bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P5-05-06: Progesterone receptor (PR) isoform-specific expansion of breast cancer stem-like cells occurs through a phospho-PR/FOXO1 driven signaling axis
Authors: Truong TH , Dwyer AR , Diep CH , Lange CA
Published: May 2019

Luminal breast cancers account for ˜75% of cases and are positive for progesterone receptor (PR) and estrogen receptor (ER) expression. PR is a classical ER-target gene and is used as a biomarker of ER activity; however, a growing body of evidence supports the role of PR as an important modifier of ER actions and a key driver of luminal breast cancer progression. Progesterone signaling is mediated by two PR isoforms: full-length PR-B and truncated PR-A, which lacks the N-terminal 164 amino acids. Little is known about PR isoform-specific actions in PR-expressing breast tumors, given that total PR expression is measured clinically. Herein, we sought to identify phenotypic differences in luminal breast cancer cells (T47D) overexpressing PR-A (T47D-YA) or PR-B (T47D-YB). We demonstrate that PR-B expression is required for anchorage-independent colony formation, while PR-A expressing cells fail to proliferate in soft agar. PR-B driven proliferation has been mapped to PR phosphorylation events, which include MAPK or CDK consensus sites such as Ser294. We demonstrate that in contrast to previous reports, PR-A is well phosphorylated at Ser294 in response to progestins (e.g. R5020) using our custom phospho-PR (Ser294) polyclonal antibody. Interestingly, Ser294 phosphorylation of PR-A occurs more rapidly and robustly following hormone treatment compared to PR-B expressing cells. Our findings indicate that PR-A is a dominant driver of stem-like expansion in breast cancer cells. PR-A tumorspheres exhibited enriched ALDH+ and CD44+/CD24- populations compared to PR-B and promoted heightened gene expression of stem-like genes (e.g. FOXO1). We demonstrate that the PR target gene and co-activator FOXO1 promotes both PR-A and PR-B phosphorylation at Ser294 and augments tumorsphere formation. Direct inhibition of FOXO1 levels abrogates phospho-PR (Ser294) levels and tumorsphere formation in PR expressing cells. Finally, we show that Ser294 is required for PR-A induced expression of stem-like genes (e.g. FOXO1) and stem-like behavior as measured by ALDH+/CD44+ tumorspheres. Taken together, our data reveal unique functions of PR isoforms as modulators of distinct and opposing pathways (i.e. proliferation versus stem-like expansion) in luminal breast cancer models. A clear understanding of PR isoform-specific actions, phosphorylation events, and the role of co-factors such as FOXO1 may lead to novel biomarkers of advanced tumor behavior and reveal new approaches to pharmacologically target PR isoforms in luminal breast cancers.

Citation Format: Truong TH, Dwyer AR, Diep CH, Lange CA. Progesterone receptor (PR) isoform-specific expansion of breast cancer stem-like cells occurs through a phospho-PR/FOXO1 driven signaling axis [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-05-06.
Abstract P5-05-10: Estrogen receptor β suppresses metastasis of inflammatory breast cancer by regulating cell cytoskeleton and cytokine signaling
Authors: Thomas C , Karagounis I , Srivastava RK , Kumar S , Karar J , Chao H-H , Kazimierczak A , Bado I , Nikolos F , Leli N , Koumenis C , Krishnamurthy S , Ueno NT , Chakrabarti R , Maity A
Published: May 2019

Inflammatory breast cancer (IBC) is the most lethal form of breast cancer that accounts for about 10% of breast cancer mortality annually in US. Poor prognosis is largely due to the high propensity of IBC tumors to develop distant metastasis that occurs directly from the gland epithelium and through lymphatic invasion in which dermal lymphatics are filled with tumor emboli. Owing to the complex metastatic process, the molecular basis of IBC aggressiveness is poorly understood, and no specific therapeutic target has been identified. Despite the lack of estrogen receptor α (ERα) in the majority of IBC tumors, estrogen may still play a role in these cancers through pathways that involve ERβ. Our tissue staining reveals expression of ERβ in more than 50% of IBCs that is reproduced in IBC cell lines. Furthermore, analysis of IBC datasets indicates correlation of receptor expression with good prognosis. We studied this association in preclinical models of IBC by knocking out ERβ in IBC cells. This promotes migration and invasion through cytoskeleton remodeling whereas re-expression of the receptor in knockout cells restores the cytoskeletal structure and migration to the levels of control cells. Consistent with increased migration, deletion of ERβ activates large gene networks of cell de-differentiation and cytokine synthesis that trigger tumor microenvironment responses to promote the motile phenotype of IBC cells. In contrast, ligands that activate the receptor inhibit signaling that contributes to metastasis in IBC. Analysis of an orthotopic xenograft model shows that IBC tumors lacking ERβ have higher propensity for metastasis compared with the ERβ-proficient tumors supporting the anti-metastatic activity of the receptor. Our findings point towards a role of ERβ in preventing distant metastases by inhibiting dissemination of IBC cells and maintaining the integrity of emboli. This function combined with distinct expression indicates the potential of ERβ to represent a unique prognostic marker and therapeutic target that can be utilized to repress IBC metastasis and eliminate its associated mortality.

