Sequential Multiple-Organ Immune-Related Adverse Events during and after Pembrolizumab Therapy in Triple-Negative Breast Cancer: A Case Report

Abstract

Introduction

Immune checkpoint inhibitors (ICIs) are an important component of triple-negative breast cancer (TNBC) treatment, and the KEYNOTE-522 regimen has established pembrolizumab combined with chemotherapy, as the standard of care. While ICIs improve outcomes, they can also induce immune-related adverse events (irAEs), affecting diverse organs. However, renal, pancreatic, and ocular toxicities are rare, and there have been few reports of sequential multi-organ irAEs in breast cancer.

Case Presentation

A 63-year-old woman with stage IIA TNBC was treated with the KEYNOTE-522 regimen. During neoadjuvant therapy, she developed fever, malaise, and mild laboratory abnormalities. Her symptoms progressed to acute kidney injury and elevated pancreatic enzymes. She was diagnosed with immune-related acute interstitial nephritis and pancreatitis and improved promptly with high-dose corticosteroids. After tapering immunosuppression, the patient developed Pneumocystis jirovecii pneumonia. Subsequently, she suffered bilateral anterior uveitis consistent with an immune-related ocular event. Surgical resection revealed a pathological complete response (pCR), and she remains under surveillance.

Conclusion

This case demonstrates three distinct irAEs affecting the kidney, pancreas, and eye, each occurring at different time points, including after discontinuation of immunotherapy. The opportunistic infection that she developed during steroid therapy emphasizes the need for prophylaxis in patients requiring prolonged immunosuppression. This case underscores the importance of multidisciplinary management and long-term vigilance for delayed and multi-organ irAEs in TNBC patients treated with ICIs.

Introduction

Immune checkpoint inhibitors (ICIs) that restore antitumor T-cell activity by targeting the programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway have reshaped treatment strategies for various malignancies. Among these ICIs, pembrolizumab, a PD-1 inhibitor, has demonstrated clinical utility with multiple tumor types. It has recently been integrated into the treatment of early-stage triple-negative breast cancer (TNBC). A pivotal trial of the KEYNOTE-522 regimen established carboplatin plus paclitaxel, followed by anthracycline- and cyclophosphamide-based chemotherapy (AC or EC) with neoadjuvant pembrolizumab, and subsequent adjuvant pembrolizumab, as the new standard of care for TNBC. This approach provides a significantly higher pathological complete response (pCR) rate and a significantly longer duration of event-free survival than chemotherapy alone [1]. These improved outcomes have led to widespread adoption of the KEYNOTE-522 regimen in clinical practice.

While ICIs have improved prognoses in various cancers, they carry a risk of immune-related adverse events (irAEs). These arise from nonspecific activation of the immune system and can involve nearly any organ system. The most common irAEs are dermatological, gastrointestinal, hepatic, and endocrine toxicities [2]. In contrast, renal toxicities such as acute interstitial nephritis, pancreatic irAEs such as autoimmune pancreatitis, and ophthalmic manifestations such as uveitis are relatively rare [3, 4]. Nevertheless, when these complications occur, they can be severe, with ophthalmic irAEs having the potential to cause loss of vision. The timely recognition and management of these less common irAEs is essential to prevent irreversible organ damage or even death.

An additional challenge posed by irAEs is that their occurrence is not limited to the period of active ICI administration. They may also manifest after treatment discontinuation, reflecting long-lasting modulation of immune responses. This potential for delayed onset underscores the need for extended vigilance in monitoring patients treated with ICIs, even after cessation of therapy [5]. Previous reports have described single-organ involvement, but the occurrence of multiple irAEs in breast cancer patients affecting distinct organs at different time points is rare.

We report a patient with TNBC treated with the KEYNOTE-522 regimen who developed multiple irAEs, including acute interstitial nephritis and pancreatitis during treatment, followed by bilateral uveitis after ICI cessation. To our knowledge, such sequential, multi-organ irAEs are rarely reported in breast cancer patients. This case highlights the diversity of irAEs and the extended duration of risk, which continues after ICI discontinuation. It also illustrates the importance of multidisciplinary management and long-term follow-up in patients treated with immunotherapy.

