteristics, treatment, and survival in elderly women are sparse.

Methods: The database of a tertiary cancer center was searched for all women aged >65 years who were diagnosed with early breast cancer in 2004-2007. Patients were divided into two age groups: 65-75 years and >75 years. Data on tumor, treatment and outcome parameters were compared.

Results: The cohort included 390 patients. The older group underwent more mastectomies but less axillary surgery or adjuvant systemic therapy. Median overall survival (OS) was 9.5 years in the older group and not reached in the younger group; the 8 year disease-free survival rates were 85% and 88%, respectively (p=0.27). Both age and tumor subtype had an effect on OS and recurrence rates (p<0.001 for OS; p=0.16 for recurrence). The worst outcome was noted in women aged >75 years with triple-negative (TN) disease.

Conclusion: Treatment approach was different between both age groups, despite similar tumor characteristics. TN subtype presented as the most aggressive disease in both age groups. Physicians should be alert to these findings and select treatment on a case-by-case basis.

Citation Format: Gal O, Ishai Y, Sulkes A, Shochat T, Yerushalmi R. Early breast cancer in the elderly: characteristics, therapy, and long-term outcome [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-15-05.
Abstract P4-03-06: Withdrawn
Authors: Irie HY , Byerly JH , Ito K , Port ER
Published: February 2018

This abstract was withdrawn by the authors.
Abstract P4-03-08: Withdrawn
Authors: Perrotta RM , Dalotto-Moreno T , Cagnoni A , Mariño KV , Rabinovich GA , Salatino M
Published: February 2018

This abstract was withdrawn by the authors.
Abstract P4-03-10: Clinical observation of lapatinib versus continued use of trastuzumab for trastuzumab-resistant HER2-positive advanced breast cancer
Authors: Yin Y , Li W , Huang X , Wang J , Fu Z , Li J
Published: February 2018

Objective: To compare the efficacy, adverse effects and survival of lapatinib versus continued use of trastuzumab for trastuzumab-resistant human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer.

Methods: Patients who began the regimen of lapatinib plus capecitabine (LC or LX) or trastuzumab beyond progression (TBP) between May 2013 and October 2016 were selected from the First Affiliated Hospital of Nanjing Medical University. All of their clinical data were recorded, including age, performance status, hormone receptor status, metastatic site, primary or acquired trastuzumab resistance, previous treatment and so on. They were followed up until death or April 30, 2017. The primary end point was progression-free survival (PFS). The efficacy and safety of the two regimens were evaluated according to Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 and Common Terminology Criteria for Adverse Events (CTCAE) version 4.0, respectively. Data were analyzed by SPSS version 19.0.

Results: In total, 95 patients were identified, including 40 treated with LX and 55 with TBP. Median follow-up time was 16.0 months. There was no difference in objective response rate (ORR) and disease control rate (DCR) between the two groups. By the end of follow-up, median PFS was 6.3 months with LX and 7.1 months with TBP (P=0.676). In patients with primary trastuzumab resisitance, longer PFS was observed in LX group compared with TBP group [median PFS: 8.0 months vs. 5.3 months, hazard ratio (HR)=0.416, 95% confidence interval (CI): 0.177-0.981, P=0.038]. The incident rate of new brain metastases during treatment was 2.5% in LX group and 10.9% in TBP group, respectively (P=0.233). Both regimens showed similar outcomes in baseline brain metastases. Grade 3-4 adverse effects included diarrhea 7.5%(3/40) and hand-foot syndrome 12.5%(5/40) in LX group, along with leukopenia 18.2%(10/55), thrombocytopenia 9.1%(5/55) and nausea/vomiting 3.6%(2/55) in TBP group.

Conclusion: LX and TBP were similarly effective for patients with HER2-positive breast cancer progressing on prior trastuzumab-containing therapy. Both were well tolerated in general. Lapatinib tended to reduce the risk of disease progression in patients resistant to trastuzumab primarily. LX or TBP after local treatment appeared to show no difference in treating patients with brain metastases.

