Long-Term Response to Pembrolizumab in Metastatic Metaplastic Breast Carcinoma: A Case Report

Introduction

Metaplastic breast carcinoma (MpBC) is a rare subtype of breast malignancy that accounts for approximately 0.2% to 1% of all invasive breast carcinomas (IBCs) [1–3]. The majority of MpBCs are triple-negative breast cancers (TNBCs) that lack expression of estrogen receptors (ERs), progesterone receptors (PgRs), and ERBB2 (HER2) [2,4,5]. Given the limited therapeutic targets, MpBC treatment remains challenging. Moreover, studies have reported that MpBCs exhibit lower response rates to conventional adjuvant chemotherapy and worse clinical outcomes after chemotherapy compared with other types of TNBC [6–9]. Most MpBCs are resistant to systemic therapy and have a poor prognosis, with limited reports of successful systemic therapy.

Recently, the KEYNOTE-522 trial reported that perioperative systemic therapy including immune checkpoint inhibitors (ICIs) improved the overall survival (OS) of patients with early-stage TNBC [10]. Moreover, the KEYNOTE-355 trial showed that chemoimmunotherapy led to clinically significant improvements in the progression-free survival of patients with advanced-stage TNBCs [11]. Given the rarity of MpBC and its unique clinical course compared with other types of TNBC, applying the results of these clinical trials to MpBCs remains controversial. A limited number of reports have demonstrated the remarkable therapeutic effects of chemoimmunotherapy for MpBC in perioperative or metastatic settings.

In our case, early recurrence was observed during conventional adjuvant therapy after upfront surgery for MpBC. However, chemoimmunotherapy based on the KEYNOTE-355 trial led to significant regression of the recurrent lesions, which remained shrunken for over 2 years.

Case Report

A 52-year-old Japanese woman noticed a rapidly growing mass in her left breast. She had no family history of cancer except for her mother, who had ovarian cancer. Physical examination revealed a 7.0×5.5-cm palpable mass in her left breast. Mammography showed a large mass with irregular margins and indistinct borders. Ultrasonography showed a hypoechoic mass measuring 5.5×4.8×3.2 cm, with suspicion of pectoralis muscle invasion. A vacuum-assisted biopsy of the breast mass revealed histological characteristics compatible with MpBC, which showed a triple-negative subtype. Moreover, the tumor cells were positive for AE1/AE3, CK5/6, and p63. Magnetic resonance imaging (MRI) revealed a tumor measuring 5.9×5.8×4.5 cm, with suspected invasion into the pectoralis major muscle (Figure 1). Staging positron-emission tomography/computed tomography (PET/CT) showed no regional or distant metastasis. Based on these findings, the patient was staged as cT3N0M0, Stage IIB MpBC. Given the patient’s maternal history of ovarian cancer, germline testing for BRCA1 and BRCA2 mutations was performed and yielded negative results. As the tumor was considered resectable, a left breast mastectomy with sentinel lymph node biopsy was performed, achieving complete resection. Histopathological analysis of the surgical sample showed that the metaplastic component consisted mostly of spindle cell carcinoma, with extensive necrosis. Carcinoma cells were positive for AE1/AE3, CK5/6, and p63 (Figure 2). Liposarcoma-like components were observed in some areas, and immunohistochemical analysis showed positivity for MDM2 and CDK4. Ultimately, a final pathological stage of pT3N0M0 IIB MpBC was established. We then planned to administer adjuvant chemotherapy consisting of 4 cycles of dose-dense epirubicin (90 mg/m2 intravenously once every 2 weeks) and cyclophosphamide (600 mg/m2 intravenously once every 2 weeks) followed by 4 cycles of dose-dense paclitaxel (175 mg/m2 intravenously once every 2 weeks), using subcutaneous pegfilgrastim. However, 3 weeks after the introduction of treatment with dose-dense epirubicin and cyclophosphamide, a mass appeared in the left anterior chest, with subsequent core-needle biopsy revealing recurrent MpBC. Computed tomography (CT) revealed multiple lung metastases and sternal metastasis (Figure 3). Given that the initial surgical specimen tested positive for PD-L1 with a combined positive score of 83.2% using PD-L1 IHC 22C3 pharmDx (Figure 4), the treatment was changed to chemoimmunotherapy consisting of pembrolizumab (200 mg intravenously once every 3 weeks), gemcitabine (1000 mg/m2 on days 1 and 8, every 21 days), and carboplatin (AUC 2 on days 1 and 8, every 21 days) as per the KEYNOTE-355 trial. Despite observing a temporary increase in the precordial mass and multiple lung metastases early after administration, significant shrinkage of the metastatic lesions was subsequently noted (Figure 5). The patient experienced treatment-related adrenal insufficiency, rash, pruritus, and anemia, all categorized as Grade 2 according to the Common Terminology Criteria for Adverse Events, version 6.0. Adrenal insufficiency developed 2 months after initiation of pembrolizumab-based therapy and was incidentally identified on routine laboratory testing, which revealed decreased levels of adrenocorticotropic hormone and cortisol, despite the absence of clinical symptoms. Hydrocortisone replacement therapy was initiated at a dose of 15 mg/day, gradually tapered over time, and ultimately discontinued after 24 months, while pembrolizumab treatment was continued without interruption. Ten months after the initiation of treatment, carboplatin plus gemcitabine was discontinued because of treatment-related adverse events, including myelosuppression, and the patient was subsequently switched to pembrolizumab monotherapy. Pembrolizumab was maintained beyond the 24-month duration applied in the KEYNOTE-355 trial because PET/CT imaging demonstrated persistent uptake in the sternal metastatic lesion and because therapeutic options would be limited in the event of disease progression. At 30 months after initiation of chemoimmunotherapy, positron-emission tomography/computed tomography (PET/CT) imaging demonstrated only mild 18F-fluorodeoxyglucose uptake in the sternal metastasis. To date, no evidence of disease progression has been observed (see Figure 6 for the clinical course timeline).

