bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract ES2-2: Clinical management of women with increased breast cancer risk based on histologic lesions
Authors: Degnim AC
Published: February 2018

The objective of this lecture is to review clinical management of women with the following histologic lesions associated with increased breast cancer risk: flat epithelial atypia (FEA), atypical ductal hyperplasia (ADH), atypical lobular hyperplasia (ALH), and lobular carcinoma in situ (LCIS). Women found to have one or more of these histologic findings in a benign breast biopsy have an increased risk of developing a future breast cancer. Published data will be reviewed that provides estimates of annual and longterm risk associated with these lesions. In addition, management of these lesions after core biopsy will be discussed, specifically the circumstances when surgical excision is recommended. Medical and surgical options for breast cancer risk reduction will be reviewed, as well as their appropriate clinical indications.

Citation Format: Degnim AC. Clinical management of women with increased breast cancer risk based on histologic lesions [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 ES2-2.
Abstract ES3-1: Drugging protein synthesis in cancer therapy
Authors: Schneider RJ
Published: February 2018

Translation of mRNAs that encode proteins with transforming, cell survival, DNA damage DNA repair and angiogenic functions requires increased levels of specific translation factors that are often overexpressed in many human cancers. Translation of these same classes of oncogenic mRNAs also requires increased activation of the protein synthesis machinery, which is stimulated by well-known signal transduction pathways, particularly the P3K-AKT-mTOR pathway and the ERK-MAPK-MNK pathway. Targeted inhibition of selective oncogenic mRNA translation through inhibition of translation-specific signal transduction pathways, or the specific inhibition of certain translation factors that are required in greater amounts for oncogenic mRNA translation, are emerging new areas in human cancer therapeutics and are in active clinical trials. Small molecule drugs have been developed that are highly specific for the key translation factors that are overexpressed in many human cancers, including breast cancers. In breast cancer, specific stage and grade-dependent alterations occur in the translation machinery and in its signal transduction pathways that correspond to locally advanced, inflammatory, endocrine-resistant ER+, hormone receptor negative and metastatic breast cancer. Many of these alterations provide actionable targets with existing drugs for exploitation of translation-specific vulnerabilities that do not target normal cells and can be synergistically combined with existing genotoxic chemotherapies, endocrine therapies, radiation therapy and immunotherapies. Current research has also begun to elucidate previously unknown translational control pathways that provide additional novel targets and potentially lower toxicity approaches. Targeting translational regulation and the protein synthetic machinery in cancer cells provides the advantage of being able to impair the expression of classes of mRNAs that are essential for cancer progression, metastasis and drug resistance, rather than targeting individual proteins or genes. These promising new therapeutics and clinical treatment strategies will be discussed.

Citation Format: Schneider RJ. Drugging protein synthesis in cancer therapy [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 ES3-1.
Abstract ES5-2: Biologic, cultural and health systems influences on breast cancer disparities in Latinas
Authors: Ramirez AG
Published: February 2018

Rationale

Breast cancer is the top cause of cancer-related deaths in Latinas, who more likely than their peers to be diagnosed at advanced disease stage. This makes it critical to reduce the time from screening to diagnosis to treatment. Latinas also face other biologic issues, as well as cultural and linguistic barriers to proper breast cancer care. Patient navigation is a means for providing access to recommended cancer screening services, follow-up, diagnosis, and treatment in medically underserved populations.

Objectives

I led a series of studies to adapt patient navigation for Latino populations, specifically to reduce delays among Latinas to proper diagnoses and care. We trained our bilingual, bicultural patient navigators to help “navigate” underserved people through the complex care system and other barriers to care (finances, transit, child care, language, culture, etc.). Navigation aims to help reduce missed appointments, reduce delays in seeking care, increase follow-up care, and cover the entire ecological framework from policy, community, organizational, interpersonal, and survivor elements.

Results

The series of studies identified Latinas' delays in time to confirmatory diagnosis and start of treatment after an abnormal mammogram; and proved that patient navigation by a bilingual, bicultural patient navigator can reduce Latinas' times to diagnosis and treatment and significantly increase the proportion of Latinas initiating treatment. Our navigation helped patients receive diagnosis 4 times faster, and treatment start 1.5 times faster, than normal. Several aspects of a navigator's services were directly related to achieving these results. As a direct result of our patient navigation activities, we navigated significantly more women from confirmed breast cancer diagnosis to treatment initiation within 30 (69%) and 60 days (97.6%), with much lower rates for non-navigated women.

Conclusion

We conclude—based on a national study that shows women with breast cancer who wait longer than 60 days have a significantly lower survival rate—that our patient navigation is likely to have saved the lives of many Latinas. We have since applied this navigation to achieve greater compliance in following prescribed treatments and improved general and cancer-specific quality of life among cancer survivors. We also, based on these successful results, developed and posted online the Patient Navigator Manual: Developing and Implementing a Patient Navigator Program manual. The bilingual manual outlines the necessary steps and provides tools to incorporate navigation for Latinos at any organization.

