IL-6 as a predictor of survival rate in liver metastatic breast cancer patients with Covid-19 infection: A case series

Abstract

Introduction and importance

Breast cancer is the most common type of cancer in women, with 30 % being metastatic breast cancer. Cancer is known to be a comorbid Covid-19 infection. Interleukin-6 (IL-6) is one of the findings of inflammatory activity due to Covid-19 infection. We report IL-6 levels as a prognostic factor for survival rate in patients with liver metastatic breast cancer.

Case presentation

We report five cases of liver metastatic breast cancer with various types of primary breast cancer. All patients are infected with Covid-19. IL-6 levels were reported to be elevated in all five patients. All patients were treated according to the national guidelines for the care of Covid-19 patients. All patients are reported to have deceased after being treated for Covid-19 infection.

Clinical discussion

Metastatic breast cancer has a low prognostic rate. Cancer has been recognized as one of the comorbidities and increases the severity and mortality of Covid-19 infection. Elevated levels of IL-6 are caused by an immune response to infection, and can worsen the outcome of breast cancer patients. Changes in IL-6 levels implicate the survival rate of metastatic breast cancer patients and outcomes during the treatment of Covid-19 infection.

Conclusion

Elevated levels of IL-6 can be a prognostic factor of the survival rate of metastatic breast cancer patients during the treatment of Covid-19 infection.

Highlights

• •Breast cancer is the most common type of cancer in women, with 30% of them being metastatic breast cancer.
• •The liver is the third most common target for cancer cell metastasis.
• •Covid-19 infection can initiate an immune response and worsen the outcome of patients with comorbidities, one of which is cancer.
• •Interleukin 6 (IL-6) is one type of proinflammatory cytokine that arises as a result of the immune response to Covid-19 infection.
• •In this case series report, changes in IL-6 levels can be a predictor of survival in patients with liver metastatic breast cancer.

1. Introduction and importance

Breast cancer is the second most common type of cancer in the world and is the most common type of cancer in women [1]. 30 % of breast cancer cases have non-nodular metastases, with the liver being the third most common location. Breast cancer metastases [2]. Covid-19 infection is caused by the SARS-CoV-2 virus, which is part of the coronavirus family [3]. The SARS-CoV-2 virus can initiate immune response through the activation of Th1 cells producing proinflammatory cytokines (Interleukin (IL)-1β, IL-6, IL-8, tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ)) to response viral infections [4]. Covid-19 infection is known to induce a cytokine storm resulting from the immune response process, which impacts the worsening of patients with comorbid diseases, one of which is cancer [5]. One of the immune responses that are often found in cancer patients with Covid-19 is IL-6 [6]. Although there have been many studies reporting the use of IL-6 as a predictive factor in the survival rate of cancer patients [7,8], there have been no studies reporting predictive factors for survival in breast cancer patients with liver metastases, especially in patients infected with Covid-19. We report IL-6 levels as a predictor of survival in liver metastatic breast cancer with SARS-CoV-2 patients between 2020 and 2022 were being managed at one of the national tertiary hospitals, located in Surakarta, Central Java, Indonesia. This case series were managed by surgeons and surgeons oncology from this hospital. This case series complies with SCARE and PROCESS guidelines [9,17].

2. Case presentation

2.1. Case 1

A 43-year-old woman presented with grade III invasive lobular nuclear carcinoma and LVI. At the time of examination, the patient was hypoxemic and received 10 L oxygen therapy via a non-rebreathing mask. The patient was infected with COVID-19 in March 2022 on hydroxychloroquine, oseltamivir, and azithromycin therapy. The patient presented with an altered mental status and worsening shortness of breath. While hospitalized, laboratory findings showed IL-6 level reached 21.76 pg/mL. One month before hospital admission, an ultrasound examination of the abdomen showed liver metastases. There was no evidence to suggest a bacterial infection. The patient's condition worsened as the hypoxia and hypotension worsened. The results of the patient's liver enzymes did not return to normal during treatment. The patient's condition continued to deteriorate clinically, eventually died from complications after 5 days hospitalization.

2.2. Case 2

A 59-year-old woman presented with ductal epithelial breast cancer and LVI. At the time of examination, this patient looked confused and had received 10 L oxygen therapy through a non-rebreathing mask. This woman was a patient with breast cancer and had undergone complete chemotherapy. The patient was infected with COVID-19 in February 2022 on hydroxychloroquine, favipiravir, and azithromycin therapy. The patient came with a state of altered mental status. While hospitalized, laboratory findings showed the patient's IL-6 level was 19.86 pg/mL. One month before admission to the hospital, an ultrasound examination of the abdomen showed liver metastases. The patient's condition continued to deteriorate clinically, and she eventually died from complications after 6 days hospitalization.

