bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P1-21-02: Distinct methylation and copy number alteration patterns in phyllodes tumors of the breast and its mimics
Authors: Muenst Simone , Vlajnic Tatjana , Soysal Savas Deniz , Frank Stefan , Hench Jürgen
Published: March 2020

Background: Phyllodes tumor (PT), a rare fibroepithelial neoplasm of the breast, poses a significant diagnostic challenge in breast pathology, as there are no generally accepted histological criteria or cutoffs to unambiguously differentiate PT variants (benign, borderline, malignant) and fibroadenomas (FA) of the breast. In recent years, genome-wide DNA methylation analysis has gained wide interest as an objective tool to distinguish all sorts of neoplasms based on their individual methylation signatures. For brain tumors, methylation-based classification already outperforms classification by conventional histology and has led to changes in the WHO tumor classification.

Materials and Methods: We have so far analyzed fresh frozen as well as formalin-fixed, paraffin-embedded tissue samples of PT (n=31) and FA (n=2) on Illumina Infinium Methylation EPIC bead chips. The resulting data were preprocessed, normalized, mapped to the genome and converted into beta values. Top differentially methylated probes were determined by the calculation of standard deviations across the dataset. Such filtered sets of methylation beta values were then compared by a dimension reduction algorithm alongside TCGA methylome datasets as well as collections from GEO and the entire diagnostic database of our institute (n=14342). In parallel, the genome-wide copy number alterations were calculated from array data for each case.

Results: In analogy to other tumor entities included in our reference cohort (brain tumors, sarcomas, carcinomas, melanomas), PT and FA of the breast show distinct DNA methylation patterns that contain a breast-specific signature as well as tumor-derived patterns. Their methylomes are distinct from breast adenocarcinoma as well as from healthy breast tissue. Two distinct groups within the PT/FA spectrum were identified so far: One group contains a high fraction of histologically malignant PT and is enriched for complex copy number alterations while the other group, also containing the currently two included fibroadenomas and, features less prominent to no copy number variants and a higher similarity to the overall normal breast tissue methylation signature.

Conclusion: The distinct methylation signatures of the histological PT/FA spectrum will not only allow the diagnostic discrimination of PTs from histological mimics such as FA or carcinomas, but will also enable the distinction of benign, borderline and malignant PTs, thus paving the way to an optimized prognostic patient stratification and clinical management.

Citation Format: Simone Muenst, Tatjana Vlajnic, Savas Deniz Soysal, Stefan Frank, Jürgen Hench. Distinct methylation and copy number alteration patterns in phyllodes tumors of the breast and its mimics [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 P1-21-02.
Abstract P1-21-06: Deregulated immune pathway associated with palbociclib resistance in breast cancer preclinical models: Integrative analysis of genomics and transcriptomics
Authors: Moon Yong Wha , Lee Eunbyeol , Hwang Sohyun , Pandey Kamal , Park Nahee , Hur Jin , Cho Young Bin , Kim Seung Ki , Lee Seung Ah , An Hee-Jung , Sohn Joohyuk
Published: March 2020

Background: Recently CDK4/6 inhibitors are being widely used to treat advanced HR-positive breast cancer. Despite promising clinical outcomes, almost all patients eventually acquire resistance to CDK4/6 inhibitors. Hence, understanding the mechanisms of acquired resistance to CDK4/6 inhibitors is crucial to develop alternate treatment strategy. Therefore, we screened genes associated with palbociclib resistance through genomics and transcriptomics in breast cancer preclinical models. Methods: We generated palbociclib-resistant cell lines, MCF7-PR and T47D-PR by exposing MCF7 and T47D cells to palbociclib for over 9 months. After confirming the acquired resistance through in vitro assays, we performed whole exome sequencing (WES) and mRNA microarray to compare genomic and transcriptomic landscape between palbociclib-sensitive and resistant cells. Real-time PCR was performed to confirm differentially expressed genes. Results: Microrray analysis revealed 651 differentially expressed genes (DEGs) (fold change ≥2) by comparing MCF7 vs. MCF7-PR cells. WES also revealed 107 mutated genes by comparing T47D vs. T47D-PR cells. Further, GO annotation of both the DEGs and mutated genes found deregulation of immune pathway commonly in MCF7-PR and T47D-PR (FDR<0.25). Representatively, activated type I interferon pathway was notable in MCF7-PR cells with annotation of the DEGs. By real-time PCR, IRF9 and SP100 were commonly increased in the resistant cells (MCF7-PR, T47D-PR) compared to each sensitive counterpart. Besides, STAT1, IFI27, IFIT2, IFIT3, and XAF1 were increased in the MCF7-PR compared to MCF7, STAT2 was also increased in the T47D-PR compared to T47D. Regarding mutations found in resistant cells, MUC4 (in MCF7-PR) and MUC16 (in T47D-PR) mutations were annotated as immune pathway including immune response activating cell surface receptor signaling or O-glycan processing, et al. Besides, RB1 mutation was detected in T47D-PR cells. Conclusions: Deregulated immune pathway was found to be associated with palbociclib resistance in preclinical breast cancer models. Further studies are warranted to evaluate whether immune pathway may be a therapeutic target to overcome CDK4/6 inhibitor resistance.

