bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P2-02-05: Sensitivity of screening mammography by density and texture: A cohort study from a population based screening programme in Denmark
Authors: von Euler-Chelpin My
Published: March 2020

Background Screening mammography works better in fatty than in dense breast tissue. Computerized assessment of parenchymal texture is a non-subjective method to obtain a refined description of breast tissue, potentially valuable in addition to breast density scoring for identification of women in need of supplementary imaging. We studied sensitivity of screening mammography by a combination of radiologist assessed BI-RADS density score and computer assessed parenchymal texture marker, MTR, in a population-based screening program, Capital Region, Denmark.

Methods Breast density was coded according to the 4th Edition of the BI-RADS density code, and MTR marker was divided into quartiles from 1 to 4. Screening data were followed-up for identification of screen-detected and interval cancers. We calculated sensitivity and specificity with 95% confidence intervals (CI) by BI-RADS density score, MTR marker, and combination hereof.

Results In total, 55 350 women were screened from 1 November 2012 to 31 December 2013. Full data were available for 54 997 women, of whom 28% had BI-RADS density score 1, 40% score 2, 27% score 3, and 5% score 4. Density and texture were strongly correlated, but the combination led to identification of subgroups with different sensitivity. Sensitivity was high, about 80%, in women with BI-RADS density scores 1 and MTR markers 1 or 2.Sensitivity was low, 67%, in women with BI-RADS density score 2 and MTR marker 4. For women with BI-RADS density scores 3 and 4, the already low sensitivity was further decreased for women with MTR marker 4. Specificity was 97-99% in all subgroups.

Conclusion Our study showed that women with low density constituted a heterogenous group. Classifying women for extra imaging based on density only might be a too crude approach. Screening sensitivity was systematically high in women with fatty and homogeneous breast tissue.

Sensitivity and specificity by combination of density score (BI-RADS) and texture marker (MTR), Denmark 2012-13

MeasureSensitivity % (95% CI)Specificity % (95% CI)BI-RADS 178 (69-85)99 (98-99)MTR 181 (70-90)99 (98-99)MTR 271 (54-85)99 (99-99)MTR 382 (48-98)98 (98-99)MTR 4BI-RADS 275 (70-81)97 (97-97)MTR 173 (57-85)98 (97-98)MTR 277 (66-85)97 (97-97)MTR 380 (64-88)97 (97-98)MTR 467 (51-81)97 (97-98)BI-RADS 369 (62-76)97 (97-97)MTR 171 (52-86)97 (96-98)MTR 2MTR 377 (66-87)97 (97-98)MTR 461 (46-72)97 (97-98)BI-RADS 447 (30-65)98 (97-98)MTR 157 (29-82)98 (97-99)MTR 2MTR 3MTR 441 (21-64)97 (97-98)

Citation Format: My von Euler-Chelpin. Sensitivity of screening mammography by density and texture: A cohort study from a population based screening programme in Denmark [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-02-05.
Abstract P2-05-08: Integrin alpha6beta4 signaling switches double strand break repair from homologous recombination to non-homologous end joining to alter TNBC cells response to cisplatin
Authors: Chen Min , Marrs Brock , Qi Lei , Knifley Teresa , Jarrett Stuart G , Weiss Heidi L , Stewart Rachel L , D'Orazio John A , O'Connor Kathleen L
Published: March 2020

Integrin α6β4 is highly expressed in triple negative breast cancer (TNBC) and drives aggressiveness by stimulating proliferation, angiogenesis, cell migration, invasion and metastasis. Signaling from this integrin stimulates DNA repair and apoptosis resistance, suggesting that it could contribute to therapeutic resistance. Upon testing this hypothesis, we found that integrin α6β4 signaling promoted a three-fold greater sensitivity to cisplatin but exhibited no difference in the response to other chemotherapies tested. Mechanistic investigations revealed that integrin α6β4 stimulated quicker and higher amplitude activations of ATM, Chk2, p53, and 53BP1, which required the β4 signaling domain. Genetic manipulation of gene expression demonstrated that mutant p53 cooperated with integrin α6β4 for cisplatin sensitivity and was necessary for downstream phosphorylation of 53BP1 and enhanced ATM activation. Additionally, we discovered that integrin α6β4 preferentially activated DNA-PKc in response to cisplatin, which led to formation of DNA-PKc-p53 complexes and 53BP1 activation. As a result, integrin α6β4 shifted double strand break repair from homologous recombination (HR) to non-homologous end joining (NHEJ), as demonstrated by HR and NHEJ reporter assays, in normal culture which was amplified by cisplatin treatment. Furthermore, DNA-PKc inhibition blocked integrin α6β4 enhanced cisplatin sensitivity. This signaling, against the backdrop of prominent losses and gains of select DNA repair molecules in breast cancer as a whole, may lead to a novel HR-deficiency that characterizes TNBC and their response to select chemotherapies. In summary, we discovered a novel function of integrin α6β4 in switching DSB repair from HR to NHEJ that results in cisplatin sensitivity in TNBC.

