bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract ES9-2: ES9-2 Metastatic TNBC: New targets/new strategies
Authors: Moulder SL
Published: March 2017

Triple negative breast cancer (TNBC) is a diagnosis of exclusion as these tumors lack ER, PR and HER2. Through advances in molecular profiling, the heterogeneity of TNBC has been revealed as subsets with molecular features targetable with either investigational or existing FDA approved drugs. Basal-like TNBCs (BL1 and BL2) are associated with proliferative gene signatures. BL1 tumors demonstrate at higher rate of pCR to standard chemotherapy compared to other subtypes. The BL2 subset demonstrates gene ontologies involving growth factor signaling such as EGFR and IGF1R. Preclinical models demonstrate that basal-like TNBCs have high sensitivity to cisplatin and relative resistance to PI3K inhibitors in cell culture and xenografts. Germ line aberrations in BRCA1 and BRCA2 lead to a defect in DNA repair in cancers harboring such mutationsand these tumors appear to be more sensitive to therapy inducing DNA breaks, such as those induced by platinum based therapies or PARP inhibition. Approximately 30% of TNBCs display mesenchymal features and carry a high rate of molecular aberrations that activate the PI3K/Akt/mTOR axis with clinical data suggesting that this subgroup may be responsive to therapeutic regimens targeting this pathway. Approximately 10-15% of TNBCs are associated with expression of androgen receptor (AR+ or LAR) and are characterized by the expression of luminal genes and a high rate of PI3K activation/mutation. Response to AR and/or PI3K directed therapy has been demonstrated in preclinical models and AR inhibition has demonstrated response in early phase clinical trials. Lastly, though breast cancer is generally considered a non-immunogenic malignancy, some TNBCs have tumor infiltrating lymphocytes. Novel agents to enrich immune response have been associated with durable responses in a subset of patients with metastatic TNBC. In summary, molecular characterization has identified subsets of TNBC that show promising response to existing or emerging targeted agents.

Citation Format: Moulder SL. ES9-2 Metastatic TNBC: New targets/new strategies [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr ES9-2.
Abstract MS1-2: MS1-2 Breast cancer immunotherapy: Building on clinical success
Authors: Emens LA
Published: March 2017

Breast cancer has long been considered immunologically silent, but it is now clear that the immune system is active in this disease. Breast cancers can naturally induce tumor infiltrating lymphocytes (TIL), which represent a biomarker of the endogenous immune response. Increasing data support the association of TIL with a better prognosis for breast cancer patients, and also suggest that the presence of TIL can predict response to standard breast cancer therapies. These observations have stimulated intense interest in harnessing the natural breast cancer-specific immune response for therapeutic benefit. Breast cancer vaccines that activate the breast cancer-specific immune response have been tested for many years, with minimal clinical success to date. This is likely due to both inadequate vaccination platforms and dominant mechanisms of immune suppression active within the breast tumor microenvironment. In the tumor microenvironment, the immune checkpoint pathway governed by the programmed cell death-1 (PD-1) receptor and its ligand PD-L1 has emerged as a significant mechanism of immune resistance in a variety of cancers, including breast cancer. Several monoclonal antibody antagonists of PD-1 or PD-L1 unleash the activity of tumor-specific T cells in multiple types of cancer, resulting in durable clinical responses that translate into an overall survival benefit. Early data in breast cancer reveal that these agents have activity in some patients with triple negative and estrogen receptor-positive breast cancer, with response rates that range from about 5-44%. Antagonists of the PD-1 pathway are typically well-tolerated in breast cancer patients, with unique immune-related adverse events that are quite manageable. Selecting patients for PD-L1 expression appears to enrich for responders to single agent therapies that target PD-1/PD-L1. Based on early clinical data, agents that target the PD-1 pathway are under accelerated clinical development for breast cancer treatment. The challenge moving forward is converting immunotherapy non-responders to responders. Combination immunotherapies that integrate standard breast cancer therapies and/or multiple innovative immune-based therapies to simultaneously promote T cell activity and relieve multiple mechanisms of immune suppression at the tumor site have the greatest potential for enhancing the clinical activity of immunotherapy for breast cancer patients.

Citation Format: Emens LA. MS1-2 Breast cancer immunotherapy: Building on clinical success [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr MS1-2.
Abstract MS2-2: MS2-2 The latest breakthroughs on the translational aspects of DNA repair pathways
Authors: Powell SN
Published: March 2017

Genomic instability exists in the majority of human cancer, and there is an underlying DNA repair defect driving the instability in most cases. There are seven defined DNA repair pathways that, when inactive, can produce genome wide patterns of mutations. Current cancer genomics can provide a significant insight into the underlying DNA repair defect. This information can be used to select targeted therapies or suggest a more likely response to immune checkpoint blockade.

To use acquired homologous recombination (HR) deficiency as an example of this paradigm, we have found that large scale genomic rearrangements and segmental copy number changes are found in breast cancers without a known germline mutation and see a strong link to biallelic alterations in homologous recombination genes. We detected a genetic etiology of HR deficiency in 90% of studied HR-deficient cases, whereas HR-proficient tumors only showed biallelic HR gene mutations in <7% of cases tested. The goal now is to develop genomic biomarkers that could be used to identify cancer patients who would benefit from therapy with PARP inhibitors and other novel agents, such as those identified by studies of synthetic lethality.