Citation Format: Yong Wha Moon, Eunbyeol Lee, Sohyun Hwang, Kamal Pandey, Nahee Park, Jin Hur, Young Bin Cho, Seung Ki Kim, Seung Ah Lee, Hee-Jung An, Joohyuk Sohn. Deregulated immune pathway associated with palbociclib resistance in breast cancer preclinical models: Integrative analysis of genomics and transcriptomics [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 P1-21-06.
Abstract P2-04-03: The roles of fucosylation in promoting tumorigenic signaling in breast cancer
Authors: Snyder Kara , Ren Hui , Lester Daniel , Fang Bin , Koomen John , Lau. H Eric
Published: March 2020

Fucosylation is an important form of protein glycosylation involved in the progression of cancer. Aberrant fucose and fucosylated serum protein/oligosaccharide levels have been previously described in breast cancer (BC). Fucosylation has been reported impact proliferation and key signaling pathways (e.g., ERK1/2, p38 MAPK, and E-selectin) in human breast invasive ductal carcinoma. However, precise roles and functions of fucosylated proteins function in BC remain largely unclear. In our preliminary analyses, we performed immunofluorescent lectin staining of BC tissue microarrays and cell lines grown in vitro and found that fucosylation is increased in BC vs. normal breast tissues. To study the functional contributions of fucosylation to BC biology, we either pharmacologically or genetically suppressed fucosylation in BC cell lines. The treated or modified cell lines were characterized for their ability to grow/proliferate in 2D or 3D, as well as on adhesion to extracellular matrix (ECM). We observed that inhibiting fucosylation blunted BC cell proliferation, particularly in 3D, and attenuated adhesive capacity. To determine the mechanism(s) underlying the biological functions of fucosylation in BC cells, we performed parallel fucosylated and phosphoproteomic mass spectrometric analyses on BC cells that were either pharmacologically or genetically inhibited for fucosylation to identify: (i) all fucosylated proteins in BC cells and (ii) signaling pathways that comprise directly fucosylated proteins and that are significantly altered in activity (phosphorylation). All filtered hits were subject to Ingenuity Pathway Analysis. Thirteen signaling pathways were identified in common amongst both pharmacologically or genetically modulated BC groups. These pathways clustered into the following 3 major functional groups: cell-cell/cell-matrix contact, RNA processing, and endosomal/phagosomal dynamics. The most fucosylated proteins included integrins. We validated the direct fucosylation of integrins and further dissected the molecular and functional contributions of fucosylation to integrin signaling in vitro and in vivo in mouse models of breast cancer. Our data identify new roles for fucosylation in regulating key signal transduction pathways in BC. How integrin signaling and BC cell biology is regulated by fucosylation, as well as potential clinical utility of fucosylated integrins for BC, will be discussed.

Citation Format: Kara Snyder, Hui Ren, Daniel Lester, Bin Fang, John Koomen, Eric Lau. H. The roles of fucosylation in promoting tumorigenic signaling in 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 P2-04-03.
Abstract P2-04-05: Loss of Ste20-like kinase induces a basal/stem-like phenotype in HER2-positive breast cancers
Authors: Al-Zahrani Khalid N , Abou-Hamad John , Pryce Ben , Cook David P , Hodgins Johnathan , Labreche Cedrik , Robineau-Charette Pascale , de Souza Christiano , Bell John , Auer Rebecca , Ardolino Michele , Vanderhyden Barbara , Schramek Daniel , Sabourin Luc
Published: March 2020

Over the past two decades, the mammalian Ste20-like kinase (SLK) has been characterized for its role in regulating cellular migration, proliferation and apoptosis in fibroblasts and myoblasts. In mammary epithelial cells, SLK has been shown to be required for efficient epithelial-to-mesenchymal transition and to be activated downstream of the HER2/Neu-oncogene to control chemotactic cellular migration. Here, we assessed the role of SLK in HER2/Neu-induced mammary tumorigenesis in vivo. As SLK is activated downstream of HER2/Neu, we hypothesized that the loss of SLK would significantly delay tumor progression in a mouse model of HER2-positive breast cancer. As we have shown that global attenuation of SLK kinase activity results in embryonic lethality, a conditional SLK knockout mouse model was generated. To study the role of SLK in HER2-positive breast cancer, we crossed these conditional SLK knockout mice with mice expressing HER2/Neu linked to Cre recombinase in the mammary luminal epithelium. Unexpectedly, we have demonstrated that conditional deletion of SLK significantly accelerates Neu-induced mammary tumor onset and decreases overall survival. SLK deletion results in the induction of Sox10 which drives mammary stem/progenitor activity and cooperates with HER2/Neu to drive tumor growth. Using the Cancer Genome Atlas, we have supported previous findings and validated Sox10 as a potential biomarker of the Triple-negative Breast Cancer subtype. Furthermore, we have uncovered that SLK deletion results in enhanced activation of AKT. We provide evidence that Sox10 induction requires signaling through a novel AKT/Sox9-dependent pathway following SLK deletion. Taken together, our data suggests that SLK may be required to maintain cells in a fully differentiated state and that loss of SLK in HER2/Neu-induced breast cancer drives a more basal/stem-like phenotype through the induction of Sox10.

