Luminal Type Research Articles

The impact of tumour biology on the management of primary breast cancer in older women—based on a research programme in Nottingham

: The incidence of breast cancer increases with age. Average life expectancies are increasing; the older population is expanding globally. This presents a huge challenge on an international scale in the coming years as more older people are living with breast cancer. Despite this, most research in this field remains focused in younger patients. In this article, we outline the current issues facing understanding of the biology of primary breast cancer in older women with regards to treatment decision making. The main treatment dilemmas concern (I) primary treatment [surgery versus non-operative therapies in estrogen receptor (ER) positive and negative tumours] and (II) adjuvant treatment (such as endocrine therapy or chemotherapy). We then discuss work in this field from the Nottingham Breast Cancer Research Centre, which includes biological assessment of a large (N=1,758) cohort of older (aged ≥70 years) women with primary breast cancer with long-term follow-up data. At a biological level, we understand breast cancer belongs to four main subtypes [luminal A, luminal B, human epidermal growth factor receptor 2 (HER2) over-expression, or triple negative breast cancer (TNBC)], with treatment plans based upon these. The Nottingham group have found a biological cluster unique to older women with primary breast cancer (low ER luminal type), which is not seen in their younger (<70 years) counterparts, as well as differences between age and clinical outcome in patients with ER-positive, HER2-positive and TNBC. This adds further evidence that the biology of breast cancer in older women is different to that of younger women and therefore, should be treated as such.

Usefulness of Staging Chest CT in Breast Cancer: Evaluating Diagnostic Yield of Chest CT According to the Molecular Subtype and Clinical Stage.

The aim of this study is to investigate the clinical utility of staging chest CT in breast cancer by evaluating diagnostic yield (DY) of chest CT in detection of metastasis, according to the molecular subtype and clinical stage. This retrospective study included 840 patients with 855 breast cancers from January 2017 to December 2018. The number of patients in clinical stage 0/I, II, III and IV were 457 (53.5%), 298 (34.9%), 92 (10.8%) and 8 (0.9%), respectively. Molecular subtype was identified in 841 cancers and there were 709 (84.3%) luminal type, 55 (6.5%) human epidermal growth factor receptor 2 (HER2)-enriched type and 77 (9.2%) triple-negative (TN) type. The DYs in clinical stage 0/I, cII, cIII and cIV were 0.2% (1/457), 1.7% (5/298), 4.3% (4/92) and 100.0% (8/8), respectively. The DYs in luminal type, HER2-enriched type and TN type were 1.7% (12/709), 3.6% (2/55) and 2.6% (2/77), respectively. Clinical stage was associated with the DY (p = 0.000). However, molecular subtype was not related to the DY (p = 0.343). Molecular subtype could not provide useful information to determine whether staging chest CT should be performed in early-stage breast cancer. However, chest CT should be considered in advanced breast cancer.

Abstract PS18-50: Single-cell transcriptomic analysis reveals tumor microenvironment in male breast cancer

Abstract Objectives: Male breast cancer (MBC) is a rare aggressive malignant tumor that accounts for only 1% of all breast cancers and has a worse prognosis compared with female breast cancer (FBC). However, little is unveiled regarding the mechanisms of MBC occurrence and development, and there is a lack of relevant basic research and clinical studies at a global scale. The rapid development of single-cell transcriptomic technologies has helped uncover the heterogeneity within cell populations and tumor microenvironment, as well as the clonal evolution of breast cancer cells. This study aims to explore: (1) the tumor microenvironment of MBC; (2) the heterogeneity of male/female breast cancer cells and cell subgroup differences; (3) the potential specific therapeutic targets and biological characteristics differences between MBC and FBC. Methods: Single-cell transcriptome sequencing (scRNA-seq) and single cell sequencing of T cell receptors (scTCR-seq) combined with whole genome sequencing (WGS) and immunohistochemical staining were performed to deeply analysis the heterogeneity and clonal evolution of MBC, reveal the tumor microenvironment, especially the composition and function of tumor infiltrating immune cells. We performed scRNA-seq using fresh samples from three luminal type MBC patients and two post-menopausal luminal type FBC patients. Firstly, t-SNE dimensionality reduction analysis was conducted according to different genders, different patients and subpopulation of cells, and gene expression profiles were processed and visualized using heatmap. Moreover, through comprehensive analysis of scRNA-seq and scTCR-seq results of MBC and FBC, we further explored the characteristics, interrelation and dynamic changes of various types of cells in the tumor interior, and then mined novel specific therapeutic targets. Results: Based on the single cell sequencing results, we observed a striking difference in cell subsets distribution and gene expression profiles between MBC and FBC. The cell subsets were then sorted by the proportion of MBC tumor cells, and 7 subsets were selected as potential MBC specific cellular subpopulation. Further comparative analysis with Luminal type of post-menopausal FBC samples suggested that fatty acid synthase (FASN) expression was remarkably elevated in MBC, and the overall survival was significantly decreased in MBC patients with high FASN expression. Meanwhile, MBC tumors were found to have lower rates of immune cell infiltration and higher proportion of exhausted T cells, which were also validated by immunohistochemical staining of 160 cases of pathological sections. Surprisingly, we also observed the presence of some “intermediate cells”only in MBC specimens, which exhibited simultaneous expression of cancer epithelial cell marker KRT8 and T cell marker CD3E. These “intermediate cells”showed immunosuppressive status. Conclusion: In this study, we found that the high expression of FASN and the lipid metabolism pathway may play important roles in the MBC development, providing theoretical foundation and experimental basis for further clinical trials of FASN inhibitors, as well as precision therapy and prognostic evaluation for MBC. Meanwhile, further study of the “intermediate cells” may facilitate the discovery of novel tumor immune escape strategies. Our findings also played a role in promoting the comprehensive description of tumor microenvironment of MBC and the mechanism study of its occurrence and development. Key words: male breast cancer, single-cell sequencing, tumor microenvironment, intermediate cells, fatty acid synthase Citation Format: Handong Sun, Zhonglin Wang, Yanhui Zhu, Chuang Yang, Qianghu Wang, Jifu Wei, Qiang Ding. Single-cell transcriptomic analysis reveals tumor microenvironment in male breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS18-50.

