HLRCC was a rare, autosomal dominant hereditary disorder caused by mutations in the FH gene. One manifestation of this disease was renal cell carcinoma, which predominantly presented as an aggressive form with a high propensity for early metastasis [12]. Treatment of these patients posed significant challenges, as there currently existed no standardized therapeutic regimen; instead, treatment strategies were largely based on those employed for renal cancer cases in general, often involving experimental approaches and adaptations. Here, we described a patient with HLRCC who exhibited a novel heterozygous germline FH mutation and benefited from immunotherapy. Although the patient only achieved partial response during immunotherapy, her metastatic lesions had long-term benefit in addition to the pleural effusion.
We reviewed the reports of received immunotherapy treatment in HLRCC patients (smethods). The literature revealed 5 studies including 76 HLRCC-related patients that reported the results of immunotherapy treatment in HLRCC patients. As shown in Table 1, Several case reports have confirmed the efficacy of immunotherapy or immunotherapy in combination for HLRCC patients. Therefore, we further explored the correlation between different FH gene variants and immunotherapy benefit. Information on FH germline mutations and immunotherapy in 46 HLRCC-related patients was collected.
The FH germline mutations of 46 patients were 40 variants in the FH gene, including 11 insertion/deletions, 24 missense mutations, two splice site mutations, and three exon deletions (Fig. 4). In our cohort, more mutations were concentrated in exons 5, 8 and 9, accounting for 28.3%, 17.4% and 15.2%, respectively. We first analyzed the effect of immunotherapy on OS. As shown in Figure 4, the patients who received immunotherapy had a significantly better OS than those who did not (median OS:NR vs 18.01 months, HR=0.162, p=0.0015). Then, the related of OS and FH gene was analyzed. No correlation was found between mutations in different exons of FH gene and OS as shown in Figure 4. The OS of patients who harbored mutation in FH gene kinase domain and with the non-kinase domain were compared, and no differences were found. Then, the FH mutations with high probability causing protein abnormalities was defined as class I mutation, including insertions/deletions and exon deletions; other mutations were defined as class II mutation. However, OS did not differ between the patients of harboring Class I and Class II mutation. As illustrated by our literature review and analysis, immunotherapy maybe an effective therapeutic option for HLRCC patients.
HLRCC was inherited as an autosomal dominant condition and caused by germline mutations in the FH gene (1q42.3–q43)[1, 13] . HLRCC patients were at risk for the development of cutaneous leiomyomas, early onset multiple uterine leiomyomas and an aggressive form of type 2 papillary renal cell cancer [14]. Different FH mutations were detected in different HLRCC cases. So far, more than 200 variants in FH gene had been uploaded in the Leiden Open Variant Database, including more than 100 pathogenic mutations [15]. Meanwhile, the HGMD dataset also documented these reported pathogenic and suspected pathogenic FH mutations [16]. In this study, a new nonsense mutation of FH gene was detected. Although this mutation was documented in the ClinVar database, no relevant case has been reported so far. Considering the patient's disease history and the mutated form of the FH gene, this patient was diagnosed with HLRCC. FH gene mutations were detected by WES the results revealed the same mutation status across patient’s family members. This was the first case report revealing FH p.Q376* as a pathogenic mutation.
Prompt excision of HLRCC-associated kidney tumors was critical for preventing metastasis [12]. However, no standard therapies or consensus management approaches have been established for advanced HLRCC-RCC. There have been several reports of HLRCC-RCC treatment with immunotherapy, which have attracted attention as a new therapeutic option. A recent study reported the achievement of complete response in a patient with HLRCC-RCC after 31 weeks of immunotherapy combination treatment (nivolumab plus ipilimumab)[17]. Several other cases of HLRCC-RCC also showed that immunotherapy treatment was effective[4, 17-19]. Consistent with previous studies, our study also showed that HLRCC patients who received immunotherapy had longer OS[8]. Besides, a single-arm phase II study of cabozantinib plus nivolumab demonstrated an ORR of 100% in HLRCC [10]. However, several cohorts’ studies demonstrated that the ORR of immunotherapy ranged from 16.7% to 33% in HLRCC[8, 9, 20, 21]. Therefore, a total of 46 HLRCC patients who received immunotherapy were enrolled. The correlation between FH germline variation and immunotherapy response was analyzed. As in previous reports [8, 21], there was no obvious aggregation of FH mutations. Meanwhile, our cohort indicated that immunotherapy could significantly improve the OS of HLRCC patients as reported in previous[8]. Unfortunately, no significant association was found between FH gene and treatment response inOS analysis. Our results suggest that different variants of FH gene do not affect the benefit of immunotherapy in HLRCC patients.
Programmed cell death-ligand 1(PD-L1) maybe a useful biomarker of immunotherapy treatment of HLRCC. In the case reported of monotherapy of pembrolizumab, the patient had high expression levels of PD-L1(30%) and achieved CR[18]. Another case reported showed that patients with PD-L1 of 50% and also achieved CR in immunotherapy combination treatment [17]. Fortunately, the patient also achieved partial response, and the efficacy of immunotherapy and PD-L1 expression in HLRCC patients have not been investigated in cohort studies. Thus, PD-L1 may be useful as predictors or biomarkers of treatment effects in future studies.