Citation Format: Min Chen, Brock Marrs, Lei Qi, Teresa Knifley, Stuart G Jarrett, Heidi L Weiss, Rachel L Stewart, John A D'Orazio, Kathleen L O'Connor. Integrin alpha6beta4 signaling switches double strand break repair from homologous recombination to non-homologous end joining to alter TNBC cells response to cisplatin [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-05-08.
Abstract P2-08-16: The burden and trends of breast cancer from 1990 to 2017 at the global, regional, and national level: Results from the global burden of disease study 2017
Authors: Gong Yue , Ji Peng , Hu Xin , Shao Zhi-Ming
Published: March 2020

Background: Breast cancer is a common diagnosed malignancy and the leading cause of cancer-related death worldwide. Data on burden and changing trends of breast cancer are of value for policymaking. We therefore aimed to determine the pattern of breast cancer incidence, mortality, and disability-adjusted life-years (DALYs), as well as temporal trends, from 1990 to 2017. Methods: We collected detailed information on breast cancer between 1990 and 2017 using the results of the Global Burden of Disease study in 2017. The number of incident cases, deaths and DALYs attributable to breast cancer are reported as well as age standardized rates. Estimated annual percentage changes (EAPCs) in breast cancer age standardized rate were calculated to quantify the temporal trends. Moreover, attributable burden to breast cancer risk factors were also estimated using the comparative risk assessment framework of the GBD study. Results: There were 878,686 incident cases and 349,581 deaths of breast cancer globally in 2017, contributing to 17,708,600 DALYs. The age standardized incidence rate increased between 1990 and 2017, while the age standardized mortality rate and DALY rate decreased. The corresponding EAPCs were 0.41 (95% CI: 0.35 to 0.47), -0.62 (95% CI: -0.68 to -0.55), -0.56 (95% CI: -0.63 to -0.48), respectively. These trends were heterogeneous across regions and countries. The increase in the age standardized incidence rate was more prominent in countries with a low socio-demographic index and the decrease in the age standardized mortality rate and DALY rate was more prominent in countries with a high socio-demographic index. Percentage of breast cancer deaths due to alcohol use (12.94% to 9.64%) and tobacco (7.15% to 5.14%) was decreasing while deaths due to high body-mass index (4.03% to 6.54%) and high fasting plasma glucose (5.94% to 7.26%) was increasing. Conclusion: Breast cancer remains a major public health concern globally. The trends of incidence, mortality, and DALYs were heterogeneous across regions and countries, suggesting that the allocation of appropriate health care resources for breast cancer prevention, screening and treatment should be considered.

Citation Format: Yue Gong, Peng Ji, Xin Hu, Zhi-Ming Shao. The burden and trends of breast cancer from 1990 to 2017 at the global, regional, and national level: Results from the global burden of disease study 2017 [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-08-16.
Abstract P2-13-21: Predicting symptoms and diseases after breast cancer treatment: Development of a nomogram
Authors: Heins Marianne J. , De Ligt Kelly M. , Verloop Janneke , Siesling Sabine , Korevaar Joke C.
Published: March 2020

Background: Women with breast cancer can experience a variety of late adverse effects, depending on age, treatment and time since diagnosis. We developed a nomogram that predicts which symptoms and diseases are likely to occur in breast cancer survivors up to 15 years after diagnosis. Methods: Data from the Netherlands Cancer Registry and NIVEL Primary Care Database were combined in the Primary-Secondary Cancer Care Registry, containing data about the cancer diagnosis/treatment and data from the primary care electronic health records of 12.850 Dutch women diagnosed with breast cancer between 2000-2016. From Nivel Primary Care Database 25.700 control women without breast cancer were obtained. First, Cox regression models were built, stratified by 4 age groups and 2 time windows (1-5 and 5-15 years after diagnosis), in order to determine which symptoms and diseases were more frequently experienced in cases compared to controls (p-value<.05). Second, for each significant symptom and disease, relevant treatment variables (chemo therapy (yes/no), radio therapy (yes/no, and lateralisation), hormone therapy (yes/no), axillary dissection (yes/no)) were added stepwise to the models. Variables with a p-value <.10 were included in a multivariate model and all variables with a p-value <.05 were retained in the final model. Findings: In total, 635 models were constructed, forming the basis for the nomogram. Late effects occurring more frequently in cases compared to controls independent of age and time since diagnosis were chest symptoms, lymphedema/arm symptoms, redness/infections of the skin, nausea, cystitis, insomnia and discussing euthanasia. Others were predominantly relevant 1-5 years after diagnosis, including vomiting and side-effects of medication. Interpretation: This nomogram can provide clinicians and women with breast cancer insight in which symptoms and diseases she has an increased risk to experience in the upcoming years, which is both applicable when making treatment decisions and at follow-up initiation. Besides, it may be a starting point to develop effective preventive measures to limit late side-effects of breast cancer and improve after care for women with breast cancer.

Citation Format: Marianne J. Heins, Kelly M. De Ligt, Janneke Verloop, Sabine Siesling, Joke C. Korevaar. Predicting symptoms and diseases after breast cancer treatment: Development of a nomogram [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-13-21.
Abstract P2-14-09: Results from a novel educational program to help nurses when discussing the Oncotype DX Breast Recurrence Score® with their patients
Authors: Fallowfield Lesley , May Shirley , Ramirez Amanda , Fryer Nina , Paramore Andrew , Jenkins Valerie
Published: March 2020