Synthetic lethality in human cancer is a developing area of new therapeutic discovery. HR deficiency is thought to be rescued by at least 3 different DNA repair pathways: base-excision repair, translesion synthesis and alternative end joining – all of which are active in proliferating cancer cells. In addition, even the canonical end-joining mechanism of Ku heterodimer binding to any double-stranded end is another component of handling DNA lesion intermediates. The reason for this variety of synthetic lethality has to be different critical DNA lesion intermediates. Knowledge of the DNA damage processing and the proteins involved in the rescue of lesions that would be repaired by HR can provide the basis for the identification of novel targets. I will review our progress in making RAD52 a potential target along with other initiatives for new drug discovery.

Citation Format: Powell SN. MS2-2 The latest breakthroughs on the translational aspects of DNA repair pathways [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr MS2-2.
Abstract OT1-04-03: Randomized phase II study of induction bevacizumab, etoposide and cisplatin followed by whole brain radiotherapy (WBRT) versus WBRT alone in breast cancer with untreated brain metastases (A-PLUS)
Authors: Lu Y-S , Tseng L-M , Yu J-C , Rau K-M , Chao T-Y , Chen S-C , Chiu C-F , Chang Y-C , Chen TW-W , Lin C-H , Chang D-Y , Chao T-C , Huang S-M , Huang C-S , Cheng A-L
Published: March 2017

Background For breast cancer (BC) patients with brain metastases (BM) who are not suitable for surgery/radiosurgery, whole brain radiotherapy (WBRT) remained the only standard treatment. Recently, we have demonstrated that bevacizumab preconditioning followed by etoposide and cisplatin (BEEP) is a highly effective treatment for BM of BC progressing from WBRT (Clin Cancer Res. 2015;21(8):1851). The CNS objective response rate is 77.1% according to volumetric criteria, and 60% according to RECIST 1.1. It has been demonstrated that enlarged brain tumor size is a predictor of WBRT failure. We hypothesized that, for BC with BM, induction BEEP treatment could decrease the size of brain metastases and thereby enhance effectiveness of WBRT. Methods This is a Phase II, randomized, open-labelled study (NCT02185352). Key inclusion criteria: BC with measurable brain metastatic tumor who had not received WBRT and not suitable for surgery or radiosurgery; KPS ≥30%. Key exclusion criteria: patients who had leptomeningeal metastases; history of disease progression during prior cisplatin treatment. In the experimental arm, patients will be treated by induction BEEP for three cycles followed by WBRT. In the control arm, patients will receive upfront WBRT for brain metastases. The BEEP regimen consist of bevacizumab (15 mg/kg) on Day 1 and, with a 1 day window period, followed by etoposide (70 mg/m2/day, Day 2 to Day 4) and cisplatin (70 mg/m2, Day 2), in a 21-day cycle. Stratification is based on the Graded Prognostic Assessment (GPA) score. Primary endpoint: brain-specific progression free survival (PFS) according to RECIST 1.1; key secondary endpoint: the 2-month brain-specific objective response rate (BS-ORR) of BEEP alone and WBRT alone. Other secondary endpoints include overall survival, extra-CNS tumor PFS, safety, time-to-improvement of neurological function,brain-specific PFS according to volumetric criteria, and BS-ORR. Approximately 126 patients will be 2:1 randomized. Multi-center recruitment is ongoing. To our knowledge this is the first randomized trial investigating a targeted therapy plus chemotherapy as induction regimen followed by WBRT as first line treatment for BC with BM.

Citation Format: Lu Y-S, Tseng L-M, Yu J-C, Rau K-M, Chao T-Y, Chen S-C, Chiu C-F, Chang Y-C, Chen TW-W, Lin C-H, Chang D-Y, Chao T-C, Huang S-M, Huang C-S, Cheng A-L. Randomized phase II study of induction bevacizumab, etoposide and cisplatin followed by whole brain radiotherapy (WBRT) versus WBRT alone in breast cancer with untreated brain metastases (A-PLUS) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT1-04-03.
Abstract OT2-04-02: Comparison of axillary sentinel lymph node biopsy versus no axillary surgery in patients with early-stage invasive breast cancer and breast-conserving surgery: A randomized prospective surgical trial. The Intergroup-Sentinel-Mamma (INSEMA)-trial
Authors: Reimer T , von Minckwitz G , Loibl S , Hildebrandt G , Nekljudova V , Schneider-Schranz C , Gerber B
Published: March 2017

Background:

Currently, axillary surgery for breast cancer is considered as staging procedure that does not seem to influence breast cancer mortality, since the risk of developing metastasis depends mainly on the biological behaviour of the primary. Based on this, the postsurgical therapy should be considered on the basis of biologic tumor characteristics rather than nodal involvement.

Trial design:

The goal of INSEMA is to show that early-stage breast cancer patients with reduced extent of axillary surgery are not inferior regarding invasive disease-free survival (IDFS) outcome. Patients with planned breast-conserving surgery (BCS) will be first randomized (1:4 ratio) to either no axillary surgery or axillary sentinel lymph node biopsy (SLNB). Patients with SLNB and pN+(sn) status will be secondly randomized (1:1 ratio) to either SLNB alone or completion axillary lymph node dissection (ALND) in cases with less than three involved nodes (one or two macrometastases).

