Medires Publishers - Article

Abstract

Objectives:
To report a case of a young patient with stage III bilateral triple-negative breast cancer (TNBC) and a pathogenic BRCA1 variant, exploring the toxicity associated with adjuvant therapy using olaparib and pembrolizumab after neoadjuvant chemotherapy and surgery.

Methods:
The patient received neoadjuvant chemotherapy combined with pembrolizumab according to the KEYNOTE-522 protocol. After surgery, residual disease was detected on histopathological examination, leading to the initiation of adjuvant therapy with a combination of olaparib and pembrolizumab. Clinical monitoring was conducted, including regular blood counts and imaging studies. Following treatment, the patient developed pancytopenia and fever, prompting hospitalization and further diagnostic investigation.

Results:
Bone marrow biopsy confirmed the diagnosis of hemophagocytic lymphohistiocytosis (HLH), a rare immune-mediated condition. The patient was treated with corticosteroids and showed a positive clinical response.

Discussion:
HLH is a rare but serious complication of immunotherapy, and the data on standardized treatments are limited. This case highlights the importance of early detection, differential diagnosis, and management of rare adverse events in patients undergoing combination therapies.

Conclusion:
This case underscores the need for vigilant monitoring for rare immune-mediated conditions, such as HLH, in patients receiving adjuvant therapies for TNBC.

Introduction

Triple-negative breast cancer (TNBC) is a histological subtype of breast cancer characterized by the absence of both hormone receptor (HR) and human epidermal growth factor receptor type 2 (HER2) expression [1]. TNBC accounts for approximately 10–20% of all breast cancer cases and is more commonly observed in young women and those with hereditary genetic mutations, particularly in the BRCA1 and BRCA2 genes [2]. Studies indicate that up to 19.5% of patients with TNBC harbor BRCA1/2 mutations [3].
The standard treatment for locally advanced TNBC is currently neoadjuvant therapy with chemotherapy and immunotherapy, in accordance with the KEYNOTE-522 trial. In this study, 1,174 patients with stage II or III TNBC were randomized to receive 200 mg of pembrolizumab intravenously every three weeks or a placebo, in combination with weekly carboplatin and paclitaxel for 12 consecutive weeks. This was followed by four cycles of doxorubicin + cyclophosphamide or epirubicin + cyclophosphamide every 21 days. After surgery, patients continued to receive pembrolizumab or placebo for nine cycles in the adjuvant setting [4].
The addition of immunotherapy resulted in an increased complete pathological response rate, observed in 64.8% of the pembrolizumab + chemotherapy group, compared to 51.2% in the placebo + chemotherapy group. Additionally, the inclusion of pembrolizumab led to an improvement in overall survival (OS), making this regimen the preferred treatment option in this scenario.The estimated overall survival at 60 months was 86.6% (95% CI, 84.0 - 88.8) in the pembrolizumab–chemotherapy group, compared to 81.7% (95% CI, 77.5 - 85.2) in the placebo–chemotherapy group (P = 0.002) [5]. However, there was a 4.6% increase in adverse events of grade 3 or higher. Adverse events related to treatment were more frequent in the immunotherapy group than in the placebo group, including neutropenic fever (14.6% vs. 12.1%), anemia (2.6% vs. 2.1%), and pyrexia (2.6% vs. 0.3%) [4].
Patients with HER2-negative breast cancer carrying pathogenic or probably pathogenic variants in BRCA1 or BRCA2, who are at high risk of recurrence, are candidates for receiving adjuvant olaparib for one year, as recommended by the OlympiA study [6]. This treatment has significantly improved invasive disease-free survival and overall survival [7].
For the TNBC cohort, the inclusion criteria were as follows: patients treated with adjuvant chemotherapy who had axillary node-positive disease or an invasive primary tumor measuring at least 2 cm on pathological analysis, and patients treated with neoadjuvant chemotherapy who did not achieve a pathological complete response [6].
A total of 1,815 patients were included in the safety analysis comparing olaparib with placebo. Adverse events of grade 3 or higher in the olaparib group included anemia (8.7%), neutropenia (4.8%), leukopenia (3%), fatigue (1.8%), and lymphopenia (1.2%). Blood transfusions were infrequent, with 5.8% of patients in the olaparib group and 0.9% in the placebo group requiring at least one transfusion. A grade 5 event related to acute myeloid leukemia has also been reported [6].
Checkpoint inhibitors have revolutionized the treatment of certain tumors. However, when anti-PD1 or anti-PD-L1 therapies are used as monotherapy, immune-mediated adverse events of any grade are reported in 60–75% of cases, with grade 3 events occurring in 10–15% of patients [8]. The use of poly ADP ribose polymerase (PARP) inhibitors (iPARP) is associated with a higher risk of developing myelodysplastic syndrome and acute myeloid leukemia compared to the general population. In randomized clinical trials, the incidence of these adverse events following iPARP treatment is 0.73% [9].
Hemophagocytic syndrome is a rare and potentially fatal condition. It is characterized by overstimulation of the immune system, leading to systemic inflammation and cytokine release, which can result in multiple organ failure. These syndromes may be primary or secondary to infections, autoimmune conditions, or drug exposure. Hemophagocytosis caused by immunotherapy poses a significant clinical challenge. Although immunotherapy aims to mobilize T cells against the tumor, it can inadvertently trigger a pathological hyperinflammatory state as a side effect [10].
This clinical case involves a patient with a pathogenic BRCA1 variant and locally advanced TNBC, who underwent neoadjuvant chemotherapy and immunotherapy, followed by surgical intervention. Due to the presence of residual invasive disease identified in the histopathological report after neoadjuvant treatment, a combination of pembrolizumab and olaparib was prescribed during the maintenance phase. However, the patient subsequently developed grade 4 hematological toxicity. The investigation and management of this adverse event are thoroughly detailed in this report.
A search on PubMed using the keywords “Hemophagocytic lymphohistiocytosis/cytokine [and] pembrolizumab” yielded four case reports. One of these cases involved a similar scenario to the one described here immunotherapy in early-stage breast cancer treatment. Reported a female patient who developed hemophagocytic lymphohistiocytosis during neoadjuvant breast cancer treatment, which included pembrolizumab and chemotherapy. This patient suffered a serious condition secondary to hemophagocytosis requiring advanced life support therapies. The report emphasizes the importance of prompt recognition and early collaboration with specialists to make the correct diagnosis prevent fatal outcomes [11].

