bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract OT2-07-11: Ixazomib in combination with carboplatin in pretreated women with advanced triple negative breast cancer, a phase I/II trial (AGMT MBC-10 trial)
Authors: Rinnerthaler G , Gampenrieder SP , Petzer A , Pusch R , Fridrik M , Rossmann D , Balic M , Egle D , Rumpold H , Singer C , Bartsch R , Melchardt T , Ulmer H , Mlineritsch B , Greil R
Published: February 2018

Background: Triple-negative breast cancer (TNBC) comprises a heterogeneous group of diseases which are generally associated with a poor prognosis. Up to now, no targeted treatment beyond anti-VEGF therapy is approved for TNBC so far and cytotoxic agents are the mainstay for the treatment of advanced tumor stages. Ixazomib is a selective, and reversible inhibitor of the proteasome, which has been mainly investigated in the treatment of multiple myeloma. In a preclinical study triple-negative breast cancer cells were treated with bortezomib, a first generation proteaseome inhibitor, alone and in combination with cisplatin, which had a synergistic effect. Clinical data are available for carboplatin plus bortezomib in metastatic ovarian and lung cancers showing remarkable antitumor activity and good tolerability. Based on this rational, the MBC-10 trial will evaluate the toxicity profile and efficacy of ixazomib in combination with carboplatin in patients with advanced TNBC.

Trial Design: Patients with metastatic TNBC pretreated with at least one prior line of chemotherapy for advanced disease with a confirmed disease progression and measurable disease are eligible for this study. Patients will receive ixazomib in combination with carboplatin on days 1, 8, and 15 in a 28-day cycle. The phase I part of this study uses an alternate dose escalation accelerated titration design. After establishing the maximum tolerated dose (MTD), accrual continues to evaluate the efficacy and safety of the combination (phase II, including 41 evaluable patients). All patients will continue on study drugs until disease progression, unacceptable toxicity or discontinuation for any other reason. Primary endpoint of the phase II is overall response rate, secondary endpoints include safety profile, progression-free survival and quality of life. This trial is open for patient enrollment since November 2016 in six Austrian cancer centers. Accrual is planned to be completed within two years. ClinicalTrials.gov Identifier: NCT02993094

Citation Format: Rinnerthaler G, Gampenrieder SP, Petzer A, Pusch R, Fridrik M, Rossmann D, Balic M, Egle D, Rumpold H, Singer C, Bartsch R, Melchardt T, Ulmer H, Mlineritsch B, Greil R. Ixazomib in combination with carboplatin in pretreated women with advanced triple negative breast cancer, a phase I/II trial (AGMT MBC-10 trial) [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 OT2-07-11.
Abstract P1-01-10: Expression of adipocyte fatty acid binding protein promotes obesity-associated mammary tumor growth
Authors: Sauter ER , Li B , Hao J , Kong M
Published: February 2018

Background: Obesity increases the risk of many types of cancer, including breast cancer. The underlying mechanisms that drive obesity-related breast cancer remain unclear. Fatty Acid Binding Proteins (FABPs) are a family of cytosolic proteins which are organ specific and coordinate lipid transportation. Adipocyte FABP (A-FABP) is highly expressed in adipose tissues and may provide a link to obesity-associated breast cancer risk. We previously observed that A-FABP serum levels were associated with obesity, and decreased with surgically induced weight loss. In this report, we evaluate the role of A-FABP in promoting obesity-associated mammary tumor growth. Hypothesis: Deficiency of A-FABP in mice decreases obesity-associated mammary tumor progression. Methods: Weaned wild type control and A-FABP-deficient (genetically depleted A-FABP-/-) female mice (n=15/group) were randomly grouped and fed either a high fat diet (HFD) (60% fat) or a low fat diet (LFD) (10% fat). After 6 months on the diets, serum was collected from the tail vein and measured for levels of circulating A-FABP by ELISA. E0771 mammary tumor cells (0.5x106/mouse) were injected into the mammary fat pad and tumor volume measured at 3-day intervals. The student's t-test was used to compare A-FABP levels and ANOVA to compare tumor sizes in the lean and obese mice. Results: HFD-fed control mice exhibited a significant increase in body weight (31.5±2.13g) compared to LFD-fed control mice (19.86±0.36) (p<0.01). Serum levels of A-FABP were correspondingly elevated in obese (104.9±8.3 ng/ml) vs. lean controls (31.8±5.4 ng/ml) (p<0.01). Interestingly, although A-FABP deficient mice fed a HFD were more obese than HFD-fed control mice (final body weight 43.4g vs. 31.5 g) (p<0.05), tumor growth in the A-FABP deficient mice was significantly less than in controls (p<0.0001), suggesting that A-FABP expression is critical for obesity-associated mammary tumor growth. Long term tumor growth in lean A-FABP deficient vs. control mice was not significantly different. Thus, A-FABP deficiency appears to uncouple obesity and mammary tumor growth in HFD-induced obese mice. Impact: A-FABP is associated with obesity related breast/mammary cancer, and appears to be an important driver of tumor development. Downregulation of this protein may be useful to prevent and/or treat these tumors.