Background Discussing risk of recurrence and potential treatment benefit in early breast cancer can be challenging, especially when dealing with anxious patients and/or those with difficult social circumstances. UK patients usually have access to specialist breast care nurses (SBCN) who discuss in further detail the implications that the Oncotype DX Breast Recurrence Score® result may have for:- treatment decisions, risks and benefits of chemotherapy and the potential impact on patients’ well-being and lifestyle. We developed an innovative communication skills workshop to assist SBCNs with these encounters. Methods The 6 hour workshops comprised:- 2 didactic presentations, one on the data underpinning the OncotypeDX® risk scores and cut-offs post TAILORx and another on the psychology of risk which included interactive exercises about numeracy, communication, and tolerance to uncertainty. Attendees then split into small groups for two practical sessions led by experienced facilitators. First they viewed one of 2 filmed scenarios of oncologists explaining Recurrence Score results with patients. The SBCNs then met with the same simulated patient just seen on film, who was now ‘in clinic’ a week later and keen to discuss her test result further. During these practical sessions facilitators engaged and encouraged the SBCNs to consider and practice different ways of handling the patients’ difficult questions. At completion of each session the simulated patients provided feedback and suggestions. Attendees completed 11 item pre/post workshop questionnaires probing their self-confidence when discussing complex issues surrounding the Recurrence Score® result. Results A total of 69 UK SBCNs participated. There were significant and positive improvements in mean change scores of self-rated confidence for all 11 issues, (P<0.004; Bonferonni) including handling discussions of scores post TAILORx. Workshops were rated as informative (9.6/10), useful (9.5/10) and enjoyable (9.6/10) with 68/69 (99%) recommending it to colleagues. Conclusion Nurses can play an important role helping patients’ decision-making; they are also usually fearful of role-play but most found the innovative practical sessions especially helpful. Our results showed that improved self-confidence, a key element required to lead to a transfer of communication skills into a clinic setting, was achieved in this six hour workshop.

Citation Format: Lesley Fallowfield, Shirley May, Amanda Ramirez, Nina Fryer, Andrew Paramore, Valerie Jenkins. Results from a novel educational program to help nurses when discussing the Oncotype DX Breast Recurrence Score® with their patients [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-14-09.
Abstract P2-16-07: Randomized controlled trial of neoadjuvant eribulin mesylate versus paclitaxel in women with operable breast cancer (JONIE-3 study)
Authors: Kawate Takahiko , Ishikawa Takashi , Miura Daishu , Hasegawa Yoshie , Tachibana Akihiko , Horiguchi Jun , Hayashi Mitsuhiro , Miyashita Masaru , Kubota Tomoyuki , Narui Kazutaka , Suzuki Masato , Akazawa Kouhei , Kohno Norio
Published: March 2020

Background: Eribulin mesylate (ERI) improved the overall survival in metastatic breast cancer (BC) patients. However, the efficacy has not been reported in early breast cancer. We performed the neoadjuvant chemotherapy (NAC) study based on hypothesis that ERI is less toxic, particularly in peripheral neuropathy, and has similar efficacy to paclitaxel (PTX) in patients with operable BC. Methods: This is a multicenter open label randomized phase 2 study (UMIN000012817). Patients were randomly assigned to either ERI (1.4mg/m2, d1 and d8, q21 days, 4 cycles) followed by FEC (fluorouracil 500 mg/m2, epirubicin 100 mg/m2, and cyclophosphamide 500 mg/m2) (ERI-FEC) or PTX (80mg/m2, weekly, 12 cycles) followed by FEC (PTX-FEC) with stratified by ER, HER2, and menopausal status. Trastuzumab was added in patients with HER2 positive disease. Primary endpoint was the incidence of peripheral sensory and motor neuropathy (PSN and PMN) with Grade 1 or higher according to CTCAE ver.4.0. Secondary endpoints were pathological complete response (pCR) rates (ypT0/is/ypN0), clinical response rates (CR+PR), adverse events, disease-free survival (DFS) and patient neurotoxicity questionnaire (PNQ) analysis. Here, we report 3 year’s DFS and PNQ analysis in this study Results: Between December 2013 to March 2016, 121 cases were enrolled and 5 cases were excluded from the primary assessment. One hundred sixteen cases were finally randomized and treated by ERI-FEC in 58 cases and PTX-FEC in 57 cases. A median follow-up time of ERI-FEC and PTX-FEC was 54.2 and 51.4 months, respectively. Three year-DFS rate were 89.7% in the ERI-FEC group (95% CI 51.1 - 57.3) and 86.0% in the PTX-FEC group. (p=0.561). The incidences of PSN and PMN were significantly lower in the ERI-FEC group than the PAX-FEC group at the end of treatments (previously reported). PNQ analysis after treatments is now undergone. Conclusion: DFS was not different between them. Although the pCR rate was lower in ERI-FEC than PAC-FEC as reported at the previous meeting. ERI was more favorable on adverse events than PTX during NAC treatments. Long-term results on neurotoxicity of these two drugs will be presented at the meeting.

Citation Format: Takahiko Kawate, Takashi Ishikawa, Daishu Miura, Yoshie Hasegawa, Akihiko Tachibana, Jun Horiguchi, Mitsuhiro Hayashi, Masaru Miyashita, Tomoyuki Kubota, Kazutaka Narui, Masato Suzuki, Kouhei Akazawa, Norio Kohno. Randomized controlled trial of neoadjuvant eribulin mesylate versus paclitaxel in women with operable breast cancer (JONIE-3 study) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-16-07.
Abstract P2-16-11: Impact of progesterone receptor status on response to neoadjuvant chemotherapy in oestrogen receptor positive breast cancer patients
Authors: Boland Michael R , Ryan Eanna J , Nugent Timothy , Gilroy Darina , Kennedy John , Alazawi Dhaffir , Boyle Terence J , Connolly Elizabeth M
Published: March 2020

