scholarly journals Heterogeneity of Breast Cancer Associations with Common Genetic Variants inFGFR2according to the Intrinsic Subtypes in Southern Han Chinese Women

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Huiying Liang ◽  
Xuexi Yang ◽  
Lujia Chen ◽  
Hong Li ◽  
Anna Zhu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative ◽  
Chinese Women ◽  
Intrinsic Subtype ◽  
Han Chinese ◽  
Dependent Manner ◽  
Intrinsic Subtypes ◽  
Luminal A ◽  
Luminal B ◽  
Common Genetic Variants

GWAS have identified variation in theFGFR2locus as risk factors for breast cancer. Validation studies, however, have shown inconsistent results by ethnics and pathological characteristics. To further explore this inconsistency and investigate the associations ofFGFR2variants with breast cancer according to intrinsic subtype (Luminal-A, Luminal-B, ER−&PR−&HER2+, and triple negative) among Southern Han Chinese women, we genotyped rs1078806, rs1219648, rs2420946, rs2981579, and rs2981582 polymorphisms in 609 patients and 882 controls. Significant associations with breast cancer risk were observed for rs2420946, rs2981579, and rs2981582 with OR (95% CI) per risk allele of 1.19 (1.03–1.39), 1.24 (1.07–1.43), and 1.17 (1.01–1.36), respectively. In subtype specific analysis, above three SNPs were significantly associated with increased Luminal-A risk in a dose-dependent mannerPtrend<0.01; however, only rs2981579 was associated with Luminal-B, and none were linked to ER−&PR− subtypes (ER−&PR−&HER2+ and triple negative). Haplotype analyses also identified common haplotypes significantly associated with luminal-like subtypes (Luminal-A and Luminal-B), but not with ER−&PR− subtypes. Our results suggest that associations ofFGFR2SNPs with breast cancer were heterogeneous according to intrinsic subtype. Future studies stratifying patients by their intrinsic subtypes will provide new insights into the complex genetic mechanisms underlying breast cancer.

scholarly journals Associations of Genetic Variants at Nongenic Susceptibility Loci with Breast Cancer Risk and Heterogeneity by Tumor Subtype in Southern Han Chinese Women

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Huiying Liang ◽  
Hong Li ◽  
Xuexi Yang ◽  
Lujia Chen ◽  
Anna Zhu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Triple Negative ◽  
Chinese Women ◽  
Intrinsic Subtype ◽  
Han Chinese ◽  
Susceptibility Loci ◽  
Luminal A ◽  
Luminal B

Current understanding of cancer genomes is mainly “gene centric.” However, GWAS have identified some nongenic breast cancer susceptibility loci. Validation studies showed inconsistent results among different populations. To further explore this inconsistency and to investigate associations by intrinsic subtype (Luminal-A, Luminal-B, ER−&PR−&HER2+, and triple negative) among Southern Han Chinese women, we genotyped five nongenic polymorphisms (2q35: rs13387042, 5p12: rs981782 and rs4415084, and 8q24: rs1562430 and rs13281615) using MassARRAY IPLEX platform in 609 patients and 882 controls. Significant associations with breast cancer were observed for rs13387042 and rs4415084 with OR (95% CI) per-allele 1.29 (1.00–1.66) and 0.83 (0.71–0.97), respectively. In subtype specific analysis, rs13387042 (per-allele adjusted OR = 1.36, 95% CI = 1.00–1.87) and rs4415084 (per-allele adjusted OR = 0.82, 95% CI = 0.66–1.00) showed slightly significant association with Luminal-A subtype; however, only rs13387042 was associated with ER−&PR−&HER2+ tumors (per-allele adjusted OR = 1.55, 95% CI = 1.00–2.40), and none of them were linked to Luminal-B and triple negative subtype. Collectively, nongenic SNPs were heterogeneous according to the intrinsic subtype. Further studies with larger datasets along with intrinsic subtype categorization should explore and confirm the role of these variants in increasing breast cancer risk.