Abstract PS13-07: Neoadjuvant adriamycin plus cyclophosphamide followed by docetaxel (AC4-D4) vs 5-fluorouracil, epirubicin plus cyclophosphamide followed by docetaxel (FEC3-D3) in stage II or III operable breast cancer : Randomized phase III neo-shorter trial (NCT02001506)

Abstract Background: Two neoadjuvant anthracycline and taxane containing chemotherapy regimens have been widely used. The objective of the study was shorter duration of 6 cycles of FEC3-D3 is comparable to 8 cycles of AC4-D4 Method: Enrolled patients (pts) were diagnosed clinically stage II or III breast cancer between November 2012 and December 2015 at Asan Medical Center, Seoul, Korea. Pts were stratified according to hormone receptor and HER2 expression status and randomized 1:1 to AC4-D4 and FEC3-D3 arm. The primary endpoint was pathologic complete response (pCR) and the secondary end points were 3 year disease-free survival (3Y DFS) and toxicities.Result: Among 252 pts enrolled, 1pt ineligible for screening; 10 pts discontinued treatment due to progressive disease (7 pts in AC4-D4 arm and 3 pts in FEC3-D3), 17 pts dropped out due to withdrawal of written consent and 2 pts unable to complete study. Two hundred twenty two pts receiving surgery were included for this analysis. Baseline characteristics are well balanced between two arms- median age (47 vs 48), % of TNBC (24% vs 26%) in AC4-D4 (N=126) vs FEC3-D3 arm (N=125) respectively. Baseline median Ki-67 labeling index was 50% (range, 10%-90%). By ITT analysis, pCR was achieved in 18/126 (14.3%) pts of AC4-D4 arm and 15/125 (12.0%) pts in FEC3-D3 arm, respectively (p=0.17). According to per protocol, in AC4-D4 arm, 95/103 pts achieved clinical response (6 complete response [CR] and 89 partial response [PR]) and among them 18 pts (17.5%) achieved pCR. In FEC3-D3 arm, 97/119 pts achieved clinical response (4 CR and 93 PR) and among them 15 pts (12.6%) achieved pCR. With a median follow up of 64.1 months, 3Y DFS (77.0% in AC4-D4 vs. 74.9% in FEC3-D3) was comparable between two arms (p=0.79). The most common adverse event (AE) was Grade 3/4 neutropenia. 44/126 (34.9%) pts in AC4-D4 arm vs 39/125 (31.2%) pts in FEC3-D3 arm. The most common Grade 3/4 non-hematologic AE was hyperglycemia (3.2%). Dose modification was done in 37/126 (29.4%) pts in AC4-D4 arm and 25/125 (20.0%) pts in FEC3-D3 arm, respectively (p=0.09). Multivariate analyses showed that ≥50% of baseline Ki-67 labeling index [hazard ratio (HR) 2.1 (95% confidence interval (CI),1.20-3.72; p=0.009)], ≥40% of pre-treatment Ki-67 labeling index reduction after neoadjuvant chemotherapy(NACT) [HR 2.1 (95% CI,1.20-3.66; p=0.01)], and ≥4 lymph node metastases at surgery [HR 2.2 (95% CI,1.24-3.80; p=0.07)] were independent predictive factors for 3Y DFS. Of note, in patients with non-pCR, ≥ 40% reduction of Ki-67 after NACT was associated with better 3Y DFS in luminal type [HR 2.9 (95% CI,1.51-5.65; p=0.001)]. Conclusion: Both NACT AC4-D4 and FEC3-D3 showed comparable outcomes in terms of pCR, 3 year DFS and toxicities. ≥50% of baseline Ki-67 labeling index and ≥40% reduction of Ki-67 labeling index after NACT were independent for 3Y DFS. Shorter neo-adjuvant FEC3-D3 could be an alternative to AC4-D4 in stage II or III operable breast cancer.Keywards: Neoadjuvant, AC followed by docetaxel, FEC followed by docetaxel, operable breast cancer Citation Format: Inhwan Hwang, Jeong Eun Kim, Jae Ho Jeong, Jin-Hee Ahn, Kyung Hae Jung, Byung Ho Son, Sei-Hyun Ahn, Hee Jin Lee, Gyungyub Gong, Sung-Bae Kim. Neoadjuvant adriamycin plus cyclophosphamide followed by docetaxel (AC4-D4) vs 5-fluorouracil, epirubicin plus cyclophosphamide followed by docetaxel (FEC3-D3) in stage II or III operable breast cancer : Randomized phase III neo-shorter trial (NCT02001506) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS13-07.