Citation Format: Ramirez AG. Biologic, cultural and health systems influences on breast cancer disparities in Latinas [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 ES5-2.
Abstract ES8-3: Circulating complexes of stromal and tumor cells in breast cancer metastasis
Authors: El-Ashry D
Published: February 2018

The establishment of breast cancer metastases at sites distant from the primary lesion site is predicated on the ability of breast cancer cells to mobilize from the primary tumor, survive in circulation, and colonize in a suitable and permissive metastatic niche. While quantitation of individual CTCs has prognostic value in breast cancer patients with metastatic disease, and elevated counts of CTCs may associate with poor outcome in early breast cancer, recent evidence from mouse models indicates that CTCs in clusters have a greater capacity to produce metastases than individual CTCs and new studies in breast cancer suggest that the presence of CTC clusters in patients can be prognostic. We have found in breast cancer patients, clusters of circulating cells that include CTCs, immune cells, and stromal cells found in the tumor microenvironment, specifically cancer associated fibroblasts (CAFs). Like CTC and circulating CAF (cCAF) counts, the incidence and number of CTC/cCAF clusters increases with disease stage.

While the clinical significance of circulating complexes of CTCs and stromal cells remains to be fully elucidated, the recent identification of cCAFs in the peripheral blood of patients with metastatic breast cancer, traveling individually or in clusters with CTCs emphasizes the potential importance of stromal cells as circulating mediators of cancer metastasis. Preclinical murine models of breast cancer metastasis provide opportunities to observe the composition, dynamics, and behavior of these circulating CTC/stromal cell complexes, and to interrogate mechanisms driving their mobilization and clustering. Identifying the cellular components in these circulating complexes, and understanding the mechanisms by which they facilitate breast cancer metastasis, may provide novel therapeutic avenues for the treatment or prevention of metastatic breast cancer.

Citation Format: El-Ashry D. Circulating complexes of stromal and tumor cells in breast cancer metastasis [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 ES8-3.
Abstract GS5-05: Primary endocrine therapy for ER-positive ductal carcinoma in situ (DCIS) CALGB 40903 (Alliance)
Authors: Hwang ES , Duong S , Bedrosian I , Allred J , Wisner D , Hyslop T , Caudle A , Guenther J , Hudis C , Winer E , Esserman L , Hylton N
Published: February 2018

Background: Standard treatment for ductal carcinoma in situ (DCIS) consists of surgery, often followed by adjuvant radiation therapy or endocrine therapy. This current approach is thought to represent overtreatment for some patients. This study was undertaken to determine whether an alternate approach of primary endocrine therapy alone could result in measurable radiographic changes in unresected estrogen receptor (ER)-positive DCIS.

Methods: A phase II open-label single arm multi-center cooperative group trial (CALGB 40903) was conducted for postmenopausal patients diagnosed with ER-positive DCIS. All eligible patients underwent baseline mammography and MRI, followed by 6 months of preoperative therapy with letrozole. Follow up breast MRI was obtained at 3 and 6 months of treatment. The primary endpoint was change in total MRI volume of DCIS enhancement from baseline to 3 months and from baseline to 6 months. Secondary endpoints were change in MRI maximum diameter over baseline and change in mammographic extent of disease over baseline. Endpoints were analyzed via 2-sided paired t-tests (a=0.05).

Results: From 8/1/12 to 2/1/16 108 patients were enrolled; Of the 77 patients who completed letrozole treatment per protocol, 66 patients were assessable. 2 additional patients who did not complete treatment per protocol were considered assessable and thus included in the analysis for a total of 68 patients. Median age of the cohort was 62.7 years. DCIS nuclear grade was low in 10% of patients, intermediate in 49%, and high in 40%. 82% of patients had ER-positive, PR-positive DCIS. The total mean MRI volume decreased from baseline to 3 months by 1.93 cm3 (p<0.001) and from baseline to 6 months by 1.82 cm3 (p<0.001). There was no significant difference in tumor volume between 3 and 6 months. Mean total mammographic tumor diameter decreased from baseline to 6 months by 3.31 mm2 (p=0.078).

Conclusions: In a cohort of postmenopausal women treated with 6 months of preoperative endocrine therapy for ER-positive DCIS, MRI volume decreased markedly by 3 months, while mammographic extent of disease was not altered significantly. Correlation of imaging changes with pathology and baseline biomarkers will be conducted. These results will help determine whether MRI could be an effective modality for monitoring treatment response in some patients treated with primary endocrine therapy for ER-positive DCIS.

Citation Format: Hwang ES, Duong S, Bedrosian I, Allred J, Wisner D, Hyslop T, Caudle A, Guenther J, Hudis C, Winer E, Esserman L, Hylton N. Primary endocrine therapy for ER-positive ductal carcinoma in situ (DCIS) CALGB 40903 (Alliance) [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 GS5-05.
Abstract MS2-3: Tailoring systemic therapy for patients with lobular breast cancer
Authors: Colleoni MA
Published: February 2018

Recent developments in breast cancer treatment include an increasing awareness of the role of systemic therapies in selected subgroups of patients. A consequence of this strategy is the importance of accurate and reliable histopathological assessment. Through the identification of lobular breast cancer, that account for up to 15% of all invasive breast carcinomas, it is possible to select patients with correlates of responsiveness to therapy other than important indicators of outcome. It was in fact demonstrated that the response to neoadjuvant chemotherapy is significantly lower in lobular breast carcinomas, if compared with the ductal histotype. Also the value of adjuvant chemotherapy in lobular carcinomas was recently questioned, while the magnitude of the effect of adjuvant trastuzumab is similar in lobular and ductal breast cancer. The diagnosis of lobular breast cancer might be relevant also for the selection of endocrine agents in the adjuvant treatment. In particular the relative effectiveness of letrozole compared with tamoxifen was shown to be greater for patients diagnosed with lobular breast cancer. Nevertheless, the use of available information has been limited in tailoring therapy on patients with the lobular subtype, due to the relative rarity of the disease, the absence of prospective studies and the limited number and size of retrospective analysis. The development of effective therapies for these patients should not rely on information mainly contributed from small retrospective analyses. Prospective tailored research through international cooperation is key to make progress and reach consensus on how to treat individual patients with lobular breast carcinomas.

