Serological Biomarkers in Metastatic Breast Cancer: History
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Contributor:
Leonel Pekarek
,
Alicia Sánchez Cendra
,
Eduardo D. Roberts Cervantes
,
Cristina Sánchez Cendra
,
Oscar Fraile-Martinez
,
Cielo García-Montero
,
Raul Diaz-Pedrero
,
Diego Torres-Carranza
,
Laura Lopez-Gonzalez
,
Soledad Aguado-Henche
,
Antonio Rios-Parra
,
Luis M. García-Puente
,
Natalio García-Honduvilla
,
Julia Bujan
,
Melchor Alvarez-Mon
,
Miguel A. Saez
,
Miguel A. Ortega

Breast cancer is one of the most common malignancies worldwide and the most common form of cancer in women. A large proportion of patients begin with localized disease and undergo treatment with curative intent, while another large proportion of patients debuts with disseminated metastatic disease. In the last subgroup of patients, the prognosis in recent years has changed radically, given the existence of different targeted therapies thanks to the discovery of different biomarkers. Serological, histological, and genetic biomarkers have demonstrated their usefulness in the initial diagnosis, in the follow-up to detect relapses, to guide targeted treatment, and to stratify the prognosis of the most aggressive tumors in those with breast cancer. Molecular markers are currently the basis for the diagnosis of metastatic disease, given the wide variety of chemotherapy regions and existing therapies.

  • metastatic breast cancer
  • serum biomarkers
  • histopathological biomarkers
  • MicroRNA