Case Report

A 63-year-old woman presented with a palpable mass in her right breast in June 2024. A core needle biopsy revealed invasive ductal carcinoma, solid type, with the following pathological features: estrogen receptor (ER) 1%, progesterone receptor (PgR) 0%, human epidermal growth factor receptor 2 (HER2) 0, Ki-67 80%, and histological grade 3. Clinical staging of the breast tumor was found to be cT2N0M0, stage IIA (Fig. 1a). Staging with contrast-enhanced computed tomography (CT) also revealed an 8-cm tumor in the left ovary (Fig. 1b). For this, the patient underwent a total hysterectomy with bilateral salpingo-oophorectomy in July 2024. Pathological analysis confirmed the ovarian mass to be high-grade serous carcinoma, pT2bN0M0, stage IIB. Genetic testing for pathogenic variants of the BRCA1/2 germline was negative. The patient’s medical history was unremarkable, indicating only that she had seasonal allergic rhinitis and had fractured her wrist in childhood. There was no relevant family history.

Fig. 1.

Breast magnetic resonance imaging and pelvic computed tomography findings in a 63-year-old woman with triple-negative breast cancer. a Breast MRI showing a 3-cm early-enhancing mass in the upper outer quadrant of the right breast. b Contrast-enhanced pelvic CT showing an 8-cm multilocular cystic mass suspicious for ovarian carcinoma.

In August 2024, we initiated the KEYNOTE-522 regimen with neoadjuvant therapy consisting of pembrolizumab plus carboplatin and paclitaxel, followed by anthracycline- and cyclophosphamide-based chemotherapy (EC) with pembrolizumab. During the fourth pembrolizumab plus chemotherapy cycle, the patient developed persistent fever, malaise, and mild abnormalities in laboratory test values, including slightly elevated serum creatinine and C-reactive protein. Initial imaging showed subtle bilateral renal swelling, and acute pyelonephritis was suspected.

One week later, the patient’s renal function had markedly deteriorated, with a serum creatinine level of 3.29 mg/dL and an estimated glomerular filtration rate of 12 mL/min. CT showed bilateral renal enlargement with perirenal fat stranding (Fig. 2a). Her serum pancreatic enzymes were significantly elevated (amylase 1,014 U/L, lipase 2,235 U/L), and there was mild pancreatic swelling on CT imaging (Fig. 2b). She was diagnosed with immune-related acute interstitial nephritis and pancreatitis. We discontinued pembrolizumab and treated the irAEs with high-dose oral prednisolone (50 mg/day, 1 mg/kg). This led to rapid improvements in renal function and pancreatic enzymes. The steroid dose was gradually tapered off, and the patient was discharged after 22 days of hospitalization.

Fig. 2.

Imaging and clinical course of a 63-year-old woman with triple-negative breast cancer treated with immune checkpoint inhibitors who developed immune-related nephritis and pancreatitis. a CT showing bilateral renal enlargement (arrows). b Abdominal CT showing mild pancreatic swelling (arrow). Diffusion-weighted MRI showing patchy high signal intensity in the pancreatic parenchyma, with corresponding low signal on the ADC map (arrows), findings compatible with pancreatitis. c Clinical course of serum amylase (AMY) and creatinine (Cre) levels during corticosteroid therapy. Both improved rapidly after initiation of prednisolone (PSL). d Chest CT showing diffuse bilateral ground-glass opacities, suggestive of Pneumocystis jirovecii pneumonia during steroid treatment.

In December 2024, approximately a month after discontinuation of corticosteroid therapy, the patient presented again with a high fever. CT imaging showed diffuse bilateral ground-glass opacities in the lungs (Fig. 2d). Laboratory testing revealed elevated C-reactive protein and mildly increased serum β-D-glucan. She was negative for cytomegalovirus antigenemia. Based on her clinical presentation and prior corticosteroid use, she was diagnosed clinically with Pneumocystis jirovecii pneumonia (PJP). This was treated with a 3-week course of oral atovaquone, resulting in clinical and radiological improvements.

