Sk Lee

P5-14-02: Clinicopathologic and Prognostic Difference of Screen Detected Breast Cancer Compared with Symptomatic Breast Cancer.

Background: Breast cancer screening program makes it possible to detect early cancer, thus to reduce breast cancer mortality. The authors studied clinicopathologic characteristics and prognosis of screen detected invasive breast cancer compared with symptomatic breast cancer. Furthermore, we compared the result according to molecular subtypes (luminal A, luminal B, Her2, triple negative), so intended to identify the role of screening in each subtypes. Material and Methods: From January 2002 to June 2008, 3141 patients who underwent operation for the treatment of invasive ductal carcinoma(NOS) at Samsung medical center were included. Among them, 1025 patient were screen detected, 2116 patient were symptomatic, out of screening over 2 years. We reviewed the medical records retrospectively. Result: Screen detected breast cancer was associated with older patients, smaller tumor size, more hormone receptor- positive, less lymph node involvement, lower stage and reduced mortality compared with symptomatic breast cancer (P Conclusion: Compared to symptomatic breast cancer patients, screen detected breast cancer patients have favorable pathological and molecular characteristics, so better outcomes. According to the molecular subtype, only in luminal A subtype, screen detected breast cancer shows both overall and disease free survival benefit, and also acts as an independent prognostic factor itself. So, screening program seems to have a different efficacy depending on the molecular subtype of breast cancer Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-14-02.

Abstract P6-09-08: Identification of ESR1 mutation in breast cancers using targeted ultra-deep sequencing data analysis

Introduction: Estrogen Receptor 1 (ESR1) gene encodes an estrogen receptor, which regulates cell proliferation and promotes tumor progression in estrogen receptor(ER)-positive breast cancer (BC). Therefore, endocrine therapy that inhibiting ER downstream signal, is the most effective treatment strategy in ER-positive BC. However, about 25% of patients with primary disease and almost all patients with metastases will present with or eventually develop endocrine resistance. And genetic alteration of ESR1 is now identified as the endocrine resistance mechanism. However, a few data from clinical trials or public data base exists and could not reflect real world clinic. Therefore, we aimed to identify the frequency and type of ESR1 genetic alterations in BCs through this large scaled study. Methods: We performed targeted ultra-deep sequencing (CancerSCAN™) using BC tissue specimens. This sequencing was covered entire coding area of ESR1 gene and also detected copy number alteration and translocation of ESR1. Results: Targeted ultra-deep sequencing of ESR1 was performed using 618 BC tissues. Of 618 tissue samples, 253(40.9%) were MBCs, 362(58.6%) were early BCs (EBCs) and 3 were not identified. In terms of subtypes, 220 ER-positive BCs, 122 ER-positive and HER2-positive BCs, 119 HER2-positive and 153 triple-negative BCs (TNBCs) were included. BCs from patients under 40 year-old were 277(44.8%)(Median: 43.0, range: 23.5 -75.6). ESR1 genetic alterations were identified in 21 BCs (5 EBCs and 16 MBCs). In EBCs, 3 cases were observed in TNBCs and 2 cases were in ER-positive BCs (2.6% and 1.2%, respectively). All five EBC were treatment naive status. Of 16 cases of ESR1 alterations in MBCs, 10 cases of ESR1 alterations were detected in ER-positive BCs (17.6%), 5cases in ER and HER2-positive BCs(6.7%) and 1 in HER2-positive BCs (1.2%). All ER-positive MBCs were treated with more than one line of endocrine therapy. Most commonly detected genetic alteration was single nucleotide variant (SNV) (15 of 21, 71.4%). Thirteen were in ligand binding domain and two cases occurred in activation function-1 (AF-1) domain (P79A and G145S). D538G and V392I were most frequently mutated loci followed by Y537N (3, 3 and 2 cases, respectively) and only metastatic ER-positive BCs harbored ESR1 activating mutation. Four copy number (CN) amplification in 2 ER-positive and 2 ER and HER2-positive BCs, one CN deletion in TNBC and one ESR1 fusion in ER and HER2-positive BC were also detected (19.0%, 4.8% and 4.8%, respectively). In frame ESR1 fusion was occurred between ESR1 and NPHS1 genes. Conclusion: In this experimental study, ESR1 genetic alterations were frequently detected in ER-positive MBC but ER-negative or EBC also harbored. The type of genetic alterations varied including SNVs, CN alterations and translocation and ESR1-NPHS1 fusion is the novel genetic alteration that has not been reported. To identify the role of ESR1 genetic alteration in ER-negative BCs and novel translocation, further functional validation would be warranted (Clinical trials.gov Number :NCT02591966). Citation Format: Kim J-Y, Park K, Park W-Y, Nam SJ, Kim SW, Lee JE, Lee SK, Jung HH, Yu JH, Ahn JS, Im Y-H, Park YH. Identification of ESR1 mutation in breast cancers using targeted ultra-deep sequencing data analysis [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P6-09-08.