Citation Format: Yin Y, Li W, Huang X, Wang J, Fu Z, Li J. Clinical observation of lapatinib versus continued use of trastuzumab for trastuzumab-resistant HER2-positive advanced breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-03-10.
Abstract P4-03-13: Combined estrogen receptor alpha and XPO1 targeting to overcome endocrine resistance
Authors: Madak Erdogan Z , Kulkoyluoglu E
Published: February 2018

The majority of breast cancer-specific deaths occur in women with recurrent, ERα (+), metastatic tumors that are initially responsive to endocrine therapy yet become endocrine-resistant. There is a critical need for novel therapeutic approaches to re-sensitize recurrent ERα (+) tumors to endocrine therapies. The objective of this study was to elucidate mechanisms of improved effectiveness of combined targeting of ERα and XPO1, a nuclear transport protein in overcoming endocrine resistance. Using Cignal Finder pathway profiling, Seahorse metabolic profiling and GC/MS whole metabolite profiling, we found that combination of 4-OH-Tamoxifen (4-OH-Tam) and Selinexor (SXR), a highly selective XPO1 inhibitor that is currently in clinical trials for leukemia and prostate cancer, inhibited Akt phosphorylation by changing the phosphorylation status and localization of the kinase. Since we observed dramatic changes in Akt activity, we hypothesized that metabolic pathways and consequently metabolic profile of breast cancer cells would change in the presence of 4-OH-Tam and SXR. These cells were more dependent on mitochondria for energy production. Their glucose and fatty acid dependency decreased in the presence of SXR and cells were more dependent on glutamine as the mitochondrial fuel source. We demonstrated that combined targeting of XPO1 and ERα rewires metabolic pathways and induce autophagy. Remodeling metabolic pathways to regenerate new vulnerabilities in endocrine-resistant tumors is novel, and given the need for better strategies for improving therapy response of relapsed ERα (+) tumors, our findings show great promise for combined targeting of ERα and XPO1 in the clinic to reduce cancer recurrences.

Citation Format: Madak Erdogan Z, Kulkoyluoglu E. Combined estrogen receptor alpha and XPO1 targeting to overcome endocrine resistance [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-03-13.
Abstract P4-06-05: Not presented
Authors: Patel R , Rosen B , Baron P , Beitsch P , Whitworth P , Compagnoni G , Barbosa K , Grady I , Lee L , Schonholz S , Ruiz A , Robertson Y , Rock D
Published: February 2018

This abstract was not presented at the symposium.
Abstract P4-06-10: Withdrawn
Authors: Smith DJ , Sauter CT , Zhang C , Chen Z , Gogineni K
Published: February 2018

This abstract was withdrawn by the authors.
Abstract P4-06-18: Clinical application of multigene panel testing and genetic counseling for hereditary/familial breast cancer risk assessment: Prospective single center study
Authors: Lee E-S , Han W , Kim Y , Rhu J , Park JH , Kim K-E , Ju YW , Kim R , Lee H-B , Moon H-G , Noh D-Y
Published: February 2018

Background

The identification of individuals at elevated risk for hereditary cancers has allowed the development of consensus recommendations for cancer screening and prevention. The introduction of multigene panels may identify more individuals with breast cancer gene mutations than does testing for BRCA1/2 alone. Therefore, the multigenerational panel increase the need for genetic counseling suggesting preventive approach or cancer-specific screening to patients and family members. The rapid clinical introduction of multigene panel testing, however, have several issues such as low- to moderate-risk gene mutations and clinical recommendations. We collect the mutation results and clinical recommendations after testing with multigene panel and giving genetic counseling.

Methods

We had developed multigene panel consisted of 64 genes related to hereditary cancer through previous study and prospectively enrolled 104 individuals who were appropriate candidates for hereditary breast cancer evaluation. The patients were tested with 64-gene panel(Celemics) and results were provided by us 4˜10 weeks later. We checked the family history of cancer and made a pedigree before testing.

Result

Among 104 participants, 26 patients harbored deleterious mutations, most commonly in high to moderate-risk breast/ovarian cancer genes (BRCA1/2, BRIP, RAD51 and RAD51D), Lynch syndrome gene(MSH6) and other genes(FH, SPINK1). We recommended the cancer-specific screening and/or preventive approach for mutation-positive patients and suggested additional genetic test for the family members. Among them, 6 (23%) patients received Risk reducing procedures (Prophylactic mastectomy or oophorectomy) and most of them(19 patients(73%)) received cancer specific screening.

Conclusion

We demonstrate the use of multigene panel testing for hereditary breast cancer and will suggest the process of the genetic counseling including indication and results analysis with multigene panel testing.

Citation Format: Lee E-S, Han W, Kim Y, Rhu J, Park JH, Kim K-E, Ju YW, Kim R, Lee H-B, Moon H-G, Noh D-Y. Clinical application of multigene panel testing and genetic counseling for hereditary/familial breast cancer risk assessment: Prospective single center study [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-06-18.