In January 2025, the patient experienced a rapid decrease in her visual acuity and conjunctival hyperemia. Ophthalmologic evaluation revealed bilateral anterior uveitis, and immune-related uveitis was diagnosed. Treatment with topical betamethasone and tropicamide led to gradual improvement of ocular symptoms. Tropicamide was discontinued after approximately 8 months, whereas topical corticosteroid therapy is still ongoing at the time of the last follow-up. Systemic corticosteroids were not reintroduced, as ocular inflammation remained well controlled with topical therapy alone, and no long-term visual impairment has been observed.

In February 2025, the patient underwent a right total mastectomy with sentinel lymph node biopsy. Histopathological examination of the surgical specimen demonstrated a pathological complete response (pCR). We administered no systemic therapy postoperatively, and she remains under careful surveillance through regular follow-up. Figure 3 shows a schematic timeline summarizing the onset and management of each irAE.

Fig. 3.

Clinical course of a patient with triple-negative breast cancer treated with pembrolizumab, showing sequential immune-related adverse events.

Discussion

Recent advances in systemic therapy, particularly the incorporation of ICIs into perioperative treatment strategies, have significantly altered the therapeutic landscape for early-stage TNBC. The KEYNOTE-522 regimen established pembrolizumab combined with neoadjuvant chemotherapy as a new standard of care, demonstrating significant improvements in pCR and event-free survival. Accordingly, ICIs have become an essential component of guideline-recommended therapies for TNBC and other malignancies [1, 6]. However, the nonspecific activation of the immune system induced by ICIs can result in irAEs, which can affect virtually any organ. The majority of irAEs are cutaneous, gastrointestinal, hepatic, and endocrine. Renal, pancreatic, and ocular toxicities are uncommon [2, 7].

Our patient experienced three distinct irAEs, each affecting a different organ and occurring at a different time point. These were acute interstitial nephritis, pancreatitis, and bilateral uveitis. Nephritis is reported in 2–5% of patients treated with ICIs, with acute interstitial nephritis being the most typical histological subtype [3]. Immune-related pancreatitis is even less common, with an incidence of <1% in most studies of ICI-treated cohorts [7, 8]. Uveitis and other ocular toxicities are also rare, with an estimated incidence in patients treated with ICIs of about 0.1% [4]. The occurrence of these three irAEs in a single patient highlights the broad spectrum of immune-mediated toxicities associated with pembrolizumab.

When diagnosing immune-related nephritis and pancreatitis, alternative etiologies must be considered. In this case, infectious causes were unlikely given negative blood cultures, absence of urinary tract infection, and progressive renal dysfunction despite antimicrobial therapy. Metabolic and biliary causes of pancreatitis were excluded based on the absence of alcohol use, normal serum calcium and triglyceride levels, and lack of biliary obstruction on imaging. Toxicity related to cytotoxic chemotherapy was considered unlikely. Carboplatin-associated nephrotoxicity is typically mild and non-immune-mediated, and pancreatitis induced by carboplatin or paclitaxel is exceedingly rare. In contrast, this patient developed rapidly progressive renal dysfunction with characteristic imaging findings and marked pancreatic enzyme elevation occurring nearly simultaneously. Although renal biopsy and autoimmune serologies were not performed, the prompt response to high-dose corticosteroids and simultaneous multi-organ involvement strongly support an immune-mediated pathogenesis rather than chemotherapy-related toxicity.

Another important feature of this case was the delayed onset of uveitis, which did not manifest until after discontinuation of pembrolizumab. This reflects the enduring immunomodulatory effects of ICIs, with memory T-cell populations persisting for months or years [9]. Therefore, vigilance for irAEs should extend beyond the treatment period, and patients should be carefully monitored over a lengthy follow-up period, even after cessation of therapy.