Citation Format: Thomas C, Karagounis I, Srivastava RK, Kumar S, Karar J, Chao H-H, Kazimierczak A, Bado I, Nikolos F, Leli N, Koumenis C, Krishnamurthy S, Ueno NT, Chakrabarti R, Maity A. Estrogen receptor β suppresses metastasis of inflammatory breast cancer by regulating cell cytoskeleton and cytokine signaling [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-05-10.
Abstract P5-07-10: The prognostic significance of estrogen formation as a consequence of aromatase expression in tumor microenvironment
Authors: Kim TH , Lee A , Han JW , Jung SJ , Byun K-D
Published: May 2019

Estrogen synthesis via aromatase in adipose tissue has an important role in progression of postmenopausal breast cancer. The increased local concentrations of estrogen in breast cancer via aromatase overexpression within the tumor tissue have been demonstrated by some investigators. Although aromatase inhibitor is the standard endocrine therapy for postmenopausal breast cancer patients, it is not uncommon for patients to have poor compliance to the drugs due to their side effects. This research is based on the hypothesis that if aromatase expression is related to prognosis and if therapeutic effect varies depending on the degree of aromatase expression, then this study may be able to suggest a new guideline in terms of choosing between aromatase inhibitors and tamoxifen.

Methods: 154 postmenopausal breast cancer patients who underwent surgery and aromatase inhibitor therapy in Busan Paik Hospital, Inje University from January 2005 to December 2010 were enrolled. Patients with DCIS or stage IV breast cancer were excluded. Patients' clinicopathological data were collected and TMA blocks were created for immunohistochemistry studies to examine aromatase expression.

Results: The recurrence has occured in 7 patients (6.9%). Stage, tumor size and number of lymph node metastasis were related to increased risk of recurrence (p=0.051, 0.043, 0.001). The aromatase expression in cancer cells had significant correlation with clinical stage (p=0.041). There was also a positive correlation between Ki67 and aromatase expression in cancer tissue (p=0.006). However, aromatase expression in cancer, stromal, and adipose tissue had no relationship with recurrence (p=0.410, 0.627, 0.552).

Correlation between clinicopathologic factors and aromatase expression (Linear by linear association and Spearman's correlation coefficient test)Site of aromatase expressionERPRKi67P53BMIStageIn Cancer0.6060.5920.0060.4510.9560.041In Stroma0.2200.4710.5840.3290.3670.229In Adipose0.9880.2650.1590.1170.7701.000

Conclusions: Aromatase expression in cancer cells was correlated with clinical stage. This implies that aromatase expression might have a role of prognostic marker in addition to role of treatment indicator. There was no direct correlation between aromatase expression and recurrence.

Citation Format: Kim TH, Lee A, Han JW, Jung SJ, Byun K-D. The prognostic significance of estrogen formation as a consequence of aromatase expression in tumor microenvironment [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-07-10.
Abstract P5-09-09: CHEK2: the third susceptibility BReast CAncer (BC) gene?
Authors: Gomes VL , Machado P , Fragoso S , Santos S , Coelho I , Parreira J , Rodrigues P , Rodrigues F , Clara A , Bento S , Luís A , Opinião A , Vaz F
Published: May 2019

INTRODUTION:

Considered a medium penetrance gene, CHEK2 codes for a kinase that is a key component of the DNA damage-signaling pathway. CHEK2 pathogenic variants were previously associated with breast and colorectal families and also with Li-Fraumeni phenotypes. Next generation sequencing (NGS) allowed for systematic inclusion of CHEK2 into gene panels. In here, we characterize the growing subgroup of CHECK2 BC families identified through our multidisciplinary program.

METHODS: Identification and review of CHEK2 families identified between 01/2000-06/2018 (until 2014 only the c.1100delC was tested (MLPA, MRC Holland); since 2014 NGS methods used were either,Trusight Cancer sequencing panel (Illumina, San Diego, CA, USA) or BRCA MASTR Dx (Multiplicom, Niel, Belgium). Carriers were included in a prospective follow up program.

RESULTS: 3646 index pts consented on gene testing. Most hereditary families (HF) were BRCA1/2 (374) (92%) but among non-BRCA HF bigger subgroups were 16 CHEK2, 10 Tp53 and 5 PALB2 HF. All CHEK2 index pts were diagnosed with only 3 different pathogenic variants: c.1100delC (9) c.319+2T>A (6) and c.593-1G>T (1 case of the only male BC pt in all CHEK2 pedigrees).

Index pts: mostly (93,8%) to females, with a mean age at first cancer diagnosis of 39 years (yrs) (30-52), 62,5% between 30-39yrs. With the exception of a Non Hodgking's Lymphoma index case, all index pts had BC(93,8%), 68,8% of which were ductal carcinomas and 12,5% of intraductal, all strongly positive for the estrogen receptor. With a mean follow up of 8,26yrs (3-15), secondary cancer cases occurred in 37,5% of index pts (mostly, 12,5%, BC at a mean of 53yrs (41-59).

Family phenotypes: data form 98 relatives (53,5% females) revealed diagnoses of BC (31,6%), prostate (8,1%), colorectal (7,1%) cancers. Only 22,2% of family cancers were diagnosed before 50yrs.

VUS: Among several complex variants of unknown significance, c.1036C>T;p.Arg346Cys co-segregates in a predominantly male family with 3 prostate, 1 male and 1 female BC.

DISCUSSION AND CONCLUSIONS:

In the Portuguese population, emerging recurrent pathogenic variants in the CHEK2 gene, make it the most important non-BRCA BC gene so far. Carriers are included in prospective follow up but non-CHEK2 relatives are a challenge to genetic testing, as well as pedigree review, that questions its classification as a medium penetrance gene (or suggest the role of modifier factors).