Introduction Breast cancer patients respond differently to neoadjuvant chemotherapy (NAC) based on hormone receptor subtype. Oestrogen receptor positive/Her-2 receptor negative (ER+HER-) patients respond poorest but the effect of progesterone receptor (PR) status on response within this group has not been elucidated. The aim of this study was to assess the impact of PR status on response to NAC in ER+HER- breast cancer patients. Methods All patients receiving NAC over a seven-year period (2011-2017) were retrospectively identified from a prospectively maintained database within a specialised breast referral unit. Clinicopathological details were collated for all patients found to be ER+HER-. Primary outcomes including breast complete pathological response (PCR) rate and axillary PCR rate were compared between patients found to be progesterone receptor positive and negative. Secondary outcomes including grade and presence of lymphovascular invasion were also assessed. Results 206 patients were identified (151 in the ER+PR+HER- group and 55 in the ER+PR-HER- group). When compared with the PR+ group, patients found to be PR negative were more likely to achieve a breast PCR (3.3% vs 25.4%; Chi Square test; p=0.001), which was confirmed on multivariate analysis (p=0.001).In patients who were initially node positive, PR negativity was associated with a higher rate of axillary nodal PCR compared to those found to be PR positive(12.2% vs 25.5%; Chi Square test; p=0.04). ER+PR-HER- patients were more likely to have higher grade tumours but not LVI. Conclusion Over a quarter of ER+HER- patients who are PR negative will have a complete pathological response to NAC in the breast and axilla. Such patients should be considered for NAC at diagnosis.

Citation Format: Michael R Boland, Eanna J Ryan, Timothy Nugent, Darina Gilroy, John Kennedy, Dhaffir Alazawi, Terence J Boyle, Elizabeth M Connolly. Impact of progesterone receptor status on response to neoadjuvant chemotherapy in oestrogen receptor positive breast cancer patients [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-16-11.
Abstract P3-02-11: Topographical ues overlaid with fructose-like molecules to assess breast cancer recruitment in nanofiber scaffolds
Authors: Que Carolynn , Hanumantharao Samerender Nagam , Vogl Brennan , Tanasova Marina , Rao Smitha
Published: March 2020

Tumorigenesis is a complex process involving numerous cellular signaling cascades and environmental factors. While 2D cultures for stiffness measurements and more recently 3D cultures to demonstrate differences in cell structures have been reported, very little is known about the impact of sugars in cell recruitment. In this study, we report the fabrication of 3D-scaffolds with different morphologies obtained by electrospinning with fluorescent fructose-like molecular probes to study cancer cell proliferation and migration. Using a FDA approved, biocompatible and biodegradable polymer Polycaprolactone (PCL), we electrospun nanofiber scaffolds having random, aligned, and honeycomb morphologies. Scaffolds with similar morphology without the fructose mimicking analogs were fabricated and used as controls. The degradation rate of the scaffolds was also characterized to ensure long-term availability of probes and mechanical stability of PCL. Cell viability, cell morphology, formation of colonies with changes in morphology were investigated. The changes in biophysical properties of tumor microenvironment with change in morphology of the scaffolds were investigated. In vitro tests for proliferation, alignment and migration of normal breast epithelial cells (184B5), adenocarcinoma (MCF-7), pre-malignant (MCF10AneoT) and triple-negative (MDAMB231 on the scaffolds on days 1, 2, and 3 were carried out. The morphology of the scaffolds was characterized using FE-SEM; cell proliferation was assessed using CellTiter-Blue® Viability Assay; migration and cell-scaffold interactions were investigated using phalloidin for F-Actin and fructose response was determined by immunostaining for facilitative fructose transporter GLUT-5. Our data indicates that while topographical features affected cell adhesion and proliferation, cell lines that responded to the fructose-like probes tended to be more invasive. Furthermore, the preference to a specific scaffold was greatly altered by the presence of the probes with MDAMB231 showing least preference after 72 hours and pre-malignant AneoT showing highest preference. However, there was no significant difference in the cell numbers between scaffolds with probes and those without for the pre-malignant cells while this difference was noticeable in the control cell lines. Further investigation into specific response to glucose and fructose uptake through their major transporters GLUT2 and GLUT5 are currently ongoing.

Citation Format: Carolynn Que, Samerender Nagam Hanumantharao, Brennan Vogl, Marina Tanasova, Smitha Rao. Topographical ues overlaid with fructose-like molecules to assess breast cancer recruitment in nanofiber scaffolds [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-02-11.
Abstract P3-03-04: Role of ABL kinase signaling in metastatic breast cancer colonization of the brain
Authors: McKernan Courtney Michelle , Pendergast Ann M
Published: March 2020

Breast cancer brain metastasis (BCBM) occurs in approximately 50% of late-stage Human Epidermal Growth Factor Receptor 2-positive (HER2+) breast cancer patients. BCBM may result in cognitive decline and cranial neuropathies and is associated with a median survival rate of nine months. Current therapies for BCBM, such as whole brain radiation therapy, can enhance cognitive impairment while targeted therapies and chemotherapy are ineffective. Despite the increased patient survival due to HER2 targeted therapies, patients often relapse due to brain metastases. Recently, our laboratory has discovered a role for Abelson (Abl) family of tyrosine kinases, ABL1 and ABL2, in breast cancer metastasis. Evaluation of 279 HER2+ breast cancer patients demonstrates a correlation between high expression of ABL1 and decreased distant metastasis free survival. Expression of ABL1 and ABL2 increase in brain metastatic breast cancer cells compared to parental cells, suggesting a role for the Abl kinases in breast cancer brain metastasis. I have found that treatment with the allosteric Abl kinase inhibitor GNF5 decreases colonization of the brain by two distinct human HER2+ breast cancer cell lines. Increasing evidence suggests that HER2 is upregulated in breast cancer cells colonizing the brain and may interact with the brain microenvironment to promote outgrowth. Both pharmacologic and genetic inhibition of the Abl kinases decreases HER2 protein expression in brain metastatic HER2+ breast cancer cells, potentially ablating the cell’s ability to proliferate in the brain. These data support a role for Abl kinases in promoting colonization of the brain by breast cancer cells. Due to its blood-brain barrier penetrance and efficacy in pre-clinical mouse models, Abl kinase-specific allosteric inhibitors may provide a novel therapeutic strategy for HER2+ breast cancer brain metastasis.