Abstract PS1-15: Does breast cancer subtype impact margin status in patients undergoing partial mastectomy?

Abstract BACKGROUND: It is known that breast cancer subtype (e.g., luminal vs. triple negative (TN)) can affect response to systemic therapy and prognosis; however, it is less well-understood whether these subtypes affect margin status and should therefore alter surgical management. METHODS: Data from two randomized trials evaluating cavity shave margins (CSM) on margin status in patients undergoing partial mastectomy (PM) were used for this analysis. The data were restricted to patients who had invasive carcinoma present in the PM specimen, and in whom data for all three receptors (ER, PR and HER-2) were known. Patients were classified as luminal if they were ER and/or PR+, HER-2 enriched if they were ER and PR negative but HER-2 positive, and TN if they were negative for all three receptors. We evaluated the impact of subtype on the margin status at the time the surgeon had completed their standard PM, prior to randomization to CSM vs. no CSM. Non-parametric statistical analyses were performed using SPSS Version 26. RESULTS: 350 patients were included in this cohort for analysis. The median patient age was 64 (range; 32-94 years) and the median invasive tumor size was 1.2 cm (range; 0.6-8.0 cm). 326 (93.1%) were luminal type, 22 (6.3%) were triple negative, and 2 (0.6%) were HER-2 enriched. Subtype was significantly correlated with race (black patients were more likely to have TN disease than white patients, 22.2% vs. 3.8%, p=0.001), palpability (TN tumors were more likely to be palpable than luminal cancers 54.5% vs. 29.8%, p=0.007) and grade (78.9% of TN cancers were high grade vs. 13.5% of luminal cancers p&amp;lt;0.001). Subtype did not correlate with Hispanic ethnicity, node positivity, nor lymphovascular invasion (p&amp;gt;0.05 for all). While patients with TN and HER-2 enriched tumors were more likely to receive neoadjuvant therapy, this did not reach statistical significance (p=0.117). Surgeons were no more likely to take selective margins on the basis of molecular subtype (p=0.413). In this cohort, the overall positive margin rate was 33.7%. This did not vary based on molecular subtype (positive margin rate: 33.7% for patients with luminal tumors vs. 36.4% for those with TN tumors, p=0.425). On multivariate regression controlling for molecular subtype, race, grade and palpability, the only factor which predicted positive margin status was grade (p=0.005), with high grade tumors being significantly more likely to have a positive margin than low grade tumors, independent of other factors (OR=3.503, 95% CI: 1.638-7.494, p=0.001). CONCLUSION: While molecular subtype correlates with race, tumor grade and palpability, it does not predict margin status. Therefore, molecular subtype should not, independent of other factors, influence surgical decision-making. Citation Format: Andrew Fenton, Elisabeth Dupont, Theodore Tsangaris, Carlos Garcia-Cantu, Marissa Howard-McNatt, Akiko Chiba, Adam Berger, Edward Levine, Jennifer Gass, Kristalyn Gallagher, Sharon Lum, Ricardo Martinez, Alliric Willis, Sonali Pandya, Eric Brown, Amanda Mendiola, Mary Murray, Naveenraj Solomon, Maheswari Senthil, David Ollila, David Edmonson, Melissa Lazar, Jukes Namm, Fangyong Li, Meghan Butler, Noreen McGowan, Maria Herrera, Yoana Avitan, Brian Yoder, Laura Walters, Tara McPartland, Victor Haddad, Hongwei Ma, Ming Xie, Anees Chagpar. Does breast cancer subtype impact margin status in patients undergoing partial mastectomy? [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS1-15.

Abstract PS5-19: Exploratory biomarker analysis of Young-PEARL [palbociclib plus exemestane with GnRH agonist versus capecitabine in premenopausal women with HR (hormone receptor)-positive, HER2-negative metastatic breast cancer (MBC)] study

