Preoperative Systemic Chemotherapy Including Immune Checkpoint Inhibitors for Patients with Tumor-Associated Dermatomyositis

Triple-negative breast cancer (TNBC) is characterized by high aggressiveness, high recurrence rates, high metastatic potential, and poor prognosis compared with other subtypes [1] and accounts for approximately 10–24% of all breast cancers [2]. Preoperative systemic chemotherapy is currently the primary treatment for TNBC and significantly improves patient prognosis. The recent KEYNOTE-522 trial [3] in which the anti-programmed cell death protein-1 antibody pembrolizumab (a so-called immune checkpoint inhibitors [ICIs]) was added to preoperative systemic chemotherapy, demonstrated a significantly higher rate of pathologic complete response in patients who received pembrolizumab plus preoperative chemotherapy (64.8%) compared to those who received placebo plus preoperative chemotherapy (51.2%) in TNBC. A trend toward overall survival extension was also observed.

Dermatomyositis (DM) is a rare autoimmune inflammatory myopathy that primarily affects the skin and muscles, with an incidence of approximately 9.63 per 1,000,000 [4]. Skin lesions are usually the first symptoms and include erythematous rashes with or without orbital edema. Muscle involvement often presents as symmetrical proximal muscle weakness, and patients may also present with systemic manifestations such as arthralgia, dyspnea, dysphagia, dysphonia, and dysphonia [5]. According to epidemiologic statistics, 15–30% of cases of DM are associated with malignancy [6]. It is estimated that the incidence of cancer in patients with DM is 5–7 times higher than for the general population, although the pathophysiology of this association is still incompletely understood [7]. A study from Asia showed that DM is the second most common disease associated with breast cancer in women [8]. There are no definitive diagnostic methods or criteria to determine whether DM is associated with a malignancy or exists independently, and there are no treatment guidelines related to breast cancer associated with DM. Individualized treatment is based on clinical cases.

ICIs are monoclonal antibodies that specifically target the inhibitory receptors on T cells known as immune checkpoint molecules. These act as negative co-regulators that inhibit further T-cell activation and are essential for maintaining self-tolerance [9]. Tumor cells often escape host immunity through immune checkpoint dysregulation, and ICIs are immunomodulators that enhance antitumor immune responses [10‒12]. However, this mechanism of action can also manifest in an autoimmune-like attack on healthy cells, known as immune-related adverse effects (irAEs), including DM. In other words, administering of ICIs to patients with cancer and comorbid DM may worsen DM. There are virtually no data on the use of ICIs in patients with cancer with autoimmune diseases. To date, there are no reports on the use of ICIs in patients with breast cancer and a preexisting history of autoimmune disease (not a newly diagnosed tumor-associated syndrome following the use of ICI, but a previously existing tumor-associated syndrome). There are few reports on the safety and efficacy of ICIs in patients with autoimmune diseases and a history of cancer. A French retrospective cohort study of 112 patients demonstrated that recurrence of autoimmune disease and the appearance of other irAEs occurred frequently in approximately half of the cases. However, in most cases, these events did not necessitate the discontinuation of ICIs.

This report describes a case of a patient diagnosed with DM as a paraneoplastic syndrome associated with TNBC, who was treated with preoperative chemotherapy including ICIs. The treatment plan demonstrated a significant clinical response and remission of DM.

A 44-year-old female patient presented with a rash, muscle weakness, and a mass in her left breast. The patient had noticed a mass in her left breast since October 2020 but had not sought medical attention. In December 2022, the patient noticed facial flushing and swelling of her eyelids. The patient was seen by her previous physician, who diagnosed her with cancer of the left breast. Subsequently, a rash appeared on her face, neck, and both fingers, and by the end of the year, she had progressive muscle weakness and difficulty standing. Blood tests conducted early the next year showed abnormally high creatine kinase levels. She was admitted to the hospital’s collagen unit on suspicion of myositis (day 1). The patient was diagnosed with DM, and the laboratory tests suggested a single anti-transcription intermediate factor-1γ antibody (anti-TIF-1γ Ab), confirming DM. Physicians in the Department of Collagen Diseases initiated a semi-pulse steroid regimen (methylprednisolone 250 mg/day) on day 3 after admission. The rash and muscle strength gradually improved, and the dose of prednisolone was reduced to 60 mg on day 6. However, due to the presence of cancer in the patient’s left breast, tumor-associated DM (paraneoplastic syndrome) was suspected, and the patient was referred to our department on day 9. As the patient had locally advanced TNBC (cT4N2M0, stage IIIC), the decision was made to administer preoperative chemotherapy, including an ICI (day 1, 8, 15: carboplatin [CBDCA] AUC 5 mg/mL* min + paclitaxel 80 mg/m², day 1: pembrolizumab 200 mg/body, every 3 weeks for 4 cycles, followed by day 1: doxorubicin 60 mg/m² + cyclophosphamide 600 mg/m², day 1: pembrolizumab 200 mg/body, every 3 weeks for 4 cycles).

