Elevated CA15-3 Levels in Myeloid Disorders: Clinicopathological Correlation

doi:10.21203/rs.3.rs-1315740/v1

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Research Article

Elevated CA15-3 Levels in Myeloid Disorders: Clinicopathological Correlation

https://doi.org/10.21203/rs.3.rs-1315740/v1

This work is licensed under a CC BY 4.0 License

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posted 22 Feb, 2022

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Background

Serum tumor markers are beneficial to patients with advanced cancer because they help in early diagnosis, determining prognosis, predicting response to certain medications, and monitoring therapy. The prognostic value of cancer antigen 15 − 3 (CA15-3) serum level changes in breast cancer is very well established. The main cause behind the elevation of CA 15 − 3 is metastatic breast carcinoma. In this study, we will run a record review to study comprehensively the clinical association between chronic myeloid disorders and CA15-3 elevation.

Method

In this retrospective study, we run CA15-3 on 106 patients with different myeloid disorders diagnosed between 2008 and 2021 from several tertiary care centers in Saudi Arabia, Jeddah. Majority of which (38 cases) were diagnosed with chronic myeloid leukemia (35.8%). Others had essential thrombocytosis (22.6%), chronic myeloproliferative neoplasm (20.8%), myelofibrosis (7.5%), acute myeloid leukemia (4.7%), myelodysplastic syndrome (4.7%) and polycythemia vera (3.8%).

Result

An increase in CA15-3 was seen in 50% of all cases. In particular, polycythemia vera showed an elevation in 100% of cases (4 out of 4). Second in expressivity is myelodysplastic syndrome (80%, 4 out of 5 cases). Close in value is myelofibrosis (75%, 6 out of 8 cases). The least association is noted between CA15-3 and essential thrombocytosis (16.7%, 4 out of 24 cases).

Conclusion

When CA 15–3 levels is considered during the time of myeloid disorder diagnosis, it shows an independent predictive value. More research is needed to determine the utility of these serum biomarkers in myeloid disorders decision-making. This is a through case series of chronic myeloid disorders inclusive of all myeloproliferative neoplasms besides myelodysplastic syndrome describing the association with CA15-3.

Both normal and malignant cells release tumor markers. When cancer is present, the levels are substantially greater. It is a low-cost, minimally intrusive diagnostic method. Yet, for it to be a viable technique of diagnosis, it must be able to detect tumors in their earliest stages.¹ To determine whether further care modifications should be made, tumor markers are also useful in assessing cancer prognosis following chemotherapy and radiotherapy.

CA 15 − 3 is a useful serum tumor marker for breast cancer. The incidence of breast cancer has been progressively growing throughout the years. When a patient treatment fails, their quality of life and their chances of survival are severely reduced.² To enhance the prognosis, it is vital to establish accurate indicators that may be used to guide treatment decisions. Breast cancer metastasis detection, prognosis assessment, treatment response prediction and disease recurrence rely heavily on CA15-3 serum tumor marker. As a result, CA15-3 has been the foremost broadly utilized serum tumor markers within the clinical fields for a long time.³

CA 15 − 3 is one of several chemicals known as tumor markers, which can rise as a cancer develops and regress as a tumor responds to treatment.⁴ CA 15 − 3 is a breast tissue antigen that is frequently measured. Other benign and malignant conditions according to certain researches can also express elevation in CA 15 − 3. The CA 15 − 3 levels can be also increased in chronic active liver disease, liver cirrhosis, sarcoidosis, hypothyroidism and megaloblastic anemia.⁵

CA15-3 Antigens are Y-shaped proteins that serve as a cell's unique "signature" in the body. Despite the fact that the CA 15 − 3 antigen does not cause cancer, it can develop in number as cancer cells that quickly grow. The extent of CA 15 − 3 antigens is directly proportional with the tumor growth rate. As a sign of disease progression (metastases to bone or liver), CA15-3 can be elevated as well. CA 15 − 3 antigens are elevated in the majority of metastatic breast carcinoma cases, in contrast to early stages where it has low incidence of elevation.⁶ For these reasons, CA 15 − 3 can be used to monitor breast cancer that has metastasized to other regions of the body at stage 4. In addition, the oncologist can analyze the effectiveness of a cancer treatment by monitoring CA 15 − 3 readings on a regular basis.

To our knowledge, there is no thorough case series inclusive of all myeloid disorders, particularly myelodysplastic syndrome outlining the association with CA15-3. Thus, the objective of this study was to investigate this association.

Alinity i CA 15-3 is a two-step chemiluminescent microparticle immunoassay from Abbott, designed to detect DF3 antigens in serum. Reactivity with two monoclonal antibodies is used to measure CA15-3 (generated against human milk fat globule membrane antigens). In this study, CA15-3 is conducted in 106 serum samples obtained from patients with different myeloid disorders at multiple referral centers. CA15-3 is flagged as high when it raises above 25 U/mL. The patients were diagnosed with bone marrow aspirate and trephine biopsy along with applicable flowcytometry molecular markers (i.e. JAK2 and BCR-ABL were utilized). This retrospective record review of clinical records was conducted after obtaining the unit of biomedical ethics – research committee approval.