Abstract Background: Young-PEARL study showed median progression-free survival (PFS) of 20·1 months in the palbociclib plus endocrine therapy group versus 14·4 months in the capecitabine group (hazard ratio 0·659 [95% CI 0·437-0·994], log-rank p=0·0235). We conducted exploratory biomarker analysis to predict the efficacy of the trial. Methods: This was a phase II trial that randomized 184 patients with HR+ MBC in premenopausal women to palbociclib plus exemestane with GNRH agonist (Arm A, n=79) versus capecitabine (Arm B, n=62). We performed targeted sequencing (CancerSCANTM) containing 375 cancer-related genes (141 patients) and whole transcriptome sequencing (165 patients) using baseline tumor samples to examine genomic alteration in relation to drug response in terms of PFS. Result: By research-based PAM50 subtyping, 73% of patients classified as Luminal (Luminal A and Luminal B), and showed better prognosis in all patients and Arm A (p&amp;lt;0.05) in compared to no survival difference in Arm B (p=0.284). PFS difference between LumA and LumB was not statistically significant in Arm A (p=0.196). PIK3CA mutation (41%), TP53 mutation (33%), GATA3 mutation (25%), CCDN1 CNV (29%), BRCA2 mutation (14%) were the most frequently detected in this population. High TMB, TP53 mutation, ClinVar pathogenic somatic BRCA2 mutation (3.5%) showed worse prognosis in Arm A (p&amp;lt;0.05). Non-luminal patients with TP53 or BRCA2 mutations were poor prognosis in Arm A. Patients with BRCA2 pathogenic mutations showed worse prognosis regardless PAM50 subtypes, and luminal patients showed longer PFS compared to non-luminal patients among patients without BRCA2 pathogenic mutations in Arm A. RB1 loss, known as a resistant biomarker of CDK4/6 inhibitor was found in 4% of Arm A, and was associated with shorter PFS (log2 HR=2.26, 95% CI 0.51 to 4.01, p=0.011). AURKA mutation/amplification and RAD51C amplification were significantly associated to the patients with PFS less than 6 month. ESR1 mutations were found in 3.5% of patients, which was less than PEARL (29.4%) and PALOMA-3 (25.1%) trials. ESR1 mutations and ESR1/2 expression were not associated with shorter PFS. Notch 2/3/4 pathway expression was lower in patients with longer PFS (PFS more than 20month). ETIMATE ImmuneScore was higher in non-luminal compared to luminal patients, and didn’t show survival difference in Arm A, but luminal patients with low ImmuneScore showed better prognosis. The relative proportion of 22 immune cell types was deconvoluted by CIBERSORT, and T cell CD4 memory resting, Macrophage M0 and M2 were abundant. NK cell activated was higher proportion in patients with longer PFS. Low TIL patients with low interferon and high T cell regulation expression showed worse prognosis. Germline BRCA mutation and integrated analyses of genomic and transcriptomic profiles will be reported. Conclusions: The alteration of a few genes including Rb1 loss may be associated with resistance of palbociclib in HR-positive premenopausal population with MBC. Luminal type showed better prognosis, and BRCA2 pathogenic mutation showed worse prognosis regardless luminal/non-luminal type. ESR1 mutation was found in low population frequency because all patients didn’t received AI therapy. Further exploration of molecular variables is warranted to determine and validate biomarkers of efficacy. Clinical trial information: NCT02592746. Citation Format: Kyunghee Park, Gun Min Kim, Kyung Hae Jung, Seok Yun Kang, In Hae Park, Jee Hyun Kim, Hee Kyung Ahn, Woong-Yang Park, Seock-Ah Im, Yeon Hee Park. Exploratory biomarker analysis of Young-PEARL [palbociclib plus exemestane with GnRH agonist versus capecitabine in premenopausal women with HR (hormone receptor)-positive, HER2-negative metastatic breast cancer (MBC)] study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS5-19.

Expression and Gene Regulation Network of Metabolic Enzyme Phosphoglycerate Mutase Enzyme 1 in Breast Cancer Based on Data Mining

The metabolic enzyme phosphoglycerate mutase enzyme 1 (PGAM1) is a key enzyme in the glycolysis pathway, and glycolysis is closely related to cancer progression, suggesting that PGAM1 may have important functions in breast cancer. We used sequencing data from the Oncomine database and UALCAN database to analyze the expression of PGAM1 and its influence on the clinicopathological characteristics of breast cancer. LinkedOmics was used to identify genes related to PGAM1 expression, kinases, miRNAs, and transcription factors that were significantly related to PGAM1 through GSEA. cBioPortal was used to identify the alternation frequency and form of PGAM1 in breast cancer. The expression level of PGAM1 in breast cancer was significantly higher than that in normal tissues. Moreover, the expression level of PGAM1 is closely related to the molecular subtype and TP53 mutation status. The expression level of PGAM1 in HER2-positive and triple-negative tumors was significantly higher than that of luminal type. The expression level of PGAM1 in TP53-mutant tumors was higher than that in non-TP53-mutant tumors. In addition, the overall survival of patients with high PGAM1 expression was significantly worse than that of patients with low expression ( P = 0.0077 ). Through GSEA analysis, we found multiple kinases, miRNAs, and transcription factors significantly related to PFKFB4. cBioPortal analysis showed that the mutation rate of PGAM1 in breast cancer was relatively low (4%), and the main form of mutation was high mRNA expression. This study suggests that PGAM1 is a potential diagnostic and prognostic marker in breast cancer. Through data mining, we revealed the potential regulatory network information of PGAM1, laying a foundation for further research on the role of PGAM1 in breast cancer.

Comparative stemness and differentiation of luminal and basal breast cancer stem cell type under glutamine-deprivation.