Citation Format: Sauter ER, Li B, Hao J, Kong M. Expression of adipocyte fatty acid binding protein promotes obesity-associated mammary tumor growth [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 P1-01-10.
Abstract P1-02-03: The Y537S ESR1 mutation carries unique metabolomics profiling in breast cancer
Authors: Gu G , Piyarathna B , Coarfa C , Ellis L , Ando' S , Fuqua S
Published: February 2018

Background:

Estrogen receptor (ESR1) mutations occur at a high frequency in metastatic breast tumors in patients treated with hormonal therapy in the metastatic setting. We do not know if these mutations changed metabolomics and whether these metabolomics change could affect metastasis.

Experimental design and methods:

We generated ESR1 Y537S homozygous mutations using CRISPR Casp-9 technology. Globe metabolites screening was performed using 6550 Agilent QTOF instrument. Athymic mice were used in tumor xenograft studies. Affymetrix microarrays were performed to compare gene expression changes in Y537S mutant compared with parental cells. Enriched metabolite pathways and gene expression integrated analysis was analyzed by using online analysis tool http://www.metaboanalyst.ca.

Results:

We generated CRISPR ESR1 Y537S mutation homozygous knock-in clones in MCF-7 cells. In vivo experiments revealed that mutant cells are dominant drivers of metastasis. Transcriptome profiling revealed elevated expression of Hallmark pathways, including EMT and estrogen-regulated gene expression. We performed globe metabolites screening using MCF-7 Y537S and MCF-7 parental and identified 134 metabolites. Serum starvation media was used and estrogen was used as control for both cell lines. As we expected estrogen treatment induced metabolites changes in parental cells. However, metabolites in mutant cells were not changed significantly under estrogen treatment. Interestingly, metabolites in the mutant cells at baseline were remarkably upregulated (78 out of 134 identified total metabolites) indicating mutant cells in serum starvation condition had significantly different metabolomics compared with parental cells. Top upregulated pathways include protein biosynthesis, betaine metabolism and ammonia recycling. Integration of microarray gene expression and metabolites reviewed several metabolomics pathways significantly changed in mutant compared with parental cells including for example aminoacyl-tRNA biosynthesis, arginine and proline metabolism and alanine, aspartate and glutamate metabolism.

Conclusion: The Y537S ER mutation is a driver of distant metastasis in ER-positive breast cancer cells. Y537S ER mutant had globe changes of metabolites expression which was confirmed by integrated analysis combining microarray gene expression. The roles of these metabolites need to be studied to correlate with metastasis. Enzymes responsible for converting these metabolites changes could be served as potential therapeutic targets.

Citation Format: Gu G, Piyarathna B, Coarfa C, Ellis L, Ando' S, Fuqua S. The Y537S ESR1 mutation carries unique metabolomics profiling 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 P1-02-03.
Abstract P1-03-06: GNBP2 suppresses tumor growth and cancer stem cell load of triple negative breast cancer by controlling STAT3 pathway
Authors: Zhang J
Published: February 2018

Background: Gametogenetin binding protein 2 (GGNBP2) is encoded in human chromosome 17q12-q23, a region known as a breast and ovarian cancer susceptibility locus. GGNBP2 has a single C2H2 zinc finger and a consensus LxxLL nuclear receptor (NR) binding motif. We have reported that GGNBP2 suppresses ERα-positive breast tumorigenesis by acting as a nuclear receptor co-repressor to restrain ERα activity. However, the detailed molecular mechanisms of GGNBP2 and its role in triple negative breast cancer (TNBC) remain largely unclear.

Methods: A human breast cancer tissue array containing 138 human breast tumor tissues were utilized to examine GGNBP2 expression in breast cancer samples by IHC. To address the potential anti-breast tumor activity of GGNBP2 in vitro, we expressed exogenous GGNBP2 in TNBC cells, including MDA-MB-231 and Cal51 cell lines. Cell proliferation and cell cycle were assessed by cell growth curve/EdU assays and flow cytometry after propidium Iodide staining. Apoptosis was determined by flow cytometry after annexin V staining, by caspase 3/7 and caspase 9 activity assays. Cancer stem cell properties were determined by expression of CD44/CD24/ALDH1 markers. The levels of phosphorylated STAT3 and total STAT3 were determined by western blot. Quantitative PCR and Western blot were carried out to evaluate the effects of GGNBP2 overexpression on STAT3 target genes, CCND1, Mcl-1, survivin, bax and bim expression.

Results: GGNBP2 expression is down-regulated in TNBC cells and patient tumors and it is associated with poor patient survival. Overexpression of GGNBP2 significanly induces cell cycle G0/G1 phase arrest and apoptosis in TNBC cell lines. Expression of cancer stem cell markers also decreased in GGNBP2-overexpressed TNBC cells. GGNBP2 reduces the expression levels of CCND1, Mcl-1 and survivin, promotes the expression levels of bax and bim proteins. Importantly, overexpression of GGNBP2 inhibits STAT3 phosphorylation and STAT3 downstream garget gene expression, including CCND1, Mcl-1 and survivin.

Conclusion: GGNBP2 serves as a critical nuclear negative regulator of STAT3-mediated gene expression and tumorigenesis.

Citation Format: Zhang J. GNBP2 suppresses tumor growth and cancer stem cell load of triple negative breast cancer by controlling STAT3 pathway [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 P1-03-06.
Abstract P1-06-12: Optimizing the use of oncotype Dx in early breast cancer
Authors: Ruiz R , Namuche F , Flores C , Aguilar A , Gomez HL
Published: February 2018

Background: Oncotype Dx (ODX) prognosticates the risk of recurrence and predicts the benefit of adjuvant chemotherapy in estrogen-receptor-positive breast cancer (BC). However, its cost makes it prohibitive for many health care systems. Our objective was to develop a model that uses routine clinical and pathological parameters to identify ODX high risk patients which require adjuvant chemotherapy.

