Abscopal effect of radiation on bone metastases of breast cancer: A case report

Abstract

The abscopal effect is defined as the clearance of distant tumors after applying localized irradiation to a particular tumor site. It has been proposed that a mechanism for the abscopal effect might be the activation of the immune system, which leads to immunogenic tumor cell death. Here, we describe a woman with advanced breast cancer that received modified ablative radiation therapy that targeted her primary breast tumor. She experienced an apparent regression of metastatic mass in the thoracic spine. This case supported the hypothesis that the abscopal effect might be attributable to an activation of the systemic immune response.

KEYWORDS:

• Abscopal effect
• bone metastases
• radiotherapy
• breast cancer spontaneous regression

Introduction

Radiation therapy (RT) can induce a phenomenon known as an abscopal effect. This effect is observed in the treatment of metastatic cancer, where a distant non-irradiated tumor regresses after localized radiation therapy is delivered to a particular tumor site. The mechanisms underlying the regulation of abscopal events remain unclear. Recent evidence has suggested that the immune system is a major process in mediating the abscopal effect.¹ RT is thought to induce DNA damage and immunogenic cell death, which can lead to dendritic-cell activation in the tumor microenvironment. Then, these dendritic cells cross-present the tumor antigens to prime a tumor-specific T cell response.^2,3

Accumulating evidence has shown that high radiation dose with few fractions, such as stereotactic ablative body radiotherapy (SABR), could induce anti-tumor immunity,^3,4 modify tumor phenotypes, and change the tumor microenvironment.^4–7 Therefore, SABR may produce a beneficial outcome superior to conventional RT fractionation. With the continued development of new radiation technology, SABR is increasingly used in a variety of malignancies and at a variety of sites, including renal cell carcinoma, melanoma, lung cancer, and hepatocellular carcinoma.^8–15 Only two studies conducted in Japan reported an abscopal effect. The effect was observed in metastatic lymph nodes and infiltrative lymphocytes after applying a few fractions of large- dose irradiation to treat breast carcinoma.^16–17 Here, we describe a patient with stage IV, invasive ductal breast carcinoma. This patient may have benefitted from an abscopal effect of multiple fractions of high radiation dose delivered locally and precisely targeted the breast tumor and caused limited damage to the surrounding normal tissue.

Case presentation

A 65-year-old woman presented with a necrotic mass on her right breast, which bled and produced an exudate with an offensive smell. The mass on the breast was first noticed 3 years prior to the examination. She refused any conventional treatment, including surgery, chemotherapy, or hormone therapy for breast cancer with an unknown cause. She visited our outpatient clinic of Radiation Oncology in May 2012. She complained of exaggerated bleeding from her right breast, an exudate with an offensive smell, and severe pain. On physical examination, an ulcerated, bleeding, necrotic mass was noted in the upper outer quadrant of the right breast (Figure 1). A laboratory examination on patient's blood sample revealed a low hemoglobin concentration (8.3 mg/dL). Tumor markers, CEA and CEA-125, were within normal ranges (CEA <3 ng/mL); but the CA 153 level was high, at 130.2 U/mL (normal range <38 U/mL). Computed tomography (CT) of the breast showed a large, fungating mass, about 16 cm in diameter, over the left anterior chest wall and axilla. A whole body bone scan showed a metastasis in the 8^th thoracic vertebra (Figure 2A). The tumor was diagnosed as a estrogen receptor(ER+), HER-2/neu-positive, progesterone-negative, cT4N3bM1, stage IV, invasive ductal carcinoma, with metastases to the 8th thoracic vertebra and axillary lymph nodes.

Figure 1. The appearance of a breast tumor before radiotherapy.

Figure 2. (A) Bone scan before palliative radiation. (B) Bone scan after 2 years, a resolution of bone lesion.

Based on data from previous animal and clinical studies,^18–20 we developed an ablative RT with an electron beam. The shaped electron beams were delivered precisely and conformally; they targeted the local breast tumor and the involved axillary lymph nodes. A total dose of 225 Gy was delivered to the clinically involved areas in 15 fractions (15 Gy/fraction) with minimal damage to normal tissues or organs at risk. The fractions were delivered over 3 weeks, and RT was completed in June 2013. Next, based on published literature and our clinical experience, we prescribed a 50 Gy dose, delivered in 25 fractions (2 Gy/ fraction) to the metastatic thoracic bone lesion, as palliative RT.^21–23 After 2 years, a follow-up whole body bone scan showed resolution of the bone metastatic lesion (Figure 2B).