Citation Format: Khalid N Al-Zahrani, John Abou-Hamad, Ben Pryce, David P Cook, Johnathan Hodgins, Cedrik Labreche, Pascale Robineau-Charette, Christiano de Souza, John Bell, Rebecca Auer, Michele Ardolino, Barbara Vanderhyden, Daniel Schramek, Luc Sabourin. Loss of Ste20-like kinase induces a basal/stem-like phenotype in HER2-positive 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 P2-04-05.
Abstract P2-05-06: Nuclear STING localization induces chemoresistance in breast cancer
Authors: Cheradame Laura , Guerrera Chiara , Judde Jean-Gabriel , Goffin Vincent , Cairo Stefano
Published: March 2020

Efficient DNA damage repair (DDR) is crucial for a cell as aberrant repair can create deleterious mutations and genomic instability while unrepaired damage leads to cell apoptosis. Cells with altered DDR are more inclined to develop a variety of diseases, including cancers Cancer therapies including radiotherapy and chemotherapy rely on double strand break (DBS) formation to drive the killing of rapidly cycling tumor cells. As efficient DNA repair pathways can enable tumor cells to survive treatment-induced DNA damage, the identification of new actors participating in efficient DDR will help design alternative therapeutic approaches. Here we report that the well-known DNA sensor of innate immunity Stimulator of Interferon Genes (STING) is directly involved in the modulation of DSB repair efficiency in breast cancer cells. STING partly resides at the inner membrane of the nucleus where it interacts with core proteins of DNA-damage complexes and promotes its assembly with chromatin. STING silencing decreases DNA repair and cell viability, while STING overexpression protects cancer cells from genotoxic treatment. STING involvement in DNA repair is independent of the canonical STING-triggered pro-inflammatory response. In line with this observation, while overall STING expression level is positively correlated with favorable outcome in breast cancer patients, high STING expression in breast and ovarian cancer patients treated with adjuvant chemotherapy is associated with poor prognosis. This newly-identified function of STING elucidates a cell autonomous tumor-promoting mechanism complementary and independent from its well-documented role in tumor immunosurveillance.

Citation Format: Laura Cheradame, Chiara Guerrera, Jean-Gabriel Judde, Vincent Goffin, Stefano Cairo. Nuclear STING localization induces chemoresistance in 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 P2-05-06.
Abstract P2-08-14: Trends in the incidence of breast cancer following the radiological accident in Goiânia, Brazil: A 25-year analysis
Authors: Rocha Marina E , Rahal Rosemar MS , Freitas-Junior Ruffo , Correa Rosangela S , Rodrigues Danielle CN , Martins Edesio , Soares Leonardo R , Oliveira Jose C
Published: March 2020

Background: The largest radiological accident to occur in any urban area happened in a Brazilian state capital city in 1987 to the detriment of the population and the environment. One major concern regarding deleterious effects in the population was a possible increase in breast cancer incidence rates, since the literature shows that exposure of an individual to ionizing radiation is one of the risk factors for cancer. This study analyzed trends in the incidence of breast cancer over the 25-year period following the radiological accident. Methods: This ecological, population-based study was conducted to determine the incidence of breast cancer in female residents of Goiânia, Goiás, Brazil, between 1988 and 2012. The data were collected from the Goiânia population-based cancer registry. Crude and age-standardized incidence rates were calculated. The Joinpoint software program was used to calculate annual percent changes (APC) in the incidence of breast cancer. Results: Overall, 7,365 new cases of breast cancer were identified, with an annual crude incidence rate of 23.09/100,000 women in 1988 and of 71.65/100,000 women in 2012. The age-standardized incidence rate was 35.63/100,000 women in 1988 and 65.63/100,000 women in 2012. Analysis of the APC showed a significant annual increase of 4.8% in the incidence between 1988 and 2005 (p<0.0001) followed by stabilization in 2005-2012, with an APC of -3.5% (p=0.1). Conclusion: There was an increase in the incidence of breast cancer in the female residents of Goiânia, Goiás in the first 17 years of evaluation (1988-2004) followed by a period of stabilization until 2012.

Keywords: breast cancer; epidemiology; incidence; age group; Goiânia; Brazil.

Table 1. Annual percent change in the age-standardized incidence rate of female breast cancer by age in the city of Goiânia, Goiás, Brazil between 1988 and 2012.Age Group (years)Trend 1 (Years)APC^*(95%CI)pTrend 2 (Years)APC ^*(95%CI)p≤391988-20075.53.9 - 7.20.0012007-2012-7.0-15.3 - 20.140 - 491988-20054.63.6 - 5.60.00012005-2012-3.7-6.5 - -0.80.000150 - 691988-20046.34.6 - 80.00012004-2012-3.4-6.5 - -0.30.0001≥701988-20120.9-0.1 – 1.90.1–---^Significance: p >0.05; * Annual percent change (APC); * Coefficient of the incidence per 100,000 women; CI: Confidence interval.

Citation Format: Marina E Rocha, Rosemar MS Rahal, Ruffo Freitas-Junior, Rosangela S Correa, Danielle CN Rodrigues, Edesio Martins, Leonardo R Soares, Jose C Oliveira. Trends in the incidence of breast cancer following the radiological accident in Goiânia, Brazil: A 25-year 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 P2-08-14.
Abstract P2-08-25: The 5-years conditional disease free survival and overal survival for breast cancer patients in Korea
Authors: Ahn Jee Hyun , Nam Seok Jin , Kim Seok Won , Lee Jeong Eon , Chae Byung-Joo , Lee Se Kyung , Ryu Jai Min , Yu Jonghan
Published: March 2020