Methods: We retrospectively reviewed ODX and pathology reports from 190 early BC patients treated between 2014 and 2016 in a specialized cancer center. Our population was divided into a training (n:133) and validation set (n:57). In the training set, among available clinico-pathological variables (age, T, ER, PR, Ki67, Elston-Ellis grade) a multiple linear regression model was carried out to select those significantly associated with ODX. Coefficients of statistically significant variables were used to build an equation. The equation was applied in the training set. These results were confronted to ODX categories. The best threshold for selecting high risk patients was identified in the training set and tested in the validation set.

Results: Among the tested variables, tumor size (pT), progesterone receptor (PR), Ki67 and Ellston-Ellis grade were significantly associated with ODX RS (Table 1). The linear predictor is: (0.2544 x pT) – (0.0739 x PR) + (0.0861 x Ki67) + (5.4232 x Elston grade). The threshold score for this equation was set on 14 to discriminate high from low-intermediate risk patients. The test was able to correctly classify high risk patients with a sensitivity of 78%, a specificity of 72% and a negative predictive value of 98%.

Conclusion: With further refinement ODX could be omitted in patients classified as high risk by our predictor therefore restricting and optimizing the use of ODX to a smaller population of patients. The observed ODX distribution in our patients is similar to previously reported series suggesting that this equation could be informative in similar clinical settings. Additional external testing using new datasets is ongoing.

Citation Format: Ruiz R, Namuche F, Flores C, Aguilar A, Gomez HL. Optimizing the use of oncotype Dx in early 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 P1-06-12.
Abstract P1-07-15: Withdrawn
Authors: Desmedt C , Fornili M , Poncet C , Clatot F , Orenti A , Boracchi P , Di Leo A , Viale G , de Azambuja E , Sotiriou C , Crown J , Francis PA , Bonnefoi H , Piccart M , Biganzoli E
Published: February 2018

This abstract was withdrawn by the authors.
Abstract P1-07-19: Protective effect of 27-hydoxycholesterol on disease recurrence in HER2-negative luminal type of early breast cancer
Authors: Sung Hoon S , In Hae P , So-Youn J , Seeyoun L , Sun-Young K , Han-Sung K , Eun Sook L , Keun Seok L
Published: February 2018

Background: 27-hydoxycholesterol (27-HC) is a metabolite of cholesterol (Chol) and known as endogeneous selective estrogen receptor modulator (SERM). Laboratory researches showed high 27-HC could stimulate cancer cell proliferation and promote metastasis processes in hormone receptor positive breast cancer. However, there is no clinical data about the effect of 27-HC on disease recurrence in early breast cancer.

Methods: A total of 539 early breast cancer patients who underwent surgery at the National Cancer Center Hospital between 2001 and 2010 with the deposition of blood samples at Tumor Bank were accrued. The blood samples were taken with overnight fasting at surgery day. Serum 27-HC was analyzed by liquid chromatography–mass spectrometry (LC-MS). 27-HC and Chol were categorized into two groups (low vs high) by median, respectively.

Results : Hormone receptor was positive in 441 patients and negative in 98 while HER2 was positive in 81, negative in 325 and unknown in 133 patients. The median follow up time was 92 months (range 24 -153.7). The 27-HC (median, 115.73 ng/ml with the range of 29.36- 234.0) and Chol (median, 170.0 mg/dl with the range of 91- 290) showed weak correlation (ρ=0.24, P<0.001).

While 27-HC was not significant in analysis for RFS in all cases, it showed marginal significance for RFS in the subset analysis with HER2-negative luminal breast cancer patients (HR, 0.463; 95% CI, 0.208-1.031; P = 0.059). When the patients were grouped according to 27-HC and Chol level (group27HC/Chol) in luminal subgroup, it showed a trend for increasing RFS in the order of grouplow/high , grouplow/low, grouphigh/low and grouphigh/high(Ptrend= 0.009).

Conclusion : Serum 27-HC was not associated with poor RFS. High serum 27-HC could be related to good prognosis in HER2-negative luminal type of breast cancer, which may be related to the protective effect of 27-HC from disease recurrence. Further study is warranted.

Citation Format: Sung Hoon S, In Hae P, So-Youn J, Seeyoun L, Sun-Young K, Han-Sung K, Eun Sook L, Keun Seok L. Protective effect of 27-hydoxycholesterol on disease recurrence in HER2-negative luminal type of early 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 P1-07-19.
Abstract P1-07-21: Relationship between hereditary cancer syndromes and oncotype DX recurrence score
Authors: Toltzis S , Casasanta N , Lipinski S , Marino A , McHenry A , Denduluri N , Rodriguez P , Kaltman R
Published: February 2018

Background

Oncotype DX Recurrence Score (RS) is used to stratify breast tumors into those likely to respond to cytotoxic chemotherapy. Women and men with hereditary cancers tend to have tumors that are chemosensitive. We hypothesize that a high RS may harbor a signal of potential hereditary risk. This analysis aims to identify whether breast cancer patients with hereditary cancer syndromes have a disproportionate amount of high RS compared to sporadic cases.