Glutamine (gln) metabolism has emerged as a cancer therapeutic target in past few years, however, the effect of gln-deprivation of bCSCs remains elusive in breast cancer. In this study, effect of glutamine on stemness and differentiation potential of bCSCs isolated from MCF-7 and MDAMB-231 were studied. We have shown that bCSCs differentiate into CD24+ epithelial population under gln-deprivation and demonstrated increased expression of epithelial markers such as e-cadherin, claudin-1 and decreased expression of mesenchymal protein n-cadherin. MCF-7-bCSCs showed a decrease in EpCAMhigh population whereas MDAMB-231-bCSCs increased CD44high population in response to gln-deprivation. The expression of intracellular stem cell markers such sox-2, oct-4 and nanog showed a drastic decrease in gene expression under gln-deprived MDAMB-231-bCSCs. Finally, localization of β-catenin in MCF-7 and MDAMB-231 cells showed its accumulation in cytosol or perinuclear space reducing its efficiency to transcribe downstream genes. Conclusively, our study demonstrated that gln-deprivation induces differentiation of bCSCs into epithelial subtypes and also reduces stemness of bCSCs mediated by reduced nuclear localization of β-catenin. It also suggests that basal and luminal bCSCs respond differentially towards changes in extracellular and intracellular gln. This study could significantly affect the gln targeting regimen of breast cancer therapeutics.

L-type amino acid transporter 1 is associated with chemoresistance in breast cancer via the promotion of amino acid metabolism.

18F-FDG PET/CT has been used as an indicator of chemotherapy effects, but cancer cells can remain even when no FDG uptake is detected, indicating the importance of exploring other metabolomic pathways. Therefore, we explored the amino acid metabolism, including L-type amino acid transporter-1 (LAT1), in breast cancer tissues and clarified the role of LAT1 in therapeutic resistance and clinical outcomes of patients. We evaluated LAT1 expression before and after neoadjuvant chemotherapy and examined the correlation of glucose uptake using FDG-PET with the pathological response of patients. It revealed that LAT1 levels correlated with proliferation after chemotherapy, and amino acid and glucose metabolism were closely correlated. In addition, LAT1 was considered to be involved in treatment resistance and sensitivity only in luminal type breast cancer. Results of in vitro analyses revealed that LAT1 promoted amino acid uptake, which contributed to energy production by supplying amino acids to the TCA cycle. However, in MCF-7 cells treated with chemotherapeutic agents, oncometabolites and branched-chain amino acids also played a pivotal role in energy production and drug resistance, despite decreased glucose metabolism. In conclusion, LAT1 was involved in drug resistance and could be a novel therapeutic target against chemotherapy resistance in luminal type breast cancer.

The clinical behavior of different molecular subtypes of breast cancer

BackgroundBreast cancer is a heterogeneous group of tumors classified, according to different gene expressions that encodes for the hormone receptor status, into 4 main categories which are: luminal types A and B, triple negative/basal-like, and Her-2 molecular subtypes. Patients and methodsThis retrospective study included 311 breast cancer females. Patients were classified according to the expression of hormone receptors into: Luminal-A, luminal-B, HER-2 enriched and basal-like types. All groups were then studied for differences in clinical course of the disease. ResultsLuminal-B type was the commonest molecular type (43.73%). Invasive ductal carcinoma was the commonest histological type (89.1%). Stages IIB and IIIA were the commonest clinical stages (24.4% & 22.2%) respectively. Most patients had no recurrence (85.5%), the commonest recurrence was local and axillary ones (7.1%). Low grade tumors were less frequent than intermediate and high grades (3.5%, 51.1%, and 45.3%). We found a significant correlation between molecular subtypes and survival status, tumor grade, and histopathological types (P values 0.029, 0.001, and 0.006) respectively, while it was not significant with age, BMI, recurrence & metastatic disease, overall survival, and TNM stage (P values 0.648, 0.398, 0.5, 0.063 and 0.319). ConclusionLuminal types A and B are the commonest molecular subtypes of breast cancer. Luminal type A is associated with improved survival, and basal like has the highest breast cancer fatality rates. Invasive ductal carcinomas of specific types mostly found in patients with luminal types A and B, while other rare forms like Paget's disease was diagnosed HER-2 enriched types.

Evaluation of Post-Neoadjuvant Chemotherapy Pathologic Complete Response and Residual Tumor Size of Breast Cancer: Analysis on Accuracy of MRI and Affecting Factors

목적신보강화학요법을 시행한 유방암 환자에서 병리학적 관해와 잔류 암의 크기를 평가하는 데 있어 유방자기공명영상의 정확도를 분석하고 이에 영향을 미치는 인자들이 무엇인지 알아본다.대상과 방법2010년부터 2017년까지 본원에서 신보강화학요법 후 수술을 시행한 88명의 유방암 환자를 대상으로 하였다. 병리학적 관해는 수술 병리 결과에서 침윤성 유방암이 발견되지 않는 것으로 정의하였고 자기공명영상과 병리 조직의 잔류 암 크기 차이는 최대 직경으로 비교하였다. 병리학적 관해 및 자기공명영상과 병리 조직에서의 잔류 암 크기 차이에 영향을 미치는 인자를 알아보기 위해 통계분석을 시행하였다.결과전체 환자의 10%가 병리학적 관해에 도달하였다. 자기공명영상으로 관해를 예측할 때의 정확도와 곡선하부면적은 각각 90.91%, 0.8017이었다. 신보강화학요법 시행 후 유방자기공명영상과 병리 조직에서 측정한 잔류 암의 크기는 매우 강한 연관성을 보였고(r = 0.9, p < 0.001), 특히 영상에서 단일 종괴로 보였던 병변에서(p = 0.047) 그러하였다. 자기공명영상과 병리 조직 간의 잔류 암 크기는 내강형(p = 0.023), 그리고 자기공명영상에서 다초점 종괴 및 비종괴성 조영증강을 보인(p = 0.047) 환자군에서 유의미하게 큰 차이를 보였다.결론자기공명영상은 유방암의 병리학적 완전 관해와 잔류 암 크기의 평가에 있어서 정확도가 높은 검사이다. 유방암 아형과 병변의 영상의학적 소견이 자기공명영상의 정확도에 영향을 미친다.