Stage, biology, and age.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e11512-e11512
Author(s):  
Hee Jeong Kim ◽  
Beom Seok Ko ◽  
Jong Han Yu ◽  
jong Won Lee ◽  
Byung Ho Sohn ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Lymph Node ◽  
Triple Negative ◽  
Medical Center ◽  
Intrinsic Subtype ◽  
Young Age ◽  
Tnm Stage ◽  
Intrinsic Subtypes ◽  
Luminal A ◽  
Survival Difference

e11512 Background: Breast cancer subtypes are prognostic and predictive for patients. In this study, prognostic value of TNM stage, intrinsic subtype, and age were compared. Methods: We analyzed results from 7,626 breast cancer patients registered on the Asan medical center database between 1999 and 2009. We compared survival according to the TNM stage, intrinsic subtype using ER, PR, Her2- immunohistochemical staining, and age. Results: Luminal A subtype showed the best survival rates while triple negative subtype showed the worst survival rate amongst intrinsic subtypes. Survival analysis showed that Stage I triple negative breast cancer showed better survival compared to Stage III Luminal A subtype breast cancer (89.0% vs 76.6% P<0.001). Survival differences between intrinsic subtypes were more significant in lymph node positive breast cancer compared to lymph node negative breast cancer. Age did not affect survival between stages and intrinsic subtypes except for the young age subgroup (≤35), for whom there was no survival difference amongst intrinsic subtypes. Conclusions: Staging of breast cancer showed a more direct correlation to survival than known prognosis for intrinsic subtypes, as advanced, good prognostic intrinsic subtype breast cancer had worse survival than early, worse prognostic intrinsic subtype breast cancer. However for the young age group (≤35), the survival of all intrinsic subtypes were similar.

Breast cancer intrinsic subtypes by PAM50 in older women.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 1524-1524
Author(s):  
Emily Oldham Jenkins ◽  
Allison Mary Deal ◽  
Carey K. Anders ◽  
Aleix Prat ◽  
Charles M. Perou ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Biology ◽  
Continuous Variable ◽  
Intrinsic Subtype ◽  
Intrinsic Subtypes ◽  
Luminal A ◽  
Prognostic Information ◽  
Luminal B ◽  
Kaplan Meier ◽  
Treatment Data

1524 Background: Breast cancer (BC) incidence dramatically increases with age and the number of older BC patients (pts) in the U.S. is rising. Although immunohistochemical (IHC) data confirm that the incidence of luminal BC increases with age while the incidence of triple negative (TN) BC decreases, age-specific data on the frequency of BC subtypes defined by gene expression is limited. We characterized the incidence of BC intrinsic subtypes using gene microarrays according to age. Methods: Data from 2,150 pts were pooled from publicly available microarray datasets to determine the incidence of PAM50 breast cancer intrinsic subtypes (Luminal A [LumA], Luminal B [LumB], HER2-enriched [Her2E], Basal-like [Basal] and Normal-like [Norm]) by age. Adjuvant treatment data (none, chemotherapy, endocrine therapy or both) were available for 1,741 samples. Relapse-free (RFS) and overall survival (OS) differences were determined using the Kaplan-Meier method. Results: PAM50 intrinsic subtypes by age are tabulated below. The incidence of luminal (A, B, A+B) tumors increased with age (p<0.01, p<0.0001, p<0.0001, respectively), while the percentage of basal tumors decreased (p<0.0001). Basal tumors represented 13% of pts aged > 70 years (yrs); of the 70% with available IHC data, 74% were TNBC. Age as a continuous variable was not associated with RFS (p = 0.37). Subtype alone (n=2031), and after controlling for treatment (n=1645), was significantly associated with RFS (both p<0.0001). The addition of age to a multivariate analysis added no prognostic information. Conclusions: Though more favorable subtypes increase with age, older BC pts still have a substantial percentage of high-risk subtypes. Age alone was not a significant factor in outcome. Tumor biology as defined by intrinsic subtype is an important clinical predictor. [Table: see text]

scholarly journals Re-definition of claudin-low as a breast cancer phenotype

2019 ◽  
Author(s):  
Christian Fougner ◽  
Helga Bergholtz ◽  
Jens Henrik Norum ◽  
Therese Sørlie
Keyword(s):  
Breast Cancer ◽  
Breast Cancer Subtype ◽  
Breast Tumors ◽  
Intrinsic Subtype ◽  
Intrinsic Subtypes ◽  
Luminal A ◽  
Diverse Range ◽  
Luminal B ◽  
Cancer Phenotype ◽  
Definition Of