Methods

Individuals with a personal history of breast cancer who received treatment at participating research facilities and had hormone receptor positive breast cancer, Oncotype DX testing and hereditary cancer mutation testing were included. Oncotype DX RS was recorded along with the type of genetic testing and the genetic testing results. RS was categorized as low (0-17), intermediate (18-30), and high (31+). Those with deleterious mutations in any known hereditary cancer gene were considered positive. Individuals with a variant of uncertain significance (VUS) or negative genetic testing result were considered negative. Difference in distribution of tumors with low, intermediate, and high Oncotype DX results in those with hereditary breast cancers compared to those with sporadic breast cancers was determined with Chi-square.

Results

419 patients with Oncotype DX testing from two clinical sites were collected from 2013. Of those, 123 underwent genetic risk assessment. Mutations identified included the following genes: BRCA1 (1), BRCA2 (5); CHEK2 (3); BRIP1 (3); NBN (2); MSH6 (1). Of those testing positive for a deleterious mutation, the number of patients with RS results in each category were 5, 4 and 6 for low, intermediate and high, respectively. For those considered negative on hereditary cancer panel testing, the RS results were 76, 52 and 8, respectively. Of those with high RS, 43% had deleterious mutations. Chi square test was statistically significant for a difference between the RS of those with deleterious hereditary mutations versus those with sporadic cancers (p = 0.000086).

Conclusions

High RS may indicate a higher likelihood of harboring a hereditary cancer syndrome. Further investigation with larger numbers and multivariate analysis is needed to validate if a high RS serves as an independent predictor of benefit from genetic counseling and testing.

Citation Format: Toltzis S, Casasanta N, Lipinski S, Marino A, McHenry A, Denduluri N, Rodriguez P, Kaltman R. Relationship between hereditary cancer syndromes and oncotype DX recurrence score [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 P1-07-21.
Abstract P1-08-07: Withdrawn
Authors: Khandelwal S , Gollahon L , Boylan M , Spallholz J
Published: February 2018

This abstract was withdrawn by the authors.
Abstract P1-12-02: Clinical efficacy of a humanized monoclonal antibody against the Lewis-Y antigen (Ley): Results of a phase II clinical trial
Authors: Testa L , Serrano SV , Arai RJ , Zorzetto MC , Freitas-Junior R , Maletz O , Mano MS , Hoff PM
Published: February 2018

Background. The Lewis-Y (Ley) antigen is a blood group-related antigen expressed in over 70% of epithelial cancers. It is expressed in 44% of breast cancers.

Objectives. The primary endpoint was to evaluate the clinical efficacy of hu3S193, a humanized monoclonal antibody against the Lewis-Y antigen, in advanced hormone positive breast cancer after failure of at least one line of endocrine therapy.

Methods. This multicenter, single arm, phase II trial enrolled eligible patients to receive hu3S193 weekly at a dose of 20 mg/m2 intravenously. Efficacy was measured as clinical benefit rate (objective response or stable disease for at least 24 weeks).

Results. Of 49 patients screened, 27 (55%) were Ley positive. Of these 27, only 20 were eligible for efficacy analysis. No complete or partial responses were observed. Five patients had stable disease for 24+ weeks (clinical benefit rate 25%). One patient remains on study drug maintaining stable disease for over 2 years. This patient had high expression of Ley. The most common treatment-related adverse events were headache (50%), cough (45,5%) and nausea/vomiting (31,8%).

Conclusions. Hu3S193 lacked sufficient activity in is trial and the investigators stopped accrual at the first interim analysis. High expression of Ley might play a role in selecting patients to this strategy.

Citation Format: Testa L, Serrano SV, Arai RJ, Zorzetto MC, Freitas-Junior R, Maletz O, Mano MS, Hoff PM. Clinical efficacy of a humanized monoclonal antibody against the Lewis-Y antigen (Ley): Results of a phase II clinical trial [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 P1-12-02.
Abstract P2-02-03: Assessment of an immune response panel of serum protein biomarkers for the non-invasive detection of breast cancer
Authors: McQuary PR , Copeland KAF , Sheibani NM , Friedman LA , Korn RL , Fiorica JV , Lourenco AP , Struthers SE , Hesterberg LK
Published: February 2018

Background: Breast cancer screening guidelines (ACS) recommend annual mammography for asymptomatic women ages 45 to 54 and once every two years for women age 55 and older. Women with suspicious screening mammograms are recommended for a diagnostic mammogram and may also undergo MRI or ultrasound. Ultimately, unresolved suspicious findings frequently result in the recommendation of a breast biopsy. Approximately 10% of suspicious diagnostic mammograms are recommended for breast biopsies and a large majority of these biopsies yield benign results. We conducted a screen for serum protein biomarkers and identified a novel panel for the non-invasive detection of breast cancer with the goal of developing a diagnostic test that can reduce the number of patients with benign pathology undergoing invasive biopsies.

Methods: Serum samples were collected at 4 US sites from women with suspicious diagnostic mammogram findings (primarily BI-RADS category 4 and breast composition b/c) undergoing biopsy for evaluation of a potential malignancy. Serum samples from 136 patients (87 benign pathology and 49 malignant pathology) were evaluated on the olink® Proteomics Immune Response Panel (92 analytes). Statistical screening methodologies, such as individual t-tests with control for false discovery, were used to identify markers with the potential to distinguish benign from malignant pathology. The candidate markers were further studied and combined using generalized linear modeling to develop potential diagnostic models.