Citation Format: Courtney Michelle McKernan, Ann M Pendergast. Role of ABL kinase signaling in metastatic breast cancer colonization of the brain [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-03-04.
Abstract P3-03-10: Targeting Wnt/β-catenin pathway by antidepressant imipramine for triple negative breast cancer treatment
Authors: Rajamanickam Subapriya , Timilsina Santosh , Jatoi Ismoil , Kaklamani Virginia , Vadlamudi Ratna K , Rao Manjeet K
Published: March 2020

Aberrant activation of Wnt signaling has been implicated in various human cancers including breast cancer. Several intra-cellular signal transduction pathways are induced by Wnt, notably by Wnt/β-catenin dependent pathway. In breast cancer, triple negative breast cancer (TNBC) subtypes have increased Wnt/β-catenin signaling associated with high grade tumors, metastasis, poor prognosis and tumor regression. Importantly, significant upregulation of Wnt/β-catenin pathway and overexpression of Wnt transcriptional targets have emerged in breast cancer stem cells (BCSCs) than normal mammary epithelial stem cells. Blockade of Wnt/β-catenin signaling has been reported to suppress breast cancer growth, invasion, migration and induced apoptosis and “stemness”. WNT pathway inhibition preferentially reduces stem cell like activity in patient-derived metastatic breast cancer compared to normal cells. Collectively, these studies suggest that Wnt/β-catenin pathway could be the potential target in inhibiting TNBC growth, metastatic progression and “stemness”. We recently identified that imipramine, an FDA approved antidepressant used to treat chronic depression, inhibits TNBC growth and progression. Imipramine treatment significantly reduced cell viability, migration and invasion of breast cancer cells in general and TNBC cells in particular. Our preliminary findings demonstrated that systemic delivery of imipramine suppressed TNBC growth in orthotopic mouse xenograft model. Our studies further show that imipramine inhibits several Wnt/β-catenin catenin pathway proteins including WNT1, FZD1, β-catenin, cyclin D1 and c-myc, which are reported to support breast cancer “stemness” and metastasis. Importantly, our preliminary studies revealed that imipramine inhibits TNBC stem cells as evidenced by reduced CD44+ population. Our results suggest the therapeutic efficacy of imipramine as a single/or neo-adjuvant agent for treating TNBC patients.

Citation Format: Subapriya Rajamanickam, Santosh Timilsina, Ismoil Jatoi, Virginia Kaklamani, Ratna K Vadlamudi, Manjeet K Rao. Targeting Wnt/β-catenin pathway by antidepressant imipramine for triple negative breast cancer treatment [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-03-10.
Abstract P3-04-01: Telomere G-tail length correlates with the presence of breast cancer
Authors: Koi Yumiko , Tsutani Yasuhiro , Nishiyama Yukie , Sasada Shinsuke , Masumoto Norio , Kadoya Takayuki , Takahashi Ryou-u , Okada Morihito , Tahara Hidetoshi
Published: March 2020

Background The telomere G-tail, located at the terminal 3’-end, plays an important role in the maintenance of chromosome stability. Telomere G-tail length has been shown to be related to the presence of various cancers; however, the association between telomere G-tail length and breast cancer has remained unclear. Methods We measured the length of the leukocyte telomere G-tail using the hybridization protection assay, which has the advantages of being simple to perform, accurate and highly sensitive for G-tails as short as 20 nucleotides. The association between telomere G-tail length and presence of breast cancer was estimated by comparing breast cancer patients (n=70) and cancer-free individuals (n=83). We recruited cStage I-III breast cancer patients who underwent surgery between November 2016 and December 2017 at Hiroshima University Hospital. Cancer-free individuals included age-matched female individuals with no previous or current history of any cancer. Results The median telomere G-tail length was significantly shorter in breast cancer patients (11,886.70 ± 2,008.74 RLU/μg DNA) than in cancer-free individuals (13,336.00 ± 2,072.31 RLU/μg DNA; p < 0.01). Shortening of the telomere G-tail length was observed in the phase of ductal carcinoma in situ, and this trend was observed with or without shortening of the total telomere length. Spearman’s rank correlation analysis showed that there was no significant association between telomere G-tail length and total telomere length in breast cancer patients (ρ = -0.09; p = 0.48). In contrast, a significant correlation was found between telomere G-tail length and total telomere length in cancer-free individuals (ρ = 0.29; p = 0.01). Conclusions Our study indicated that leukocyte telomere G-tail length may serve as a novel potential biomarker for detection of breast cancer.

Citation Format: Yumiko Koi, Yasuhiro Tsutani, Yukie Nishiyama, Shinsuke Sasada, Norio Masumoto, Takayuki Kadoya, Ryou-u Takahashi, Morihito Okada, Hidetoshi Tahara. Telomere G-tail length correlates with the presence of breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-04-01.
Abstract P3-06-15: Identifying genomic alterations in stage IV breast cancer patients using MammaSeq: An international collaborative study
Authors: Soran Atilla , Sahin Mustafa , Ugras Serdar , Celik Esin , Shah Osama Shiraz , Lucas Peter C , Lee Adrian V
Published: March 2020

Background: Identification of genomic alterations present in cancer patients can aid in improving cancer diagnosis and prognosis. In this study, we aimed to identify clinically actionable variations present in stage IV breast cancer (BC) samples.