Discussion

MpBC has been considered a heterogeneous group of IBCs characterized by the differentiation of neoplastic epithelium into squamous cells and/or mesenchymal-appearing elements, including but not restricted to spindle, chondroid, and osseous cells [12]. MpBC can be classified into 6 subtypes: low-grade adenosquamous carcinoma, fibromatosis-like MpBC, spindle cell carcinoma, squamous cell carcinoma, MpBC with mesenchymal differentiation, and mixed MpBC [12]. Among these subtypes, high-grade spindle cell carcinoma, squamous cell carcinoma, and high-grade adenosquamous carcinoma have particularly poor prognoses [13,14]. The vast majority of MpBCs are TNBCs [2]. Moreover, MpBCs have shown poor response to conventional chemotherapy and OS outcomes compared with other forms of TNBCs [8]. Takala et al reported that among patients receiving palliative chemotherapy including anthracyclines, cyclophosphamide, taxanes, and cisplatin, a partial response was observed in only 6% of cases and stable disease in 18%, resulting in a median OS time with metastatic disease of only 3.4 months [15].

In recent years, chemoimmunotherapy using pembrolizumab or atezolizumab has been approved for the treatment of metastatic TNBCs, whereas ICIs have commonly been used as first-line treatments for TNBCs with PD-L1 expression [11,16,17]. Pembrolizumab has also been approved as a perioperative therapy for TNBCs. Studies have shown that neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab significantly improves pathological complete response (pCR) rates, event-free survival, and OS compared with chemotherapy alone, regardless of PD-L1 status [10,18,19]. However, given that histological subtypes of breast carcinomas had not been mentioned in the eligibility criteria, it remains unclear whether MpBCs were included in these trials. MpBCs have higher rates of PD-L1 positivity than other forms of TNBCs. In fact, Joneja et al reported that PD-L1 expression was detected in a significantly higher proportion of MpBCs (46%) than in TNBC, not otherwise specified (9%) [20]. Owing to the rarity of MpBCs, no standard treatment has yet been established, although some reports have shown that MpBCs respond remarkably well to ICIs [21–29]. Hence, ICIs may be an attractive treatment option for MpBCs.