Results: A 19-marker model resulted in an AUC of 0.94 with a sensitivity of 90% and a specificity of 80%. A 12-marker model resulted in an AUC of 0.93, yielding a sensitivity of 90% with a specificity of 77%.

Conclusions: This study reveals a novel panel of serum protein biomarkers that may allow for the non-invasive and sensitive detection of breast cancer in patients presenting with suspicious findings on mammography, thus reducing the need for invasive biopsies.

Citation Format: McQuary PR, Copeland KAF, Sheibani NM, Friedman LA, Korn RL, Fiorica JV, Lourenco AP, Struthers SE, Hesterberg LK. Assessment of an immune response panel of serum protein biomarkers for the non-invasive detection of 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 P2-02-03.
Abstract P2-02-07: Not presented
Authors: Lee SJ , Lee J , Jung JH , Park HY , Moon P-G , Baek M-C , Chae YS
Published: February 2018

This abstract was not presented at the symposium.
Abstract P2-02-11: Not presented
Authors: Shao X , Wang X , Huang P , Li G , Zou W , Chen Z , Zheng Y
Published: February 2018

This abstract was not presented at the symposium.
Abstract P2-02-20: Withdrawn
Authors: Song PY , Simmons J , Strauss W , Klem E , Carter C , Tahvilian S , Dempsey PW
Published: February 2018

This abstract was withdrawn by the authors.
Abstract P2-04-05: Not presented
Authors: Maund PR , Ermler S , Widschwendter M , Silva E
Published: February 2018

This abstract was not presented at the symposium.
Abstract P2-05-07: Whole exome sequencing of extreme responders reveals low mutation burden in metastatic breast cancer
Authors: Sohn J , Lim SM , Kim E , Kim S , Koo JS , Kim SI , Park S , Park HS , Kwon N-J , Kim GM , Kim S
Published: February 2018

Background: Extreme responders to anticancer therapy are rarely encountered in the treatment of advanced breast cancer patients, but their treatment response have not been investigated on the whole exome level. We performed whole exome analysis to characterize genomic landscape of extreme responders in metastatic breast cancer patients.

Methods: Clinical samples were obtained from patients who showed exceptional response to anti-HER2 therapy or hormonal therapy. Non-responders were selected among those who did not respond. Matched breast tumor tissue (somatic DNA) and blood samples (germline DNA) were collected from a total of 18 responders (12 ER+, 6 HER2+) and 8 non-responders (6 ER+, 1 HER2+, 1 TNBC). Whole exome sequencing using Illumina HiSeq2500 was performed on the 26 patients (52 samples). Somatic single nucleotide variants (SNVs), indels and copy number variants (CNVs) were identified for each patient genome. Group specific somatic variants and mutation burden were statistically analyzed.

Findings: Cancer exomes were characterized by 1,455 somatic single-nucleotide variants (1,327 missense, 80 nonsense, 36 splice-site, 12 start/stop-lost), 149 insertions/deletions (108 frameshift, 41 inframe), with a median of 1 mutations per Mb (0.2 to 2.7 mutations per Mb) in all patients. Responders harbored a significantly lower non-synonymous mutation burden than non-responders (median, 27 vs. 90.5, P=0.01), and copy number variation burden was also lower (median 23 vs. 31, P=0.14). Multivariate analyses of factors influencing progression-free survival showed that high mutation burden and visceral metastases were significantly related with progression.

Interpretation: Extreme responders of metastatic breast cancer are characterized by low nonsynonymous mutational burden.

Citation Format: Sohn J, Lim SM, Kim E, Kim S, Koo JS, Kim SI, Park S, Park HS, Kwon N-J, Kim GM, Kim S. Whole exome sequencing of extreme responders reveals low mutation burden in metastatic 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 P2-05-07.
Abstract P2-07-08: Prognostic relevance of claudins 4 and 7 in invasive breast carcinoma (NOS) subtypes: A large tissue microarray study
Authors: Logullo AF , Rocha RM , Stiepcich M , Soares FA , Pasini FS , Nonogaki S , Brentani MM
Published: February 2018

Molecular phenotyping has improved the understanding of a wide range of breast cancer disease. Recently, a new molecular subtype denominated “claudin-low” (CL) was described in breast cancer and correlated to worse prognosis and to CD44+/24- stem cell profile. Among 19 known claudin proteins, isotypes 4 (CL4) and 7 (CL7) are the most common in the breast biology. Objective: To verify differences in CL4 and CL7 immunoexpression between Luminal A, HER-2, and triple negative breast cancer phenotypes; and their association to CD44/24 status and tumor prognosis. Design: Estrogen and progesterone receptor status (ER/PR), HER-2, CL4 and CL7 expression and CD44/24 profiles were evaluated in 803 invasive ductal breast carcinomas arranged into four tissue microarrays (TMA) and results were correlated with prognosis and important clinical data. Results: 503 (62.6%) cases were positive for CL4 and 369 (46.0%) cases for CL7. The majority (199/283, 70.3%) of CL4 negative cases were clustered in the luminal A subtype whereas 63 (22.3%) showed triple negative profile and the remaining 21 cases (7.4%) exhibited positive HER-2 expression (p<0.001). Claudin 7 negative samples (44.2%) tended to follow the same pattern. CL4 positive expression was significantly associated to HER-2 expression, presence of lymph nodes and increased tumor grades and inversely correlated to ER and PR expression. However, there was no association between CL7 expression and any of these features. Both CL4 and CL7 did not show correlation to the stem cell markers (CD44+/CD24-) or worse prognosis (survival and disease-free interval). Conclusion: Claudins 4 and 7 immunoexpression did not provide additional prognostic information within breast cancer subtypes.