1. Introduction. Epidemiology, Diagnosis, Molecular Classification, and Prognosis of Metastatic Breast Cancer

Breast cancer is the most common form of cancer in our population and the leading cause of cancer-related death in women in most developed and undeveloped countries. In 2022, approximately 3 million cases of breast cancer were diagnosed worldwide, and more than 600,000 deaths occurred in the same period, representing approximately 13% of all malignancies diagnosed worldwide [1]. In women, breast cancer accounts for a quarter of all neoplasms diagnosed, with an overall incidence of 50 cases per 100,000 women [2]. It should be noted that there are differences within developed countries with regard to incidence, with Belgium having the highest rate of diagnosis at 113 cases per 100,000 women [3]. In recent decades, there has been a 30–40% increase in the incidence of breast cancer due to the systematic implementation of mammography screening programs in at-risk age groups, which has allowed the detection of disease at earlier stages and has undoubtedly improved the prognosis [4]. Different risk factors have been described, of which several stand out. For example, age is a major risk factor for metastatic breast cancer (MBC). Women over 50 years of age are at higher risk than younger women. Studies have also found a higher incidence of MBC in post-menopausal women. A family history of breast cancer is another risk factor for MBC; women with a family history of breast cancer have an increased chance of developing it. Previous diagnosis of breast cancer is also an indicator of potential risk [5]. Women who have already been diagnosed with breast cancer are at higher risk for MBC. The risk increases depending on the stage of the initial cancer, the presence of metastasis, and the type of treatment received. Certain gene mutations, such as BRCA1 and BRCA2, TP53, CDH1, PTEN, and STK11, can greatly increase the risk of MBC [6]. Mutations to these genes can be either inherited or acquired over a person’s lifetime. Another risk factor is obesity and being overweight which is associated with a greater risk of developing MBC, even in women with no family history of the disease, and it is related to a worse prognosis [7]. Studies have found a correlation between excessive and regular alcohol consumption and an increased risk of developing MBC. This association is especially true for women aged 55 and over [8]. Long-term use of hormone replacement therapies, such as birth control pills or hormone replacement therapy (HRT), has been associated with an increased risk of developing MBC [9]. These are just some of the risk factors associated with MBC. Today, the prognosis has undoubtedly improved following the implementation of screening programs. Breast cancer screening is important because it can detect cancer at an early stage when treatment is most effective. In this regard, the U.S. Preventive Services Task Force (USPSTF) has developed guidelines for breast cancer screening that are widely used by healthcare professionals. The 2021 guidelines recommend that women at average risk of breast cancer should begin mammography screening at age 50 and continue to be screened every two years until age 74 [10].
Diagnosis of breast cancer begins with a physical examination and imaging tests of the breast, such as a mammogram or ultrasound, to detect any suspicious lumps or areas of thickening. If a lump is found, the next step is usually a needle biopsy to obtain tissue samples from the area in question, which are examined microscopically for cancer cells [11]. Additional tests may include MRI (magnetic resonance imaging) for high-risk patients (such as BRCA-positive mutations), CT (computed tomography), or PET (positron emission tomography) scans to obtain additional information on the extent of the cancer and whether it has spread to other areas of the body [12]. All imaging tests allow stratification of the extent of the disease according to tumor size, lymphatic extension, and distant dissemination. Approximately 64% of women are diagnosed with local involvement, 27% with regional involvement (locoregional lymph node involvement), and 6% are diagnosed at an advanced stage. Regardless of the diagnostic staging, histological and pathological markers are essential to classify the type of neoplasm [13][14].
At present, the expression of hormone receptors and HER2/neu (also known as ErbB-2 tyrosine kinase) are used for molecular classification with different therapeutic and prognostic implications. The classification proposed by Kapp et al. explains that 71% represent the HER2-negative group with positive hormone receptors, while 12% are positive for both markers (HER2 and hormone receptors), another 12% are negative for both markers and are the worst prognostic group, and 5% are only positive for HER2 [15][16]. As with the diagnostic classification, the treatment of MBC can be divided according to the expression of different molecular markers, given the existence of targeted therapies. In HER2-negative metastatic tumors with positive hormone receptors, the first-line treatment is based on hormone blockade with aromatase inhibitors or an antiestrogen associated with a CDK 4/6 inhibitor, such as palbociclib. In triple-negative tumors, it is important to assess PD-L1 status in order to administer immunotherapy. In November 2020, the FDA granted accelerated approval to pembrolizumab, an anti-PD-L1 antibody, in combination with chemotherapy for the treatment of patients with metastatic TNBC whose tumors express PD-L1 (CPS ≥ 10), and in the case of null PD-L1 expression, therapy is based on chemotherapy, although with limited clinical benefit [17]. In addition, it is important to assess BRCA1 and BRCA2 expression in these patients, given the clinical benefit of administering poly ADP ribose polymerase (PARP) inhibitors as targeted therapy, which has changed the prognosis of these patients. On the other hand, in HER2-positive metastatic tumors, the first-line treatment is based on trastuzumab, pertuzumab, and chemotherapy with taxanes [18]. It should be noted that MBC presents numerous lines of treatment, highlighting the different clinical trials that are currently being carried out that demonstrate the usefulness of new therapies, such as the combination of conjugated antibodies with chemotherapy such as trastuzumab deruxtecan [19].

2. Serological Markers in Metastatic Breast Cancer

Over time, different biomarkers have been incorporated into the study and development of cancer treatments. These biomarkers have been gradually introduced into clinical practice at different levels of care (early detection and diagnosis, prognostic and predictive factors, etc.). They can be measured both in the tumor tissue itself and in biological samples. There are different detection techniques, such as immunohistochemistry, fluorescence in situ hybridization (FISH), or polymerase chain reaction (PCR), for sequencing genetic material. Nowadays, more precise and productive techniques, such as Next-Generation Sequencing (NGS), which performs an exhaustive analysis of the genetic material through the sequencing of multiple DNA fragments in parallel, are being used [20]. This technique has the limitation that it is not available in all centers. On the other hand, multigene panels such as Oncotype DX and MammaPrint have been commonly used to assess the risk of breast cancer recurrence and the benefits of targeted therapy [21]. In recent years, techniques such as liquid biopsy have been developed in which researchers can study, through a blood test, the presence or absence of certain genetic mutations in relation to a tumor process [22]. Mutations in either of the type 1 or 2 breast cancer susceptibility genes (BRCA1 and BRCA2) account for the majority of hereditary breast cancers. Numerous mutations in these genes have been identified that affect proper DNA repair and cause irregularities in DNA synthesis [23].
In general, pathogenic variants in these genes are implicated in approximately 15 percent of women with familial breast cancer [24], with an autosomal dominant inheritance pattern, a particularly early disease onset, and a higher incidence of tumors of other organs, such as the fallopian tubes, prostate, or pancreas. Therefore, patients carrying these mutations should be offered surveillance with imaging studies or analytical controls from time to time [25].
Knowing whether patients are carriers of this mutation is predictive because therapies such as olaparib are approved by the Food and Drug Administration (FDA) for the treatment of patients with HR+/HER2− MBC with germline BRCA mutations [26].
As for tumor markers in breast cancer, those molecules that researchers can detect in blood and whose presence can guide us in the diagnosis of a given tumor have a sensitivity of 25–30% in locoregional tumors and 75–85% in metastatic tumors [25]. They are not very specific, so they are not useful for diagnosis or screening, and their main application is to monitor disease progression and/or response to a given treatment.