After initiation of a personalized ablative RT, the follow-up breast CT images at 3 months, 12 months, and 4 years showed a remarkable shrinkage and nearly complete regression of the breast tumor (Figure 3B-D). Additionally, a remarkable reduction in the axillary lymph nodes was also noted. From December 2013 to present, the patient has reported feeling very well, and no further tumor recurrence was reported. Laboratory findings showed normal levels of tumor markers. Continuous checking showed that the CA15-3(EIA) and CEA levels decreased to the normal range (Figure 4). No abnormal finding was observed in routine follow-up with abdominal ultrasound and CT. We also acquired a biopsy at the local radiation site in 2015 that confirmed no recurrence. The biopsy report indicated no sign of tumor cells, except fibrosis. The patient continues to survive at present, she has returned to work, and reports a good quality of life.

Figure 3. The axial computed tomography of the upper chest and axilla.(A) before radiotherapy; (B) Three months after radiosurgery, shrinkage of the local breast tumor (C) CT image after 1 year, nearly complete regression of locally breast tumor (D) CT image after 4 years, complete remission of the local breast tumor, we supposed that an abscopal effect had occurred. (E) Follow-up CT after 5 years confirmed a complete remission and the biopsy result showed fibrosis at the local tumor site.

Figure 4. Time course of breast cancer biomarkers. The time course during follow-up shows changes in the serum tumor biomarkers, CEA 153 and CEA, after modified ablative radiotherapy.

Discussion

The patient of this study was the first to receive multiple fractions of high radiation dose that directly targeted a local breast tumor with minimal damage to normal tissues or organs at risk. This technique of delivering multiple fractions of high radiation dose was designed for a particular patient that refused all standard treatments. We have termed this technique “modified ablative RT”; it resembles radiosurgery, except that we delivered more than 5 dose fractions.

The mechanisms underlying the abscopal effect of RT have not been clearly understood. Some proposed mechanisms include immune-mediated tumor regression, cytokine effects, tumor growth inhibition, or tumoricidal effects.^24–27 The immunological activation and the response against non-irradiated malignant lesions is in part due to the release of tumor antigens in the tumor microenvironment and the release of inflammatory factors induced by irradiation at the target tumor site.^28–30 Another mechanism proposed was that radiation-elicited immunogenic cell death acts synergistically with other biological effects. Many proposed mechanisms have been supported by animal studies.^30–35 Other proposed mechanisms include the promotion of T-cell recruitment and function associated with irradiation, and the involvement of other mediators, such as TGF-β antagonists or p53.^36–40 More recently, several clinical trials have tested immune check point inhibitors, such as anti CTLA-4, anti PD-1, and anti PD-L1/L2 agents in a variety of tumor types with applicable results.^41–42 Some studies have suggested that a dual immune checkpoint blockade combined with RT might elicit an optimal abscopal response.^43–44

The tumor immunity induced by RT may be influenced by the radiation dose and fractionation. High-dose radiation has greater capacity than low-dose radiation for inducing host anti-cancer immune defenses.⁴⁵ Recently, with the advanced technology of online image guidance systems and complex planning techniques, the intensify radiotherapy can now be delivered precisely in a small number of high (5–30 Gy) individual doses to a targeted tumor volume to minimize the local recurrence.^44–47 Clinical studies have indicated that conventional fractions (1.8 or 2.0 Gy/fraction) or hypofractionated (3 × 9.5 Gy, 5 × 6 Gy) RT could induce host anti-cancer immune defenses to strengthen the systemic efficacy of immunotherapeutic strategies for treating different cancers.^48–52 Despite increasing evidence in support of the hypothesis that an abscopal effect arises from the initiation of an immune-mediated process triggered by high-dose radiation, several clinical trials investigating the combination of immunotherapy and RT in breast cancer patients are actively ongoing.⁵³ This approach represents a promising option for cancer treatment in clinical practice.

Conclusions

We described a rare abscopal effect, where metastasis was ameliorated at a site distant from the primary site of tumor irradiation. We postulate that a strong immunogenic response and subsequent abscopal regression in the remaining site of disease may due to the substained inflammatory response in this case.

Author contributions

AC conceived the study and drafted the manuscript; HL participated in the study design and interpretation. All authors read and approved the final manuscript.

Conflict of interest

The authors declare no conflict of interest related to this study

Sponsorship

No funding or grant supported this study

Authors' submitted files for original images

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Ethics approval and consent to participate

This work did not require any written patient consent.

Consent for publication

Not applicable.

Availability of data and materials

The datasets supporting the conclusions of this article are included within the article.

Acknowledgments

We would like to thank the patient for her willingness to share her case for this study.

Funding

This work did not receive any specific funding.