Background: Most of breast cancer patients survive for a long-term period. The existing assessment of survivors’ prognosis has had some limitations in breast cancer because it is based on an evaluation at the time of diagnosis. Conditional survival reflects change over time after diagnosis and treatment of cancer. Conditional disease-free survival (CDFS) and conditional overall survival (COS) can provide more accurate prognosis to breast cancer patients. In this study, we aimed to determine 5-years CDFS and COS according to disease-free period after diagnosis and treatment of breast cancer in Korea. Method: We retrospectively reviewed clinical data of 5664 patients aged 16 to 86 who underwent curative surgery for breast cancer between January 2000 and December 2008 at Samsung Medical Center, a single tertiary hospital in Korea. The CDFS and COS rates were based on cumulative DFS and OS estimates up to 15 years using the Kaplan-Meier method. Results: At baseline, each 5-years DFS and OS were 88.0% and 93.8%. For patients who kept disease free status from 1 to 9 years after surgery, the 5-years CDFS rates were calculated as 88.7%, 90.7%, 91.6%, 91.1%, 91.5%, 91.0%, 89.5%, 86.1% and 86.1%, respectively. The 5-year COS rates of the patients who had survived from 1 to 9 years after surgical treatment were calculated as 92.6%, 92.1%, 91.2%, 91.0%, 89.4%, 85.6%, 80.7%, 75.3%, and 73.0%, respectively. Conclusion: Our study showed that 5-years CDFS and COS for most patients who have breast cancer in Korea seemed to be good prognosis for a long time. However, cancer recurrence tended to occur after a long period postoperatively. Further study is required to identify risk factors associated with recurrence after several years in Korean breast cancer patients.

Citation Format: Jee Hyun Ahn, Seok Jin Nam, Seok Won Kim, Jeong Eon Lee, Byung-Joo Chae, Se Kyung Lee, Jai Min Ryu, Jonghan Yu. The 5-years conditional disease free survival and overal survival for breast cancer patients in Korea [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 P2-08-25.
Abstract P2-08-26: Cardiovascular events and mortality in a population-based cohort treated for ductal carcinoma in situ
Authors: Yoo Tae-Kyung , Chae Byung Joo , Han Kyung Do , Kim DaHye , Ahn Juneyoung , Park Woo-Chan , Oh Se Jeong
Published: March 2020

Background: Ductal carcinoma in situ (DCIS) patients are mostly diagnosed through cancer screening programs, suggesting that this population may have a healthy screenee effect of being more health-conscious, have lower comorbidity and belong to a higher socio-economic class. In this population-based cohort, we assessed the likelihood of cardiovascular events and mortality in DCIS patients, comparing with a control group of non-DCIS patients. Methods: Using the Korean National Health Insurance Service database, 13,740 women who were diagnosed of DCIS between 2007 and 2013 were analyzed. Control group matched by age was selected three times the number of DCIS cases (n=41,200). Follow-up for comorbidities and survival was performed up to 2016. Cox proportional hazard regression analysis was used to evaluate the association between DCIS and myocardial infarction (MI) risk, cerebrovascular stroke risk and mortality rate. The DCIS group was divided into pure DCIS patients and DCIS patients with subsequent invasive breast cancer for analysis. Results: Compared to the control group, patients with DCIS history were more likely to have hypertension, diabetes mellitus, dyslipidemia and the Charlson’s Comorbidity Index score was significantly higher. Patients with DCIS history also had higher income and were more likely to live in urban districts. Despite of higher comorbidity rate, pure DCIS patients had a trend of lower MI risk (HR 0.710; 95% CI 0.448 - 1.125) and significantly lower stroke risk (HR 0.708; 95% CI 0.492 - 1.019). Whereas, DCIS patients with subsequent invasive breast cancer had a significantly lower MI risk (HR 0.582; 95% CI, 0.371 - 0.913) and trend of lower stroke risk (HR 0.815; 95% CI 0.610 - 1.108). Mortality rate was similar between control group and pure DCIS patients, but was higher in DCIS patients with subsequent invasive breast cancer (HR 1.629; 95% CI 1.339 - 1.983). The trend of lower risk for cardiovascular events was sustained when adjusting for age, income and comorbidities (hypertension, diabetes mellitus and dyslipidemia). Conclusion: DCIS patients had a lower risk for MI and stroke compared to the control group despite of higher rate of comorbidities, which may reflect socioeconomic differences. DCIS patients with subsequent invasive breast cancer had higher mortality rate, whereas pure DCIS patients had similar survival rate compared to the control group.

Citation Format: Tae-Kyung Yoo, Byung Joo Chae, Kyung Do Han, DaHye Kim, Juneyoung Ahn, Woo-Chan Park, Se Jeong Oh. Cardiovascular events and mortality in a population-based cohort treated for ductal carcinoma in situ [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 P2-08-26.
Abstract P2-09-03: Spectrum, prevalence and clinical outcomes of germline mutations in PALB2 genes in 16501 unselected BRCA1/2-negative breast cancer patients: A multi-center analysis
Authors: Zhou Jiaojiao , Wang Honglian , Fu Fangmeng , Li Zhanwen , Liu Yun , Feng Qingjian , Wu Weizhu , Wang Hongxia , Wang Chuan , Chen Yiding
Published: March 2020