Relation Between Tumor Size and Lymph Node Metastasis According to Subtypes of Breast Cancer.

PurposeTumor size and lymph node metastasis are important factors that contribute to the progression of breast cancer. We aimed to analyze the relationship between tumor size and lymph node metastasis molecular subtype and examine the effects of nodal metastasis on overall survival (OS).MethodsWe retrospectively reviewed the data of 16,552 patients who underwent breast surgery in Samsung Medical Center between 2000 and 2015. Information on tumor size (largest diameter of the invasive component), number of positive lymph nodes, and molecular subtype were obtained. We constructed a linear regression model to evaluate the relationship between tumor size and lymph node metastasis. To determine the effect of nodal metastasis on OS, we performed a Cox proportional regression analysis with Np/T (number of metastatic lymph nodes [n]/tumor size [cm]).ResultsThis study included 12,007 patients with a median follow-up of 62 months. The linear regression coefficients were 1.043 for luminal A, 1.024 for luminal B, 0.656 for HER2, and 0.435 for triple-negative breast cancer (TNBC) subtypes. No significant difference was observed in the coefficients between the luminal A and B subtypes (p = 0.797), while all other coefficients showed significant difference. After adjusting for other risk factors, the hazard ratio (HR) of Np/T for each subtype was significant for OS: luminal A (HR, 1.134; 95% confidence interval [CI], 1.097–1.171; p < 0.001), luminal B (HR, 1.049; 95% CI, 1.013–1.086; p = 0.007), HER2 (HR, 1.069; 95% CI, 1.014–1.126; p = 0.013), and TNBC (HR, 1.038; 95% CI, 1.01–1.067; p = 0.008).ConclusionThe incidence of lymph node metastasis differed according to molecular subtype. Luminal types have higher incidence of nodal metastasis than HER2 and TNBC. The HR of Np/T was highest in luminal A subtypes and lowest in TNBC subtypes.

Role of estrogen receptor-α and estrogen receptor-β expression in the disease outcome of invasive luminal type a breast carcinoma patients: A pilot study

Background: Estrogen receptor (ER)-α and ERβ, members of family of ERs are expressed in many breast tumors. However, their role in carcinogenesis and their association with regard to the prognosis are still under the investigation and unclear because of limited data. Aims: The present cross-sectional, observational pilot study was aimed to study the immunohistochemical expression and prognostic significance of ERα and ERβ in invasive luminal Type A breast carcinoma patients. Materials and Methods: Twenty-five old diagnosed cases of luminal Type A breast carcinoma diagnosed between 2012 and 2015 were included in the study. The expression of markers ERα and ERβ was correlated with the clinical characteristics and disease outcome in 2–7 years' follow-up period. Statistical analysis was performed by SPSS version 17.0 and graph pad PRISM 5.0 version. Results: Eleven cases out of 25 were both (ERα and ERβ) positive, whereas 1 case was both (ERα and ERβ) negative. Positivity with single marker was 12 for ERα and 20 for ERβ. Adverse outcomes, i.e., recurrence, distant metastasis, and death were reported in 10 cases (40%), 8 out of which were ERα negative cases. While ERα-positive expression alone or along with ERβ expression was shown to be associated with less adverse outcomes (2 out of 10, P = 0.005). Conclusions: When both ERα and ERβ expression is present, they appear to act as allies and together presents with the better prognosis in disease outcomes of breast cancer in our study cases.

Breast cancer molecular subtypes and receptor status among women at Potchefstroom Hospital: a cross-sectional study.

Introductionthis study aimed to determine the prevalence of receptor status and molecular subtypes in women with breast cancer treated at Potchefstroom Regional Hospital, South Africa and to analyze the association of molecular subtypes with some clinicopathologic characteristics of the tumor.Methodsthe study population for this cross-sectional study consisted of 116 women with primary invasive breast cancer, treated at the hospital from 1st January 2012 to 31st December 2018. Molecular subtypes were classified by immunohistochemical surrogates as luminal A (estrogen receptor (ER) positive and/or progesterone receptor (PR) positive, HER2-; Ki-67 <30%), luminal B HER2- (ER+ and/or PR+, HER2-; Ki-67 ≥30%), luminal B HER2+ (ER+ and/or PR+, HER2+; any Ki-67), HER2 enriched (ER- and PR-, HER2+; any Ki-67), or triple-negative (ER-, PR-, HER2-, any Ki-67).Resultsthe proportions of breast cancer receptor status of ER+, PR+ and HER2-, were 71.6%, 64.7% and 75.9%, respectively. The molecular subtypes of 29.3% of patients were luminal A-type, 24.1% were luminal B HER2-, 22.4% were triple-negative, 18.1% were luminal B HER2+ and 6% were HER2-enriched. Molecular subtypes were significantly associated with tumor grade (p <0.001; Cramér's V=0.337), but independent of age (p=0.847), menopausal status (p=0.690), histology type (p=0.316), cancer stage (p=0.819), lymph node status (p=0.362), or tumor size (p=0.255).Conclusionthe study has revealed that most of the breast cancer in our setting was receptor-positive; approximately one-quarter were triple-negative. Furthermore, the study showed that luminal type A and B are the preponderant molecular subtypes. Molecular subtypes were associated with tumor grade but independent of age and menopausal status. The current study may assist in guiding the therapeutic strategy for patients with breast cancer in the Potchefstroom hospital catchment area.