Methods: DNA was extracted from formalin fixed paraffin embedded samples of breast cancer (n=41). DNA was sequenced using MammaSeqTM, a breast cancer specific NGS panel targeting 79 genes and 1369 mutations. Ion Torrent Suite 4.0 was used to make variant calls on the raw data. Resulting single nucleotide variants (SNVs) were annotated using CRAVAT toolkit. CNVkit was employed to identify copy number variations (CNVs). The PMKB and OncoKB Precision Oncology Databases were used to associate clinical significance with the identified variants.

Results: A total of 41 BC patient samples were sequenced (read depth of 94 - 13340, median of 1529). In total, 96 different alterations (84 SNVs and 12 CNVs) were identified. Frequent SNVs were seen in PIK3CA, TP53, IKBKE, ATM and MAP3K1 genes. Moreover, amplifications were found in ERBB2, FGFR and AR, and deletions in BRCA2, RUNX1 and RB1. 3 CNVs (ERRB2, FGFR and AR amplifications) and 7 SNVs (IDH1.R132H, TP53.E204*, AKT1.E17K, PI3KCA.E545K, PI3KCA.H1047R, PI3KCA.R88Q and ERBB2.V777L) were reported as clinically significant by PMKB and OncoKB.

Conclusion: We identified 96 alterations in 50 genes in 41 stage IV BC tissue samples using MammaSeqTM. Ten of these alterations were reported as clinically significant. This study highlights the potential use of cancer specific NGS panels in clinic to get better insight into the cancer patient-specific genomic alterations.

Citation Format: Atilla Soran, Mustafa Sahin, Serdar Ugras, Esin Celik, Osama Shiraz Shah, Peter C Lucas, Adrian V Lee. Identifying genomic alterations in stage IV breast cancer patients using MammaSeq: An international collaborative study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-06-15.
Abstract P3-06-16: Synergistic effect of biguanides and fatty acid β-oxidation inhibitor in triple-negative breast cancers
Authors: Park Jun Hyoung , Jung Kwang Hwa , Jia Dongya , Kaipparettu Benny A
Published: March 2020

Triple negative breast cancer (TNBC) is one of non-targetable cancers which are still poorly understood for the driver pathways and therapeutic targets. Over the past decade, cancer metabolism researches have a huge advance. Thus, it has enhanced our understanding on metabolic reprogramming in cancer therapy. We have previously shown that metabolic reprogramming to fatty acid β-oxidation (FAO) is a key energy metabolic pathway in TNBC. Moreover, we reported that FAO regulates c-Src, one of the frequently upregulated oncopathways in TNBC via autophosphorylation of Src at Y419. However, single treatment by FAO inhibitor alone cannot effectively control the tumor progression in TNBC because of metabolic reprogramming and flexibility of tumors. Therefore, proper combination therapies with other metabolic targets are necessary.

Recently increasing studies demonstrate that anti-diabetic biguanides have attractive anti-cancer effect in various cancer types including breast cancer (BC). However, its significance as an anti-cancer drug is not well established due to parallel metabolic pathways that support tumor growth. Biguanide like metformin is the most widely administered anti-diabetic agent worldwide. Phenformin, a biguanide derivative similar to metformin, has a greater potency than metformin. Like metformin, phenformin also inhibits mitochondrial electron transport chain (ETC) through complex I inhibition. In addition, biguanides lead to the activation of AMPK, which plays a important role in insulin signaling and energy sensing. Importantly, AMPK is an upstream regulator of FAO pathway because it can phosphorylate ACC to activate FAO. Considering the dependency of TNBC to FAO, we evaluated the therapeutic significance of the combination of biguanides (ETC inhibitors) and FAO inhibitors in TNBC progression and metastasis. And we investigated that targeting both ‘arms’ of the pathway can provide more effective and durable responses in TNBC treatments. Our various in vitro and in vivo studies using TNBC cell lines and PDX models suggest that the combination of both inhibitors can provide better therapeutic benefits in TNBCs. This is a rationale and cost-effective metabolic approach to overcome the currently non-targetable TNBCs. Further study toward the clinical effectiveness of this combination may offer better treatment opportunities for TNBC patients.

Citation Format: Jun Hyoung Park, Kwang Hwa Jung, Dongya Jia, Benny A Kaipparettu. Synergistic effect of biguanides and fatty acid β-oxidation inhibitor in triple-negative breast cancers [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-06-16.
Abstract P3-07-01: Breast cancer-specific mortality (BCSM) in patients age 50 years or younger with node-positive (N+) breast cancer (BC) treated based on the 21-gene assay in clinical practice
Authors: Petkov Valentina I , Kurian Allison W , Jakubowski Debbie M , Shak Steven
Published: March 2020