Citation Format: Colleoni MA. Tailoring systemic therapy for patients with lobular 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 MS2-3.
Abstract P1-01-08: DPYSL3 modulates proliferation and migration in claudin-low breast cancer
Authors: Matsunuma R , Chan DW , Kim B-J , Singh P , Han A , Malovannaya A , Perou CM , Ellis MJ
Published: February 2018

Cancer is often driven by deregulated protein kinases pathways including breast cancer. To profile the kinome at the protein level we are developing a kinase pulldown (KiP) proteomic platform that uses multiple kinase inhibitors conjugated to sepharose beads for protein kinase profiling. Mass spectrometry-base tryptic peptide sequencing is used to identify and quantify the kinome in an unbiased manner. To date, we have profiled and analyzed the kinomes of more than 50 breast cancer PDX model systems that include all five breast cancer subtypes. In these analyses we have begun to explore the kinome interactome because we have observed that KiP also pulls down breast cancer subtype specific kinase interacting proteins that may represent new biological insights. For example we have consistently identified dihydropyrimidinase-like 3 (DPYSL3) in p21-activated kinase (PAK) inhibitor KiP interactome in the claudin-low WHIM12 PDX model.

DPYSL3 is an intracellular phosphoprotein known to play a role in cell migration and metastasis. However it remains to be seen if DPYSL3 functions as a suppressor or a promoter of metastasis. We therefore generated DPYSL3 knock-down cell lines to evaluate function in claudin-low breast cancer. Proliferation levels of DPYSL3 depleted Claudin-low WHIM12 cells (DPYSL3-) were lower than those of control WHIM 12 (DPYSL3+) cells. In contrast, migration levels of DPYSL3- WHIM12 were greater than those of control cells, suggesting a pivotal role for DPYSL3 in several cellular physiologies. Additionally the activity of a PAK inhibitor (FRAX597) on migration appeared to require DPYSL3, as the inhibitory effect of FRAX579 on migration in WHIM12 was lost when DPYSL3 expression was depleted.

Additionally we find that only the long isoform of DPYSL3, not a short isoform, interacts with PAK to regulate migration, suggesting that alternative splicing of DPYSL3 may an important to the control of migration. Furthermore Snail is also negatively regulated DPYSL3 with elevated expression in DYPSL3- cells.

In conclusion, the study of the kinome interactome in breast cancer PDX identified DPYSL3 as regulator of the PAK family of kinases in a claudin low breast cancer. DPYSL3 is necessary for PAK to promote migration and may play a pivotal role in complex cellular transitions from a proliferative state versus an EMT/cell migratory state.

Citation Format: Matsunuma R, Chan DW, Kim B-J, Singh P, Han A, Malovannaya A, Perou CM, Ellis MJ. DPYSL3 modulates proliferation and migration in claudin-low 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 P1-01-08.
Abstract P1-01-13: Mucin-2 (Muc-2) modulates the biology of breast cancer
Authors: Astashchanka A , Shroka T , Jacobsen BM
Published: February 2018

Background: Metastasis and therapeutic resistance are major issues in treating patients with breast cancer. Breast tumors that secrete mucus are generally resistant to chemotherapy. One type of secreted mucin, Mucin-2 (Muc2), is expressed in some breast cancers, but is absent in non-neoplastic breast tissue, suggesting that it plays a role in modulating breast cancer biology. Whether Muc2 expression correlates with breast cancer patient survival is controversial. Thus, the effects of Muc2 on the biology of breast cancer are largely unknown. This study examined the role of Muc2 in modulating breast cancer cell proliferation in vitro and in vivo, response to chemotherapy, and metastasis.

Methods: Two novel cell lines were developed from patient derived tumor xenografts. These two cell lines, BCK4 and PT12, both express high levels of Muc2. In order to modulate Muc2 levels in both cell lines, shRNA targeted to Muc2 (shMuc2) were compared to non-targeting control shRNA (shNT). Decreased expression of Muc2 was confirmed using immunoblotting. Proliferation in vitro was measured using the IncuCyte live cell imaging system and crystal violet staining. Response to chemotherapy was measured by examining apoptosis using cleaved-caspase 3 expression. BCK4 and PT12 cells with shNT or shMuc2 were grown as solid tumors in immunocompromised mice and tumor volume measured by caliper. BCK4 cells with high Muc2 (shNT) and low Muc2 (shMuc2) were labeled with luciferase and examined in an experimental metastasis model where total disease was monitored by IVIS imaging.