Primary objective:

-IDFS after BCS (non-inferiority question)

Inclusion criteria:

-Written informed consent

-Histologically confirmed unilateral primary invasive carcinoma of the breast (core biopsy)

-Age at least 35 years

-Preoperative imaging techniques with estimated tumor size of maximal 5 cm (iT1/iT2 irrespective of hormone sensitivity or HER2 status)

-Clinically and sonographically tumor-free axilla prior to core biopsy

-In cases with cN0 and iN+, a negative core biopsy or fine needle aspiration biopsy of the suspected lymph node is required

-No clinical evidence for distant metastasis (M0)

-Planned breast-conserving surgery (R0 resection) with postoperative external whole-breast irradiation (conventional fractionation or hypofractionation)

Statistics:

The calculated total case number for per-protocol analyses is 6,740 (5,940 German and 800 Austrian patients), the expected total number of randomized patients is 7,095.

Time lines:

-First patient in: September 2015

-Last patient in: August 2019

-Final analysis: End of 2024

Present accrural: In June 2016, more than 1.000 patients were recruited in Germany and Austria.

Citation Format: Reimer T, von Minckwitz G, Loibl S, Hildebrandt G, Nekljudova V, Schneider-Schranz C, Gerber B. Comparison of axillary sentinel lymph node biopsy versus no axillary surgery in patients with early-stage invasive breast cancer and breast-conserving surgery: A randomized prospective surgical trial. The Intergroup-Sentinel-Mamma (INSEMA)-trial [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT2-04-02.
Abstract P1-02-14: Circulating cell-free DNA (CFD) measured by a simple fluorescent assay to predict relapse in triple negative breast cancer patients receiving neoadjuvant chemotherapy: A biomarker substudy of prospective observational study (NCT02001519, NCT02001506)
Authors: Park K , Woo M , Kim JE , Ahn J-H , Jung KH , Kim S-B
Published: March 2017

Background: Prior technique to measure cell free DNA(CFD) is labor-intensive and expensive, while, recently developed fluorescent CFD assay is more simple and convenient.The aim of this study was to evaluate the role of CFD measured by a fluorescent assay as a biomarker of patients with triple negative breast cancer (TNBC) received neoadjuvant chemotherapy

Methods: We prospectively enrolled patients with TNBC, clinical stage II or III (T>1.5cm or lymph node > 1.5cm), who were scheduled for neoadjuvant chemotherapy. Patients received 4 cycles of adriamycin 60 mg/m2 plus cyclophosphamide 600 mg/m2 (AC) followed by 4 cycles of cisplatin or docetaxel, and surgery. Plasma samples were obtained from patients before initial chemotherapy (baseline-CFD) and after 4 cycles of AC neoadjuvant chemotherapy (AC-CFD).

Results: This study included 72 patients who met the inclusion criteria. The mean levels of baseline-CFD and AC-CFD were 239±68 ng/mL and 210±66 ng/mL, respectively, and the CFD level was significantly decreased after AC chemotherapy.( p=0.001) The baseline-CFD was not associated with initial tumor characteristics. (T stage 1-2 vs. 3, p=0.313; N stage 0 vs. 1-3, p=0.317) There was no statistically significant difference between patients with response (CR or PR) to AC chemotherapy and those without response in terms of baseline-CFD, AC-CFD, and change of CFD between two values. (p=0.814, p=0.839, p=0.927) With 33.6 months of median follow up, there were 18 cases of relapse. Relapsed group showed numerically higher level of baseline-CFD, although it was not statistically significant. (relapse, 259 ng/mL; non-relapse, 233 ng/mL; p=0.161) We performed a ROC curve analysis of baseline-CFD for relapse, and found an area under the curve of 0.62 (95% CI, 0.46-0.78) at 222 ng/mL. Patients with baseline-CFD above 222 showed higher relapses than those below 222. (HR, 2.75; 95% CI, 0.96-7.84; p = 0.059)

Conclusions: The baseline-CFD obtained using a simple and convenient fluorescent assay could predict relapse, suggesting baseline-CFD as a potential biomarker for risk stratification of TNBC.

Citation Format: Park K, Woo M, Kim JE, Ahn J-H, Jung KH, Kim S-B. Circulating cell-free DNA (CFD) measured by a simple fluorescent assay to predict relapse in triple negative breast cancer patients receiving neoadjuvant chemotherapy: A biomarker substudy of prospective observational study (NCT02001519, NCT02001506) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-02-14.
Abstract P1-04-08: Non-nuclear SUMO dynamics regulate mammary epithelial cell transformation
Authors: Karami S , Lin F-M , Kumar S , Ren J , Bahnassy S , Bawa-Khalfe T
Published: March 2017

Objective: The reversible SUMO-posttranslational modification of protein substrates regulates various cellular processes and consistently is important for normal cell physiology. Disruption of SUMO enzymatic components supports onset of various pathophysiological disorders, including cancer. Our recent study identified a splicing event that differentially modulates expression of 2 SENP7 isoforms. The novel SENP7 variant SENP7S is the predominant SUMO protease in normal mammary epithelia; however onset of precancerous ductal carcinoma in situ (DCIS) reduces SENP7S significantly and stays low in all breast cancer (BCa) subtypes. Inversely, the full-length SENP7L isoform is upregulated in BCa and directly leads to BCa metastasis. Unlike SENP7L, SENP7S isoform contribution to carcinogenesis is unclear. Our objective is to define the biological function of this novel deSUMOylase SENP7S in normal versus cancerous epithelial cells.