Our patient showed an apparently poor response to conventional chemotherapy, as recurrent lesions appeared only a few weeks after the initiation of adjuvant chemotherapy. Conversely, administration of pembrolizumab plus gemcitabine/carboplatin as per the KEYNOTE-355 regimen significantly reduced multiple metastases and suppressed disease progression for over 2 years. A few reports have shown that chemoimmunotherapy with pembrolizumab is effective for MpBCs [22,24–26,28,29]. Gul et al were the first to report the achievement of pCR with the KEYNOTE-522 regimen as neoadjuvant chemotherapy for early-stage MpBC [24]. Ladwa et al also achieved pCR using the KEYNOTE-522 regimen for early-stage MpBC, with a recurrence-free survival of approximately 18 months [25]. Regarding the combination of palliative chemotherapy and pembrolizumab for advanced-stage MpBC, 2 reports have shown remarkable tumor shrinkage using treatment based on the KEYNOTE-355 regimen [22,26]. In a report by Adams et al, multiple metastases had become undetectable after treatment with nab-paclitaxel plus pembrolizumab, with the tumor response continuing at 6 months [22]. Koi et al showed that the administration of pembrolizumab plus gemcitabine/carboplatin promoted the disappearance of multiple pulmonary metastases [26]. Studies have also reported complete responses lasting for >2 years following chemoimmunotherapy with durvalumab or atezolizumab [21,27]. ICIs can also show remarkable efficacy in metastatic settings, and combination chemotherapy with ICIs could be a powerful option for the treatment of PD-L1-positive MpBCs, similar to that in other types of TNBCs.

Given our patient’s maternal history of ovarian cancer, hereditary breast and ovarian cancer syndrome was considered a potential underlying condition. Germline testing for BRCA1 and BRCA2 mutations was therefore performed and yielded negative results. More extensive germline genetic testing was not conducted because such testing is generally not covered by public health insurance in Japan. Nevertheless, hereditary cancer risk assessment should be considered in similar cases, particularly when a suggestive family history is present.

Discontinuation of ICIs in the absence of disease progression remains controversial. In a real-world analysis of melanoma patients who discontinued anti-PD-1 therapy with pembrolizumab or nivolumab in the absence of disease progression or treatment-limiting toxicity, disease progression was less frequent in patients with complete response (14%) than in those with partial response (32%) and stable disease (50%) [30]. Long-term follow-up data from the initial ICI trials in melanoma indicate that continued ICI administration can cause overtreatment. Pala et al demonstrated that several clinicopathological features, including tumor histology, type of treatment received, and cause of discontinuation, significantly influenced the outcomes of patients who discontinued ICIs for reasons other than disease progression [31]. They showed that the relative risk of progression or death after immunotherapy cessation was 3 and 4 times higher in patients with non-small cell lung cancer and renal cell carcinoma, respectively, than in those with melanoma. Most previous studies regarding ICI discontinuation have focused on melanoma, which has been recognized as one of the most immunogenic tumors [32]. Moreover, ascertaining whether the findings obtained in patients with melanoma can be applied to those with breast cancer remains difficult. Further studies are needed to determine whether ICIs can be discontinued in patients with TNBC, including MpBC, who exhibit long-term responses.

Conclusions

We report a case in which the combination of pembrolizumab and chemotherapy was highly effective for early recurrent MpBC. Despite insufficient evidence regarding the efficacy of ICIs for MpBC, pembrolizumab combination therapy may be a promising treatment option for patients with MpBCs. Nonetheless, further research is needed to determine the optimal ICI treatment duration in metastatic settings and the appropriateness of discontinuing treatment in patients with long-term response.