Citation Format: Gomes VL, Machado P, Fragoso S, Santos S, Coelho I, Parreira J, Rodrigues P, Rodrigues F, Clara A, Bento S, Luís A, Opinião A, Vaz F. CHEK2: the third susceptibility BReast CAncer (BC) gene? [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-09-09.
Abstract P5-09-10: Uptake of genetic testing and prevalence of mutations among minority populations: A retrospective cohort study
Authors: Nagireddy P , Ganschow P
Published: May 2019

Background: Hereditary cancer syndromes account for 5-10% of cancers. Limited data exists on the uptake of genetic testing and the prevalence of mutations in minority populations.

Objective: To estimate genetic testing uptake and prevalence of mutations in a minority population seeking care in a safety net healthcare system.

Methods: We conducted a retrospective cohort study of patients who were assessed at John H Stroger Jr., Hospital of Cook County cancer genetics risk clinic between October 2015 and March 2018 to determine the uptake of genetic testing and the prevalence of genetic mutations. Patients who met National Comprehensive Cancer Network (NCCN) guidelines for genetic testing for hereditary breast and ovarian cancer syndrome (HBOC), Lynch syndrome and familial adenomatous polyposis were included. Data was abstracted through chart review to obtain age, socio-demographics, personal cancer history, primary language, personal and family history of cancer including type of cancer and age at diagnosis, insurance status, genetic testing status and test results. Uptake of testing was calculated as the percentage of patients who underwent testing among those patients who met NCCN criteria for testing. Prevalence of mutations among those patients who underwent testing was determined and compared between different ethnicities using Chi-square test.

Results: Of 510 patients offered genetic counseling & testing, 478 (94%) underwent genetic testing. Among those who tested, 34% (n=165) were African American and 45% (n=212) were of Hispanic origin. Prevalence of any mutation was 48%(n=232), Pathogenic mutations were identified in 11% (n=54) of testers and variants of uncertain significance (VUS) were identified in 37% (n=178). Deleterious mutations and VUS rates in patients affected with hereditary cancer syndromes were 13% (n=42) and 39 % (n=132) respectively. Deleterious mutations and VUS rates in women unaffected with cancer were 9% (n=12) and 33 % (n=46) respectively. Overall mutation prevalence did not differ between affected and unaffected patients (p=0.12) or between Black and Hispanic patients (p=0.96). Deleterious mutation rate in Hispanic patients was 15.6% (CI 20.5%-10.7%) and in Black patients was 3.6% (CI 3%-4%). There was a significant difference in the percentage of deleterious mutations between Hispanic and Black patients (p=0.0009) .

Conclusion: Genetic testing uptake was high in minority populations. In the Population who were tested prevalence of pathogenic mutations was higher among Hispanics than African Americans.

Citation Format: Nagireddy P, Ganschow P. Uptake of genetic testing and prevalence of mutations among minority populations: A retrospective cohort study [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-09-10.
Abstract P5-11-09: Feasibility of tracking plasma DNA mutation kinetics in estrogen receptor positive metastatic breast cancer using a novel digital PCR amplicon sequencing assay
Authors: Kumar S , Lindsay D , Chen B , Garrett AL , Tan XM , Anders CK , Carey LA , Gupta GP
Published: May 2019

Estrogen Receptor 1 (ESR1) gene mutations in estrogen receptor positive (ER+) metastatic breast cancer (MBC) are associated with clinical resistance to endocrine therapy. A highly sensitive digital PCR (dPCR) assay was developed to evaluate the baseline abundance and kinetics of hotspot ESR1 mutations in plasma circulating tumor DNA (ctDNA) from 58 ER+ MBC patients who had progressed on at least one line of prior endocrine therapy. Consistent with prior reports, we demonstrate that detection of hotspot ESR1 mutations in plasma ctDNA is associated with shorter progression-free survival. However, after patients initiated a new course of systemic therapy, changes in plasma ESR1 mutation abundance did not correlate with the duration of disease control. To investigate whether mutational heterogeneity may account for this lack of correlation, we developed a customized dPCR multiplexed amplicon next-generation sequencing (NGS) assay to detect plasma ctDNA mutations in the complete coding sequence of ESR1 and TP53, as well as hotspot regions in PIK3CA. Assay validation revealed a 79% sensitivity and 100% specificity for detecting plasma ctDNA mutations with a lower limit of detecting a 1.6% mutant allele fraction. The NGS assay revealed non-hotspot ESR1 mutations in plasma DNA from 14 of 31 (45%) patients. We also observed dynamic changes in plasma ctDNA mutant allele fraction of PIK3CA and TP53 during systemic therapy. Changes in the cumulative mutant allele fraction of ESR1, PIK3CA, and TP53 in plasma ctDNA correlated with duration of clinical treatment response in a limited subset of patients (n=8) for whom NGS was performed at two or more time points. Thus, mutational heterogeneity limits the clinical utility of monitoring individual hotspot mutations in ESR1 over time in ER+ MBC patients. However, a plasma ctDNA NGS assay targeting ESR1, PIK3CA, and TP53 may be useful as an early predictor of response to systemic therapy.