Results: Consistently with mRNA levels, protein levels of the 2 SENP7 isoforms are also inversely expressed in human BCa versus normal mammary epithelia. SENP7S is localized in the cytosol of MCF10-2A unlike other SUMO proteases including SENP7L that are predominantly nuclear enzymes. Beta-catenin and a component of the Beta-catenin destruction complex, Axin1 are substrates for SENP7S catalytic activity as in the absence of SENP7S, Beta-catenin and Axin 1 are both SUMOylated. Consistently, SENP7S regulates Beta-catenin signaling pathway. SUMOylated Axin1 loses its interaction with Beta-catenin, allowing the Beta-catenin to escape ubiquitylation and further proteasomal degradation. SUMOylated Beta-catenin translocates to the nucleus and activates multiple target genes that potentiate cell proliferation. Increase in cell proliferation and anchorage dependent growth of non-cancerous MCF10-2A cells was observed with inhibition of SENP7S. Additionally, SENP7S depletion potentiates anchorage independent growth of MCF10-2A with significantly greater number and size of spheroids. In comparison to the control. Loss of SENP7S also potentiates the self-renewal properties of the cells, indicative of mammary epithelial cell transformation.

Conclusion: SENP7S modulates Beta-catenin stability and signaling and consequently is critical for normal mammary epithelial cell physiology. Loss of SENP7S, as observed in DCIS, initiates mammary epithelial cell transformation.

Citation Format: Karami S, Lin F-M, Kumar S, Ren J, Bahnassy S, Bawa-Khalfe T. Non-nuclear SUMO dynamics regulate mammary epithelial cell transformation [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-04-08.
Abstract P1-08-08: Identification of tumor-promoting and tumor-inhibiting genes with age dependent expression in breast cancer patients
Authors: Gu X , Zhu H , Sun L
Published: March 2017

Age is the number one risk factor for breast cancer development. The breast cancer incidence rate increases with age, following beta distribution, which is approximately linear in range from 30 to 70 years old [1]. Transcriptome alterations have been shown to promote tumorigenesis for many types of cancers. Therefore, we hypothesize that the genes with altered expression during aging may promote breast cancer development and/or progression. Using The Cancer Genome Atlas data, we extracted whole transcriptome profiling data of matched normal tissues from 82 female patients with age at diagnosis and menopausal status available. First, we applied simple linear regression to study the association between gene expression level and age at diagnosis on all the 82 patients. 258 upregulated and 240 downregulated genes are identified, which are associated with age. Secondly, 493 upregulated and 254 downregulated genes are identified that are altered by menopause by comparing post-menopausal to pre-menopausal patients (FDR < 0.05). Exclusion of these menopause affected genes from those genes affected by age (258 upregulated and 240 downregulated) results in 148 upregulated and 189 downregulated genes during aging. Thirdly, by comparing matched tumor and adjacent normal samples, 3356 upregulated and 3124 downregulated genes are found to be associated with tumorigenesis. Overlapping of tumorigenesis associated genes with age dependent genes result in 14 upregulated and 24 downregulated genes that are both age and tumorigenesis associated. This discovery is being validated with normal breast tissues from donors in GTEx cohort. Experimental manipulation of the upregulated genes in seven breast cancer cell lines, representing five subtypes of breast cancer, demonstrated their essential role in promoting tumor malignancy, suggesting the upregulation is not merely passenger event. In a large mixed cohort, this panel of genes have significant predictive value in relapse free survival of breast cancer patients.

Funding: CPRIT Research Training Award (RP140105); NIH R01CA192564

Reference:

Francesco Pompei and Richard Wilson (2001). Age Distribution of Cancer: The incidence Turnover at Old Age. Human and Ecological Risk Assessment: Vol. 7, No. 6, pp. 1619-1650.

Citation Format: Gu X, Zhu H, Sun L. Identification of tumor-promoting and tumor-inhibiting genes with age dependent expression in breast cancer patients [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-08-08.
Abstract P1-10-05: Omitting radiotherapy in women ≥ 65 years with early breast cancer and favorable histopathology after breast-conserving surgery, sentinel node biopsy and adjuvant endocrine therapy is safe
Authors: Villman KKA , Wickberg Å , Killander F , Lindman H , Bjöhle J , Edlund P , Tennvall-Nittby L , Bachmeier K , Carlberg M , Blomqvist C , Ahlgren J , Liljegren G
Published: March 2017

Background: The benefit of radiotherapy in older women with endocrine responsive early breast cancer treated with breast-conserving surgery and endocrine therapy is unclear. The aim of this study was to verify if omission of radiotherapy in a predefined cohort of patients with good prognosis early breast cancer after breast conservation is safe.