Introduction: The 21-gene Breast Recurrence Score® assay was shown in SWOG 8814 to predict chemotherapy (CT) benefit for patients (pts) with N+ BC and Recurrence Score® (RS) result≥31 but not RS <18. In TAILORx, endocrine therapy was non-inferior to chemoendocrine therapy in 6,711 randomized pts with RS results 11-25 and N0 disease, although subgroup analyses suggested that pts age 50 years and younger with RS results 16-25 may derive some CT benefit. As we await the randomized RxPONDER results for RS 0-25 in N+ pts, we characterize BCSM in N+ pts diagnosed at age 50 years or younger by RS groups in the population-based SEER study of pts treated according to Recurrence Score results. Methods: Recurrence Score results were provided electronically to SEER registries per their linkage methods (Petkov npj Breast Cancer 2016). Eligible pts were diagnosed (Jan 2004 - Dec 2014) with N+ (micrometastases, 1-3 positive nodes), HR+, HER2-negative BC, and had no prior malignancy or multiple tumors. BCSM estimates by reported CT use were computed using TAILORx/RxPONDER cut-points of 11, 15, 20, and 25, and should be interpreted cautiously given known under-reporting of CT use to SEER, lack of randomization, and limited follow-up. Results: Among 2,588 eligible pts with Recurrence Score results, 417 (16%) had RS 0-10, 756 (29%) had RS 11-15, 715 (27%) had RS 16-20, 350 (14%) had RS 21-25, and 350 (14%) had RS 26-100. Median follow-up time was 41 months (interquartile range 24-65.) There was a significant association between Recurrence Score result and BCSM (p<0.0001) without and with adjustment for tumor size, grade, and reported CT use. Reported CT use and 5-year BCSM increased with increasing Recurrence Score result (Table.)Conclusions: Reported CT and 5-year BCSM in young pts with N+ BC increased with increasing Recurrence Score results in real-world clinical practice. 5-year BCSM was less than 2% in young pts with Recurrence Score result 0-25 and CT use reported as no or unknown. Pts with Recurrence Score result 26-100 have increased risk of BCSM despite high reported CT use.

5-year BCSM, by RS Group and Reported CT UseCT reported as 'No/Unknown'CT reported as 'Yes' RS GroupN (%)5-y BCSM ±SEN (%)5-y BCSM ±SE0-10295 (71%)0.0% ±0.0122 (29%)0.0% ±0.011-15471 (62%)0.5% ±0.3285 (38%)2.3% ±1.416-20368 (51%)1.3% ±0.9347 (49%)1.6% ±0.921-25119 (34%)1.6% ±1.6231 (66%)1.2% ±1.226-10049 (14%)4.4% ±4.3301 (86%)6.1% ±2.0

Citation Format: Valentina I Petkov, Allison W Kurian, Debbie M Jakubowski, Steven Shak. Breast cancer-specific mortality (BCSM) in patients age 50 years or younger with node-positive (N+) breast cancer (BC) treated based on the 21-gene assay in clinical practice [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-07-01.
Abstract P3-08-51: Association between BRCA mutational status and survival in patients with breast cancer: A meta-analysis
Authors: Liu Miao , Wang Shu
Published: March 2020

Background: BRCA mutated breast cancer is associated with an aggressive phenotype with marked differences in histological grade and distant metastases and sensitive to PARPi and platinum therapy. Studies evaluating role of BRCA mutations on the survival outcomes in breast cancer (BC) patients have given confounding results due to the differences in clinical and pathological status among study population. Therefore, we assessed the impact of BRCA mutations on survival of BC patients, based on their baseline characteristics and follow-up durations. Methods: Using PICO framework, articles comparing survival outcomes of BC patients having BRCA mutations against sporadic BRCA phenotype were retrieved from PubMed, EMBASE and Cochrane Library. Overall survival (OS) was the primary outcome, with disease free survival (DFS), distant metastasis free survival (DMFS) and breast cancer specific survival (BCCS) as the secondary outcomes. Hazard ratio (HR) with 95% confidence interval (CI) was used for analysis. Sub-group analysis was performed for survival based on age, tumor stage, estrogen receptor status, triple negative breast cancer (TNBC) status, tumor stage (Stage I-III vs I-IV) and follow-up durations. Results: Altogether, 30 articles with 35,972 patients (mean age 45.6 years) were included in the analysis. In BRCA1/2+ group, no significant difference in OS and DFS than BRCA- group were observed (HR: 0.98, 1.36, respectively),have a better DMFS in BRCA- patients than that in BRCA1/2+ patients (HR: 1.32; 95% CI: 0.71, 2.44). However, the difference observed between the groups was insignificant (P = 0.3825). BRCA1+ patients had significantly lower OS (HR [95%CI]: 1.2 [1.08, 1.33]; P<0.001),poor BCSS at 10 years follow-up. DMFS was significantly poor in BRCA1+ patients compared with BRCA- patients both at 5 years follow-up (HR [95%CI]: 1.07 [1.04, 1.10]; P<0.0001) and 10 years follow-up (HR [95%CI]: 1.21 [1.13, 1.29]; P<0.0001).BRCA2+ patients had significantly lower DFS (HR [95%CI]: 1.35 [1.1, 1.67]; P = 0.0049) and BCSS (HR [95%CI]: 1.46 [1.26, 1.7]; P<0.0001) than BRCA2- patients. Among TNBC patients, OS was non-significantly better in BRCA1/2+ patients (HR 0.96, P = 0.803) than in BRCA- patients. However, DFS was significantly poor in BRCA1+ TNBC patients than BRCA1-/TNBC patients (HR [95% CI]:1.65 [1.08, 2.54]; P = 0.0216).Conclusion: BRCA1/2 mutation is associated with poor prognosis in patient with breast cancer. Hence, BRCA testing might help assess patient prognosis and treatment such as PARPi and platinum.