Citation Format: Kumar S, Lindsay D, Chen B, Garrett AL, Tan XM, Anders CK, Carey LA, Gupta GP. Feasibility of tracking plasma DNA mutation kinetics in estrogen receptor positive metastatic breast cancer using a novel digital PCR amplicon sequencing assay [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-11-09.
Abstract P5-12-08: Not presented
Authors: Botticelli A , Cerbelli B , Pisano A , Naso G , Monti M , Ascierto PA , Costarelli L , Magri V , Mauri M , Pignataro MG , Campagna D , Pernazza A , Nuti M , Fortunato L , Della Rocca C , D'Amati G , Marchetti P
Published: May 2019

This abstract was not presented at the conference.

Citation Format: Botticelli A, Cerbelli B, Pisano A, Naso G, Monti M, Ascierto PA, Costarelli L, Magri V, Mauri M, Pignataro MG, Campagna D, Pernazza A, Nuti M, Fortunato L, Della Rocca C, D'Amati G, Marchetti P. Not presented [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-12-08.
Abstract P5-13-01: Not presented
Authors: Foerster M , Zietsman A , Galakunde M , Anele A , Adisa C , Schuz J , Dos Santos Silva I , McCormack V
Published: May 2019

This abstract was not presented at the conference.

Citation Format: Foerster M, Zietsman A, Galakunde M, Anele A, Adisa C, Schuz J, Dos Santos Silva I, McCormack V. Not presented [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-13-01.
Abstract P5-13-11: Impact of public health insurance “Seguro Popular” on breast cancer recurrence at Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (INCMNSZ), Mexico City
Authors: Mejía-Fernández L , Medina-Franco H , Armengol-Alonso A
Published: May 2019

Introduction. Public health insurance called Seguro Popular (SP) for breast cancer treatment (BCT) was instituted in Mexico in 2007. Our third level center was enrolled until 2011. SP covers systemic BCT (WHO 20th model list essential medicines). The aims were: 1) Describe frequency and type of breast cancer recurrence (BCR), 2) compare which factors were contributing to recurrence of breast cancer patients (pts) before and after the implementation of SP. Methods. Pts with diagnosis of breast cancer (BC) from 2004 to 2018 were analyzed and pts with BCR whom primary tumor (PBC) was treated and followed at INCMNSZ were recruited. They were divided into two groups according to access to SP: pts without Seguro Popular (non-SP) and, pts with SP. Xi-square, non-parametric tests and Kaplan-Meier curves (log-rank test) were used. Logistic regression was done for multivariate analysis. A p-value <0.05 was considered significant. Results. Between 2004 and 2018, 929 pts with BC were diagnosed; 438 non-SP and 473 SP. Ninety-one (9.7%) had a BCR (loco-regional or distant) during this period. Median follow-up was 125 months. The BCR proportion was higher within non-SP than in SP (74 (16.8%) vs 17 (3.5%) pts) (p=<0.05). Median age at diagnosis was higher in non-SP (p=0.028). Distant relapses were higher in non-SP than in SP (44 (59.4%) vs 8 (47%) pts). St Gallen 2017 Luminal A/B subtypes were most common in non-SP compared to SP where Basal-like subtype was higher (p=0.048). Luminal-A subtype had the best survival among non-SP compared to SP in which HER2 non-luminal had the higher survival (p<0.001). Conclusions. Experience with SP at our center shows promising results in the improvement of BCR. Access to adequate systemic management (hormone-blocking and HER2 targeted therapy) has a positive impact on recurrence, disease-free survival, and cancer-specific global survival. A longer follow-up time is required in the SP group (prospective cohort) to confirm these findings, especially in luminal tumors with late recurrence risk. Efforts should be made in the Mexican public health system to secure basic and continuous access to BCT.

Citation Format: Mejía-Fernández L, Medina-Franco H, Armengol-Alonso A. Impact of public health insurance “Seguro Popular” on breast cancer recurrence at Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (INCMNSZ), Mexico City [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-13-11.
Abstract P5-13-20: Overall survival of women with breast cancer treated with newly approved targeted drugs in Manitoba: A population based study
Authors: Devgan S , Bucher O , Geirnaert M , Niraula S
Published: May 2019

Background: Cancer drugs are approved based on the results of clinical trials in selected, rigorously monitored groups of participants. The ultimate goal of new cancer drug approvals is to improve outcomes, preferably overall survival, at population level compared to existing standard of care.

Methods: We conducted a population based study using data from the provincial Manitoba cancer registry, Manitoba Health, and electronic patient records. We collected data on patient demographics, toxicity outcomes, and efficacy outcomes including recurrence and Overall Survival (OS) of patients who were treated with the 10 most frequently used new targeted cancer drugs between January 2005 and December 2017 in Manitoba. Patient demographics were reported using descriptive statistics. Toxicity events were reported in frequency, and Kaplan-Meier curves were used for time-to-event outcomes.

Results: Four breast cancer drugs – Trastuzumab Emtansine (T-DM1), pertuzumab, fulvestrant, and palbociclib qualified for inclusion. During the timeframe, 71 women were treated with T-DM1, 100 with pertuzumab, 102 with Fulvestrant, and 21 with palbociclib. Patient demographics, disease stage, and line of therapy were comparable to those reported in pivotal trials leading to approval of these drugs. Median OS was 15.82 months for T-DM1, 25.34 months for pertuzumab, 14.65 months for fulvestrant, and not assessable for palbociclib – of note, these were consistently about half the median OS duration reported in pivotal trials leading to approval of the respective drugs. [For example, median OS in pivotal trials was 55.6 months for pertuzumab, 29.9 months for T-DM1, up to 26.4 months for fulvestrant, and 37.5 months (one trial) for palbociclib]. Serious toxicities were observed more frequently than reported in the literature – detailed results will be presented.