Chemotherapy was initiated on day 10 after admission due to the rapid growth of the breast cancer. Following the initiation of chemotherapy, the mass in the left breast decreased each week progressively, and certain symptoms like facial edema and weakness were gradually alleviated. No side effects were observed, except for grade 2 constipation. Prednisolone was reduced by 10 mg every 2 weeks, and from day 43, the dose was reduced by 5 mg–35 mg. The course of treatment and blood test values, including creatine kinase, are shown in Figure 1. After ensuring the patient’s satisfactory progress, she was discharged from the hospital on day 47. Chemotherapy was continued on an outpatient basis. However, since neutropenia persisted at grade 3 on days 57, 64, and 71, the dose of paclitaxel was reduced to 65 mg/m² starting with cycle #4-1 (day 71). The patient developed a fever during the night following cycles #3-3, #4-1, and #4-2, but the patient did not fulfill the criteria for febrile neutropenia. Also, the patient showed no signs of infection on the fever workup, including blood culture, urinalysis, and X-rays. The patient was switched to AC + pembrolizumab with G-CSF on day 92. The last preoperative chemotherapy dose was administered on day 155. Figure 2 shows the change in the status of the left chest and skin disease. On day 184, the patient underwent a left mastectomy and axillary lymph node dissection. She had a good postoperative course and was discharged on the 9th postoperative day. The pathology report indicated pT4b (55 mm) N0 (0/20), and the response to chemotherapy was grade 1b. Postoperative treatment will include postmastectomy radiation therapy and pembrolizumab.

Autoimmune diseases associated with malignancy can be classified into three categories: preexisting autoimmune diseases, tumor-associated syndromes (paraneoplastic syndrome), and de novo immune-related adverse events (irAEs). DM is a rare, idiopathic inflammatory myopathy characterized by proximal skeletal muscle weakness and evidence of muscle inflammation. DM, unlike polymyositis (PM), is characterized by the presence of various cutaneous manifestations such as heliotrope rash, poikiloderma, Gottron papules, and severe systemic symptoms. The most common causes of death in patients with DM and PM are cancers, pulmonary and cardiac complications, and infection.

The association between inflammatory myopathy and cancer has been recognized since the report of 2 cases of PM and gastric cancer in 1916 [13]. Evidence supporting this link includes epidemiologic data from large population studies and the improvement of myopathy following cancer treatment However, there are no definitive diagnostic methods to distinguish tumor-associated DM from idiopathic DM. Cancer can be diagnosed before, simultaneously with, or after the diagnosis of inflammatory myopathy [14]. The peak incidence of a cancer diagnosis in DM and PM occurs simultaneously with and during the first year after the diagnosis of the muscle disease, and falls off gradually over the subsequent 5 years of follow-up [14‒17].

In the present case, the patient had been aware of a left breast mass for 2 years before the onset of skin symptoms and muscle weakness. The rapid growth of the breast mass, concurrent with the rapid onset and worsening of DM symptoms, suggested tumor-associated DM (paraneoplastic syndrome). This diagnosis was further supported by the patient’s positive anti-transcription intermediate anti-TIF-1γ Ab results. In a meta-analysis conducted by Selva-O’Callaghan et al. [18], the presence of anti-TIF-1γ Ab was associated with an 18-fold increased risk of malignancies. Further investigations into the correlation of anti-TIF-1γ Ab with malignancies in patients with DM/PM have reported that the antibody’s specificity is such that its absence in patients with autoimmune disease may potentially rule out the presence of underlying cancer [19]. It is hypothesized that anti-TIF-1γ Ab is produced in antitumor immune responses [20]. These data indicate that the existence of anti-TIF-1γ Ab in cases of DM/PM is highly associated with a visible or hidden cancer, and the autoimmune disorder is likely a paraneoplastic manifestation [21].