A total of 53 out of 106 patients (50%) were noted to have elevated CA15-3. The aforementioned patients are breast cancer free. A diagnosis of polycythemia vera was found to be the mostly correlated (100% of patients). Closer values are depicted by myelodysplastic syndrome (80%) and myelofibrosis (75%). On the other hand, essential thrombocytosis shows the least percentage of relation (16.7%). [Table-1] Patients with elevated CA15-3 were 25 females and 29 males with an average age of 56 (range 13–91). [Table-2] Despite the fact that breast cancer is more common in females, CA15-3 high level has a weak association with gender as shown by Chi-Square test applied on our patients’ sample. [Table-3]

The CA 15 − 3 is an immunoassay that quantitatively measures DF3 antigen. CA 15 − 3 test parameters utilize the DF3 and 115D8 monoclonal antibodies, prepared against metastatic breast carcinoma and milk-fat globule membranes, respectively.^7–12 That explains the frequent elevation of CA 15 − 3 is encountered in patients with breast cancer. Researchers have recommended that the CA 15 − 3 assay may be useful for treatment response follow up as the values variability is directly correlated with disease progression.^7,13−18 Further publications stated that increasing CA 15 − 3 levels are detected in patients at risk for recurrent breast malignancy.^{14–16, 19}

Several benign breast and liver diseases demonstrated a rise in CA15-3. Additionally, non-mammary malignancies including lung, colon, pancreas, liver, ovary, cervix, and endometrium showed increased levels of CA15-3 as well. Most normal individuals have CA15-3 values within normal limit.^13,20,21

CA 15 − 3 is an epitope of (MUC1), a large transmembrane glycoprotein translated from MUC1 gene.²² Yin and colleagues investigated the effect of blocking MUC1 oncoprotein cytoplasmic tail to prompt terminal differentiation of chronic myelogenous leukemia cells.²³ Subsequently, Rughetti et al. described that CA15.3 (soluble MUC1) levels were higher in Ph-negative myeloproliferative chronic disorders patients, specifically more evident in polycythemia vera patients and in female cases.²⁴ In this study, our findings are concordant with the polycythemia vera association. In addition, it also highlights the association between CA15-3 and myelodysplastic syndrome, which may introduce CA15-3 as a potential targetable antigen for further studies.

The value of this marker can assist in diagnostic and prognostication. Yet, future studies are warranted in this direction.

Breast cancer is tracked by the CA 15 − 3 biomarker. The CA 15 − 3 antigen is a protein that cancer cells release into the bloodstream. Although the CA 15 − 3 antigen is intimately linked to breast cancer, it is also linked to other malignant and non-cancerous disorders. To our knowledge, this is the first comprehensive case series of myeloid disorders inclusive of myelodysplastic syndrome, showed this particular association. The raise in serum CA 15–3 levels is associated with a variety of myeloid disorders, especially polycythemia vera, myelodysplastic syndrome and myelofibrosis. Our work, we feel, will help shed light on potential hematological malignancies research efforts in the future.

Data Availability Statement:

All data generated or analysed during this study are included in this published article [Tables 1-3].

Statement of Ethics:

This study was approved by the Committee of Biomedical Ethics at King Abdulaziz University, Jeddah, KSA (No. 362-21). All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants involved in the study. Minor participants’ informed consent have been obtained from a parent and/or legal guardian.

Author Contribution Statement

Both authors designed research, performed research, contributed vital new reagents or analytical tools, analyzed data, and wrote the paper.

Conflict-of-Interest Disclosure

None of the authors has a relevant conflict of interest.

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Table-1: Relation between myeloid disorders and elevated CA15-3

Clinical diagnosis	Number of cases	Number of cases with high CA15-3	Percentage
Polycythemia Vera	4	4	100%
Myelodysplastic Syndrome	5	4	80%
Myelofibrosis	8	6	75%
Chronic myeloproliferative Neoplasm	22	13	59%
Chronic Myeloid Leukemia	38	21	55.3%
Acute myeloid Leukemia	5	1	20%
Essential thrombocytosis	24	4	16.7%
Total	106	53	50%

Table-2: Distribution of patients with elevated CA15-3.

GENDER
		Frequency	Percent
Valid	Female	24	45.3
	Male	29	54.7
	Total elevate CA15-3 cases	53	100.0

Table-3: Chi-Square test applied on our patients’ sample.

Chi-Square Tests
	Value	df	Asymptotic Significance (2-sided)
Pearson Chi-Square	5753.125^a	5656	.180
Likelihood Ratio	813.189	5656	1.000
Linear-by-Linear Association	.070	1	.792
N of Valid Cases	105
a. 5814 cells (100.0%) have expected count less than 5. The minimum expected count is .01.

No competing interests reported.

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posted 22 Feb, 2022

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Elevated CA15-3 Levels in Myeloid Disorders: Clinicopathological Correlation

Status:

Version 1

Abstract

Background

Method

Result

Conclusion

Introduction

Methods

Result

Discussion

Conclusion

Declarations

References

Tables

Competing Interests

Status:

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