Citation Format: Logullo AF, Rocha RM, Stiepcich M, Soares FA, Pasini FS, Nonogaki S, Brentani MM. Prognostic relevance of claudins 4 and 7 in invasive breast carcinoma (NOS) subtypes: A large tissue microarray 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 P2-07-08.
Abstract P2-09-26: Frequency and mechanisms of elevated somatic mutation burden in metastatic breast cancer and response to immune checkpoint blockade
Authors: Cobain EF , Robinson DR , Wu Y-M , Lonigro R , Vats P , Rabban E , Kumar-Sinha C , Schott AF , Smerage JB , Morikawa A , Burness ML , Van Poznak CH , Griggs J , Wicha M , Hayes DF , Chinnaiyan AM
Published: February 2018

Background: Immune checkpoint blockade (ICB) is effective in the treatment of various malignancies. Thus far, however, results in breast cancer have been mixed. Elevated tumor mutational load, and subsequent increased likelihood of forming immunogenic neoantigens, has been correlated with response to ICB. Mutational load observed in breast cancers varies widely. However, most studies have assessed mutational load using primary tumors. Few studies have explored the frequency of high mutational load, molecular mechanisms accounting for this phenomenon, and its potential impact on response to ICB in metastatic breast cancer (MBC).

Methods: From 2011-2016, 124 patients (pts) with MBC of varying subtypes underwent research biopsy of their metastatic disease for whole genome, exome and transcriptome sequencing of tumor and matched normal sample through the Michigan Oncology Sequencing Center (Mi-OncoSeq). Those pts with elevated somatic mutation load were defined as having greater than 10 mutations per megabase of targeted sequencing and mutational signatures accounting for high mutation load were noted. Pts treated subsequently with ICB were followed to assess response.

Results: Twelve MBC pts had high mutation load (10% of cohort). Eight pts had estrogen receptor (ER) positive MBC and 4 pts had metastatic triple negative breast cancer (TNBC). In 5 cases, a clear mutational signature accounting for high mutation load was evident. Two TNBC cases harbored an APOBEC mutational signature in addition to 1 TNBC and 2 ER positive tumors displaying a microsatellite instability signature (MSI-H). Among the tumors with MSI-H signature, 1 case was associated with a pathogenic germline alteration in MLH1. Two pts were subsequently treated with ICB on a clinical trial. One pt came off study after 3 months due to progressive brain metastases and another had partial response to therapy lasting 7 months.

Conclusions: Elevated somatic mutation burden in MBC is observed in approximately 10% of pts, and is detected in both ER positive and TNBC. Since high mutation burden has been associated with increased likelihood of response to ICB, identification of this genomic feature could have important therapeutic implications for MBC pts.

Citation Format: Cobain EF, Robinson DR, Wu Y-M, Lonigro R, Vats P, Rabban E, Kumar-Sinha C, Schott AF, Smerage JB, Morikawa A, Burness ML, Van Poznak CH, Griggs J, Wicha M, Hayes DF, Chinnaiyan AM. Frequency and mechanisms of elevated somatic mutation burden in metastatic breast cancer and response to immune checkpoint blockade [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 P2-09-26.
Abstract P2-10-01: Validation that a histone gene signature predicts anthracycline response in early breast cancer
Authors: Spears M , Kornaga E , Lyttle N , Liao L , Bayani J , Quintayo M-A , Yao CQ , D'Costa A , Boutros PC , Twelves CJ , Pritchard KI , Levine MN , Nielsen TO , Shepherd L , Bartlett JMS
Published: February 2018

Background: The use of anthracycline-based chemotherapies has improved overall and disease free survival in breast cancer. However, anthracyclines can have significant toxicities including cardiotoxicity and leukemia. It is, therefore, imperative to identify those patients who will benefit from adjuvant anthracycline treatment and patients who could be spared unnecessary toxicities and be considered for alternative adjuvant therapy. Previous work performed by our laboratory identified a histone gene expression signature as a predictive marker of anthracycline benefit in the BR9601 clinical trial. In this study we validate the 18 histone gene signature in the MA.5 clinical trial and examine the role of the signature in individual intrinsic subtypes of breast cancer.

Methods We analysed the CCTG MA.5 clinical trial in a prospectively planned retrospective biomarker approach to validate this signature and tested the role of intrinsic subtyping as predictive markers of anthracycline benefit. RNA was extracted from patients in the MA.5 adjuvant trial evaluating the addition of epirubicin (E) to CMF and analysed using NanoString technology. Log-rank analyses validated the predictive values of the signature on distant relapse-free survival (DRFS). Cox-regression models tested independent predictive value on DRFS in the presence of treatment, age, tumour size, nodal status, HER2, ER status and grade, and treatment by marker interactions.

Results Analysis of the MA.5 clinical cohort revealed that patients whose tumour had low histone gene signature expression experienced increased DRFS (HR: 0.54, 95% CI 0.38-0.76, p=0.001) when treated with CEF compared with patients treated with CMF alone. Conversely, there was no apparent benefit of CEF vs CMF in patients with high histone gene expression signature (HR: 1.01, 95%CI 0.66-1.55, p=0.963). After multivariate analysis and adjustment for HER2, nodal status, age, grade and ER, the treatment by marker interaction for the gene signature was 0.54 (95%CI 0.31-0.94, p=0.030) for DRFS.

