Long-term Response of Metastatic Hereditary Leiomyomatosis and Renal Cell Carcinoma Syndrome Associated Renal Cell Carcinoma to Bevacizumab Plus Erlotinib After Temsirolimus and Axitinib Treatment Failures

In this case report, we describe a man with advanced renal cell carcinoma (RCC) which was thought to be a sporadic papillary type 2 RCC initially but it turned out hereditary leiomyomatosis and RCC syndrome (HLRCC) associated RCC. His tumor was rapidly progressing despite temsirolimus and subsequent axitinib, and there was no available option. At that time, guidelines did not specify systemic treatment in metastatic HLRCC-associated RCC (NCCN guideline now mentions bevacizumab plus erlotinib in this population).

We used bevacizumab plus erlotinib referring to AVATAR trial (NCT01130519). He achieved a very deep and long-lasting response to bevacizumab plus erlotinib therapy and no unexpected adverse events.

HLRCC is a rare hereditary cancer, characterized by skin leiomyomas, uterine myomas, and RCC. Although it has been regarded as a very rare disease, it seems not so rare than previously thought. In a study by Carlo et al.,¹ the authors examined the prevalence of germline mutations in advanced RCC in unselected population for family history of cancer, age at onset, multifocal tumors, or personal history of multiple malignant tumors. Interestingly, FH was the most frequent RCC-associated genes in non-clear cell RCC, which was detected in 7 out of 74 nccRCC patients. Furthermore, aside HLRCC syndrome, there is CpG island methylator phenotype (CIMP) in type 2 papillary RCC.² CIMP-associated tumors showed decreased expression of FH mRNA and increased expression of genes associated with cell-cycle progression and response to hypoxia regardless of germline or somatic FH mutation. Like HLRCC-associated RCC, CIMP-associated tumors showed increased expression of key genes involved in glycolysis (HK1, LDHA, and PDK1), the pentose phosphate pathway (G6PD), and fatty acid synthesis (FASN).² It means that this subset of papillary type 2 RCC can be a similar metabolic phenotype to HLRCC-associated RCC, and can be a candidate of bevacizumab plus erlotinib treatment.

We also reported multicenter retrospective analysis about the efficacy and safety of bevacizumab plus erlotinib for HLRCC-associated RCC in the Republic of Korea.³ That report was the first real-world outcome of the treatment of advanced HLRCC-associated RCC. In Korea, HLRCC was an unfamiliar disease entity, and medical oncologists are only recently aware that there are patients in Korea. We identified 10 patients with advanced HLRCC-associated RCC who received bevacizumab plus erlotinib. Median age at diagnosis was 41 years, and five of the patients had received the combination as first- or second-line treatments. The ORR was 50% and the median PFS and OS were 13.3 and 14.1 months, respectively. Most adverse events were predictable and manageable by conventional measures, except for one instance where a patient died of gastrointestinal bleeding.

In my opinion, medical oncologist, urologist, and pathologists should be increasingly aware of HLRCC-associated RCC, and bevacizumab plus erlotinib should be the first-line treatment for this condition unless other promising data are published.

Written by: Inkeun Park, Division of Medical Oncology, Department of Internal Medicine, Gachon University Gil Medical Center, Republic of Korea.

Reference:
1. Prevalence of Germline Mutations in Cancer Susceptibility Genes in Patients With Advanced Renal Cell Carcinoma. Carlo MI et al. JAMA Oncol 2018;4:1228-1235.
2. Comprehensive Molecular Characterization of Papillary Renal-Cell Carcinoma. TCGA. N Eng J Med 2016;374:135-45.
3. Bevacizumab Plus Erlotinib Combination Therapy for Advanced Hereditary Leiomyomatosis and Renal Cell Carcinoma-Associated Renal Cell Carcinoma: A Multicenter Retrospective Analysis in Korean Patients. Choi Y et al. Cancer Res Treat 2019.

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