The claudin-low breast cancer subtype is defined by gene expression characteristics and encompasses a remarkably diverse range of breast tumors. Here, we investigate genomic, transcriptomic, and clinical features of claudin-low breast tumors. We show that claudin-low is not simply a subtype analogous to the intrinsic subtypes (basal-like, HER2-enriched, luminal A, luminal B and normal-like) as previously portrayed, but is a complex additional phenotype which may permeate breast tumors of various intrinsic subtypes. Claudin-low tumors were distinguished by low genomic instability, mutational burden and proliferation levels, and high levels of immune and stromal cell infiltration. In other aspects, claudin-low tumors reflected characteristics of their intrinsic subtype. Finally, we have developed an alternative method for identifying claudin-low tumors and thereby uncovered potential weaknesses in the established claudin-low classifier. In sum, these findings elucidate the heterogeneity in claudin-low breast tumors, and substantiate a re-definition of claudin-low as a cancer phenotype.Contact informationC.F. [email protected]. [email protected]. [email protected]. [email protected]

scholarly journals Inflammatory Breast Cancer: Clinical Characteristics and Influence of Molecular Subtypes on Treatment Response

2021 ◽  
Vol 107 (1_suppl) ◽  
pp. 12-12
Author(s):  
D Aissaoui ◽  
M Bohli ◽  
R Ben Amor ◽  
J Yahyaoui ◽  
A Hamdoun ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Treatment Response ◽  
Inflammatory Breast Cancer ◽  
Hormone Receptor ◽  
Triple Negative ◽  
Molecular Subtypes ◽  
Luminal A ◽  
Her2 Positive ◽  
Luminal B ◽  
Significant Difference

Introduction: Inflammatory Breast Cancer (IBC) is a rare and very aggressive breast cancer with poor prognosis. The prevalence is different from a country to another. In Tunisia, it is about 5 to 7% of breast cancer. The aim of this study is to describe the epidemiological and histopathological features of patients with inflammatory breast cancer and to evaluate the treatment response according to the molecular subtypes. Methods: This retrospective review identified 31 patients with no metastatic IBC treated in our radiotherapy department between December 2019 and November 2020. IBC was confirmed using the clinical criteria. Baseline clinic-pathological and treatment information was retrieved from medical records. Statistical analysis was performed with IBM SPSS V.20. Results: Median age was 51.3 years [27-68]. 48% of tumors were grade 3. The average tumor size was 36mm [10-90]. The histological type was ductal carcinoma in 97%. Vascular invasion was noted in 24 patients (77%). Thirty patients were classified as stage IIIB and one patient was IIIC. 74% were hormone receptor positive and 45% were HER2 positive. Luminal B was the predominant subtype (52%) followed by Her2 positive (32%), Luminal A (23%), and triple negative (3%) All patients had chemotherapy: neoadjuvant for 26 patients (84%) and adjuvant for 5 patients (16%). Nine patients (29%) had tumor pathological complete response (pCR). Partial response was observed in 18 patients (58%). Lymph node pCR was noted in 16% of cases (n=5). Endocrine therapy and trastuzumab were given to 76% and 45% of patients, respectively. The influence of the molecular subtype was not statistically significant on the response to neoadjuvant treatment. The highest rate of pCR were 43% for Her2positive, then 27%, 21% and 9% for Luminal B, Luminal A and Triple negative, respectively (p=0.2). Conclusion: Our study showed a high percentage of hormone receptor and Her2+ (74% and 45% respectively) in IBC. Luminal B was the most frequent subtype. Anthracycline-based chemotherapy and trastuzumab improved the pCR rate: 44% for Her2positive. Triple negative showed poorer pCR than other breast cancer subtype without a significant difference. A larger study is warranted to confirm our findings.