Results: Decreased Muc2 expression decreased proliferation in BCK4 and PT12 cells versus non-targeting control cells both in vitro and in vivo. Treatment with the chemotherapeutic Docetaxel induced minimal apoptosis in BCK4 control cells with high Muc2 however, apoptosis was significantly increased in BCK4 cells with reduced Muc2. In an experimental metastasis model, mice injected with BCK4 cells containing low Muc2 had decreased disease burden versus those injected with control cells with high Muc2. Endogenous Muc2 expression in wild-type BCK4 cells increased with addition of EGF and this effect was abolished by addition of the EGF-receptor inhibitor, Erlotinib.

Conclusions: Muc2 expression plays an important role in mediating proliferation, apoptosis and metastasis of breast cancer cells. These data suggest that Muc2 is important in controlling the biology of Muc2 positive breast tumors. In addition, Muc2 may be important in guiding treatment and predicting outcomes in breast cancer patients.

Citation Format: Astashchanka A, Shroka T, Jacobsen BM. Mucin-2 (Muc-2) modulates the biology 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 P1-01-13.
Abstract P1-01-18: Disrupting interactions between human breast cancer cells, adipocytes, and macrophages
Authors: Vallega KA , Sang Q-XA
Published: February 2018

An increasing number of studies have found that other cells in the tumor microenvironment can influence tumor cells. Adipocytes, which were once thought to function only in energy storage, are now considered an active endocrine organ that secretes pro-inflammatory cytokines and proteases. In human breast cancer patients, invading tumor cells are surrounded by mature adipocytes. The breast cancer cells cause the adipocytes to undergo phenotypic changes and overexpress pro-inflammatory cytokines and matrix metalloproteinases (MMPs), such as MMP-3 and MMP-11. The presence of the changed adipocytes then increases the invasion capacity of breast cancer cells. Obesity is an important breast cancer risk factor. It causes changes to adipocytes and the surrounding microenvironment by invasion of macrophage cells. The effects of obesity-induced macrophage invasion have not been well characterized in the sector of breast cancer-adipocyte crosstalk. A novel 3D co-culture system was used to investigate how macrophage-induced inflammation can worsen this crosstalk, and what changes are involved in cytokine expression, adipocyte de-differentiation, breast cancer aggressiveness, and extracellular matrix (ECM) composition. When macrophage conditioned media was added to adipocytes and breast cancer cells in co-culture, the breast cancer cells showed increased cell proliferation and migration abilities. Experimental co-culture (adipocytes, breast cancer cells, macrophage conditioned media) showed almost twice the number of cells than the control co-culture (adipocytes, breast cancer cells, non-conditioned media). Interestingly, breast cancer cells alone in macrophage conditioned media did not show an increase in proliferation. This shows that macrophages may not affect breast cancer proliferation directly, as all three cell types are needed for increased proliferation of breast cancer cells. Introducing macrophages into this crosstalk also resulted in increased migration abilities. After 24 hours, breast cancer cells grown in experimental co-culture migrated further to close a wound than breast cancer cells grown in control co-culture. These results show that macrophages can affect adipocyte-breast cancer cell crosstalk. This may help explain why obese breast cancer patients have worse prognosis than non-obese breast cancer patients. Further investigation into these effects may identify targets to improve prognosis and abate breast cancer aggressiveness in obese breast cancer patients.

Citation Format: Vallega KA, Sang Q-XA. Disrupting interactions between human breast cancer cells, adipocytes, and macrophages [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 P1-01-18.
Abstract P1-02-02: FASN inhibition by TVB-3166 associates with breast cancer subtype
Authors: Gruslova AB , Chen C-L , Wang C-M , Elledge RM , Kaklamani VG , Lathrop K , Huang TH , Brenner A
Published: February 2018

Fatty acid synthase (FASN) is overexpressed in numerous tumor types, including breast carcinomas, and promotes changes in the genetic program controlling lipid biosynthesis. While inhibiting FASN appears to be an attractive therapeutic approach under development, the success of this approach may depend on the identification of tumor subtypes with specific metabolic requirements. Applying a comprehensive profile of circulating tumor cells (CTC) using canonical pathway gene sets, we identified a correlation of metabolic subtypes with breast tumor subtype. A lipogenic subtype is strongly associated with Luminal A subtype, whereas the glycolytic subtype associated with Luminal B tumors. The triple negative subtype was more heterogeneous and had the expression of both sets of gene. Such a difference in the metabolic profile may dictate differential sensitivity to inhibitors targeting de novo lipid synthesis, including FASN. This was supported by in vitro studies using selective FASN inhibitor, TVB-3166. Exposure to TVB-3166 over 14 days incubation in Advanced MEM with 1% charcoal-stripped FBS selectively inhibited growth and viability of Luminal A breast cancer cells, but had no effect on Luminal B subtype. This was further confirmed in short-term patient derived cultures. Mechanistic studies suggest that TVB-3166 quickly disrupts FA synthesis leading to the disruption of the lipid raft architecture and tumor cell death through an apoptotic mechanism. In conclusion, our findings highlight that success of targeting cancer metabolism directly may depend on identification of tumor subtypes with specific metabolic requirements.