The predictive impact of the histone signature was independent of intrinsic subtype.

Conclusion The histone gene expression signature is an independent predictor of anthracycline benefit and could be a potential candidate diagnostic assay for patients with early breast cancer.

Citation Format: Spears M, Kornaga E, Lyttle N, Liao L, Bayani J, Quintayo M-A, Yao CQ, D'Costa A, Boutros PC, Twelves CJ, Pritchard KI, Levine MN, Nielsen TO, Shepherd L, Bartlett JMS. Validation that a histone gene signature predicts anthracycline response in early 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 P2-10-01.
Abstract P2-12-08: Rates of re-excision surgery after implementation of consensus guidelines on margins for breast- conserving surgery in stage I and II invasive breast cancer: A Nova Scotian experience
Authors: Drohan AE , Helyer LK
Published: February 2018

Background: In Canada, most women with early invasive breast cancer will be treated with breast-conserving surgery (BCS). The proportion of patients requiring re-excision surgery after BCS varies province to province. Until recently, there was no universally accepted definition for adequate margin width following BCS. The Society of Surgical Oncology (SSO) and American Society for Radiation Oncology (ASTRO) published consensus guidelines in 2014 to help regulate practice. The objective of this study was to determine the proportion of patients undergoing re-excision surgery before and after guideline implementation at our institution.

Methods: We performed a retrospective review of all patients with invasive breast cancer and/or ductal carcinoma in situ (DCIS) who underwent re-excision surgery between October 1, 2010- October 31, 2011 (pre-guideline) and October 1, 2014- May 30, 2016 (post-guideline). The proportion of patients requiring re-excision surgery was calculated for each time period and patient characteristics and clinical outcomes were compared.

Results: There were 188 patients identified who underwent BCS in the pre-guideline time period and 411 patients in the post-guideline time period. The proportion of patients undergoing re-excision surgery significantly decreased from 13.8 % to 7.8 % after guideline implementation (p = 0.02). Patient characteristics were similar between those who underwent re-excision before and after guideline implementation. In patients requiring re-excision surgery, histological and pathological features were similar between time periods. Margin width and indication for re-excision surgery varied between time periods. Among women who had re-excision surgery in the pre-guideline group, most (50%) had an invasive cancer margin > 1 mm. However, after guideline implementation, a frankly positive invasive cancer margin was the most common indication for re-excision surgery (65%). No significant differences in clinical outcomes were observed between patients who underwent re-excision surgery before and after guideline implementation.

Conclusion: The proportion of patients undergoing re-excision surgery after BCS has significantly decreased after SSO-ASTRO guideline implementation at our institution. This data suggests that among women with invasive breast cancer and/or DCIS, the implementation of SSO-ASTRO guidelines has led to a 43.5% decline in re-excision surgery.

Citation Format: Drohan AE, Helyer LK. Rates of re-excision surgery after implementation of consensus guidelines on margins for breast- conserving surgery in stage I and II invasive breast cancer: A Nova Scotian experience [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 P2-12-08.
Abstract P2-13-01: Differential efficacies of DNA damaging agents in basal-like TNBC subtypes
Authors: Shaffer CV , Robles AJ , Risinger AL , Mooberry SL
Published: February 2018

New approaches are needed to improve long term survival for patients with metastatic triple negative breast cancer (TNBC). Women with metastatic TNBC have a worse 3-year survival compared to women with metastatic HER2+ or ER/PR+ disease.1 Identifying the molecular vulnerabilities of TNBC subtypes could provide for optimal treatment strategies. Gene expression analyses of TNBC patient samples by Lehmann and Bauer, et al. identified 6 subtypes of TNBC.2 Based on the analysis of laser dissected tumor samples, the number of tumor subtypes was reduced from 6 to 4.3 Both analyses identified two types of basal-like cancers, basal-like 1 (BL1) and basal-like 2 (BL2).2,3 The BL1 subtype is defined by the amplified expression of genes involved in cell division and DNA damage response, and RNA polymerase.2 BL2 cancers express high levels of genes involved in growth factor signaling, glycolysis, and gluconeogenesis.2 They show that cell lines representative of the BL1 and BL2 subtypes of TNBC are more sensitive to cisplatin than cell lines representing the other TNBC subtypes. The BL1 or BL2 categorization, however, failed to predict sensitivity to olaparib.2 BL1 and BL2 representative cell lines responded differently when treated with veliparib; BL1 cells were more sensitive than BL2 cells.2 We investigated the response of BL1 and BL2 cells to a variety of DNA damaging agents to determine if the BL1 or BL2 subtype was predictive of sensitivity to a particular drug. DNA damaging agents, including alkylating agents, anti-metabolites, topoisomerase inhibitors, and PARP inhibitors were tested in cells resenting the BL1 and BL2 subtypes. HCC1806 cells (BL2) were found to be selectively sensitive to gemcitabine when compared to HCC1937 cells (BL1). The panel of drugs and cell lines was expanded to further understand the sensitivity of BL1 and BL2 subtypes to a variety of DNA damaging agents. Our goal is to provide preclinical evidence for the informed use of specific DNA damaging agents in the treatment of patients with BL1 or BL2 subtypes of TNBCs.