2.3. Case 3

A 50-year-old woman had grade III invasive ductal carcinoma and LVI. At the time of examination, this patient had decreased oxygen saturation to 96 % and received 10 L oxygen therapy through a non-rebreathing mask. This woman had undergone chemotherapy. The patient was infected with COVID-19 in February 2022 on hydroxychloroquine, oseltamivir, and azithromycin therapy. While hospitalized, laboratory findings showed IL-6 level was 20.11 pg/mL. One month before admission to the hospital, an ultrasound examination of the abdomen showed liver metastases. There was no evidence to suggest a bacterial infection. The patient's condition worsened as the hypoxia and hypotension worsened. The patient's condition continued to deteriorate clinically and eventually died from complications after 6 days hospitalization.

2.4. Case 4

A 58-year-old woman had tubular carcinoma and LVI. At the time of examination, this patient was breathless and received 3 L of oxygen via a nasal cannula. This woman was a patient with breast cancer and had undergone chemotherapy. The patient was infected with COVID-19 in March 2022 on hydroxychloroquine, oseltamivir, and azithromycin therapy. The patient came in with worsening shortness of breath. While hospitalized, laboratory findings showed IL-6 level was 16.23 pg/mL. Two months before admission to the hospital, an ultrasound examination of the abdomen showed liver metastases. There was no evidence to suggest a bacterial infection. The patient's condition continued to deteriorate clinically, and she eventually died from complications after 3 days hospitalization.

2.5. Case 5

A 55-year-old woman presented with grade II infiltrative mammary ductal carcinoma No Special Type (NST) and LVI. On examination, this patient was breathless and received 3 L of oxygen via a nasal cannula. This woman was a patient with breast cancer and had not started chemotherapy. The patient was infected with COVID-19 in January 2022 on hydroxychloroquine, oseltamivir, and azithromycin therapy. The patient presented with an altered mental status and worsening shortness of breath. While hospitalized, laboratory findings showed IL-6 levels in patients were 17.87 pg/dL. One year before admission to the hospital, an ultrasound examination of the abdomen showed liver metastases. The patient's condition after being diagnosed with liver metastases was still good, but the patient's condition worsened clinically after exposure to COVID-19. There was no evidence to suggest a bacterial infection. The patient's condition continued to deteriorate clinically, and she eventually died of complications after 5 days hospitalization.

Summary of all clinical findings and history treatment in patient are showed Table 1 and Table 2.

Table 1.

Summary of cases.

Case	Liver metastasis	Time liver metastasis found	History of COVID-19	IL-6 LEVEL	IL-6 level status	Outcome
1	Yes	1 month before Covid-19 infection	Yes	21.76 pg/mL	Increase	Deceased
2	Yes	1 month before Covid-19 infection	Yes	19.86 pg/mL	Increase	Deceased
3	Yes	1 month before Covid-19 infection	Yes	20.11 pg/mL	Increase	Deceased
4	Yes	2 month before Covid-19 infection	Yes	16.23 pg/mL	Increase	Deceased
5	Yes	1 year before Covid-19 infection	Yes	17.87 pg/dL	Increase	Deceased

Table 2.

History of cytostatic treatment and COVID-19 treatment in these five cases.

Case	Cytostatic medicines	COVID-19 medicines
1	Not started	Hydroxychloroquine, Oseltamivir, Azithromycin
2	Aromasin, Zometa	Hydroxychloroquine, Favipiravir, Azithromycin
3	Epirubicin, Paxus, Tamofen	Hydroxychloroquine, Oseltamivir, Azithromycin
4	Capecitabine, Zometa, Paclitaxel, Cysplatin, Carboplatin	Hydroxychloroquine, Oseltamivir, Azithromycin
5	Not started	Hydroxychloroquine, Oseltamivir, Azithromycin

3. Clinical discussion

In this retrospective study, we present five cases that were primary ductal carcinoma with differences in the trend of liver enzyme levels in each patient with liver metastatic breast cancer infected with Covid-19. Metastatic breast carcinoma (MBC) is known to have different histopathological structures and clinical biomarkers when compared to primary breast cancer lesions that can affect the success of therapy [10]. The 5-year survival rate of MBC patients is lower than that of early breast cancer (26 % versus 90 %) [11]. This finding underlies the treatment of early stage cancer patients may provide better prognostic results because metastases have not expanded and provide a more optimal microenvironment for treatment [12].

The patient was eventually diagnosed with liver metastatic breast cancer a month until a year before Covid-19 infection with an ultrasound examination of the abdomen as one of the standard procedures to perform breast cancer staging. Liver metastasis from breast cancer cells is a process of extravasating tumor cells into the parenchyma of the liver from the blood circulation system [18]. At a point, the tumor cell will enter a dormant state and form clinically detectable metastases in six phases called the intravasation phase, the premetastatic phase, the tumor-infiltrating microvascular phase, the pre-angiogenic micrometastatic phase, the angiogenic micrometastatic phase, and the growth phase [18].