Background: PALB2 (Partner and Localizer of BRCA2) is a breast cancer predisposition gene, which plays a critical role in homologous recombination via interacting with BRCA1/2 and RAD51 when DNA break. However, the clinical relevance of PALB2 germline mutations in Chinese breast cancer patients remains unknown. We attempted to illustrate the full prevalence and spectrum of PALB2 germline mutations in Chinese breast cancer population, and to investigate the clinical outcomes of PALB2 germline mutations. Patients and methods: A total of 21216 unselected breast cancer patients were enrolled from multiple clinical centers in China. After evaluation of the DNA quality and clinical information, 16501 eligible BRCA1/2-negative breast cancer patients were analyzed. A group of 5890 Chinese women without cancer was enrolled as healthy controls. PALB2 screening was based on next-generation sequencing, by screening complete coding sequence and intron-exon boundaries of PALB2. Clinical information was synchronously collected. Results: The 79 PALB2 deleterious germline mutations included 25 nonsense mutations, 47 frameshift mutations, and 7 splicing mutations. The hotspot region for PALB2 mutations was exon4. A total of 41 novel mutations were identified in PALB2. Among the 16501 BRCA1/2-negative breast cancer patients and 5890 healthy women, PALB2 deleterious mutation carriers account for 0.97% (n=160) and 0.19% (n=11) separately. PALB2 mutations were significantly associated with increased breast cancer risk (OR: 5.23, 95% CI 2.89-9.49; P<0.0001), and especially in women aged 30 or younger (OR: 11.97, 95% CI 3.76-34.39; P<0.0001). PALB2 mutation carriers were significantly more likely to be triple negative breast cancers and have bigger tumors, positive axillary lymph nodes, bilateral breast cancers, family history of breast and/or ovarian cancer and family history of any other cancer, than noncarriers. Conclusions: The PALB2 mutations confer a moderately increased breast cancer risk in women, but relatively highly increased breast cancer risk in those aged 30 or younger. PALB2 mutation status is associated with distinct clinical characteristics in breast cancer. Key words:PALB2, breast cancer, germline mutations, next-generation sequencing

Citation Format: Jiaojiao Zhou, Honglian Wang, Fangmeng Fu, Zhanwen Li, Yun Liu, Qingjian Feng, Weizhu Wu, Hongxia Wang, Chuan Wang, Yiding Chen. Spectrum, prevalence and clinical outcomes of germline mutations in PALB2 genes in 16501 unselected BRCA1/2-negative breast cancer patients: A multi-center 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 P2-09-03.
Abstract P2-09-10: Genetic variants of CCL5 signaling pathway genes in susceptibility and prognosis of triple negative breast cancers in Arab population
Authors: Al-Bader Salha Bujassoum , Shan Jingxuan , Bedognetti David , Chouchane Lotfi
Published: March 2020

Background:Triple-negative breast cancer (TNBC) has a higher rate of early relapse and mortality compared to other types of breast cancer (BC). CCL5 and its signaling pathway have been linked to TNBC. Methods:We characterized variants in CCL5and that of six other CCL5 signaling genes (CCND1, ZMIZ1, CASP8, NOTCH2, MAP3K21 and HS6ST3) among 1,082 unrelated Arab subjects, including 196 TNBC, accessed their association with BC-specific overall survival (OVS) and progression-free survival (PFS), and correlated CCL5 expression with CCL5genotypes. Results: CCND1 rs614367-TTgenotype was highly associated with the TNBC risk (OR = 5.14; P = 0.004) and the rs614367-Tallele was associated with decreased PFS in TNBC. A decreased risk of lymph node metastasis was associated with the MAP3K21rs1294255-C allele, particularly in rs1294255-GC (OR = 0.47; P = 0.001). CCL5variants (rs2107538and rs2280789) were linked to CCL5 serum and mRNA levels. In the TCGA TNBC/Basal-like cohort the MAP3K21rs1294255-G allele was associated with a decreased OVS. High expression of CCL5in breast tumors was significantly associated with an increased OVS in all BC patients, but particularly in TNBC/Basal-like patients. Conclusion:Genetic variation in CCL5 signaling genes may predict not only TNBC risk but also disease aggression.

Citation Format: Salha Bujassoum Al-Bader, Jingxuan Shan, David Bedognetti, Lotfi Chouchane. Genetic variants of CCL5 signaling pathway genes in susceptibility and prognosis of triple negative breast cancers in Arab population [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 P2-09-10.
Abstract P2-10-17: Tissue prevalence and cellular heterogeneity of 9p24.1 amplification in TNBC in African American women
Authors: Anderson Karen S. , Naab Tammey , Koslosky Lori K , Anderson Megan , Lewis Michael , Kanaan Yasmine , Afsari Ali , Ricks-Santi Luisel , Pockaj Barbara A. , Barrett Michael T
Published: March 2020

Introduction: Amplification of chromosome 9p24.1 encoding PDL1, PDL2, and JAK2 (the PDJ amplicon) has been detected in 5-25% of triplenegative breast cancers (TNBC), and is associated with poor outcome and activation of the JAK/STAT pathway. Here, we have developed a robust multiplexed fluorescence in situ hybridization (FISH) assay for detection of 9p24.1 amplification, and assessed the frequency and cellular distribution of the PDJ amplicon in a cohort of African American (AA) women with TNBC. Methods: The FISH assay combines three chromosome 9 probes to simultaneously target JAK2 and PD-L1 (9p24.1, PDJ), chromosome 9q22, and the 9q34.1 regions. This enables discrimination of PDJ amplicons from whole chromosome 9p arm gains and from chromosome 9 ploidies that occur in the background of genomic instability in aneuploid cancer genomes. Fifty cells were scored for each probe and the average copy number was obtained. We defined PDJ amplification as PDJ>4, PDJ/9q22 ratio≥2, and/or PDJ/9q34.1 ratio≥2. The assay was benchmarked to array CGH of flow sorted TNBC tissue from Mayo Clinic Arizona (n=14). Tissue microarrays from TNBC PDX tumors (n=20) and from African American women with TNBC (n=87) were assessed. Results: Using selected TNBC tissue with known CGH data, the FISH assay tightly correlated with PDJ copy number in 13/14 cases. The discordant case was negative by CGH on a biopsy with low tumor content, but FISH positive on tissue section (PDJ >7.5 and a PDJ/9q22 ratio=4). Of 20 TNBC PDX tumors, 5 were amplified by FISH. Twelve of 87 (14%) of tumors had PDJ amplification by FISH, of which ten were from breast tissue and two were from lymph node. Of these 12, PDJ>4 (n=0), PDJ/9q22 ratio≥2 (n=6), and PDJ/9q34.1 ratio≥2 (n=10). Significant intratumoral variation was observed with the presence of single cells with >10 PDJ copies in 8/17 (47%) amplified and 0/90 non-amplified total cases. Conclusion: 9p24.1 (PDJ) amplification encoding JAK2, PD-L1, and PD-L2 is detected by three-color FISH in 14% of TNBC from African American women. Individual cells with ≥10 copies of PDJ was seen exclusively in 8/17 amplified cases. We identified 5 PDX tumors which may provide valuable preclinical models for the amplicon. The association of this biomarker with clinical outcome will be presented.