Conclusion: Despite impressive improvements in outcomes reported in clinical trials leading to approval of new targeted therapies for breast cancer, such agents only yield modest OS at population level which was often worse than even the control groups used in pivotal clinical trials. Given the main aim of new interventions are to improve outcomes at population level, future research should explore causes, and identify solutions to minimize such efficacy-effectiveness gaps. Cautious patient selection, early identification and management of toxicities, and increasing resources available to individual patients may minimize such gaps.

Citation Format: Devgan S, Bucher O, Geirnaert M, Niraula S. Overall survival of women with breast cancer treated with newly approved targeted drugs in Manitoba: A population based study [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-13-20.
Abstract P5-14-08: Not presented
Authors: Galindo-Vázquez O , Baragalló-Rocha E , Cabrera-Galeana P , Costas-Muñiz R , Lerma A , Esparza-Arias N
Published: May 2019

This abstract was not presented at the conference.

Citation Format: Galindo-Vázquez O, Baragalló-Rocha E, Cabrera-Galeana P, Costas-Muñiz R, Lerma A, Esparza-Arias N. Not presented [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-14-08.
Abstract P5-18-12: Effectiveness of Oncotype DX DCIS scoring in a community setting
Authors: Wheeler JA , Vaghefi H , Liu F , Owens V , Morris L , Denham F , Coody L
Published: May 2019

The Oncotype DX DCIS Score was developed to assist in determining a low risk for recurrence subgroup of patients who can avoid radiation therapy following breast conserving surgery. We sought to evaluate our experience using the Oncotype DX DCIS Score and to see if a greater number of patients who did not receive radiation therapy were experiencing a local recurrence than the score predicted.

Between February 23, 2011 and November 29, 2017, 145 women were diagnosed with ductal carcinoma in situ (DCIS) without an invasive component. 126 (87%) underwent breast conserving surgery. Thirty-five underwent Oncotype DX DCIS Score, of whom 26 (74%) were low risk, four were intermediate risk (11%), and five were high risk (14%).

The scores ranged from 0 (7 patients) to 100 (1 patient). Of the 26 patients with low risk scores, one chose to undergo mastectomy, three received radiation therapy, 20 chose observation without radiation therapy, and two patients were unknown because they had no further treatment or follow-up at our facility. Two of the four intermediate risk patients underwent radiation therapy and two did not. Four of the five high risk patients underwent radiation therapy, but one did not.

Twenty-two of the 35 patients who underwent Oncotype DX Score met the criteria for size (based on grade) and margins (at least 3 mm). Ten patients had margins that were less than 3 mm but met the size criteria. Two patients did not meet the size criteria but had at least 3 mm margins. One patient did not meet either the size or margin criteria. None of our 20 patients with low risk Oncotype DX DCIS Score and who met both the size and margin criteria recurred.

With the median follow-up of approximately 2-1/2 years, three of the 21 patients (14%) with low or intermediate risk scores who underwent Oncotype DX DCIS Score and did not receive radiation therapy suffered a local recurrence. The predicted average recurrence risk for these patients based on their Oncotype DX DCIS Score was 12%. Two of these patients who recurred had margins less than 3 mm, and one patient met the size and margin criteria, but had an intermediate risk score.

By comparison, five of 61 (8%) of patients who underwent breast conserving surgery and adjuvant radiation therapy had a local recurrence.

Twenty of the 23 (87%) low risk Oncotype DX DCIS Score patients did not receive radiation therapy and overall 20/35 (57%) of the patients undergoing Oncotype DX DCIS Score did not receive radiation therapy.

Although the follow-up is still relatively short, Oncotype DX DCIS Score allows a considerable number of women to avoid adjuvant radiation therapy.

Citation Format: Wheeler JA, Vaghefi H, Liu F, Owens V, Morris L, Denham F, Coody L. Effectiveness of Oncotype DX DCIS scoring in a community setting [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-18-12.
Abstract P6-01-05: Detection of HER2 positive tumor cells using functionalized iron oxide nanoparticles
Authors: Bischoff FZ , Mathieu K , Vargas J , Pang L , Kulp AM , Dewing A , Liu X , Bast RC , Hazle J , Zhang M
Published: May 2019

Background: Iron oxide nanoparticles (NPs) have been used for a variety of in-vivo and ex-vivo applications within the biomedical sciences. Moreover, when intended for clinical in-vivo applications, NPs need to meet rigorous requirements to ensure safety as well as bio-functionality including blood circulation time and specificity for cellular targets. PrecisonMRX® NPs are extensively characterized superparamagnetic NPs composed of a 25nm magnetite cores that are currently employed in a variety of in-vivo applications including non-invasive/in vivo diagnosis of cancer, Magnetic Particle Imaging, MRI, and magnetic hyperthermia.

Objective: Here we report on the extensive pre-clinical development and functionality of antibody (Herceptin)-conjugated NPs for in-vivo and ex-vivo detection of HER2+ tumor cells by Magnetic Relaxometry (MRX).

Results: We observed: 1) specific binding and detection of HER2 positive tumor cells in-vitro; 2) specific detection of HER2+ tumors in mice; 3) binding and amplitude of magnetic signal to be proportional to the level of HER2 expression in-vitro and in-vivo; 4) the nanoconstruct remains stable in circulation; 5) the particles do not induce a pro-inflammatory response nor activate complement; 6) the particles are biodegradable; and do not induce acute or delayed signs of morbidity in mice.