On the other hand, ICIs have an adverse effect profile that often mimics the phenotype of autoimmune disorders. Mechanistically, immune-related adverse events (irAEs) are presumed to result from the removal of physiologic inhibition of subclinical autoreactivity and excessive immune responses. Patients with autoimmune disease have historically been excluded from most ICI clinical trials because of the potential for increased toxicity. It is important to distinguish between preexisting autoimmune diseases, tumor-associated syndromes, and irAEs when assessing treatment options. In this case, the decision to consider a paraneoplastic syndrome was based on the coincidence of tumor progression and exacerbation of DM, as well as the positive anti-TIF-1γ Ab results. The true nature of DM is the infiltration of lymphocytes and macrophages into muscle fibers due to an autoimmune abnormality, which is hypothesized to be tumor-related. Casciola-Rosen et al. [22] found that the antigenic fingerprints in some adenocarcinomas, such as breast cancer, are highly similar to the regenerating muscle cells of patients with DM patients, suggesting that the antitumor response may initiate the immune response in DM.

The primary treatment for advanced TNBC is chemotherapy, often combined with ICIs. In this case, chemotherapy, including pembrolizumab, was chosen as the most effective option despite the patient’s DM. It was hypothesized that ongoing steroid treatment for DM would mitigate irAEs while posing a concern for reduced ICI efficacy due to baseline immunosuppression. The patient was diagnosed with locally advanced breast cancer that was rapidly progressing, and it was impossible to perform surgery for complete resection. After a comprehensive assessment, we selected the chemotherapy regimen with the most potential therapeutic benefit and implemented it safely. We hypothesize that the lack of DM exacerbation during pembrolizumab treatment supports our initial assessment that the PM was a paraneoplastic syndrome rather than a preexisting autoimmune disease. ICI could logically be considered to exacerbate preexisting autoimmune diseases; however, in this case, the absence of DM exacerbation suggests that our assumption about the paraneoplastic nature of the PM was correct. This case highlights the importance of individualized treatment planning for patients with malignancy-associated autoimmune diseases. A nuanced understanding of disease pharmacology and pathophysiology is necessary to optimize outcomes, particularly in cases with limited precedent. In light of the findings of this case study, it is not possible to recommend ICI combination therapy for all patients with autoimmune diseases. It is essential to compare the efficacy and side effects of ICI treatment with the degree of symptoms associated with the tumor-associated syndrome and the progression of cancer and to consider the optimal treatment after weighing the benefits and disadvantages.

This is the first case report of a patient with breast cancer and tumor-associated DM (paraneoplastic syndrome) treated with ICI-containing preoperative chemotherapy. The patient completed chemotherapy and underwent surgery without significant adverse events, underscoring the need for continued investigation into this complex interplay of autoimmune diseases and cancer therapy. The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000543579).

Ethical approval was not required for this study in accordance with local or national guidelines. Written informed consent was obtained from the patient for publication of the details of their medical case and any accompanying images.

The authors declare that they have no competing interests.

Akihiko Shimomura received grants from Chugai Pharmaceutical, AstraZeneca, Pfizer, and Eisai, outside the submitted work; other authors have no conflicts of interest. No private or public funding was received for this study.

Yukino Kawamura and Akihiko Shimomura drafted the manuscript. Akihiko Shimomura revised the manuscript. Akihiko Shimomura, Yukino Kawamura, Tomoko Taniyama, Hoshie Hirai, Kazuki Hashimoto, Yayoi Honda, Dai Kitagawa, and Chikako Shimizu were involved in the treatment of the patient and have approved the manuscript. All authors contributed to collecting the relevant literature and data analysis and reviewing and critically interpreting the information.

All data generated or analyzed during this study are included in this article and its online supplementary material files. Further inquiries can be directed to the corresponding author.