Citation Format: Karen S. Anderson, Tammey Naab, Lori K Koslosky, Megan Anderson, Michael Lewis, Yasmine Kanaan, Ali Afsari, Luisel Ricks-Santi, Barbara A. Pockaj, Michael T Barrett. Tissue prevalence and cellular heterogeneity of 9p24.1 amplification in TNBC in African American women [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 P2-10-17.
Abstract P2-11-13: Specific aspect of utilization of the prognostic multigene assay for invasive lobular carcinoma at early stage: Oncotype Dx in the prospective French cohort PONDx
Authors: Douchet Gaëlle , Curtit Elsa , Bourgeois Hugues , Richard Sandrine , Zilberman Sonia , Mahi Younes , Gligorov Joseph
Published: March 2020

Introduction: Invasive lobular carcinoma (ILC) differs from invasive ductal carcinoma (IDC) in a number of biological features with possible implication in treatment choice particularly for adjuvant chemotherapy. Multigene assay are being used increasingly to guide therapy for endocrine responsive breast cancer without HER2 overexpression or amplification at early stage. But if their interest is well defined for IDC, there are few data for ILC. Our study examine the impact of a multigene assay, Oncotype Dx (ODx), for the population of lobular breast cancer. Patients and methods: It was a retrospectively analysis of a French prospective cohort of patients (PONDx), with use of ODx (n= 882 patients). We studied and compared the specifics aspects of the use and the results of ODx for the ILC ( n= 125 (14,2%)) and IDC patients (n= 691 (78.3%)). We took account of the clinicopathological features, the Recurrence Score (RS), resulting of ODx and its impact on decision making. Results: In our cohort ILC were more frequently grade 2 tumours, had a significantly larger size, and lower Ki67 than IDC. RS distribution was lower for ILC (p<0,007): 66,4% of ILC had RS<18, 28,8% had RS from 18 to 30 and 4,8% had RS>30 ; whereas for IDC RS<18 for 52,2%, RS 18-30 for 36,8% and RS>30 for 11%. But there was a similar overall rate of change in treatment decision for ILC (46,4%) and IDC (43%) and a de-escalation of treatment (for no adjuvant chemotherapy) for 67,7% of ILC and 57,1% of IDC with initial indication of adjuvant chemotherapy. On the other hand, about 10% of patients with no initial indication of chemotherapy had an escalation of treatment after ODx for adjuvant chemotherapy. The analysis of the whole population shows a correlation of the lobular histologic type with low RS in univariate or multivariate analysis. Conclusion: RS is clearly prognostic for ILC and IDC. The predictive value of chemotherapy benefit was prospectively demonstrated for IDC, but not so clearly for ILC. In the PONDx cohort, despite a larger size of tumors, the RS of ILC was lower showing different biological features among the gene studied by ODx. The impact on decision making of ODx was similar for ILC and IDC, showing the interest of genomic assay in decision making independently from histologic subtypes (between ILC and IDC).

Citation Format: Gaëlle Douchet, Elsa Curtit, Hugues Bourgeois, Sandrine Richard, Sonia Zilberman, Younes Mahi, Joseph Gligorov. Specific aspect of utilization of the prognostic multigene assay for invasive lobular carcinoma at early stage: Oncotype Dx in the prospective French cohort PONDx [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 P2-11-13.
Abstract P2-12-04: Efficacy of intravenous (IV) NEPA and oral NEPA, fixed NK1/5-HT3 receptor antagonist (RA) combination agents, for prevention of chemotherapy-induced nausea and vomiting (CINV) following anthracycline-cyclophosphamide (AC)-based chemotherapy
Authors: Aapro Matti , Schwartzberg Lee
Published: March 2020

Background: The antiemetic guideline-based standard of care for prevention of CINV in patients receiving AC-based chemotherapy is the combination of an NK1 RA, a 5-HT3 RA, and dexamethasone (DEX). An IV formulation of NEPA (fixed combination of the NK1 RA, fosnetupitant and 5-HT3 RA, palonosetron) was recently approved in the United States. Two studies were completed in patients receiving cisplatin (Phase 3) or AC (Phase 3b) to assess the safety of IV NEPA, with specific attention paid to injection-site/hypersensitivity reactions as such events have occurred with other NK1 RAs, particularly in the AC setting. No treatment-related injection-site reactions were reported in >1300 infusions of IV NEPA. Oral NEPA was previously shown to be superior to palonosetron in a Phase 3 AC study. This analysis presents the efficacy data of IV NEPA and oral NEPA in the AC setting.