Conclusion: Precision MRX® nanoparticles offer great clinical promise including the in- vivo detection of tumor cells by magnetic relaxometry. Given the stability and safety of these NPs, our pre-clinical results support progressing to clinical testing. A first-in human ex-vivo clinical research study design and strategy will be discussed.

Citation Format: Bischoff FZ, Mathieu K, Vargas J, Pang L, Kulp AM, Dewing A, Liu X, Bast RC, Hazle J, Zhang M. Detection of HER2 positive tumor cells using functionalized iron oxide nanoparticles [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-01-05.
Abstract P6-02-01: Not presented
Authors: Luo J , Chen Q , Tang L , Yang L , Han E , Chen Y , Yuan L
Published: May 2019

This abstract was not presented at the conference.

Citation Format: Luo J, Chen Q, Tang L, Yang L, Han E, Chen Y, Yuan L. Not presented [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-02-01.
Abstract P6-02-10: Early ultrasound evaluation for prediction of treatment response to neoadjuvant chemotherapy in triple negative breast cancer patients
Authors: Adrada BE , Candelaria R , Moulder S , Lane D , Santiago L , Arribas E , Hess KR , Valero V , Thompson A , Helgason T , Ravenberg E , Yang W , Rauch GM
Published: May 2019

Background: Triple negative breast cancer (TNBC) is molecularly heterogeneous disease. Genomic profiling to identify the distinct TNBC subtypes is costly with long turnaround time. Early ultrasound after two cycles of neoadjuvant chemotherapy (NAC) has the potential to identify patients who are likely to have pathological complete response. Suspected non-responder patients can undergo comprehensive genetic testing and triaged for specific targeted therapeutic trials.

Aim: To determine the value of ultrasound evaluation after two cycles of NAC to predict complete pathologic response in TNBC breast cancer patients.

Methods: 98 patients enrolled in “A randomized triple Negative Breast Cancer Enrolling Trial to Confirm Molecular Profiling Improves Survival” (Artemis) at the University of Texas MD Anderson Cancer Center had ultrasound evaluation before treatment and after two cycles of NAC (Adriamycin and Cyclophosphamide). Three-dimensional measurements of the tumor were obtained at baseline and after 2 cycles of the NAC. Change in the tumor volume after 2 cycles of NAC was calculated. Residual cancer Volume (RCB) was calculated based on the final histopathology at surgery. Linear regression analysis evaluated associations between residual cancer burden (RCB) and change in volume of the index tumor.

Results: Median tumor size at diagnosis was 3 cm, range 0.6-11.9cm. Median size after two cycles was 2 cm, range 0.6-12.8 cm. RCB 0-I was seen in 55% of patients (54/98). Linear regression analysis demonstrated that of 22 patients with volume reduction >75%, 18 patients (82%) had RCB0-I (95%CI, 61%-93%).

Conclusion: Our data suggest that ultrasound exam after 2 cycles of NAC can identify TNBC patients who are unlikely to respond to standard NAC. These non-responder TNBC patients can be triaged for additional genetic testing and subsequent targeted clinical trials. Study on the larger number of patients is currently on the way.

Citation Format: Adrada BE, Candelaria R, Moulder S, Lane D, Santiago L, Arribas E, Hess KR, Valero V, Thompson A, Helgason T, Ravenberg E, Yang W, Rauch GM. Early ultrasound evaluation for prediction of treatment response to neoadjuvant chemotherapy in triple negative breast cancer patients [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-02-10.
Abstract P6-02-18: Hepatic complications of breast cancer
Authors: Wong MJ , Choi H
Published: May 2019

Background

Breast cancer is the most common malignancy and the leading cause of cancer death in women in the United States. Nearly 30% of women with metastatic breast cancer will have liver metastases, with a median survival from time of 4.23 months from time of metastatic diagnosis. Hepatic involvement of breast cancer is common and can result from metastatic tumor burden or treatment with chemotherapy or radiation. Being able to recognize and diagnose hepatic involvement of breast cancer is of utmost importance, as it has a dramatic effect on patient prognosis and management.

Learning Objectives

To familiarize multidisciplinary clinical team members with the radiographic presentations of hepatic complications of breast cancer in a variety of imaging modalities including computed tomography, dual-energy computed tomography, ultrasound, and MR. This will facilitate accurate and prompt diagnosis and treatment of hepatic involvement of breast cancer.

Abstract

Our educational pictorial essay demonstrates the typical appearance of hepatic metastases on multiple imaging modalities, as well as atypical presentations such as hyperdense, hypervascular, or hypoechoic lesions and pseudoprogression. We will show examples of hepatic metastases presenting as pseudocirrhosis, left lobar atrophy, capsular retraction, as well as sequelae of pseudocirrhosis such as malignant ascites, varices, portal vein thrombosis, and biliary obstruction. We will discuss the radiographic appearance of the liver after being treated with locoregional liver-directed techniques such as surgical resection, ablation, and chemoembolization. Importantly, we will illustrate examples of hepatic complications from systemic therapy including steatohepatitis from tamoxifen, as well as hepatic fibrosis from gemcitabine.

Conclusion

Clinicians must have a thorough understanding of the hepatic complications of cancer to ensure excellent diagnostic accuracy and management.