2.1. Serological CA15-3. Most Clinical Marker Used in MBC

In many patients with breast tumors, the production of carbohydrate antigen 15-3 (CA 15-3) and carbohydrate antigen 27-29 (CA 27-29) is increased [27]. Therefore, guidelines from the American Society of Clinical Oncology (ASCO) expert panel suggest that it is reasonable to assess markers such as CA 15-3 and CA 27-29 initially in patients with metastatic disease. If CA 15-3 and/or CA 27-29 are elevated, there would be no need to monitor other markers, but if not, serial measurement of carcinoembryonic antigen (CEA) levels may be useful [28][29]. CA 15-3 is a protein naturally produced by breast cells; it binds to the high-molecular-weight DF3 antigen located at the apical border of breast epithelial cells. Its elevation varies according to the type of disease; therefore, its measurement is not useful in all cases. This marker is elevated in less than 50% of women with localized or early breast cancer but is elevated in 80% of cases of advanced breast cancer, and in some individuals, it is not detected at any stage of the disease [30][31]. CA 15-3 may be elevated in other cancers (colon, lung, pancreatic, ovarian, or prostate) and in other non-tumor situations (cirrhosis, hepatitis, and benign breast disease). The increase in CA 15-3, the first sign of tumor recurrence in 37% of patients with metastases, has been demonstrated by authors such as De Cock et al. in 730 patients, which shows its importance in the follow-up of these patients [32].

2.2. Serological CA 27-29. Supporting Serological Monitoring

In this sense, another of the markers that have gained importance in recent years is CA 27-29. CA 27-29, also known as MUC-1 (mucin 1), is a large transmembrane glycoprotein expressed on the surface of various epithelial cells. Overexpression of CA 27-29 has been observed in breast cancer cells, particularly in advanced stages of the disease. Elevated serum levels of CA 27-29 have been associated with tumor burden and metastatic spread in breast cancer patients [33]. Several studies have shown that CA 27-29 levels may be useful for monitoring disease progression in patients with MBC and have shown that an increase in CA 27-29 levels may precede radiological evidence of disease progression, suggesting that it may serve as an early indicator of treatment failure or tumor recurrence. In this regard, CA 27-29 levels have been found to correlate with treatment response in patients with MBC. For example, a decrease in CA 27-29 levels after systemic treatment, such as chemotherapy or targeted therapy, may indicate a favorable response, while persistently elevated or rising levels may suggest resistance or lack of response to treatment [34]. On the other hand, elevated CA 27-29 levels have been associated with a worse prognosis in patients with MBC. Higher baseline CA 27-29 levels may predict shorter progression-free survival and overall survival in these patients, underlining its potential as a prognostic marker [35].
Although serological markers offer a non-invasive approach to monitoring MBC, their diagnostic and prognostic utility as stand-alone markers remains limited. The low sensitivity and specificity of these markers can lead to false-positive or false-negative results. Combining several markers or incorporating them into a panel with other diagnostic tools, such as imaging and histopathology, may increase their clinical utility. In conclusion, further research is needed to identify new serological markers and explore their potential in personalized medicine. The integration of serological markers with tumor molecular profiling and advances in liquid biopsy technology may pave the way for improved diagnostic and prognostic tools in the treatment of MBC.

This entry is adapted from the peer-reviewed paper 10.3390/ijms24098396

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