Methods: Eligibility criteria were: consecutive patients with age ≥ 65 years, breast-conserving surgery (sector resection + sentinel node biopsy), clear margins, unifocal T 1 N0, Elston grade 1 and 2, estrogen receptor-positive. After informed consent adjuvant endocrine therapy, either tamoxifen or an aromatase inhibitor, was prescribed for 5 years. Primary endpoint was ipsilateral breast tumor recurrence (IBTR). Secondary endpoints were contralateral breast cancer, recurrence-free survival (RFS) and overall survival (OS).

Results: Between 2006 and 2012, we included 603 women from 14 Swedish centers. Two patients did not fulfill the inclusion criteria and were excluded from the analysis. Median age was 71 years (range 65 to 90). At a median follow-up of 59 months (range 2 to 110) 13 IBTR (cumulative incidence at five years, 1.3% (95% CI, 0.6% to 2.7%), 4 regional recurrences (one combined with IBTR), 2 distant recurrences both without IBTR or regional recurrence and 11 contralateral breast cancers was observed. Twenty-nine patients were diagnosed with tumors of other origin. Seven of them were endometrial cancers. There were 39 deaths. Only one of the deaths (2.6%) was due to breast cancer and 11 (28.2%) were due to other cancers (2 endometrial cancers). Five-year overall survival was 93.9% (95% CI, 91.4% to 95.7%).

Conclusion: This study demonstrates, with a median follow-up of 59 months, that breast-conserving surgery and endocrine therapy without radiotherapy is a safe treatment option in women with early breast cancer and favorable histopathology aged ≥ 65 years. The risk of IBTR is comparable to the risk of contralateral breast cancer. The low rate of breast cancer deaths indicates that breast cancer mortality is of secondary importance in this subset of women.

Citation Format: Villman KKA, Wickberg Å, Killander F, Lindman H, Bjöhle J, Edlund P, Tennvall-Nittby L, Bachmeier K, Carlberg M, Blomqvist C, Ahlgren J, Liljegren G. Omitting radiotherapy in women ≥ 65 years with early breast cancer and favorable histopathology after breast-conserving surgery, sentinel node biopsy and adjuvant endocrine therapy is safe [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-10-05.
Abstract P1-10-10: Risk factors of locoregional recurrence, locoregional failure pattern and role of postmastectomy radiotherapy for T1-2 breast cancers with 1-3 positive axillary lymph nodes
Authors: Wang S , Peng R , Jin J , Wang W , Song Y , Liu Y , Liu X , Yu Z , Fang H , Ren H , Li Y
Published: March 2017

This abstract was not presented at the symposium.
Abstract P1-11-13: Re-excision rate in breast conservation surgery after neoadjuvant chemotherapy
Authors: Song JH , Park JY , Choi JE , Bae YK , Lee SJ
Published: March 2017

Background : The goal of neoadjuvant chemotherapy is to reduce tumor size and convert mastectomy to breast-conservation surgery (BCS). In response to neoadjuvant chemotherapy, the regression rate and pattern of breast cancer is variable. And the re-excision rate to secure negative resection margin is reported limitedly in this case. The purpose of this study was to compare the re-excision rate and BCS success rate of patients who received and who did not received neoadjuvant chemotherapy.

Method : In this retrospective cohort study, between January 2009 and December 2012, total 256 women were included who had clinical T2 breast cancer and were planed to receive BCS as initial operation or neoadjuvant chemotherapy. Fifty-nine patients of them received neoadjuvant chemotherapy. Clinical data were collected including age, preoperative or initial clinical tumor size, mammographic microcalcifications, ultrasound multifocality and axillary nodal status, retrospectively. In the resected specimen from BCS, we reviewed the pathologic tumor size, multifocality, histologic type, hormone receptor and Her-2-neu status, ki67, DCIS and EIC component. The re-excision rate and BCS success rate were investigated. Univariate analysis and regression model were used for identify clinicopathologic factors associated with re-excision. To reduce the effect of selection bias, propensity score matching-based anaylsis was also performed.

Results : Of the 256 patients, 178 patients (90.4%, 178/197) received BCS finally in neoadjuvant group and 56 patients (94.9%, 56/59) in non-neoadjuvant group (p=0.406). There was no statistical difference in the re-excision rate between two groups (35.6% (21/59) in neoadjuvant group vs 34.0% (67/197) in non-neoadjuvant group, p=0.946). In propensity-matched cohorts (N=118), the re-excision rate was same in two groups (35.6% (21/59) in neoadjuvant group vs 35.6% (21/59) in non-neoadjuvant group, p=1.000). BCS success rate was higher in neoadjuvant group(94.9% 56/59) than non-neoadjuvant group (86.4%(51/59)), but there was no statistical difference (p=0.205). In this cohorts, clinicopathologic factors associated with re-excision were pathologic multifocality (OR=4.56, p=0.0142), high ki67 (≥50%) (OR=0.7, p=0.0243) and DCIS component (OR=2.67, p=0.0261) in logistic regression model.

Conclusion: This study showed neoadjuvant chemotherapy could increase the BCS success rate but could not decrease the re-excision rate. The re-excision rate is more associated with pathologic finding rather than effect of neoadjuvant chemotherapy.