Real-world evidence indicates that although most irAEs occur within the first few months after initiating ICIs, a minority of events occur in a delayed manner, with systematic pharmacovigilance data showing that approximately 2.3% of reported irAEs occur beyond the typical early treatment period [10]. Additionally, multi-organ or sequential irAE patterns have been observed in clinical cohorts, with up to 16% of patients developing involvement of more than one organ system, either concurrently or sequentially, across various solid tumors treated with PD-1/PD-L1 inhibitors [11]. These observations support that irAEs can manifest both during and after treatment discontinuation and may involve different organ systems over time, aligning with the delayed and multi-organ presentation observed in our case.

In addition to the three irAEs, our patient also developed PJP during steroid tapering. This demonstrates the importance of infection prophylaxis in the management of high-grade irAEs. While prolonged corticosteroid therapy is the treatment of choice for nephritis and pancreatitis, it can increase susceptibility to opportunistic infections. Current guidelines recommend prophylaxis against PJP in patients treated with ≥20 mg/day of prednisone or its equivalent for more than 4 weeks [5]. This case underscores the balance required between immunosuppression for irAE management and the associated risk of infection.

Our understanding of the pathogenesis of the diverse range of irAEs remains incomplete, but several mechanisms have been proposed. Epitope spreading, in which immune responses initially directed against tumor antigens expand their reach to include self-antigens, may underlie toxicities such as nephritis and pancreatitis, which share features with classical autoimmune conditions [2, 8, 12]. Organ-specific immune microenvironments may further amplify these immune responses. Renal tubular epithelial cells and pancreatic acinar cells can upregulate the presentation of antigens under inflammatory cytokine stimulation. This facilitates self-antigen recognition and tissue damage [13, 14]. In contrast, the delayed onset of uveitis in our patient suggests a mechanism more consistent with long-term immune reprogramming, whereby memory T-cell clones induced by PD-1 blockade persist after treatment cessation, triggering ocular inflammation [9]. Thus, different mechanisms, including epitope spreading in visceral organs and persistent memory T-cell activity in ocular irAEs, may predominate, depending on the site of toxicity.

In the eye, immune privilege is usually maintained by the blood-retina barrier, the absence of lymphatic drainage, and local mediators of immunosuppression such as TGF-β and Fas ligand, which exert anti-inflammatory effects in the retina [15]. However, the uveal tract is highly vascularized and expresses relatively high levels of PD-L1 [16]. Hence, blockade of the PD-1/PD-L1 pathway may unleash a disproportionate immune response in uveal tissue, contributing to the development of uveitis in patients treated with ICIs. Thus, the eye is unique in its susceptibility to disruption of both immune privilege and PD-L1-mediated local tolerance, which can result in clinically significant inflammation.

This case study illustrates the occurrence of multiple irAEs across different organs during and after pembrolizumab treatment for TNBC using the KEYNOTE-522 regimen. It highlights the importance of multidisciplinary collaboration in the management of irAEs, careful attention to opportunistic infections during immunosuppressive therapy, and long-term follow-up for the detection of delayed toxicities. Awareness of such atypical sequential irAEs is becoming ever more important with the increasing implementation of ICIs in the treatment of early-stage breast cancer. From a clinical perspective, this case emphasizes the need for a high index of suspicion for immune-related toxicity even when symptoms are atypical, mild at onset, or occur after discontinuation of immunotherapy in the curative setting. 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/10.1159/000550528).

Acknowledgments

We would like to thank the staff and nurses for their kind cooperation. We would also like to thank the patient and her family.

Statement of Ethics

In accordance with local or national guidelines, ethical approval was not required for this study. Written informed consent was obtained from the patient for the publication of this case report and accompanying images.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

This study was not supported by any sponsor or funder.

Author Contributions

R.M. and S.I. wrote the manuscript. S.S., N.H., R.H., and M.T. interpreted the data and critically revised the manuscript. All authors approved the final version of the manuscript.

Funding Statement

This study was not supported by any sponsor or funder.

Data Availability Statement

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