Citation Format: Gruslova AB, Chen C-L, Wang C-M, Elledge RM, Kaklamani VG, Lathrop K, Huang TH, Brenner A. FASN inhibition by TVB-3166 associates with breast cancer subtype [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 P1-02-02.
Abstract P1-02-08: Reprogramming glucose metabolism and energy production in breast cancer cells
Authors: Kim H , Dong J , Xu J , Li D , Zheng Z , Ye N , Zhang Z , Chen H , Zhou J , Shen Q
Published: February 2018

Most mammalian cells use glucose as a main fuel source. Glucose is metabolized via glycolysis to pyruvate, which enters the mitochondria and then generates ATP through Krebs cycle in normal condition. However, metabolism is characteristically reprogrammed and cancer cells or highly proliferative cells preferably generate ATP through lactate production by lactate dehydrogenase (LDH/LDHA), referred to as the Warburg effect or metabolic reprogramming toward aerobic glycolysis. Efficient control of energy metabolism is the key to maintaining metabolic homeostasis, and disturbance in energy balance provokes diseases such as obesity, diabetes and cancer. However, the mechanisms underlying efficient energy metabolic homeostasis and breast cancer development are poorly understood. HJC0152, a novel small molecule glucose metabolism modulator, was developed using structure- and fragment-based drug design strategies and molecular modeling techniques. Aggressively growing and metastatic breast cancer cells of triple-negative subtype (MDA-MB-231) treated with HJC0152 showed decreased activity and protein level of LDHA, which resulted in a decrease lactate production. In addition, these cells also exhibited decreased glucose uptake and HK2 protein level. Furthermore, the amount of intracellular ATP in MDA-MB-231 cells was significantly reduced. Our findings suggest that HJC0152 is capable of reprogramming caner metabolism by modulating glucose metabolism and ATP production. These results may provide a rationale to develop HJC0152 as an effective therapeutic for cancer and other metabolic diseases with aberrant glucose metabolism. In addition, HJC0152 can serve as a molecular probing tool for elucidating the key factors responsible for developing breast cancer and other metabolic diseases.This work was supported by Grants P50 CA097007, and P30DA028821 (JZ) from the NIH, CPRIT (JZ), John Sealy Memorial Endowment Fund (JZ), DFI Grants from MD Anderson Cancer Center (QS), Holden Family Research Grant in BC Prevention (QS), and NCI PREVENT Program HHSN26100002 (QS).

Citation Format: Kim H, Dong J, Xu J, Li D, Zheng Z, Ye N, Zhang Z, Chen H, Zhou J, Shen Q. Reprogramming glucose metabolism and energy production in breast cancer cells [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 P1-02-08.
Abstract P1-07-36: Outcomes and failure of primary endocrine therapy for operable breast cancer in the elderly: A regional North-east of England study
Authors: Thomas R , Rowell R , Crichton S , Cain H
Published: February 2018

Introduction

Primary Endocrine therapy (PET) to treat oestrogen receptor (ER) positive operable breast cancer in the elderly is used widely in the UK. A previous Cochrane analysis revealed its inferiority in long-term local control in comparison to surgery. As such, current guidance from the Society of International Geriatric Oncologists (SIOG) suggest that PET should be reserved for patients with a reduced life-expectancy (2-3 years) or for those considered unfit for surgery. Inaccurate assessment of life expectancy could lead to treatment failure which is potentially catastrophic for the patient.

The aim of this study was to evaluate treatment failures in elderly breast cancer patients treated with PET and to determine predictors of failure.

Methods

A retrospective observational study was performed on consecutive patients with ER positive early stage breast cancer treated with PET between 2005 and 2015 in the three breast units in the north east of England. The primary outcome measure was treatment failure and the secondary outcome measure was disease progression.

Results

488 patients were included with mean follow up 31 months (SD 23). 465 (95.2%) patients were started on Letrozole as their initial therapy. Overall, 206 patients were still alive with their disease controlled at the end of follow up, 219 had died with their disease controlled and 63 (12%) experienced treatment failure. Kaplan-Meier survival analysis predicted at 3 years 40% of patients to have died with controlled disease and 10% to have failed, leaving 50% living beyond this point with controlled disease. Regression analysis identified younger age [SHR 0.96 (95% CI 0.94 to 0.99) p 0.013], larger tumours [SHR 1.03 (1.01 to 1.06) p 0.015], grade 3 cancers [SHR 3.58 (1.93 to 6.63) p<0.001] and axillary lymph node metastases [SHR 1.93 (1.06 to 3.52) p 0.030] were all independent predictors of treatment failure. Disease progression was reported in 86 (17.6%) of patients.

Conclusions

This is the largest retrospective series conducted evaluating PET treatment failure. Our comparably low rate of failure in comparison to that in the literature (12-85%) reflects good clinical acumen. Clear predictors of failure have been identified, which support previous analyses, further validating our results. Patients are able to live longer term (beyond 3 years) and maintain local disease control, which may represent a viable long-term treatment in the absence of risk factors for failure. Further work on our series is underway examining the effect of decision-making on PET outcomes.