Case Report

The patient was a 30-year-old woman with no prior comorbidities, carrying a germline BRCA1 mutation. Her mother had passed away from ovarian cancer associated with a pathogenic variant in the same gene. The patient had been under strict surveillance by a breast specialist, who ordered a breast ultrasound and mammography in April 2022, both of which yielded normal results. In October 2022, the patient reported increased sensitivity in one breast, prompting a repeat breast ultrasound. This examination revealed a hypoechoic nodular area of indeterminate etiology in the left breast, measuring 12 mm x 11 mm x 17 mm, along with an axillary lymph node on the left side measuring 17 mm x 11 mm.
A magnetic resonance imaging (MRI) scan of the breasts was conducted on October, 2022 (Figure 1), revealing a non-circumscribed nodule in the right breast, located at the junction of the lateral quadrants and lower lateral quadrant, at the 8 to 9 o’clock position, measuring 12 mm x 11 mm x 11 mm. Additionally, a segmental non-mass enhancement was observed in the left breast, occupying the entire upper half, and measuring 80 mm x 70 mm x 57 mm, with areas of interspersed parenchyma. Axillary lymphadenopathy was noted at levels I, II, and III.

Figure1: Breast MRI performed on October, 2022

The patient underwent a biopsy, and the histopathological report confirmed a diagnosis of grade 3 invasive ductal carcinoma. Immunohistochemistry (IHC) revealed HR-negative breast carcinoma in the right breast, with a HER2 score of 0 and Ki67 of 80%. In the left breast, IHC also revealed HR-negative breast carcinoma, with a HER2 score of 0 and Ki67 of 85%.
Systemic staging examinations were performed, including brain magnetic resonance imaging, computed tomography (CT) of the chest and abdomen, and bone scintigraphy (BS), all of which showed no evidence of metastatic disease. The initial clinical staging was cT1cN0 in the right breast and cT3cN3 in the left breast.
Neoadjuvant treatment was administered according to the KEYNOTE-522 protocol between November 2022 and April 2023 [4]. The patient exhibited excellent tolerance and an objective clinical partial response in both the breast and axillary regions. Following neoadjuvant treatment, bilateral mastectomy, right axillary sentinel lymph node biopsy, and left axillary dissection were performed on April 2024. Pathological examination revealed a pathological complete response in the right breast (ypT0ypN0 [00/01]). However, on the left side, the patient still had residual disease, with invasive carcinoma measuring 18 mm, grade 2, and one positive axillary lymph node out of six evaluated (ypT1cypN1a). The surgical margins were clear on both sides.
Given the patient’s diagnosis of bilateral TNBC associated with a germline BRCA1 mutation, as well as the significant residual disease in the left breast, the case was reviewed by the institutional national tumor board. It was recommended that the patient receive adjuvant radiotherapy, followed by nine additional cycles of pembrolizumab, in accordance with the KEYNOTE-522 protocol, in combination with olaparib, as supported by the OlympiA study [4,7].
Although there are no data in the literature regarding the concomitant use of pembrolizumab and olaparib in this particular clinical context, safety data for this combination are available. For instance, the phase II study OPEB-01/APGOT-OV4 addressed this by evaluating the use of olaparib, pembrolizumab, and bevacizumab in treating ovarian cancer, which revealed manageable side effects [12].
Pembrolizumab was maintained, and olaparib was initiated at a dose of 300 mg every 12 hours, four weeks after the completion of radiotherapy. However, after having already completed 9 cycles of adjuvant pembrolizumab, the patient developed hematological toxicity, initially characterized by thrombocytopenia and anemia. Gradual dose reduction of olaparib was employed according to the guidelines. Even so, given the persistent toxicity despite the minimum permitted dose, the drug was suspended in December 2023.
One week after discontinuation of PARPi, the patient was hospitalized with fever and developed pancytopenia, which required transfusion, associated with elevated lactic dehydrogenase, hyperferritinemia, and increased transaminase levels (Figure 2). Empirical antibiotic therapy was started, but given the persistent fever and cytopenia, the patient was evaluated by the hematology team. At this point, bone marrow neoplastic infiltration, myelodysplasia due to PARP inhibitors [13], and immune-mediated events associated with pembrolizumab were among the primary hypotheses.