Abstract P1-02-11: Clinical utility of serial monitoring of circulating tumor DNA (ctDNA)in patients with neoadjuvant chemotherapy (NAC) for locally advanced breast cancer (LABC)

Introduction: Circulating tumor DNA (ctDNA) is a new biomarker which could guide further treatment. Characterization of tumor mutation profiles is required for informed choice of therapy, given that biological agents target specific pathways and effectiveness may be modulated by specific mutations. It would have clinical utility for neoadjuvant setting also. Thus, we assess the potency of ctDNA to predict tumor response to neoadjuvant chemotherapy(NAC) in locally advanced breast cancer(LABC). Methods: We performed targeted deep sequencing of 30 plasma DNAs and 10 matched germline DNAs from 10 LABC patients. Serial plasma DNAs were collected at diagnosis, after 1st NAC and curative surgery. For the target enrichment, we designed RNA baits covering a total of ~202kb regions of human genome including a total of 83 cancer-related genes. We constructed the sequencing libraries according to the optimized protocol that we recently reported and sequenced on Illumina HiSeq2500 aiming a mean sequencing depth of ~10,000. After excluding unmapped reads, PCR duplicates and off-target reads, the coverage depths for plasma DNA and germline DNA samples were 2,627x and 4,833x on average, respectively. NAC response was measured by residual cancer burden(RCB) score, calculated as a continuous index combining pathologic measurements of primary tumor and nodal metastases for prediction of distant relapse-free survival. Results: We analyzed ctDNA and primary tumor tissues from 10 patients with LABC scheduled NAC followed by operation in Samsung Medical Center. Of ten LABCs, one excluded from analysis because of angiosarcoma of breast. Five samples were triple-negative breast cancers (BCs), 2 were HER2 positive BCs and others were ER positive BCs. In tumor response, 1 patient had pathologic complete response (pCR), 1 had RCB class I, 4 and 3 patients did RCB class II and III. Of 83 genes, in analysis of ctDNA at BC diagnosis, we found 2 to 6 mutations in each samples and 3 mutations were detected averagely. Most common mutation was TP53 (6 patients), followed by PIK3CA mutation. By measuring these mutations in serial ctDNA, we found that ctDNA had disappeared after first cycle of NAC in patient with pCR. In two patients with RCB class I, ctDNA had decreased by more than 10 percent (the level of ctDNA(pg/ml): 455.9 to 30.4, 5.8 to 0.0) of primary plasma sample after first NAC. Two patients increased level of ctDNA had tumor response with RCB class III and one patient had distant tumor recurrence within 3 months after curative surgery. However, correlation between the level of ctDNA and initial stage was not observed. Conclusions: This preliminary result suggests that serial monitoring of ctDNA would be a potiential surrogate marker to predict tumor response and recurrence during NAC in LABC patients. Further results with long-term outcomes are warranted. Citation Format: Kim J-Y, Park D, Jung HH, Bae SY, Yu JH, Lee SK, Kim SW, Lee JE, Nam SJ, Ahn JS, Im Y-H, Park YH. Clinical utility of serial monitoring of circulating tumor DNA (ctDNA)in patients with neoadjuvant chemotherapy (NAC) for locally advanced breast cancer (LABC) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-02-11.