References

1. Diamond JR, Finlayson CA, Borges VF. Hepatic complications of breast cancer.Lancet Oncol. 2009;10:615–621.

2. Wyld L, Gutteridge E, Pinder SE, James JJ, Chan SY, Cheung KL, Robertson JF, Evans AJ, 2003 Prognostic factors for patients with hepatic metastases from breast cancer Brit J Cancer 89: 284–290.

3. Adike A, Karlin N, Menias C, Carey EJ. Pseudocirrhosis: A case series and literature review. Case Rep Gastroenterol. 2016;10(2):381–91

4. Agarwal K, Jones DE, Burt AD, et al. Metastatic breast carcinoma presenting as acute liver failure and portal hypertension. Gastroenterol Hepatol. 2002;97:750–751.

Citation Format: Wong MJ, Choi H. Hepatic complications of breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-02-18.
Abstract P6-05-08: LINC02273 interacts with hnRNPL and promotes metastasis through directly activating AGR2 in breast cancer
Authors: Xiu B , Chi Y , Ji W , Zhang Q , Wu J
Published: May 2019

The prognosis of breast cancer patients with metastasis is still poor even improved by current treatment modalities. Unveiling new biomarkers and molecular mechanisms that underlie metastasis are of vital importance for the treatment of breast cancer. The recent discovery of long noncoding RNAs (lncRNAs) has gained widespread attention. To identify critical lncRNAs that contributed to breast cancer metastasis, we profiled their expression in 5 pairs of primary tumors and lymph nodes metastasis loci by HTA2.0 microarray. LINC02273 is significantly upregulated in metastasis loci and its high expression is associated with poor diseases free survival in a validation set of 254 patients. LINC02273 was mainly located in the cell nucleus . RACE-PCR showed two isoforms and the longest one was the most abundant isoform in breast cancer. Through transwell assay, 3D spheroid invasion assay and mice xenograft metastasis model, we found that LINC02273 promoted breast cancer cell migration, invasion and metastasis. Via mass spectrometry, hnRNPL was found to interact with LINC02273 to enhance its stability, which was further confirmed by Actinomycin D inhibition assay and luciferase reporter assay. Furthermore, ChIRP-seq and ChIP-seq showed that LINC02273 stimulated oncogene AGR2 expression by directly binding to the AGR2 promoter region and increasing H3K27ac modification. Triplex formation assay was performed for verification. We demonstrated that the expression level and oncogenic ability of AGR2 were regulated by hnRNPL through LINC02273. Clinical data and mouse xenograft tumors also revealed the positive correlation of AGR2 and LINC02273. In conclusion, LINC02273, which is stabilized by hnRNPL can promote breast cancer metastasis through upregulation of AGR2 and may serve as a prognostic biomarker for breast cancer.

Citation Format: Xiu B, Chi Y, Ji W, Zhang Q, Wu J. LINC02273 interacts with hnRNPL and promotes metastasis through directly activating AGR2 in breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-05-08.
Abstract P6-09-06: BRCAness as a prognostic marker in triple-negative breast cancer patients treated with neoadjuvant chemotherapy: A multicenter retrospective study
Authors: Kosaka Y , Yamamoto Y , Nishimiya H , Ibusuki-Yamamoto M , Hirota Y , Tanino H , Iwase H , Nakamura S , Akashi-Tanaka S
Published: May 2019

Background: Triple negative breast cancer (TNBC) has several subtypes. Identification of markers associated with recurrence and poor prognosis in TNBC patients is critically needed. BRCAness is a set of traits in which BRCA1 dysfunction, arising from gene mutation, methylation or deletion, results in DNA repair deficiency. In the present study we evaluated the clinical significance and prognosis of BRCAness in a multicenter retrospective study.

Methods: Ninety-four TNBC patients treated with neoadjuvant chemotherapy (NAC) were enrolled from three hospitals in Japan for this retrospective study. Of these patients, 86 (91.5%) were treated with anthracyclines and taxanes. BRCAness was determined from 94 core needle biopsy (CNB) specimens prior to NAC and 50 surgical specimens without pathological complete response (pCR). The samples were assessed using multiplex ligation-dependent probe amplification (MLPA) and the amplicons were scored. Samples with scores >0.5 were defined as having BRCAness.

Results: Of the 94 TNBC patients, 51 (54.3%) had BRCAness in CNB specimens. There were no significant differences in pCR rate or recurrence between the BRCAness and non-BRCAness groups. Among surgical specimens, the BRCAness group (19/50, 38%) had a significantly shorter recurrence-free survival (RFS) and disease-specific survival (DSS) compared with the non-BRCAness group (p < 0.01 and p < 0.05). The BRCAness group had independent prognostic factors for recurrence and survival in multivariate regression analysis.

Conclusions: The BRCAness of surgical specimens is a useful marker to predict prognosis in TNBC patients after NAC. A clinical trial to assess the clinical impact of platinum-containing drugs with BRCAness is planned.

Citation Format: Kosaka Y, Yamamoto Y, Nishimiya H, Ibusuki-Yamamoto M, Hirota Y, Tanino H, Iwase H, Nakamura S, Akashi-Tanaka S. BRCAness as a prognostic marker in triple-negative breast cancer patients treated with neoadjuvant chemotherapy: A multicenter retrospective study [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-09-06.
Abstract P6-09-07: Expression of miR-106b in circulating tumor cells is associated with EMT and prognosis in metastatic breast cancer patients
Authors: Tan W , Liang G , Xie X , Tan L , Sanders AJ , Liu Z , Ling Y , Zhong W , Jiang WG , Gong C
Published: May 2019

# Co-first author: W.T., G.L., X.X.

* Co-Correspondence: C.G. and W.G.J.