Methods: Data is compiled from the IV NEPA Phase 3b study as well as from an oral NEPA registration study in females with breast cancer undergoing AC-based chemotherapy. IV NEPA was administered as a single 30-minute infusion and oral NEPA was given as a single capsule 60 minutes prior to AC. Patients also received DEX prior to AC on Day 1 only. Complete response (CR: no emesis/no rescue medication) rates are summarized for the acute (Day 1), delayed (Days 2-5) and overall (Days 1-5) phases of Cycle 1 for each treatment/study and also pooled for oral NEPA across the 2 studies. No formal statistical comparisons were performed.

Results: Patient characteristics were similar in both studies. CR rates were comparable for IV NEPA and oral NEPA in the individual studies as well as with oral NEPA when pooled across the 2 studies (Table).

Cycle 1 Complete Response IV NEPA StudyOral NEPA Study Pooled Studies % Patients IV NEPAOral NEPAOral NEPAOral NEPA(N = 200)(N = 202)(N = 708)(N = 910)Acute (0-24 h)86.588.688.388.4Delayed (25-120 h)75.578.776.476.9Overall (0-120 h)73.077.273.974.6

Conclusions: Both IV and oral formulations of NEPA in combination with DEX represent guideline-compliant single-dose antiemetic agents that are highly effective over 5 days in patients receiving AC-based chemotherapy.

Citation Format: Matti Aapro, Lee Schwartzberg. Efficacy of intravenous (IV) NEPA and oral NEPA, fixed NK1/5-HT3 receptor antagonist (RA) combination agents, for prevention of chemotherapy-induced nausea and vomiting (CINV) following anthracycline-cyclophosphamide (AC)-based chemotherapy [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 P2-12-04.
Abstract P2-12-15: Efficacy of Lymphdiaral™ in breast cancer patients with lymphedema
Authors: Younus Jawaid , Black Morgan , Kligman Lyn , Leung Brenda
Published: March 2020

Background: Lymphedema has been a prevalent and often severe side effect for patients receiving treatment for breast cancer typically resulting in physical and psychosocial distress as well as decreased quality of life. With no widely effective or safe drug treatment(s) for lymphedema, this study aimed to assess the efficacy of combined Lymphdiaral™ drops and ointment for treatment-related lymphedema. Methods: This open label, randomized, parallel-group trial ran over 12 weeks with a final follow-up visit at 24 weeks. One hundred and thirty-four (n = 134) patients were consented to the study. Of these, 119 patients were randomized to either standard care group (compression garment) or treatment group (compression garment plus Lymphdiaral™ drops and ointment) and follow-up data was obtained. The primary objective was the reduction in lymphedema as measured by change in arm volume. Results: The values for the arm volumes did not show a statistically significant decrease in both the standard care or treatment groups. Additionally, there was no statistical difference in arm volume reduction between the groups. Conclusions: This first randomized trial shows, that the homeopathic drug combination of Lymphdiaral™ drops and ointment does not improve lymphedema in breast cancer patients.

Citation Format: Jawaid Younus, Morgan Black, Lyn Kligman, Brenda Leung. Efficacy of Lymphdiaral™ in breast cancer patients with lymphedema [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 P2-12-15.
Abstract P2-15-11: A phase II trial of genexol-PM and doxorubicin in patients with advanced Her-2 negative breast cancer
Authors: Cho Eun Kyung , Yun Hyo Yeon , Kim Yun Yeong , Jeon Yong Soon , Park Heungkyu
Published: March 2020

Background: Genexol PM is a lyophilized polymeric micellar formulation of paclitaxel that delivers a higher paclitaxel dose with lower vehicle-related toxicities than conventional paclitaxel formulations. This study was designed to evaluate the efficacy and safety of genexol- PM and doxorubicin combination in advanced Her-2 negative Breast cancer as first line treatment.

Methods: Patients with advanced Her-2 negative Breast cancer received Genexol-PM at 260mg/m2 on day 1 and doxorubicin 50mg/m2 on day 1 of 3-week interval cycle. Six to nine cycles of combination chemotherapy were planned unless there was disease progression. The primary endpoint was objective response rate.

Results: Thirty patients received this combination chemotherapy with a median 6cycles per patient (range 1-9). The objective response rate was 67% with disease control rate 87%, Median duration of response was 5.5months (95%CI 3.0-8.1months). Median progression free survival was 7.4 months (95%CI 5.3-9.6months) and overall survival 38.7months (95%CI 21.4-55.9months). The common toxicities were alopecia(93%), peripheral neuropathy(60%), nausea(57%), neutropenia(47%). The most common G3/4 toxicities were neutropenia(43%) and neutropenic fever(27%). There was no treatment related mortality.

Conclusion: Genexol-PM, CrEL-free paclitaxel, in combination with doxorubicin demonstrated favorable antitumor activity in advanced Her-2 negative breast cancer. The most common G3/4 toxicities was neutropenia but it was manageable.