scholarly journals Diffusion-Weighted Imaging of Different Breast Cancer Molecular Subtypes: A Systematic Review and Meta-Analysis

Breast Care ◽  
2021 ◽  
pp. 1-8
Author(s):  
Hans-Jonas Meyer ◽  
Andreas Wienke ◽  
Alexey Surov
Keyword(s):  
Breast Cancer ◽  
Systematic Review ◽  
Diffusion Weighted Imaging ◽  
Triple Negative ◽  
Molecular Subtypes ◽  
Luminal A ◽  
Diagnose Breast Cancer ◽  
Luminal B ◽  
Diffusion Weighted ◽  
Adc Values

Background: Magnetic resonance imaging can be used to diagnose breast cancer (BC).Diffusion-weighted imaging (DWI) and the apparent diffusion coefficient (ADC) can be used to reflect tumor microstructure. Objectives: This analysis aimed to compare ADC values between molecular subtypes of BC based on a large sample of patients. Method: The MEDLINE library and Scopus database were screened for the associations between ADC and molecular subtypes of BC up to April 2020. The primary end point of the systematic review was the ADC value in different BC subtypes. Overall, 28 studies were included. Results: The included studies comprised a total of 2,990 tumors. Luminal A type was diagnosed in 865 cases (28.9%), luminal B in 899 (30.1%), human epidermal growth factor receptor (Her2)-enriched in 597 (20.0%), and triple-negative in 629 (21.0%). The mean ADC values of the subtypes were as follows: luminal A: 0.99 × 10–3 mm2/s (95% CI 0.94–1.04), luminal B: 0.97 × 10–3 mm2/s (95% CI 0.89–1.05), Her2-enriched: 1.02 × 10–3 mm2/s (95% CI 0.95–1.08), and triple-negative: 0.99 × 10–3 mm2/s (95% CI 0.91–1.07). Conclusions: ADC values cannot be used to discriminate between molecular subtypes of BC.

Trends in breast cancer mortality according to molecular subtypes: A population-based study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 572-572
Author(s):  
Yunan Han ◽  
Shuai Xu ◽  
Graham A. Colditz ◽  
Adetunji T. Toriola
Keyword(s):  
Breast Cancer ◽  
Cancer Mortality ◽  
Triple Negative ◽  
Molecular Subtypes ◽  
Breast Cancer Mortality ◽  
Treatment Strategies ◽  
Luminal A ◽  
Her2 Positive ◽  
Mortality Trends ◽  
Luminal B

572 Background: Breast cancer is the second leading cause of cancer death in U.S. women. On the molecular level, breast cancer is a heterogeneous disease. Heterogeneous expressions of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) are etiologically and clinically meaningful, as they map to distinct risk factors and different treatment strategies. Although breast cancer mortality has been declining since 1990, little is known about mortality trends according to molecular subtypes at the population level. Methods: We examined the incidence-based mortality rates and trends among women who were diagnosed with invasive breast cancer from 2010 through 2017 using the Surveillance, Epidemiology, and End Results (SEER) database. We defined incidence-based mortality using a moving 5-year calendar period starting in 2014. We further assessed mortality according to breast cancer molecular subtypes: luminal A (ER and/or PR positive, HER2 negative), luminal B (ER and/or PR positive, HER2 positive), HER2-enriched (HER2 over-expressed or amplified, ER and PR negative) and triple-negative (ER and PR negative, HER2 negative) tumors. We calculated annual percent changes (APC) in incidence-based mortality using joinpoint regression models. Results: Overall, incidence-based mortality for breast cancer significantly decreased by 1.5% annually from 2014 through 2017 (APC, -1.5%; 95% coefficient interval [CI], -2.3% to -0.7%; p<0.001). Incidence-based mortality decreased annually by 2.0% for luminal A breast cancer (APC, -2.0%; 95% CI, -3.7% to -0.3%; p<0.001), 2.1% for luminal B breast cancer (APC, -2.1%; 95% CI, -5.4% to 1.4%; p=0.1), 1.1% for triple-negative breast cancer (TNBC) (APC, -1.1%; 95% CI, -2.1% to -0.0%; p<0.001). However, incidence-based mortality for HER2-enriched breast cancer increased 2.3% annually during the study period (APC, 2.3%; 95% CI, -2.4% to 7.2%; p=0.2). Conclusions: Between 2014 and 2017, incidence-based mortality for luminal A, luminal B, and TNBC decreased among U.S. women, with a larger decrease observed for luminal tumors. However, incidence-based mortality for HER2-enriched breast cancer increased. The favorable incidence-based mortality trends for luminal tumors and TNBC are likely due to the continuing improvement in treatments and early detection. The increasing trend of incidence-based mortality for HER2-enriched breast cancer constitutes a priority for cancer control activities and further research.