1. Li, X. et al. Breast Cancer Res. Treat. 161, 279–287 (2017).

2. Lehmann, B. D. et al. J. Clin. Invest. 121, 2750–2767 (2011).

3. Lehmann, B. D. et al. PLoS One 11, e0157368 (2016).

Citation Format: Shaffer CV, Robles AJ, Risinger AL, Mooberry SL. Differential efficacies of DNA damaging agents in basal-like TNBC subtypes [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 P2-13-01.
Abstract P3-01-18: Determining the need for axillar lymph node dissection based on pre-neoadjuvant chemotherapy sentinel lymph node biopsy results
Authors: Semiglazov VF , Krivorotko PV , Zhiltsova EK , Dashayan GA , Zernov KU , Bessonov AA , Trufanova ES , Tabagua TT , Ivanova OA , Kanaev SV , Novikov SN , Krzivickiyi PI , Brayanceva ZV , Komayachov AV , Nikolaev KS , Gigolaeva LP
Published: February 2018

An open-label single institution study of sentinel lymph node biopsy prior to neoadjuvant chemotherapy is conducted in the N.N. Petrov research institute of oncology. So far 30 patients with locally advanced breast carcinoma (T2-4N0) were included. Mammography, breast US and SPECT are performed prior to hospitalization so as core biopsy with subsequent IHC staining to determine the levels of ER, PR, KI67 and HER2. Sentinel lymph node biopsy with the use of radiocompound is performed prior to the first cycle of neoadjuvant chemotherapy. Patients receive 4 to 6 cycles with response evaluation after cycles 2, 4 and 6 (same evaluations as at the baseline). Axillary lymph node dissection is later performed along with the definitive surgery of the primary.

Interim analysis showed: 3 of 30 patients with cN0 were node positive after sentinel lymph node biopsy, 27 were node-negative (sn)pN0. All patients with (sn)pN0 completed neoadjuvant chemotherapy with clinical response. No cases of upfront progression were detected. All patients (sn)pN0 underwent axillary dissection upon completion of the neoadjuvant therapy. No cases of nodal involvement were detected (ypN0). All of the patients considered node-positive after sentinel biopsy also underwent lymph node dissection after completion of the neoadjuvant therapy. 2 of them were pN1 and one was pN2.

Conclusion: sentinel lymph node biopsy in cN0 patients prior to neoadjuvant chemotherapy allows to determine a category of patients ((sn)pN0) in whom axillary dissection can be avoided, provided they remain clinically node-negative at the time of definitive surgery.

Citation Format: Semiglazov VF, Krivorotko PV, Zhiltsova EK, Dashayan GA, Zernov KU, Bessonov AA, Trufanova ES, Tabagua TT, Ivanova OA, Kanaev SV, Novikov SN, Krzivickiyi PI, Brayanceva ZV, Komayachov AV, Nikolaev KS, Gigolaeva LP. Determining the need for axillar lymph node dissection based on pre-neoadjuvant chemotherapy sentinel lymph node biopsy results [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 P3-01-18.
Abstract P3-05-09: Prognostic factors for therapeutic personalized peptide vaccines in patients with metastatic recurrent breast cancer
Authors: Toh U , Saku S , Iwakuma N , Takao Y , Okabe M , Akashi M , Yamada A , Shichijo S , Itoh K , Akagi Y
Published: February 2018

Background: We have previously reported the prognostic role of humoral antigen spreading response against prostate-related antigen (PRA) for metastatic recurrent breast cancer (mrBC) patients who received personalized peptide vaccine (PPV) therapy (Toh U, SABCS 2015). The prognostic effect was additionally evaluated by the clinical relevant factors including intrinsic subtype, the regimens of combined chemo-hormonal therapies in present study.

Methods:We analyzed serum IgG responses to all of the peptide candidates included PRAs (PSA, PAP and PMSA) after PPV therapy by the Luminex systemusing peripheral blood samples from 77 vaccinated mrBC patients. The clinical factors and relevant events were statistically evaluated.

Results: After 6 and 12cycles of PPV therapy, the serum IgG of anti-PSA, anti-PAP, and/or anti-PMSA increased significantly in 31 patients (PRA response group), and the median progression free survival (PFS) and median overall survival (OS) were 8.1 and 14.3 months, but were 5.1 and 10.8 months, respectively, in the remaining 46 patients with no anti-PRA IgG response (PRA non-response Group). The anti-PRA IgG level was marginally correlated withPFS (p=0.059) and OS (p=0.082) between these two groups, which was a significant prognostic factor for PFS (Log-rank: 0.009) in estrogen-positive cancer patients (ER+). The statistical analyses showed that the clinical outcome was in favor of > 60 year-old patients, those with longer PPV therapies (>3 months), and those who received combined standard hormonal therapies or bisphosphonate/anti-RANKL therapy.

Conclusions: This study indicated a clinical significance between the pre-and post- PPV therapy measurement of serum anti-PRA IgG in patients with mrBC, which may be a useful prognostic marker for monitoring peptide vaccine treatment outcomes, particularly for patients > 60 years with ER+ breast cancer. These results also suggest that the immunotherapeutic peptide vaccine could be efficiently combined with hormonal therapy, anti-HER2 therapy, and bisphosphonate/anti-RANKL therapy in mrBC patients.

Citation Format: Toh U, Saku S, Iwakuma N, Takao Y, Okabe M, Akashi M, Yamada A, Shichijo S, Itoh K, Akagi Y. Prognostic factors for therapeutic personalized peptide vaccines in patients with metastatic recurrent 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 P3-05-09.