Citation Format: Miao Liu, Shu Wang. Association between BRCA mutational status and survival in patients with breast cancer: A meta-analysis [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-08-51.
Abstract P3-08-58: Ratio of CD8 +/ FOXP3, number of FOXP3 + cells and the presence of PTEN labeling in tumor cells and association with survival in triple negative breast cancer
Authors: Tavares Monique C , Lima Geraldine E , Sampaio Cristina D , Andrande Victor P , Gonçalves Daniel G , Macedo Mariana P , Lima Vladmir C
Published: March 2020

Introduction: Triple-negative mammary carcinomas (CMTN) correspond to about 15 to 20%, the subtype being more aggressive when compared to the others. The interaction between immune system cells and cancer plays a crucial role in tumor development and progression. However, it is still unclear whether the presence of CD8 cytotoxic lymphocytes provides any prognostic information in breast cancer. Objective: To evaluate the prognostic significance of tumor-associated FOXP3 regulatory T cells (Tregs) and CD8 cytotoxic T lymphocytes (CTLs) in invasive breast carcinomas Method: This is an observational, descriptive retrospective cohort study were evaluated 76 patients diagnosed with non metastatic (stages I, II and III) TNBC. A tissue microarray (TMA) was constructed containing two cores from each tumor block. The expression of CD4, CD8, FOXP3, CD20, CD68, CD163, PD-1, PD-L1, PTEN and phosphoSTAT1 was determined by immunohistochemistry in the TMA. Results: We observed that the inflammatory infiltrate in TNBC is enriched for M2 macrophages and T lymphocytes (CD4+, CD8+ and FOXP3+). In our sample, we observed better survival associated with a higher CD8 + (p = 0.054) and CD4 + (p = 0.082) cell counts, but with no statistical significance in both situations. However, when we analyzed the association of overal survival (OS) with the ratio between the number of CD8 + cells and FOXP3 + (p = 0.007) and CD4 + and FOXP3 + (p = 0.034) and CD4 (p = 0.058) cells, we found that a higher relative proportion of CD8 + or CD4 + lymphocytes in relation to lymphocytes FOXP3 + was associated with an increase in OS. Together, these data suggest that infiltration by T lymphocytes into the tumor microenvironment should exhibit antirumor activity and promote growth control and tumor progression, as opposed to events favoring immunosuppression (regulatory lymphocyte infiltration). The number of FOXP3+ cells and the presence of PTEN staining in tumor cells were associated with OS. Conclusion: We did not observe improvement in survival, with an increase in CD8 and CD4 alone, so we found an improvement in survival, the higher the ratio between CD8 / FOXP3 being statistically significant. The number of FOXP3+ cells and the presence of PTEN staining in tumor cells were associated with OS.

Citation Format: Monique C Tavares, Geraldine E Lima, Cristina D Sampaio, Victor P Andrande, Daniel G Gonçalves, Mariana P Macedo, Vladmir C Lima. Ratio of CD8 +/ FOXP3, number of FOXP3 + cells and the presence of PTEN labeling in tumor cells and association with survival in triple negative breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-08-58.
Abstract P3-08-59: High expression microRNA-143 is associated with favorable tumor immune microenvironment and better survival of ER positive breast cancer patients
Authors: Tokumaru Yoshihisa , Oshi Masanori , Asaoka Mariko , Takeshita Takashi , Katsuta Eriko , Futamura Manabu , Yoshida Kazuhiro , Takabe Kazuaki
Published: March 2020

Background: MicroRNA-143(miR-143) is known to function as the tumor suppressor in various cancers, including breast cancer. The tumor immune microenvironment such as the balance between the T helper cell type 1 (Th1) and Th2 is reported to associate with the survival of the breast cancer patients. In this study, we hypothesized that the miR-143 has favorable effect to the tumor immune microenvironment.

Material and Methods: We obtained the clinicopathological data and survival information of 755 breast cancer patients from The Cancer Genome Atlas (TCGA) database. Survival analysis, Overall survival (OS) and Disease free survival (DFS) was conducted comparing the high and low expression groups. CYT score, CIBERSORT, and other immunological factors were used to evaluate intratumoral immune cell composition within estrogen receptor (ER) positive breast cancer patients. Also, gene set enrichment analysis (GSEA) was performed between miR-143 high and low expression groups within the ER positive group.

Results: High expression of miR-143 was significantly associated with prolonged OS only in ER positive breast cancer patients (p=0.014). Expression of miR-143 was not associated with DFS, stage, TNM factors of breast cancer patients. Within ER positive patients, the result of CIBERSORT revealed that high expression of miR-143 was associated with higher percentage of macrophage M1 (p<0.03) and lower percentage of macrophage M2 (p<0.001). There was more Th1 cells in miR-143 high group (p<0.001) whereas Th2 cells were less (p<0.001). This result was strikingly echoed by GSEA, where miR-143 high significantly enriched the genes related to Th1 cells compared with that of Th2 cells. Regulatory T cell, Lymphocyte infiltration signature score, and T cell receptor diversity were higher in the patients with high miR-143 expression (p<0.03, p<0.001, and p<0.001 respectively). CYT score that reflect cytolytic activity was higher in the high miR-143 expression group (p<0.04).

Conclusion: High expression of miR-143 was associated with improved OS in ER positive breast cancer patients. Also, miR-143 was found to associate with high Th1 and low Th2 cells as well as enriching the genes relating to Th1 cells, which may explain the favorable role of miR-143 in ER positive breast cancer.

Citation Format: Yoshihisa Tokumaru, Masanori Oshi, Mariko Asaoka, Takashi Takeshita, Eriko Katsuta, Manabu Futamura, Kazuhiro Yoshida, Kazuaki Takabe. High expression microRNA-143 is associated with favorable tumor immune microenvironment and better survival of ER positive breast cancer patients [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-08-59.