Figure2: Timeline of event

The patient underwent a bone marrow biopsy, which did not reveal any bone marrow infiltration due to solid or hematological tumors but showed intense macrophage activity and signs of hemophagocytosis (Figure 3), which was attributed to the use of pembrolizumab. Cytogenetic and molecular evaluations were conducted, showing no alterations.

Figure3: Hemophagocytosis

Associating the laboratory changes and the findings from the bone marrow biopsy, the diagnosis was completed as immune-mediated hemophagocytic lymphohistiocytosis (HLH).
Corticosteroid treatment was initiated with oral prednisone 80 mg daily in June 2023. After one week of treatment, due to the lack of improvement and the need for further hospitalization, the treatment was switched in December 2023 to intravenous dexamethasone 10 mg/m² (15 mg) daily for one week, followed by oral dexamethasone 14 mg daily for one week, and then reduced by half every two weeks until reaching a zero dose. The patient showed both laboratory and clinical improvement (Table 1). The oncological treatment was permanently discontinued.

* Maximum laboratory value

Table1: Evolution of the patient’s laboratory exams throughout hospital stay, demonstrating gradual improvement after corticosteroid therapy

Local and systemic evaluations were conducted, including breast MRI, CT scans of the chest, abdomen, and skull, BS and blood tests, all of which showed no evidence of local or distant oncological disease. The patient’s blood count has improved, and she is currently clinically stable, without recurrence and ongoing close follow-up due to the severity and aggressiveness of TNBC associated with the BRCA mutation.