Citation Format: Song JH, Park JY, Choi JE, Bae YK, Lee SJ. Re-excision rate in breast conservation surgery after neoadjuvant chemotherapy [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-11-13.
Abstract P2-01-08: A nomogram to predict the survival benefit of surgical axillary staging in T1 breast cancer patients
Authors: Chen K , Zhu L , Li S , Su F , Song E
Published: March 2017

This abstract was withdrawn by the authors.
Abstract P2-03-07: Exome sequencing of human breast cancer tissues resistant to taxanes
Authors: Endo Y , Dong Y , Kondo N , Hato Y , Hisada T , Nishimoto M , Nishikawa S , Takahashi S , Toyama T
Published: March 2017

Background: Although taxanes are a mainstay of breast cancer treatment, some cases are resistant to these drugs. This is a crucial issue in breast cancer therapy. In the emerging era of next-generation sequencing, it is possible to obtain extensive genomic information on individual tumors in a very short time. Using this technology, it was reported that specific mutations might affect therapeutic efficacy and induce resistance to specific treatment.

Objective: The aim of this study was to investigate the mechanisms of taxane resistance using whole exon sequencing and expression analyses in human breast cancer tissues.

Materials and Methods: We selected six breast cancer patients whose tumors responded well to anthracycline treatment but suffered disease progression on taxane treatment. We then performed whole exon sequencing on these samples using HiSeq (Illumia). In this way, we identified somatic mutations of candidate genes considered to be instrumental for mediating resistance to taxanes. Next, we performed mRNA expression analyses of these candidate genes in a further 122 breast cancers treated with taxanes at our institute. Finally, we correlated mRNA expression levels of these genes with clinicopathological factors and prognosis.

Results: We identified 9 mutations common to all 6 patients analyzed in this study, and a further 16 mutations shared by 5 of them. Kaplan-Meier analyses showed that high level mRNA expression of 3 of these 25 genes was significantly associated with poorer disease-free survival. Moreover, high level mRNA expression of one of these three genes was significantly associated with worse overall survival. However, there were no significant correlations between expression levels of these three genes and any clinicopathologeical features.

Conclusion: Using next-generation sequencing, we have identified three candidate genes involved in resistance to taxane treatment in breast cancer. We are now analyzing the functional attributes of these three genes.

Citation Format: Endo Y, Dong Y, Kondo N, Hato Y, Hisada T, Nishimoto M, Nishikawa S, Takahashi S, Toyama T. Exome sequencing of human breast cancer tissues resistant to taxanes [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-03-07.
Abstract P2-04-14: T cell profile associated with regional lymph node progression in breast cancer
Authors: Adhikary S , Guo Y , Sieling PA , Lee DJ
Published: March 2017

This abstract was not presented at the symposium.
Abstract P2-05-33: Refining the prognostic value of Ki67 biomarker by ataxia telangiectasia mutated (ATM) status in a retrospective study of early stage hormone receptor positive breast cancer
Authors: Feng X , Li H , Kornarga E , Dean M , Lees-Miller S , Riabowol K , Magliocco A , Morris D , Watson P , Enwere E , Bebb G , Paterson A
Published: March 2017

Purpose: The current study was designed to investigate the combined influence of ataxia telangiectasia mutated (ATM) and Ki67 on clinical outcome in early stage hormone receptor positive breast cancer (ES-HPBC), particularly in patients with smaller tumors (< 4 cm) and fewer than four positive lymph nodes.

Methods: Formalin-fixed paraffin-embedded specimens of resected primary breast tumors from 532 patients diagnosed with early stage breast cancer were used to construct a tissue microarray. Samples from 297 patients were suitable for final statistical analysis. We detected ATM and Ki67 proteins using immunohistochemistry and quantified their expression with digital image analysis. Data on expression levels were subsequently correlated with clinical outcome.

Results: Remarkably, ATM expression was useful to stratify the low Ki67 group into subgroups with better or poorer prognosis. Specifically, in the low Ki67 subgroup defined as having smaller tumors and no positive nodes, patients with high ATM expression showed better outcome than those with low ATM, with estimated survival rates of 96% and 89% respectively at 15 years follow up (p = 0.04). Similarly, low-Ki67 patients with smaller tumors, 1-3 positive nodes and high ATM also had significantly better outcomes than their low ATM counterparts, with estimated survival rates of 88% and 46% respectively (p=0.03) at 15 years follow up. Multivariable analysis indicated that the combination of high ATM and low Ki67 is prognostic of improved survival, independent of tumor size, grade, and lymph node status (p = 0.02).

Low Ki67/high ATM expression independently predicts favorable disease survival in a multivariate model in low Ki67 subgroup of ES-HPBC (Stage I-III)Variablesp valueHR (95%CI)Low Ki67/high ATM vs Low Ki67/low ATM0.020.36 (0.15-0.88)ize (T1/2 vs T3/4)0.010.16 (0.04-0.69)LN status (- vs +)0.140.49 (0.20-1.25)LVI (_- vs +)0.160.51 (0.20-1.31)Grade (1/2 vs 3)<0.00010.28 (0.11-0.67)Age (<65 vs >65)0.010.26 (0.10-0.74)

Conclusions: These data suggest that the prognostic value of Ki67 can be improved by analyzing ATM expression in ES-HPBC.

