Positive outcome of first-line therapy for a SMARCA4-deficient thoracic sarcomatoid tumor

Abstract

SMARCA4-deficient thoracic sarcomatoid tumor is a rare malignancy indicating some characteristics of a smoking-related disease. The purpose of this report is to describe a case of aggressive thoracic tumor with loss of immunochemical SMARCA4 expression and detail the results of our treatment regimen. The patient was a 58-year-old male and clinicopathologically diagnosed with a SMARCA4-deficient thoracic sarcomatoid tumor. Pembrolizumab plus carboplatin and pemetrexed resulted in significant response. This combination therapy showed potential for first-line systemic treatment of SMARCA4-deficient thoracic sarcomatoid tumors.

Introduction

SMARCA4 (BRG1), a catalytic ATPase subunit of the SWI/SNF chromatin remodeling complexes, acts as a tumor suppressor in human malignancies [1]. SMARCA4 inactivation has been detected in small-cell carcinomas of the ovary, hypercalcemic type (SCCOHTs), malignant rhabdoid tumors (MRTs) or SMARCA4-deficient thoracic sarcomas [2–4]. Recently, another group of aggressive thoracic neoplasms characterized by SMARCA4 deficiency and round cell or rhabdoid morphology have been proposed as SMARCA4-deficient thoracic sarcomatoid tumors. They primarily represented smoking-associated undifferentiated/de-differentiated carcinomas rather than primary thoracic sarcomas [5]. Recommended therapies for this type of thoracic tumors have yet to be established, although immune checkpoint inhibitors (ICIs) were shown to be promising for later-line therapies [6, 7].

Case report

A 58-year-old male was referred to our outpatient clinic with an abnormal chest radiographic finding of right pleural thickening but no symptoms. CT scans showed limited pleural thickening and pulmonary emphysema (Fig. 1a, b). The patient had a medical history of gastric ulcer and depression, but both were well managed. Although there was no family history, he had a 38 pack-year smoking history.

Fig. 1.

a, b CT scans showed limited pleural thickening and pulmonary emphysema at first visit

Four months later, he revisited presenting progressive cough and dyspnea. Vital signs were as follows: body temperature, 36.4℃; percutaneous oxygen saturation, 97% in room air. Laboratory findings were as follows: WBC count, 9000 /mm³; hemoglobin level, 16.4 g/dl; platelet count, 411,000 /mm³; serum LDH, 813 IU/ml; serum CEA, 2.6 ng/ml. CT scans detected irregularly shaped thoracic tumors, mediastinal lymphadenopathies, right pleural effusion, and adrenomegaly (Fig. 2a, c, e). Cytological findings of pleural effusion showed a poorly differentiated neoplasm with a relatively well-circumscribed cell surface and large nucleoli (Fig. 3a). Immunohistochemistry of the tumor cells were as follows: SMARCA4, negative; Claudin-4, negative; SOX2, positive; SALL-4, positive; SMARCB1, positive; TTF-1, negative or focally positive (Fig. 3b, c, d). Histological findings of the tumors were also the same. The tumor proportion score (TPS) of PD-L1 expression (22C3) was 10%. Driver mutations of EGFR, ALK, ROS1 and BRAF associated with non-small cell lung cancer (NSCLC) were not detected. The patient was diagnosed with a SMARCA4-deficient thoracic sarcomatoid tumor.

Fig. 2.

a, c, e CT scans detected irregularly shaped right thoracic tumors, pleural effusion and adrenomegaly; b, d, f significant tumor shrinkage detected 3 months after therapy was initiated

Fig. 3.

a Poorly differentiated neoplasm without any keratinization, mucinous or striated structure identifiable by hematoxylin and eosin staining; b immunohistochemical staining of SMARCA4 was negative; c Claudin-4 was negative; d SOX2 was positive

After a talc pleurodesis procedure, combination therapy of ICI plus carboplatin (CBDCA) and pemetrexed (PEM) was selected. The patient was scheduled to receive pembrolizumab (200 mg/body) every 3 weeks plus four cycles of CBDCA (area under the concentration–time curve: AUC, 5 mg/ml min) and PEM (500 mg/m²) every 3 weeks. He was repeatedly admitted to the hospital due to grade 3 anorexia. Subsequently, both CBDCA and PEM were discontinued after the third cycle. Despite a grade 1 rash of an immune-related adverse event, pembrolizumab has been administered until present. Significant tumor shrinkage comparable to partial response was detected 3 months after initiating therapy (Fig. 2b, d, f). Efficacy has so far continued for 8 months and the patient has survived for 11 months.