scholarly journals Low KIBRA Expression Is Associated with Poor Prognosis in Patients with Triple-Negative Breast Cancer

Medicina ◽  
2021 ◽  
Vol 57 (8) ◽  
pp. 837
Author(s):  
So-Woon Kim ◽  
Jinah Chu ◽  
Sung-Im Do ◽  
Kiyong Na
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Poor Prognosis ◽  
Triple Negative ◽  
Histological Grade ◽  
Growth Factor Receptor ◽  
Hippo Signaling ◽  
Luminal A ◽  
Luminal B ◽  
Epidermal Growth

Background and Objectives: Kidney and brain protein (KIBRA) is a protein encoded by the WW and C2 domain containing 1 (WWC1) gene and is involved in the Hippo signaling pathway. Recent studies have revealed the prognostic value of KIBRA expression; however, its role in breast cancer remains unclear. The aim of this study was to examine KIBRA expression in relation to the clinical and pathological characteristics of patients with breast cancer and to disease outcomes. Materials and Methods: We analyzed the expression of KIBRA and its correlation with event-free survival (EFS) outcomes in resected samples from 486 patients with breast cancer. Results: KIBRA expression was significantly different among the molecular subgroups (low KIBRA expression: luminal A, 46.7% versus 50.0%, p = 0.641; luminal B, 32.7% versus 71.7%, p < 0.001; human epidermal growth factor receptor 2 (HER2)-enriched, 64.9% versus 45.5%. p = 0.001; triple-negative, 73.6% versus 43.8%, p < 0.001). Low KIBRA expression was also associated with high nuclear grade (60.4% versus 37.8%, p < 0.001), high histologic grade (58.7% versus 37.0%, p < 0.001), and estrogen receptor (ER) negativity (54.2% versus 23.6%, p < 0.001). Low KIBRA expression was significantly associated with poor EFS (p = 0.041; hazard ratio (HR) 1.658; 95% confidence interval (CI), 1.015–2.709). Low KIBRA expression was an independent indicator of poor prognosis (p = 0.001; HR = 3.952; 95% CI = 1.542–10.133) in triple-negative breast cancer (TNBC). Conclusion: Low KIBRA expression was associated with higher histological grade, ER negativity and poor EFS of breast cancer. In particular, our data highlight KIBRA expression status as a potential prognostic marker for TNBC.

scholarly journals Analysis of prolactin receptor expression in breast cancer subtypes

2020 ◽  
Vol 66 (1) ◽  
pp. 89-94
Author(s):  
T.S. Kalinina ◽  
V.V. Kononchuk ◽  
S.V. Sidorov ◽  
L.F. Gulyaeva
Keyword(s):  
Breast Cancer ◽  
Triple Negative ◽  
Prolactin Receptor ◽  
Mrna Level ◽  
Receptor Expression ◽  
Mrna Levels ◽  
Luminal A ◽  
Her2 Positive ◽  
Tissue Samples ◽  
Luminal B