Citation Format: Feng X, Li H, Kornarga E, Dean M, Lees-Miller S, Riabowol K, Magliocco A, Morris D, Watson P, Enwere E, Bebb G, Paterson A. Refining the prognostic value of Ki67 biomarker by ataxia telangiectasia mutated (ATM) status in a retrospective study of early stage hormone receptor positive breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-05-33.
Abstract P2-08-05: Phase I/II trial of palbociclib in combination with bicalutamide for the treatment of androgen receptor (AR)+ metastatic breast cancer (MBC)
Authors: Gucalp A , Corben AD , Patil S , Feigin KN , Boyle LA , Hudis CA , Traina TA
Published: March 2017

This abstract was withdrawn by the authors.
Abstract P2-14-03: Novel visualization tools to search ongoing clinical trials and track trial results for metastatic breast cancer
Authors: Kumar M , Kissoon K , Abdulai AR , De La Torre K , Flowers M , Cohen E , Colen S , Mercier JB , Hurlbert M
Published: March 2017

Metastatic breast cancer (MBC) remains a terminal illness and is the cause of virtually all breast cancer deaths. The median survival for patients with MBC in the US is approximately 3 years from time of stage IV diagnosis. People living with MBC are in urgent need of new treatment options once current therapies no longer keep the disease under control. Access to new treatments is often through clinical trials. We have developed a novel way to visualize active clinical trials and track trial results. Methods: Clinical trials were queried from Clinicaltrials.gov and the National Cancer Institute. Trials were categorized by breast cancer subtype, line of therapy, hallmark of cancer, sponsor, phase, sample size and compound. A bubble chart was created to display data triplets (x, y, z) corresponding to three continuous variables: x and y to define the position, and z, the radius of each bubble. In our example, x and y coordinates are optimized according to an algorithm that essentially balances the bubble's gravity (i.e., action of moving towards the center of the plot), friction (i.e., velocity decay) and charge (or repulsion/attraction force). This layout is frequently used for network visualization. In addition to x, y and z, it is possible to encode other information. Results: We identified 204 clinical trials actively recruiting patients with MBC. The current webpage (www.mbcalliance.org) displays clinical trial data from 204 clinical trials in six different ways. Trials actively recruiting patients will be updated quarterly. In addition to data triplets (x, y and z) we encoded other information about trials using a color code to add three additional dimensions: phase, breast cancer subtype and sponsor type. When a user hovers over a bubble, key information about the clinical trial extracted from Clinicaltrials.gov is displayed. When a user clicks on the bubble, the user is directed to the corresponding landing page at BreastCancerTrials.org to access detailed trial information. We are employing a similar coding scheme and display characteristics for completed clinical trials results. Conclusions: We have developed a user-friendly, web tool to quickly sort and visualize ongoing clinical trials and results for completed trials to benefit both MBC patients and research scientists.

Citation Format: Kumar M, Kissoon K, Abdulai AR, De La Torre K, Flowers M, Cohen E, Colen S, Mercier JB, Hurlbert M. Novel visualization tools to search ongoing clinical trials and track trial results for metastatic breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-14-03.
Abstract P3-01-02: Trends in positive predictive values following transition from screen film to digital mammography
Authors: Motiuk DA , Dahl P , Roy E , Docktor B-J , Burrowes P
Published: March 2017

Purpose

Our health region converted from screen-film mammography (SFM) to digital mammography (DM) in 2005. DM has several advantages over SFM, including superior contrast resolution, less noise, and opportunities for image optimization through post-acquisition processing; although, the spatial resolution of DM is inferior to SFM. We sought to determine what effect this transition may have had on positive predictive values (PPVs) for malignant and premalignant lesions.

Methods

From our institution's breast biopsy database, we retrospectively reviewed core biopsy results for mammographic calcifications performed in the years 2001-2004 (SFM years) and 2009-2012 (DM years). We subsequently determined the PPV3 (detection of malignancy after biopsy) for each group of years (SFM and DM). We then performed subgroup analysis to calculate PPVs for each of ductal carcinoma in-situ (DCIS) without invasion, DCIS with invasion, and premalignant lesions. Premalignant lesions included atypical ductal hyperplasia, atypical lobular hyperplasia, and lobular carcinoma in-situ.

Results

A total of 4787 biopsies in 4633 patients were reviewed. The comparative detection of cancer after biopsy performed for mammographic calcification between SFM and DM was not statistically significant (PPV3 = 23.5% and 24.0%, respectively; P=.71). Upon further analysis, however, PPV for premalignant lesions increased (SFM=6.6% and DM=8.9%; P<.01) and PPV for DCIS without invasion increased (SFM=15.5% and DM=18.2%; P=.015), while PPV for DCIS with invasion decreased (SFM=8.0% and DM=5.8%; P<.01).

Conclusion

We observed no significant impact on PPV3 for calcifications following the transition from SFM to DM; however, our subgroup analysis suggests that with digital mammography we are now detecting a statistically significantly lower proportion of DCIS with invasion but greater proportions of DCIS without invasion and premalignant lesions. As the natural history of these lower-grade lesions, particularly in the premalignant category, is still not entirely understood, the significance of potentially detecting more of these earlier cancers/precancers is uncertain.