Discussion

Recently, Le Loarer et al. have reported 19 cases of aggressive thoracic malignancy with inactivation of SMARCA4, designated as SMARCA4-deficient thoracic sarcomas. Transcriptomic classifications of these cases were closely related to SCCOHTs and MRTs, but not to SMARCA4-mutated lung carcinomas [4]. Subsequently, 22 similar cases of undifferentiated round cell and/or rhabdoid morphology, loss of immunohistochemical SMARCA4, and lack of claudin-4 have also been proposed as SMARCA4-deficient thoracic sarcomatoid tumors. Moreover, smoking-related NSCLC type mutations of STK11, KEAP1 and KRAS were detected in a subset of SMARCA4-deficient thoracic sarcomatoid tumors [5]. SMARCA4-deficient thoracic sarcomas and SMARCA4-deficient thoracic sarcomatoid tumors share many clinicopathological characteristics, however, SMARCA4-deficient thoracic sarcomatoid tumors are distinctive as having an immunohistochemical lack of the epithelial adhesion molecule Claudin-4. At present, a recommended therapy or treatment strategy has yet to be established.

The present case showed characteristics of large compressive thoracic tumors, a history of smoking and pulmonary emphysema. Immunohistochemical findings of the neoplasm were negative for SMARCA4 and Claudin-4, and positive for SMARCB1, SOX2 and SALL-4. TTF-1 expression did not completely disappear. Companion diagnostics for lung cancer were all negative. This case was diagnosed as SMARCA4-deficient thoracic sarcomatoid tumor according to the clinical characteristics and pathological criteria [5].

In recent years, several reports have proposed the effectiveness of ICIs for SMARCA4-deficient thoracic tumors. Pembrolizumab revealed long lasting response in a thoracic malignant rhabdoid-like SMARCA4-deficient tumor, and nivolumab showed marked therapeutic effect in SMARCA4-deficient thoracic sarcoma [6, 7]. PD-L1 is a good biomarker for anti-PD-1 agents in lung cancer, but the expression level was low in the present case. High somatic tumor mutation burden (TMB) is also a promising predictive marker for ICI sensitivity, e.g., higher TMB of a nonsynonymous mutation is associated with the clinical efficacy of pembrolizumab [8]. On the other hand, BRG1-deficient NSCLC often indicates the truncating mutation of SMARCA4. Deficient BRG1 expression was predominantly detected with co-occurring mutations in KRAS, TP53, KEAP1 and STK11. It was noteworthy that mutations in KEAP1 and STK11 were associated with resistance to immunotherapy and chemotherapy [9]. In considering the co-mutation status of STK11/KEAP1 on ICIs, there is a report that patients with a pure SMARCA4 mutation were found to have numerically higher overall survival and significantly longer progression free survival than those with SMARCA4 mutation harboring STK11/KEAP1 co-mutation, those with STK11/KEAP1 mutation, and those without SMARCA4/STK11/KEAP1 mutation [10].

Since the clinical evidence for ICI monotherapy to treat SMARCA4-deficient thoracic sarcomatoid tumors was inadequate, we selected pembrolizumab plus CBDCA and PEM as the first-line therapy for the present case. The comprehensive genome profiling (CGP) assay was postponed so as not to lose the therapeutic opportunity characterized by the aggressive features of this case, thus, TMB could not be confirmed before therapy. Fortunately, pembrolizumab plus CBDCA and PEM, followed by pembrolizumab monotherapy showed significant response. Pembrolizumab seemed to play an important role in the combination therapy, although the effectiveness of each drug is yet unclear. SMARCA4-deficient tumors often harbor KEAP1/STK11 co-mutations and ICI therapy is not promising in that subset. However, ICI was effective in the present case. There has been a report of ICI effectiveness in a SMARCA4-deficient tumor without harboring KEAP1/STK11 co-mutations. Although the co-mutation status of KEAP1/STK11 is unclear in this case, the significant response is most likely due to loss of the mutation. Verification by comprehensive genome profiling (CGP) assay is necessary and will be the subject of future work. Mutations of KEAP1 and STK11 have not yet been indicated in an ICI-sensitive case [7]. At present, because ICI-resistant cases exist, chemotherapy in combination with ICI seems a valid choice. In the future, ICI monotherapy may be sufficient for the subset of SMARCA4-deficient tumors that do not harbor KEAP1/STK11 co-mutations. Further studies on co-occurring mutations of KEAP1 and STK11 in SMARCA4-deficient thoracic sarcomatoid tumors will be necessary.

Here, we have reported the case of a SMARCA4-deficient thoracic sarcomatoid tumor successfully treated with pembrolizumab plus CBDCA and PEM, followed by pembrolizumab. Since the sensitive markers of immunotherapy and chemotherapy have yet to be confirmed, this combination therapy may be considered a good option for first-line therapy of SMARCA4-deficient thoracic sarcomatoid tumors. Further case reports should contribute to establishing an optimal treatment strategy.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

For this type of study, formal consent is not required.

Informed consent

Informed consent was obtained from all individual participants included in this study.