Abstract

Background: Circulating tumor cells (CTCs) display changes in epithelial-mesenchymal transition (EMT) markers and miRNAs regulate EMT in breast cancer cells. The association between EMT characteristics and miRNA expression in CTCs of metastatic breast cancer (MBC) patients and their clinical implications remain unknown.

Methods: CTC-specific miRNAs were screened based on comparison of the miRNA profile between CTC and primary tumor. RT-PCR was used to quantity the expression levels of EMT makers and miRNA candidates. We enrolled 219 MBC patients with CTCs ≥ 5/7.5mL blood from 2 cohorts and CTCs were detected and enriched by CellSearch. Overall survival (OS) and radiological response were analyzed. CTCs were divided into epithelial- (E-CTCs) and mesenchymal-like CTC (M-CTCs) phenotypes based on a cut-off value derived from suspended breast cancer cells recovered from PBMCs.

Results: MiR-106b displayed upregulation in CTCs, with a higher level in M-CTCs than E-CTCs. Patients with E-CTCs showed better OS than those with M-CTCs (HR 1.77, 95% CI 1.14-2.78, P =0.012). CTCs from chemo-resistant MBC patients exhibited higher miR-106b. CTC-specific miR-106b was negatively associated with therapy response and OS (HR 1.73, 95% CI 1.06-2.84, P = 0.029).

Conclusions: CTC-specific miR-106b was associated with EMT phenotypes of CTCs and may predict prognosis in MBC patients.

Citation Format: Tan W, Liang G, Xie X, Tan L, Sanders AJ, Liu Z, Ling Y, Zhong W, Jiang WG, Gong C. Expression of miR-106b in circulating tumor cells is associated with EMT and prognosis in metastatic breast cancer patients [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-09-07.
Abstract P6-09-09: Analysis of serial circulating tumor cell count during neoadjuvant systemic therapy in breast cancer patients
Authors: Gwark S-C , Kim J , Kim YH , Kim MS , Park JY , Lee SB , Sohn G , Chung IY , Ko BS , Kim HJ , Lee JW , Son BH , Ahn SH
Published: May 2019

Background: We aimed to evaluate the clinical implication of circulating tumor cell (CTC) counts in correlation with prognosis and radiologic/pathologic response to therapy in locally advanced breast cancer patients undergoing preoperative systemic therapy.

Methods: From Feb 2014 to May 2017, 207 patients without distant metastasis were prospectively enrolled from AMC. CTC counts were analyzed before-during-after the therapy. CTC isolation was performed using a SMART BIOPSY™ SYSTEM Isolation kit (Cytogen, Inc., Seoul, Korea). Recurrence-free and overall survival was analyzed according to CTC counts.

Result: The mean follow-up period was 22.46 months and mean age was 46.48 years. One or more CTC was identified in 132 of 203 patients(65.0%) before NST, in 135 of 186 patients(72.0%) during NST and 103 of 171 patients(60.2%) after NST. Initial tumor burden at diagnosis -tumor size, lymph node metastasis- was not correlated with CTC positivity. Overall, CTC count ((≥1 CTC, ≥2 CTCs, and ≥5 CTCs) was not correlated with response to therapy. Using RECIST criteria, 86.5% (179/204) were responders (complete, partial response, CR/PR) and 12.1% (25/204) were non-responders (stable, progressive disease, SD/PD). 14.5% (30/207) showed a pathologic complete response (pCR), yet no association was found between CTC count/changes and radiologic/pathologic response to therapy. Also, CTC count was not correlated with prognosis among the whole population. However, HR+ tumors, CTC detection before NST was significantly associated with treatment response by RECIST criteria (responder vs. non-responder) (p=0.003, p=0.017 and p=0.023, respectively).

Conclusions: Our findings support limited value of CTC count for locally advanced breast cancers undergoing neoadjuvant systemic therapy.

Citation Format: Gwark S-C, Kim J, Kim YH, Kim MS, Park JY, Lee SB, Sohn G, Chung IY, Ko BS, Kim HJ, Lee JW, Son BH, Ahn SH. Analysis of serial circulating tumor cell count during neoadjuvant systemic therapy in breast cancer patients [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-09-09.
Abstract P6-12-01: Withdrawn
Authors: Palliyaguru DL , Chartoumpekis DV , Skoko JJ , Wendell SG , Woodcock SR , Wakabayashi N , Yagishita Y , Oesterreich S , Michalopoulos GK , Kensler TW
Published: May 2019

This abstract was withdrawn by the authors.

Citation Format: Palliyaguru DL, Chartoumpekis DV, Skoko JJ, Wendell SG, Woodcock SR, Wakabayashi N, Yagishita Y, Oesterreich S, Michalopoulos GK, Kensler TW. Withdrawn [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-12-01.
Abstract P6-13-03: Not presented
Authors: Glaspy J , Tang T , Rutty D , Yan X , Bondarenko I , Burdaeva O
Published: May 2019

This abstract was not presented at the conference.

Citation Format: Glaspy J, Tang T, Rutty D, Yan X, Bondarenko I, Burdaeva O. Not presented [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-13-03.