Abstract P1-05-15: Multi-omics and immuno-oncology profiling reveal distinct molecular signatures of young Asian breast cancers

Breast cancers (BC) in younger, premenopausal patients (YBC) tend to be more aggressive with worse prognosis, higher chance of relapse and poorer response to endocrine therapies compared to breast cancers in older patients. The proportion of YBC (age ≤ 40) among BC in East Asia is estimated to be 16-32%, significantly higher than the 7% reported in Western countries. To characterize the molecular bases of Asian YBC, we have performed whole-exome sequencing (WES) and whole-transcriptome sequencing (WTS) on tumor and matched normal samples from 134 Korean BC patients consisting of 74 YBC cases (age ≤ 40) and 60 OBC cases (age > 40). We then performed comparison analyses and integrative analyses with the TCGA BC cohort consisting of 1,116 tumors from primarily Caucasian patients, also grouped by age into YBC (age ≤ 40), IBC (40 60). Somatic mutation prevalence analysis identified 7 significantly mutated genes and the same top three genes – TP53, GATA3 and PIK3CA – were reported by the TCGA BC study. To identify differentially expressed (DE) genes and pathways in YBCs vs. OBCs, we performed logistic regression analyses while controlling for the confounding effects of tumor purity and stage. We were surprised to see a significant overlap in DE pathways between a comparison of adjacent normal tissues in younger vs. older TCGA cohorts and a comparison of YBC vs. OBC tumors, indicating that normal tissue compartment could contribute to observed differences between bulk tumors. To separately examine molecular signatures from tumor, stroma and normal compartments, we used non-negative matrix factorization (NMF) analyses to virtually dissect bulk tumor expression data and identified 14 factors including 3 factors associated with normal tissues, 1 factor associated with stroma and 1 factor associated with tumor infiltrating lymphocytes (TIL). Integrative analyses of tumor associated factors and DE pathways revealed that estrogen response, endocrine therapy resistance, and oxidative phosphorylation pathways are up-regulated in YBCs compared to OBCs while cell cycle and proliferation pathways are up-regulated in Asian OBCs. Interestingly, many immune and inflammation pathways correlated with the TIL factor were significantly upregulated in OBCs vs. YBCs. Using gene expression signatures representing distinct immune cell types, we classified our cohort into four subtypes of varying TIL activities and observed significant enrichment of the TIL-high subtype in OBCs compared to YBCs. These observations were confirmed by IHC analyses of four TIL markers (CD45, CD4, CD8 and CD163) in 120 tumors. To our knowledge, this is the first large-scale multi-omics study of Asian breast cancer and would significantly contribute to the compendium of molecular data available for studying young breast cancers. The major landmarks in the molecular landscape looked similar across BCs of different ethnicities and ages, however, we have identified a number of distinguishing molecular characteristics associated with Asian YBC. The sources for some signatures were further traced to non-tumor intrinsic compartments, indicating that tumor microenvironment may play potentially important roles in driving the carcinogenesis of young breast cancers. Citation Format: Kan Z, Ding Y, Cho S, Lee S-H, Powell E, Jung HH, Chung W, Deng S, Choi Y-l, Kim J, Park W-Y, Vizcarra P, Fernandez-Banet J, Nichols T, Ram S, Lee SK, Kim SW, Lee JE, Ching KA, Kim J-Y, Ahn JS, Im Y-H, Nam SJ, Park YH. Multi-omics and immuno-oncology profiling reveal distinct molecular signatures of young Asian breast cancers [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-05-15.