Citation Format: Thomas R, Rowell R, Crichton S, Cain H. Outcomes and failure of primary endocrine therapy for operable breast cancer in the elderly: A regional North-east of England 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 P1-07-36.
Abstract P1-13-09: Withdrawn
Authors: Ignatiadis M , Litiere S , Rothe F , Riethdorf S , Proudhon C , Fehm T , Aalders K , Forstbauer H , Fasching P , Brain E , Vuylsteke P , Guardiola E , Lorenz R , Pantel K , Tryfonidis K , Janni W , Piccart M , Sotiriou C , Rack B , Pierga J-Y
Published: February 2018

This abstract was withdrawn by the authors.
Abstract P1-13-10: Adjuvant treatment of HER2+ breast cancer: Should trastuzumab be given sequentially or concurrently with chemotherapy?
Authors: Dackus GMHE , Jóźwiak K , Van der Wall E , Van Diest PJ , Hauptmann M , Siesling S , Sonke GS , Linn SC
Published: February 2018

Background

Human Epidermal growth factor Receptor 2 positive (HER2+) breast cancers have a high risk of recurrence in the absence of systemic treatment. The monoclonal antibody trastuzumab in combination with chemotherapy has significantly improved survival. Randomized trials have given trastuzumab both concurrently and sequentially with chemotherapy. To date, only one study reported a comparison between concurrent and sequential trastuzumab, with a numerically but not statistically significant benefit for concurrent use.

Our aim is to evaluate whether there is a difference in survival between patients who received trastuzumab sequentially to chemotherapy compared to concurrently with chemotherapy using data from the population-based, Netherlands Cancer Registry (NCR).

Methods

All women diagnosed in the Netherlands with a HER2+, TanyNanyM0 breast tumor between 2005 and 2007 who received both chemotherapy and trastuzumab were identified from the NCR.

Kaplan Meier survival estimates and Cox regression were used to compare recurrence free survival (RFS) and overall survival (OS) by trastuzumab sequence. Hazard ratios (HR) were adjusted for grade, pathological T-stage, pathological N-stage, estrogen receptor (ER), progesterone receptor, radiotherapy, hormonal therapy and ovarian ablation.

Results

A total of 1,849 patients were identified, with a mean follow-up of 7.8 years. Of these, 1,260 received concurrent trastuzumab and 589 sequential trastuzumab. Most tumors were grade 3, node positive and ER+. During follow-up 358 RFS events occurred, 231 in the concurrently treated patients compared to 127 in sequentially treated patients. Regarding OS, 290 deaths were observed, 188 deaths in concurrently treated patients compared to 102 deaths in sequentially treated patients, respectively.

OS and RFS were similar among sequentially versus concurrently treated patients (adjusted HR 1.11; 95% CI 0.87-1.42; P=0.420 and adjusted HR 1.15; 95% CI 0.92-1.44; P=0.209, respectively).

Conclusion

We observed no significant difference in OS and RFS between patients who received sequential trastuzumab compared to patients treated concurrently. Based on our results no recommendation can be made favoring either of the two treatment sequences for the adjuvant treatment of HER2+ breast cancer patients.

Citation Format: Dackus GMHE, Jóźwiak K, Van der Wall E, Van Diest PJ, Hauptmann M, Siesling S, Sonke GS, Linn SC. Adjuvant treatment of HER2+ breast cancer: Should trastuzumab be given sequentially or concurrently with chemotherapy? [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 P1-13-10.
Abstract P1-15-02: Benefit of adjuvant chemotherapy in disease-free survival for T1N0 triple negative breast cancer
Authors: Morante Z , De la Cruz-Ku G , Pinto J , Araujo J , Fuentes H , Enriquez D , Luque R , Eyzaguirre E , Saavedra A , Luján M , Neciosup S , Gomez H
Published: February 2018

Background: Although chemotherapy is not recommended in low-risk early breast cancer, triple-negative breast cancers (TNBC) have twice risk of recurrence despite an aggressive treatment. In this study we evaluated the role of chemotherapy in the outcome of T1N0 TNBC patients in terms of disease-free survival (DFS) and overall survival (OS).

Methods: We evaluated a retrospective cohort T1N0 TNBC patients diagnosed between 2000 to 2014 at the Instituto Nacional de Enfermedades Neoplasicas (Lima-Peru). Survival rates differences were assessed by Log-rank test and prognostic factors were identified using the Cox proportional hazards model.

Results: We identified 123 T1N0 TNBC patients. The median age was 51 years (range: 28-85), where 38.5% were premenopausal. Thirty-six (29.3%) were pT1a/b and 87 were pT1c (70.7%). ACT was administered more frequently in pT1c patients (74.7% vs 55.6%; P=0.036). Locoregional relapse and distant metastases rates were 8.3% vs 19.5% and 5.6% vs 16.1% for tumors pT1a/b and pT1c, respectively. The median of follow-up was 8.8 years. Independent prognostic factors were pT stage and treatment with ACT. In relation to pT stage, DFS rates were 97% vs 78% (at 5-years) and 97% vs 70% (at 8-years) for pT1a/b vs pT1c patients, respectively (HR=4.8; 95%CI:1.46-17.0; P=0.015). In the other hand, patients treated with ACT had a better outcome with DFS rates to 5-years of 86% vs 74% and 8-years of 81% vs 65% (HR: 0.41, 95%CI: 0.17-0.97, p=0.043). Our study had not statistical power to evaluate benefit of ACT in pT1a/b patients. In cases with pT1c tumors, treatment with ACT was the only factor associated with a better DFS (HR=0.29, 95%CI: 0.11-0.77, p=0.012). Because the low mortality in our cohort, OS was not evaluable.

Conclusions: Treatment with adjuvant chemotherapy reduces the recurrence risk in 71% among pT1cN0 TNBC.