Citation Format: Motiuk DA, Dahl P, Roy E, Docktor B-J, Burrowes P. Trends in positive predictive values following transition from screen film to digital mammography [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-01-02.
Abstract P3-04-05: Identification of SAR439859, an orally bioavailable selective estrogen receptor degrader (SERD) that has strong antitumor activity in wild-type and mutant ER+ breast cancer models
Authors: Shomali M , Cheng J , Koundinya M , Weinstein M , Malkova N , Sun F , Hebert A , Cindachao M , Hoffman D , McManus J , Levit M , Pollard J , Vincent S , Besret L , Adrian F , Winter C , El-Ahmad Y , Halley F , Hsu K , Lager J , Garcia-Echeverria C , Bouaboula M
Published: March 2017

Estrogen receptor positive (ER+) breast cancer accounts for 70% of all breast cancers and is primarily treated with endocrine therapy. Approximately 40% of patients on endocrine therapy will become resistant via a number of mechanisms. There is evidence that in many cases ER continues to play a central role, including mutations in ER leading to a constitutively active receptor. Estrogen receptor degraders like fulvestrant are effective in shutting down ER signaling; however, poor pharmaceutical properties limit fulvestrant clinical activity and prevent it from achieving maximum receptor blockade.

We describe the discovery of SAR439859, a novel, orally bioavailable SERD that is a potent antagonist and degrader of ER both in vitro and in vivo. SAR439859 has robust activity in multiple ER+ breast cancer cell lines including cells that are resistant to tamoxifen as well as cell lines harboring ER mutants. Across a large panel of ER+ cells, SAR439859 demonstrated broad and superior ER degradation activity than most SERDs undergoing clinical testing. This leads to a profound inhibition of ER signaling, better inhibition of cell growth and results in improved in vivo efficacy. SAR439859 demonstrated tumor regression in all ER+ BC models including MCF7-ESR1 mutant-Y537S model, as well as patient-derived xenograft model that is resistant to endocrine therapies. Furthermore, SAR439859 displays limited cross-resistance with other class of SERDs.

Taken together, these results suggest that SAR439859 would be of therapeutic benefit in metastatic BC setting for patients harboring wild type or mutant ER. SAR439859 is being advanced toward the clinic.

Citation Format: Shomali M, Cheng J, Koundinya M, Weinstein M, Malkova N, Sun F, Hebert A, Cindachao M, Hoffman D, McManus J, Levit M, Pollard J, Vincent S, Besret L, Adrian F, Winter C, El-Ahmad Y, Halley F, Hsu K, Lager J, Garcia-Echeverria C, Bouaboula M. Identification of SAR439859, an orally bioavailable selective estrogen receptor degrader (SERD) that has strong antitumor activity in wild-type and mutant ER+ breast cancer models [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-04-05.
Abstract P3-04-23: Combination therapy of targeted anticancer pathways and estrogen receptor ligands and their responses in de novo andtamoxifen resistant cell models
Authors: Gutgesell LM , Xiong R , Thatcher GRJ , Tonetti DA
Published: March 2017

Approximately 75% of breast cancers are classified as Estrogen Receptor positive (ER+). Tamoxifen, a selective estrogen receptor modulator (SERM), is the standard of care for many of these ER+ breast cancer patients. Unfortunately, tamoxifen resistance occurs in almost 50% of patients within 5 years of treatment, and endocrine-independence accompanying resistance also negates the effects of aromatase inhibitors. Combination therapy is increasingly used in non-cytotoxic therapeutic approaches in many types of cancer. The potential exists that endocrine resistance can be lessened, eliminated, or overcome through targeted therapy in combination with endocrine therapy. Inhibition of kinase signaling (e.g. via CDK4/6 or PI3K) and other pathways (e.g. HSP90) are expected to be effective in combination with endocrine therapy. We have discovered a variety of ER ligands with potential as endocrine therapeutic agents, based upon a single chemical scaffold with a diverse set of pharmacological responses: including SERMs, selective ER downregulators (SERDs), selective estrogen mimics (SEMs), and selective human ER partial agonists (ShERPAs). To predict which agents in combination with these endocrine-targeted ligands would be of potential therapeutic benefit it was necessary to develop 3D spheroidal cultures of ER+ breast cancer cell lines: including endocrine-dependent lines; and cell lines made endocrine-independent either by extended exposure to tamoxifen or extended deprivation of estradiol. In contrast to 2D cultures, drug response in 3D spheroidal cell cultures was predictive of response to treatment in mouse xenograft studies. Growth of endocrine-dependent cell lines was, as expected, inhibited by SERDs; and endocrine-independent, tamoxifen-resistant cell lines were also sensitive to SERD treatment, although one cell line was largely resistant. Growth of all three tamoxifen-resistant cell lines was inhibited by SEMs/ShERPAs. Importantly, regardless of the type of endocrine therapeutic agent studied, concentrations leading to saturation of the target (ER) did not cause cell death. Equally, all endocrine therapies studied benefited from combination treatment with other agents, leading to enhanced cell death.

Citation Format: Gutgesell LM, Xiong R, Thatcher GRJ, Tonetti DA. Combination therapy of targeted anticancer pathways and estrogen receptor ligands and their responses in de novo andtamoxifen resistant cell models [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-04-23.