Breast cancer (BC) is the most common cancer among women. It is known that the prolactin receptor (PRLR) may play a role in breast carcinogenesis, but the available data are often contradictory. To get a more complete picture of the relationship between the receptor and mammary gland carcinogenesis, we examined the association between changes in PRLR expression level and tumor subtype (and its main characteristics). To do this, using real-time PCR, we evaluated the level of PRLR mRNA in BC tissue samples and untransformed adjoining tissue samples (89 pairs). Since the androgen receptor (AR) has begun to be seen as a prognostic marker in breast cancer, we also evaluated the association between mRNA levels of AR and PRLR. We found a significant increase in PRLR expression in luminal subtypes; the highest level of PRLR mRNA was detected in luminal A subtype. In HER2-positive ER-, PR-negative BC, the PRLR mRNA level decreases in tumor tissues compared with untransformed tissues. High PRLR expression is also associated with smaller tumor size in luminal B HER2-negative subtype. In ER-, PR-negative tumors, PRLR expression is associated with AR expression: PRLR mRNA level is increased when AR mRNA level is reduced by more than 8 times in triple-negative tumors; in contrast, in HER2-positive subtype it decreases more significantly when AR expression is reduced by more than 3 times. A tendency towards an increase in PRLR expression with an increase in the AR mRNA level was also discovered in luminal subtypes. The level of PRLR expression depends on the age of patients. In luminal A, PRLR expression is higher in patients under 65 years. In contrast, in luminal B HER2-negative and triple-negative BC, reduced PRLR expression was observed in patients under the age of 40 years and under the age of 50 years, respectively. In this group of patients under the age of 40 years with luminal B HER2-negative BC, ER expression was also reduced (0-4 score according to the IHC assay). Thus, PRLR probably plays a different role in the development and progression of BC: in luminal A and luminal B HER2-positive subtypes PRLR may act as an oncogen, and in luminal B HER2-negative and ER-, PR-negative subtypes can play a tumor suppressor role.

scholarly journals Apparent diffusion coefficient cannot predict molecular subtype and lymph node metastases in invasive breast cancer: a multicenter analysis

BMC Cancer ◽  
2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Alexey Surov ◽  
Yun-Woo Chang ◽  
Lihua Li ◽  
Laura Martincich ◽  
Savannah C. Partridge ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Diffusion Coefficient ◽  
Triple Negative ◽  
Molecular Subtype ◽  
Luminal A ◽  
Ki 67 ◽  
Luminal B ◽  
Apparent Diffusion ◽  
Adc Values ◽  
Her 2

Abstract Background Radiological imaging plays a central role in the diagnosis of breast cancer (BC). Some studies suggest MRI techniques like diffusion weighted imaging (DWI) may provide further prognostic value by discriminating between tumors with different biologic characteristics including receptor status and molecular subtype. However, there is much contradictory reported data regarding such associations in the literature. The purpose of the present study was to provide evident data regarding relationships between quantitative apparent diffusion coefficient (ADC) values on DWI and pathologic prognostic factors in BC. Methods Data from 5 centers (661 female patients, mean age, 51.4 ± 10.5 years) were acquired. Invasive ductal carcinoma (IDC) was diagnosed in 625 patients (94.6%) and invasive lobular carcinoma in 36 cases (5.4%). Luminal A carcinomas were diagnosed in 177 patients (28.0%), luminal B carcinomas in 279 patients (44.1%), HER 2+ carcinomas in 66 cases (10.4%), and triple negative carcinomas in 111 patients (17.5%). The identified lesions were staged as T1 in 51.3%, T2 in 43.0%, T3 in 4.2%, and as T4 in 1.5% of the cases. N0 was found in 61.3%, N1 in 33.1%, N2 in 2.9%, and N3 in 2.7%. ADC values between different groups were compared using the Mann–Whitney U test and by the Kruskal-Wallis H test. The association between ADC and Ki 67 values was calculated by Spearman’s rank correlation coefficient. Results ADC values of different tumor subtypes overlapped significantly. Luminal B carcinomas had statistically significant lower ADC values compared with luminal A (p = 0.003) and HER 2+ (p = 0.007) lesions. No significant differences of ADC values were observed between luminal A, HER 2+ and triple negative tumors. There were no statistically significant differences of ADC values between different T or N stages of the tumors. Weak statistically significant correlation between ADC and Ki 67 was observed in luminal B carcinoma (r = − 0.130, p = 0.03). In luminal A, HER 2+ and triple negative tumors there were no significant correlations between ADC and Ki 67. Conclusion ADC was not able to discriminate molecular subtypes of BC, and cannot be used as a surrogate marker for disease stage or proliferation activity.

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