Pro-inflammatory cytokines for example IL-6 also play an important role in the progression, chemoresistance, and metastatic formation of breast cancer, especially in trans-signaling pathways [19.20]. IL-6 production is regulated by various transcription factors such as NF-kB, CCAAT/enhancer-binding protein a, and activator protein 1 [20]. The activation of these transcription factors leads to the overexpression of this cytokine during inflammation and its expression is also known to be epigenetically regulated in breast cancer [20]. The higher level of IL-6 in many types of a tumor may promote the development of human cancer, activates oncogenic pathways, and suggests a strong link between the cytokine and cancer [20]. IL-6 in the trans-signaling pathway recruits T cells at the site of inflammation by triggering the expression of T cell-attracting chemokines [20]. Tumor-secreted IL-6 has been recently reported to enhance metastatic potential by educating monocyte-dendritic progenitors to prime distant organs for breast cancer metastasis which gives rise to immunosuppressive macrophages and promotes metastasis in vivo [19]. In this report, we are limited to stating that IL-6 plays a role in MBC because it was not measured before the confirmation of COVID-19 infection. It also does not routinely assess for breast cancer patient evaluation procedures in our hospital.

Based on a meta-analysis by Udomsinprasert et al. (2021), the presence of circulating pro inflammatory IL-6 in COVID-19 patients is associated with disease severity and decreased patient survival rate [13]. Circulating levels of IL-6 in severe COVID-19 patients was significantly higher than in non-severe patients [13]. In line with the above-mentioned findings, this meta-analysis revealed that severe COVID-19 patients had significantly increased circulating IL-6 levels, compared to those with non-severe COVID-19 [13]. In a study by Liu et al. (2020), an increase in IL-6 levels that exceeds the cutoff value (7 pg/mL) can be a prognostic factor and an independent factor of disease severity [14]. These findings are also accompanied by the presence of lung damage due to the inflammatory activity of the immune response that affects patient mortality [14].

Our findings showed changes in IL-6 levels that exceeded the cutoff limit of the five cases. Patients with metastatic breast cancer have a lower immune response so they are susceptible to viral infections. In addition, the high level of IL-6 in our patient that have a liver metastatic breast cancer may be caused or multiplied by COVID-19 infection. This can cause viral infections to spread to attack cancer cells due to the expression of ACE2 and TMPRSS2 which are receptors for the SARS-CoV-2 virus [15]. This condition then leads to an increase in viral load and immune titration leading to an increase in inflammation in the body and an impact on the worsening of the patient's prognosis [16]. In the meta-analysis by Coomes and Haghbayan (2020), IL-6 concentrations sign demonstrated 2.9-fold higher levels in patients with complicated Covid-19 compared with patients with the noncomplicated disease. IL-6 level is also positively correlated with bilateral pulmonary involvement and maximum body temperature which may affect the patient's prognosis [21]. Also in this case series, all studies experienced worsening conditions and deceased during treatment, even though the patient also received cytostatic treatment previously. IL-6 can promote tumor growth and induce therapeutic resistance [22]. Matched-analysis by Bertuzzi et al. (2021), propensity score matching performed considering multivariable statistically significant factors in COVID-19 demonstrated the active cancer population a 1.92× risk of death compared to the non-cancer population [23]. From the study on 557 consecutive patients, 126 patients died (23 %), of whom 23 were cancer patients. Considering the cancer patients cohort, the fatality rate was 50 % (CI 95 %: 34.9;65.1), whereas in the non-cancer subgroup was 20.2 % (CI 95 %: 16.8;23.9) [23]. Our findings suggest dynamic changes in IL-6 levels as a possible prognostic factor in patients with liver metastatic breast cancer and represent the prognosis and clinical outcome during treatment.

4. Conclusion

Our findings suggest that IL-6 may be a prognostic factor in the clinical outcome of liver metastatic breast cancer patients. These findings can be scientific evidence in the management of metastatic breast cancer patients with Covid-19 infection, given the limited clinical studies related to the development of patient management.

Consent

Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.

Ethical approval

This case series based on ethical approval from Health Research Ethics Comitte Dr. Moewardi General Hospital 274/III/HREC/2020 (date of approval: March, 4^th 2020).

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author contribution

Dea Alberta Setiawati

Data collection, data analysis and interpretation, writing the paper

Widyanti Soewoto

Study concept, data analysis and interpretation

Ikhdin Radiamin Saadhi

Data analysis and interpretation

Guarantor

Dea Alberta Setiawati

Widyanti Soewoto

Ikhdin Radiamin Saadhi

Research registration number

N/A.

Conflict of interest statement

No conflict of interest.