Discussion

This clinical case involves a young patient with a pathogenic BRCA1 variant who was diagnosed with stage III bilateral TNBC. After receiving neoadjuvant chemotherapy and immunotherapy, followed by surgery, residual disease was identified. Consequently, the medical team decided to add olaparib to pembrolizumab for maintenance therapy. However, the patient was later diagnosed with rare immune-mediated hemophagocytic lymphohistiocytosis (HLH).
Hemophagocytic lymphohistiocytosis (HLH) is a rare and potentially fatal syndrome caused by hyperinflammation and immune-mediated tissue damage. Primary HLH occurs mainly in childhood due to mutations in genes that encode proteins essential for the activity of T lymphocytes and natural killer (NK) cells. Acquired or secondary forms of the disease mainly result from infections, malignancies, autoimmune disorders, or drugs [14]. Malignancy-associated HLH is a serious condition, with an incidence as high as 1%. It is more common in hematological cancers and has a median overall survival of 1.5 to 2.5 months. Poor prognoses in these cases may be associated with delayed diagnosis, as HLH is a rare syndrome with signs that can mimic other clinical conditions, such as sepsis [15].
HL diagnosis must meet at least five of eight criteria, which include fever, splenomegaly, two or more cytopenias (hemoglobin < 9 g/dL, platelets < 100,000/µL, absolute neutrophil count < 1000/µL), hypertriglyceridemia ≥ 265 mg/dL and/or hypofibrinogenemia ≤ 150 mg/dL, hemophagocytosis in the bone marrow, spleen, or lymph nodes, decreased NK cell activity, hyperferritinemia ≥ 500 ng/mL, and serum levels of soluble interleukin-2 receptor ≥ 2400 U/mL [10,12]. Histopathological findings include widespread accumulation of mature lymphocytes and macrophages, sometimes with hemophagocytosis, especially affecting the spleen, lymph nodes, bone marrow, liver, and cerebrospinal fluid [16]. Diagnosis can be challenging due to the rarity of the condition and its similarity to other clinical conditions. The presence of ferritinemia greater than 10,000 μg/L has a sensitivity of 90% and specificity of 96% for the diagnosis of HL [14]. In the case reported here, the diagnosis was made based on the association between signs of hemophagocytosis in the bone marrow biopsy and clinical-laboratory criteria.
Pembrolizumab is a monoclonal antibody that blocks the PD-1 pathway. This pathway is an immune checkpoint that can be engaged by tumor cells to inhibit active T cell immune surveillance. Therefore, blocking this pathway enhances the activity of cytotoxic T lymphocytes and anti-tumor immunity. The goal of increasing the cytotoxic activity of T lymphocytes is to cause tumor regression; however, checkpoint inhibitors also affect normal host tissues [17].
Immune-mediated adverse events can occur at any time during treatment, as well as after discontinuation, and can range in severity from mild to severe, and even life-threatening. Hematological events are rare, with the most frequent being thrombocytopenic purpura and hemolytic anemia [8]. An analysis of the World Health Organization (WHO) database demonstrated that HL secondary to immunotherapy typically occurs 6.7 weeks after the start of treatment, with the highest incidence observed in melanoma and lung cancer treatments. In this database, all reported cases were classified as serious events, and there were no cases associated with breast cancer, such as the one reported here [18]. The syndrome has been described as secondary to the use of CAR-T cells, blinatumomab (a monoclonal antibody directed at CD3 and CD19), and immune checkpoint inhibitors [19].
The occurrence of immune-mediated hemophagocytosis in patients with TNBC treated with immunotherapy highlights a rare but potentially lethal therapeutic challenge. Immunotherapy-induced HL is characterized by persistent fever, pancytopenia, and tissue damage, necessitating early diagnosis and rapid intervention. While the treatment of HL due to other causes is based on corticosteroid therapy and chemotherapy with etoposide, methotrexate, and cyclosporine, some evidence suggests that HL secondary to immunotherapy responds well to high-dose corticosteroid therapy [7]. Current guidelines recommend suspending immunotherapy and starting corticosteroids as first-line treatment. Depending on the severity and progression of the condition, corticosteroids alone may not be sufficient; however, there are currently no specific guidelines for the treatment of HL secondary to immunotherapy [17]. In such cases, dexamethasone is the corticosteroid of choice due to its increased CNS penetration compared to prednisone and its longer half-life [20]. Anti-interleukin-6 antibodies, such as tocilizumab, have proven effective in stabilizing and inducing remission in cases of hemophagocytic syndrome secondary to checkpoint inhibitor therapy, as reported by Alejandro Olivares-Hernández et al. in 2021 [19]. The successful use of tacrolimus for the treatment of diseases secondary to pembrolizumab and refractory to corticosteroids and etoposide has also been described [21].
In our knowledge, this is the first report of HLH in a patient receiving olaparib plus pembrolizumab as adjuvant treatment for breast cancer. Although the adverse event was attributed to the use of immunotherapy, it remains unclear whether the iPARP inhibitor played any role in its occurrence. In the absence of a phase III trial evaluating the efficacy of this combination, the adjuvant treatment for patients with TNBC harboring germline BRCA mutations should be individualized.

Conclusion

HL induced by anti-PD1 inhibitors in patients with TNBC presents both a diagnostic and therapeutic challenge. Adverse events associated with checkpoint inhibitors may become more common with the increasing use of these drugs in cancer treatment. Early identification and appropriate management of these complications are essential to avoid adverse outcomes. This case report presents a rare adverse event associated with immunotherapy and emphasizes the critical role of accurate diagnosis for effective management. The collective insights gained from similar cases may contribute to a deeper understanding of immunotherapy-induced HL and improve future patient care.

Data Availability Statement

The authors confirm that the data supporting the findings of this study are available within the article and its supplementary materials.
Data sharing is not applicable to this article as no data were created or analysed in this study

Authors’ contributions:
DJP, GVG, MPA: project administration, writing-original draft, writing–review & editing.
ANR: conceptualization, supervision, writing – review & editing.
IGR, BPSA, CGS, BSG, EMF: writing-original draft
All authors approved the submitted version.

Declarations

Acknowledgements: Written consent for publication was obtained. The authors would like to thank the patient for his consent to publish this case report.
Funding: The authors declare that this study did not receive financial support.
Conflicts of interests: The authors declare no conflict of interest.
Ethical approval: Ethical review and approval were required for this case report in accordance with local legislation and institutional requirements. This study was registered at: 79944424.6.0000.0227
Consent: Written consent for publication was obtained.

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