Citation Format: Eun Kyung Cho, Hyo Yeon Yun, Yun Yeong Kim, Yong Soon Jeon, Heungkyu Park. A phase II trial of genexol-PM and doxorubicin in patients with advanced Her-2 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 P2-15-11.
Abstract P2-16-14: HER2-positive breast cancer: Combined 18F-FDG PET and CGFL/Curie nomogram to predict pathologic complete response after preoperative chemotherapy with trastuzumab
Authors: Vincent Laura , Jankowski Clémentine , Cortet Marion , Arnould Laurent , Ladoire Sylvain , Coudert Bruno , Desmoulins Isabelle , Charron-Barra Céline , Beltjens Françoise , Rouzier Roman , Reyal Fabien , Humbert Olivier , Cochet Alexandre , Coutant Charles
Published: March 2020

Background The aim of this study was to compare the value of 18F-fluorodesoxyglucose positron emission tomography (18F-FDG PET/CT) with CGFL/Curie nomogram to predict a pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) in women with human epidermal growth factor 2 (HER2)-positive breast cancer treated by trastuzumab. Methods Fifty-one women with HER2-positive breast cancer treated with trastuzumab plus taxane-based NAC, were retrospectively included from January 2005 to December 2015. For 18F-FDG PET/CT, the analyzed predictor was the maximum standardized uptake value of the primary tumor and axillary nodes after the first course of NAC (PET2.SUVmax). pCR was defined by no residual infiltrative tumor but in situ tumor was accepted. Accuracy of CGFL/Curie nomogram and PET2.SUVmax was evaluated measuring sensitivity (Se), specificity (Sp), positive predictive value (PPV) and negative predictive value (NPV). For each predictor, receiver operating characteristic (ROC) curve was created. To evaluate the correlation between predictors, the Spearman coefficient was calculated. Combined prediction was evaluated testing predictor’s associations. Results For CGFL/Curie nomogram’s performances, Se, Sp, PPV and NPV were respectively: 76% (CI95%: 58-90%), 57% (CI95%: 43-66%), 55% (CI95%: 42-65), 77% (CI95%: 59-90%). For PET2.SUVmax’s performances, Se, Sp, PPV and NPV were respectively: 67% (CI95%: 48-81%), 77% (CI95%: 64-97%), 67% (CI95%: 48-82%), 77% (CI95%: 64-87%). ROC curves for these predictors were similar; the areas under the curve were 0.6 (CI95%: 0.56-0.64) for PET2.SUVmax and 0.55 (CI95%: 0.50-0.59) for CGFL/Curie nomogram. Spearman coefficient was 0.23. Combined prediction was more efficient with Se at 80%, VPN at 76%, Sp at 78% and VPP at 81 %. Conclusions CGFL/Curie nomogram and PET2.SUVmax were two efficient predictors of pCR in patients with HER2-positive breast cancer. Combined prediction has an improved accuracy.

Citation Format: Laura Vincent, Clémentine Jankowski, Marion Cortet, Laurent Arnould, Sylvain Ladoire, Bruno Coudert, Isabelle Desmoulins, Céline Charron-Barra, Françoise Beltjens, Roman Rouzier, Fabien Reyal, Olivier Humbert, Alexandre Cochet, Charles Coutant. HER2-positive breast cancer: Combined 18F-FDG PET and CGFL/Curie nomogram to predict pathologic complete response after preoperative chemotherapy with trastuzumab [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 P2-16-14.
Abstract P2-16-21: Novel use of a precision medicine tool in the neoadjuvant therapy setting
Authors: Beitsch Peter , Whitworth Pat , Lee Laura , Ruiz Antonio , Brown Rick , Gold Linsey , Baron Paul , Patel Rakesh
Published: March 2020

Background: Molecular genomic profiles are increasingly used to guide treatment of refractory cancers and are on the forefront of personalized medicine for select patients. The neoadjuvant chemotherapy (NAC) setting provides a meaningful opportunity to compare genomic profiles to pathologic response. We report profiles to response in a novel multi center registry.

Methods: An ongoing IRB (WIRB) approved registry at 6 community breast practices submitted tumor samples prior to treatment for genomic/proteomic analysis (Paradigm, Phoenix, AZ.) Tumor response and associated molecular profiles were analyzed. The test evaluated over 137 genomic alterations with known actionable variations including mutations, gene-fusions, copy number variations, MRNA expression and protein expression analysis by IHC.

Results: 76 patients were enrolled and 42 have completed treatment including definitive surgery and have reported data as of this date. The vast majority of patients had invasive ductal carcinoma with 16% having triple negative biology and 20% having Her2 biology. Of the triple negative patients with reported surgical results, 42% had a complete response or minimal residual disease, and the remaining 58% had a partial response. Of the patients with HER2 biology, 85% had a complete response and the remaining a partial response. 17% of patients with luminal biology had a complete response; the remaining had only a partial response or progression. Overall, 15 patients had a complete response, 4 had minimal residual disease and the remaining (over 50%) had a partial response, stable or progressive disease. Patients who did not achieve a complete response had multiple molecular aberrations with unique markers not present in patients with PCR. These included markers of known or possible drug resistance (IGFR1, CAIX), poor prognostic markers (TP53, MET, PTEN), biomarkers of response to approved treatment that were not utilized and other markers of potential response and research.

Conclusions: Comprehensive genomic testing may predict resistant biology and provide additional targets for treatment or clinical study. Genomic analysis earlier in the patient’s care path may improve response rates by suggesting modifications in standard protocols or identifying clinical trials as potential first line options. Repeat genomic analysis may also suggest options for targeted adjuvant therapy for residual cancer after neoadjuvant therapy.

Citation Format: Peter Beitsch, Pat Whitworth, Laura Lee, Antonio Ruiz, Rick Brown, Linsey Gold, Paul Baron, Rakesh Patel. Novel use of a precision medicine tool in the neoadjuvant therapy setting [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 P2-16-21.