Citation Format: Morante Z, De la Cruz-Ku G, Pinto J, Araujo J, Fuentes H, Enriquez D, Luque R, Eyzaguirre E, Saavedra A, Luján M, Neciosup S, Gomez H. Benefit of adjuvant chemotherapy in disease-free survival for T1N0 triple negative breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-15-02.
Abstract P2-01-09: Circulating tumor cells (CTCs) in the venous drainage of the breast in patients with primary breast cancer
Authors: Hattori M , Nakanishi H , Yoshimura A , Adachi Y , Iwase M , Gondo N , Kotani H , Sawaki M , Yatabe Y , Iwata H
Published: February 2018

Background:

CTCs are shed from tumors and circulate in the peripheral blood after passing through the drainage vein. Axillary lymph node dissection (ALND) provides access to the lateral thoracic vein which flows directly into the axillary vein. In this preliminary study, we evaluated the feasibility of detecting CTCs in the peripheral blood and in the lateral thoracic venous blood for breast cancer patients who underwent ALND.

Methods:

From June 2016 to March 2017, breast cancer patients who underwent ALND in our institute were eligible for this study. A peripheral blood sample,10ml, was drawn just before the surgery or one day before the surgery. A lateral thoracic venous blood sample was taken from the resected breast just after resection. A blood sample of 0.2ml or more was necessary for CTC isolation. The CTCs in the peripheral blood before surgery (periCTC) and in the blood from the lateral thoracic vein of the resected breast (ltvCTC) were quantitatively examined by using a size-selective CTC isolation platform.

Results:

A total of 21 patients with median age 51 years (37-75) were enrolled to the study. Of the 21 patients, 38% were premenopausal, 52% had neoadjuvant chemotherapy. Fifty-seven percent were ER and/or PgR positive, 24% were HER2 positive. Fifty-seven percent were stage II disease and 43% were stage III. In 3 patients, we couldn't obtain sufficient blood samples from the lateral thoracic vein. Of the remaining 18 patients, we were able to obtain the median 0.5ml (0.2-2.0) blood samples from the lateral thoracic vein. CTCs were detected in peripheral blood in 15 patients (71%) and median periCTC count was 1 CTC/10ml (0-39). In lateral thoracic venous blood, CTCs were detected in all patients who had sufficient blood samples and the median ltv CTC count was 35.5 CTC/ml (2.5-370). In 5 of 6 patients whom CTCs in peripheral blood samples were not detected, CTCs could be detected in the blood samples from lateral thoracic vein.

Conclusion:

CTCs can be detected in the peripheral blood and in the blood from lateral thoracic vein in patients with localized breast cancer, and can be detected at a higher rate and at a higher concentration in the blood from lateral thoracic vein than in peripheral blood.

Citation Format: Hattori M, Nakanishi H, Yoshimura A, Adachi Y, Iwase M, Gondo N, Kotani H, Sawaki M, Yatabe Y, Iwata H. Circulating tumor cells (CTCs) in the venous drainage of the breast in patients with primary 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 P2-01-09.
Abstract P2-04-06: Changes of DNA methylation in the development of breast cancer
Authors: He C , Lin N , Shendre A , Jiang G , Lin H , Wan J , Liu Y
Published: February 2018

Aberrant DNA methylation plays an important role in breast cancer initiation and progression via inactivation of tumor suppressor genes and activation of oncogenes. To better understand the changes of DNA methylation in the development of breast cancer, we analyzed genome-wide DNA methylation DNA data in breast tumor, adjacent normal tissue, and normal breast tissue from healthy women. Using the IIILumina MethylationEPIC array, we investigated approximately 850,000 CpG sites. After quality control, 747,803 probes were retained and included the further analysis. To identify DNA methylation markers associated with breast cancer, we performed differential methylation analysis using ChAMP package implemented in Bioconductor. We identified 590 CpG sites that were differentially methylated (P<1X10-4) between tumor and normal, and 637 between tumor and adjacent normal tissue samples. Further pathway analyses revealed that changes in DNA methylation between tumor and normal breast tissue were mainly involved in neurogenesis and neuro differentiation, oxidative stress, insulin secretion and epithelial morphogenesis; while changes in DNA methylation between tumor and adjacent normal tissue were mainly involved in angiogenesis, cell morphogenesis, and cell component movement. We further validated our findings using RNA-seq data. Our results suggested distinct DNA methylation changes involved in different biological pathways, reflecting potential causal and reactive biological mechanisms in the initiation and the progression of breast cancer.

Citation Format: He C, Lin N, Shendre A, Jiang G, Lin H, Wan J, Liu Y. Changes of DNA methylation in the development 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 P2-04-06.
Abstract P2-05-06: Not presented
Authors: Agrawal V , Cheung YH , Keswarpu P , Somlo G , Abu-Khalaf M , Sikov W , Varadan V , Harris L , Dimitrova N
Published: February 2018

This abstract was not presented at the symposium.
Abstract P2-09-33: Not presented
Authors: Tokunaga E , Takizawa K , Masuda T , Ijichi H , Koga C , Tajiri W , Tanaka J , Nakamura Y , Taguchi K , Ishida M
Published: February 2018

This abstract was not presented at the symposium.
Abstract P2-10-06: Identifying patients sensitive to anthracycline-containing therapy with quantitative proteomic and genomic profiling
Authors: Schwartz S , Cecchi F , Tian Y , Yau C , Szeto C , Rübner M , Erber R , Beckmann MW , Hartmann A , Benz S , Hembrough T , Fasching P
Published: February 2018

Background: Selecting chemotherapy based on tumor biology can improve response rates and avert toxicity. Studies of the relationship between tumor expression of TOP2A protein and response to anthracycline-based chemotherapy have yielded contradictory results. Here we used mass spectrometry (MS) to evaluate associations between tumor molecular profiles and pathological complete response (pCR) in breast cancer patients treated with neoadjuvant anthracycline-containing therapy.