Triple-negative breast cancer. Modern molecular genetic concepts and their clinical significance

Triple negative breast cancer (BC) is a heterogeneous group of carcinomas that substantially differ in clinical, morphological, and molecular genetic characteristics, tumor response to chemotherapy, and prognosis. These features define triple negative BC today as a special clinical problem that has not yet been completely solved. The review is devoted to the description and systematization of the currently available literature data concerning molecular and genetic features and differences in a fairly significant group of breast carcinomas with a severe, aggressive course and an extremely poor prognosis. The review presents the existing molecular genetic classification of triple negative BC based on the results of studies conducted by M.D. Burstein (2015) and B.D. Lehmann (2016), which determines the presence of 4 tumor-specific subtypes: basal-like type (type 1 and type 2), mesenchymal, and luminal androgen receptor types. The paper reflects the main stages of transformation of the proposed classification over the past decade and an attempt has been make to describe the molecular characteristics of each subtype of these carcinomas.

Comparison with 2019 of breast surgery activity and breast cancer prognostic factors in a French cancer center during the first 6 months of the COVID-19 pandemic

Introduction The rapid spread of the COVID-19 pandemic left departments of surgery, especially in oncology unprepared. The diagnostic and therapeutic management of breast cancer in Paoli Calmettes Institute cancer center underwent a major reorganization. Methods This study aimed to describe whether there was a change in the rate of surgical activity and type of tumors treated since the beginning of the outbreak (year 2020 was divided into 3 periods: before March the 17th = P1, between March the 17th and May the 11th = P2, from May the 11th to July 31st = P3) and compared to 2019. Results Over the three periods, a 12.71% decrease in the overall breast cancer surgery activity (n = 967 vs 1062) and a 18.05% decrease in new breast cancer surgery (n = 709 vs 581) was observed. The second period (P2) was the most critical one in both situations. During P2 a higher rate of large tumors, grade SBR 3 and negative endocrine receptor tumors were observed, there was also fewer Luminal A-like histological type diagnosed , during P3 fewer cT0 tumors and finally during both P2 and P3 there was a higher rate of neo-adjuvant chemotherapy. Conclusion This challenging period led to the diagnosis of higher stage and more aggressive histological types of breast cancers subsequently leading to more aggressive treatments.

Investigation of Candidate Genes and Pathways in Basal/TNBC Patients by Integrated Analysis.

Purpose:This study aims to identify the key pathway and related genes and to further explore the potential molecular mechanisms of triple negative breast cancer (TNBC).Methods:The transcriptome data and clinical information of breast cancer patients were downloaded from the TCGA database, including 94 cases of paracancerous tissue, 225 cases of Basal like type, 151 cases of Her2 type, 318 cases of Luminal type A, 281 cases of Luminal type B, and 89 cases of Normal Like type. The differentially expressed genes (DEGs) were identified based on the criteria of |logFC|≥1.5 and adjust P < 0.001.Their functions were annotated by gene ontology (GO) analysis and Kyoto Encyclopedia of differentially expressed genes & Genomes (KEGG) pathway analysis. Cox regression univariate analysis and Kaplan-Meier survival curves (Log-rank method) were used for survival analysis. FOXD1, DLL3 and LY6D were silenced in breast cancer cell lines, and cell viability was assessed by CCK-8 assay. Further, the expression of FOXD1, DLL3 and LY6D were explored by immunohistochemistry on triple negative breast tumor tissue and normal breast tissue.Results:A total of 533 DEGs were identified. Functional annotation showed that DEGs were significantly enriched in intermediate filament cytoskeleton, DNA−binding transcription activator activity, epidermis development, and Neuroactive ligand−receptor interaction. Survival analysis found that FOXD1, DLL3, and LY6D showed significant correlation with the prognosis of patients with the Basal-like type (P < 0.05). CCK-8 assay showed that compared with Doxorubicin alone group, the cytotoxicity of Doxorubicin combined with siRNA-knockdown of FOXD1, DLL3, or LY6D was much significant.Conclusion:The DEGs and their enriched functions and pathways identified in this study contribute to the understanding of the molecular mechanisms of TNBC. In addition, FOXD1, DLL3, and LY6D may be defined as the prognostic markers and potential therapeutic targets for TNBC patients.

Black Hole Accretion Correlates with Star Formation Rate and Star Formation Efficiency in Nearby Luminous Type 1 Active Galaxies

Abstract We investigate the relationship between black hole accretion and star formation in a sample of 453 z ≈ 0.3 type 1 active galactic nuclei (AGNs). We use available CO observations to demonstrate that the combination of nebular dust extinction and metallicity provides reliable estimates of the molecular gas mass even for the host galaxies of type 1 AGNs. Consistent with other similar but significantly smaller samples, we reaffirm the notion that powerful AGNs have comparable gas content as nearby star-forming galaxies and that AGN feedback does not deplete the host of cold gas instantaneously. We demonstrate that while the strong correlation between star formation rate and black hole accretion rate is in part driven by the mutual dependence of these parameters on molecular gas mass, the star formation rate and black hole accretion rate are still weakly correlated after removing the dependence of star formation rate on molecular gas mass. This, together with a positive correlation between star formation efficiency and black hole accretion rate, may be interpreted as evidence for positive AGN feedback.

The ROSAT Raster survey in the north ecliptic pole field

The north ecliptic pole (NEP) is an important region for extragalactic surveys. Deep and wide contiguous surveys are being performed by several space observatories, most currently with the eROSITA telescope. Several more are planned for the near future. We analyse all the ROSAT pointed and survey observations in a region of 40 deg2 around the NEP, restricting the ROSAT field of view to the inner 30′ radius. We obtain an X-ray catalogue of 805 sources with 0.5−2 keV fluxes &gt; 2.9 × 10−15 erg cm−2 s−1, about a factor of three deeper than the ROSAT All-Sky Survey in this field. The sensitivity and angular resolution of our data are comparable to the eROSITA All-Sky Survey expectations. The 50% position error radius of the sample of X-ray sources is ∼10″. We use HEROES optical and near-infrared imaging photometry from the Subaru and Canada/France/Hawaii telescopes together with GALEX, SDSS, Pan-STARRS, and WISE catalogues, as well as images from a new deep and wide Spitzer survey in the field to statistically identify the X-ray sources and to calculate photometric redshifts for the candidate counterparts. In particular, we utilize mid-infrared (mid-IR) colours to identify active galactic nucleus (AGN) X-ray counterparts. Despite the relatively large error circles and often faint counterparts, together with confusion issues and systematic errors, we obtain a rather reliable catalogue of 766 high-quality optical counterparts, corresponding redshifts and optical classifications. The quality of the dataset is sufficient to look at ensemble properties of X-ray source classes. In particular we find a new population of luminous absorbed X-ray AGN at large redshifts, identified through their mid-IR colours. This populous group of AGN was not recognized in previous X-ray surveys, but could be identified in our work due to the unique combination of survey solid angle, X-ray sensitivity, and quality of the multi-wavelength photometry. We also use the WISE and Spitzer photometry to identify a sample of 185 AGN selected purely through their mid-IR colours, most of which are not detected by ROSAT. Their redshifts and upper limits to X-ray luminosity and X-ray–to–optical flux ratios are even higher than for the new class of X-ray selected luminous type 2 AGN (AGN2); they are probably a natural extension of this sample. This unique dataset is important as a reference sample for future deep surveys in the NEP region, in particular for eROSITA and also for Euclid and SPHEREX. We predict that most of the absorbed distant AGN should be readily picked up by eROSITA, but they require sensitive mid-IR imaging to be recognized as optical counterparts.

Molecular Subtyping of Triple Negative Breast Cancer by Surrogate Immunohistochemistry Markers.

Triple negative breast cancer (TNBC) is a heterogeneous disease and an attempt was made to classify TNBCs into surrogate molecular subtypes using immunohistochemical markers. Tissue microarrays were constructed for 245 cases of TNBCs. For classification of TNBCs immunohistochemistry was done on tissue microarrays for cytokeratin 5/6, 4/14 (CK5/6, CK4/14), epidermal growth factor receptor (EGFR), vimentin, E-cadherin, claudin 3 and 7, androgen receptor (AR) and aldehyde dehydrogenase1A. The TNBCs were classified into basal-like 1 (BL1) type (CK5/6+, CK4/14+, EGFR- n=32; 13.1%), basal-like 2 (BL2) type (EGFR+, n=4; 1.6%), mesenchymal type (Vimentin+, E-cadherin ̅, claudin 3-and 7-, n=70; 28.6%), luminal androgen type (AR+, n=41; 16.7%), mixed type (n=37; 15.1%), and unclassified type (n=61; 24.9%). Luminal androgen receptor subtype showed apocrine features, and was associated with older age group, lower proliferation index and high frequency of lymph node metastasis. Basal subtype was cellular with rich stromal lymphocytic infiltrate. Mesenchymal stem like subtype was associated with younger age group with metaplastic and mesenchymal features. Mesenchymal stem like and unclassified subtype had shorter overall survival with median of 68.2 and 69.2 months, respectively, and the BL2 had median disease-free survival of 35.4 months. On immunohistochemistry TNBC is a heterogeneous entity composed of 6 major subtypes. Immunohistochemical subtyping of TNBC can provide information on prognostication and selection of appropriate targeted therapy for these patients.