Methods: Patients were selected from the ERNEST-B (Erlangen Neoadjuvant Study Breast), which is a retrospective cohort study. Archived tumor samples from anthracycline-treated breast cancer patients (n=133) were microdissected and solubilized. In each tumor sample, TOP2A and other target proteins were quantitated with a mass spectrometry assay. Molecular profiling also included RNA sequencing of the tumor and whole genome sequencing of both tumor and matched normal tissue sections. The cohort was dichotomized into high and low expressors of TOP2A using a protein level cutoff of 515 amol/ug of tumor protein. The difference in pCR (ypT0ypN0) rates between high and low expressors of TOP2A was assessed using a z-test for differences in proportion.

Results: TOP2A protein was detected in 84 of 133 (63%) tumor samples from anthracycline-treated patients (range: 178 to 3044 amol/ug). Patients whose tumor expressed TOP2A protein above the cutoff of 515 amol/ug had higher pCR rates than patients with lower TOP2A expression (35.5% vs. 12.1%; odds ratio (OR): 4.48 [95% CI: 1.53-13.28], Fisher' exact test p = 0.004). The difference retained statistical significance in a logistic regression model adjusting for HR and HER2 status (OR: 2.23 [95% CI: 1.15-4.30], p=0.017). In a separate cohort of 19 breast cancer patients who did not receive anthracycline, there was no association between TOP2A protein expression level and pCR rate. Results from a validation cohort as well as the genomic analysis will be presented at the meeting.

Conclusions: In a retrospective analysis of anthracycline-treated breast tumors, TOP2A expression was associated with a higher rate of pCR. Targeted proteomics may predict the response of breast cancer patients to anthracycline-based therapy.

Citation Format: Schwartz S, Cecchi F, Tian Y, Yau C, Szeto C, Rübner M, Erber R, Beckmann MW, Hartmann A, Benz S, Hembrough T, Fasching P. Identifying patients sensitive to anthracycline-containing therapy with quantitative proteomic and genomic profiling [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 P2-10-06.
Abstract P2-10-07: A prospective clinical utility study of the impact of the 21-gene recurrence score (RS) assay in the treatment of estrogen receptor positive (ER+), HER2 negative (HER2-), 1-3 node positive (N+) breast cancer (BC)
Authors: Sun J , Fenton D , Baxter S , Chan A , Roberts S , Feng X , Lohrisch C , Gelmon K , Shenkier T , Chia S
Published: February 2018

Background:

The 21-gene RS is routinely used in node negative ER+, HER2- BC to help guide chemotherapy treatment decision making. There is emerging use of the RS in limited N+ BC, though the results from the randomized clinical trial (RxPONDER) is pending. The objective of the study is to determine whether the results of the 21-gene RS will alter physician treatment decisions in ER+ HER2- limited N+ BC.

Methods:

Consenting patients (pts) with ER+, HER2-, 1-3 N+ (microscopic or macroscopic) early stage BC participated in this prospective, multi-center British Columbia Cancer Agency (BCCA) study. Treating physicians completed a questionnaire after an initial visit with the patient to document their treatment recommendation before obtaining the RS assay. At a subsequent visit, the assay result and final treatment recommendations were discussed and physicians completed a second questionnaire on the final treatment plan. The statistical assumption of the study was based upon anticipating an overall treatment decision change rate (from chemo-hormonal therapy to hormone only, or vice-versa) to be at least 30%.

Results:

Out of 84 pts enrolled, 82 went on to have RS testing. 57% of pts had T1 tumors, 40% T2 and 2% T3 tumors. The majority of pts (77%) had N1 macroscopic disease compared to 23% that had microscopic nodal involvement. 63% of cases were grade 2, followed by 23% grade 1 and 14% grade 3. 60% of RS were low (<18), 33% intermediate (18-30) and 7% were high (>30). In 53% of cases there was an altered treatment plan (49% switched from chemo-hormonal therapy to hormone only, and 4% switched from hormone only to chemo-hormonal therapy). Of the 49% that switched to hormone only, 68% had a low RS and 33% had an intermediate RS. All 4% that switched to chemo-hormonal therapy had an intermittent RS.

Conclusions:

This multi-centered Canadian study showed that in 53% of cases, treatment recommendations were changed based on the RS. This suggests that there is clinical utility for the RS in 1-3 N+, ER+, and HER2- breast cancer.

Citation Format: Sun J, Fenton D, Baxter S, Chan A, Roberts S, Feng X, Lohrisch C, Gelmon K, Shenkier T, Chia S. A prospective clinical utility study of the impact of the 21-gene recurrence score (RS) assay in the treatment of estrogen receptor positive (ER+), HER2 negative (HER2-), 1-3 node positive (N+) breast cancer (BC) [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 P2-10-07.