Renal Cell Carcinoma

8. HEREDITARY AND SYNDROME SPECIFIC RCC

Five to eight percent of RCCs are hereditary; this proportion could be underestimated due to the limitations of available studies. To date there are more than ten hereditary RCC syndromes associated with specific germline mutations, RCC histology, and comorbidities. Hereditary RCC syndromes are often suggested by family history, age of onset and presence of other lesions typical for the respective syndromes. Median age for hereditary RCC is 37 years; 70% of hereditary RCC tumours are found in the lowest decile (age 46 years or younger) of all RCC tumours [178].

Hereditary kidney tumours are found in the following entities: VHL syndrome; hereditary papillary RCC (HPRCC); Birt-Hogg-Dubé syndrome; Fumarate hydratase-deficient RCC (FHD-RCC), previously called hereditary leiomyomatosis and RCC (HLRCC); tuberous sclerosis complex; Hereditary SDH deficient paraganglioma/ pheochromocytoma (HPP) syndrome; Phosphatase and tensin homolog (PTEN) hamartoma syndrome (PHTS); and BRCA-1 associated protein 1 (BAP1) tumour predisposition syndrome).

RCC can also be associated with the following syndromes: Hyperparathyroidism-jaw tumour (HJT) syndrome, Chromosome 3 translocation (Cr3T) syndrome, and MITF-related melanoma and renal cell carcinoma predisposition syndrome. Renal medullary carcinoma can be included because of its association with hereditary haemoglobinopathies [65,682-685].

8.1. Microphthalmia associated transrciption factors (MiTF) associated translocation tumours

Although not hereditary, somatic fusion translocations of TFE3 and TFEB may affect 15% of patients with RCC younger than 45 years and 20-45% of children and young adults diagnosed with RCC [686].

Table 8.1: Syndrome-specific RCC hystotypes and extra-renal organ involvement patterns [187, 687, 688]

Data on estimated prevalence/incidence are based on https://www.orpha.net.

Recently published recommendations for the selection of germline genetic testing panels in patients with cancer, including RCC [689] stated that germline genetic testing should be distinguished from biomarker testing (i.e. tumour genomic profiling). To establish whether gene variants identified in a tumour are germline, germline genetic testing must be performed. With advancements in next-generation sequencing technology, genetic panels now encompass an expanding list of available genes. Specific recommendations have been set for the following domains: a) family history collection; b) germline multigene panel testing; c) genes to be included in multigene panels; and d) germline testing in association with somatic genetic tumour testing [689]. For RCC, the genes recommended for testing and inclusion in multigene panels are: BAP1, FH, FLCN, MET, SDHA, SDHAF2, SDHB, SDHC, SDHD PTEN, VHL (more strongly recommended) and TSC1/TSC2 (less strongly recommended).

8.2. Management of hereditary and syndrome specific RCC

Hereditary RCC often presents with multifocal, de-novo recurring and bilateral tumours, which requires individualized management.

Patients with hereditary kidney cancer syndromes may require repeated surgical intervention [690,691]. In most hereditary RCCs nephron-sparing approaches are recommended. To avoid multiple repetitive partial nephrectomies, thermal ablation can be considered in the treatment paradigm. A registry based retrospective analysis of 53 patients with inherited RCC syndromes evaluated percutaneous cryoablation for primary mean 2.46 cm tumours demonstrating within mean follow up of 30.4 months estimated five-year local recurrence free survival of 96% (95% CI 75-99), metastases free survival 96.4% (95%CI 77-99%), CSS 90.9% (95% CI 51-99%) and OS 90.9% (95%CI 51-99%). Complication rate was 1.7% and 7.4% had more than 25% reduction in kidney function [692].

The exceptions to nephron-sparing approaches are FHD-RCC and high-grade SDH syndromes for which immediate surgical intervention is recommended due to the aggressive nature of these tumours. For other hereditary syndromes such as VHL, surveillance is recommended until the largest tumour reaches 3 cm in diameter: this to limit the number of repeat interventions [693,694]. Active surveillance for VHL and other non-aggressive hereditary tumours, should, in individual patients, follow the size, growth rate and location of the tumours, rather than applying a standardised follow-up interval. Regular screening for both renal and extra-renal lesions should follow international guidelines for these syndromes [694]. Multidisciplinary and co-ordinated care should be offered, where appropriate [695]. In FHD-RCC, renal screening in relatives has shown benefit in detecting early-stage RCCs [46], with HLRCCs appearing to have unique molecular profiles.

In the metastatic setting, systemic therapeutic options for fumarate hydratase-deficient RCC with high metastatic potential include ICI monotherapies which offer a better disease control rate than TKI monotherapies. In a phase II trial, ORR of 51 % of combination of erlotinib and bevacizumab was achieved [654]. Another trial expressed a favorable response to ICI/TKI combinational therapy compared to bevacizumab plus erlotinib [92].

Succinate dehydrogenase (SDH)-deficient RCC has a low risk of metastasis (12 %) with exception of high-grade with risk 70 %. Due to rarity of disease, no evidence for systemic therapy [654].

8.2.1.von-Hippel-Lindau-disease-associated RCC

Patients with VHL disease often develop RCC and tumours and cysts in other organs including adrenal glands, CNS, retinal haemangioblastomas, and pancreas, and commonly undergo several surgical resections in their lifetime. In VHL disease, belzutifan, a HIF-2α inhibitor, has been approved by the US Food and Drug Administration [696] for the treatment of ccRCC and other neoplasms associated with VHL for the treatment of tumours that do not require immediate surgery. Approval was based on the results from a phase II, open-label, single-arm trial in 61 patients with tumours not larger than 3 cm [584]. Belzutifan induced partial responses with an RCC ORR of 49%, and a disease control rate of 98.4% after 21.8 months treatment. All patients with pancreatic lesions had an ORR of 77%, and those with CNS haemangioblastoma had a 30% response rate. In total, 33% of patients reported > grade III adverse events, and seven patients (11.5%) discontinued the treatment. In the treatment with pazopanib for VHL only 52% continued with the treatment after 24 weeks [697]. A longer follow-up at 37.8 months, ORR for RCC was increased to 64%, with a median time to response of 11.1 months (range, 2.7 to 30.5). Median duration of response per Kaplan-Meier estimate was not reached (range, 5.4+ to 35.8+ months). Thirty-four of 39 patients with a confirmed response (87%) remain in response as of the data cut-off date (September 2022) [698].

With favourable efficacy results and with relatively low-grade side effects, belzutifan seems to be a valuable contribution to the treatment of patients with the VHL disease. The EMA has not yet considered belzutifan for approval in VHL disease.

8.2.2. TFE3-rearranged RCC

TFE3-rearranged RCC showed objective response rate 25 % with ICI and 0 % with TKI and more prolonged OS (62.4 months with ICI vs. 10.3 with TKI). Cabozantinib may be an exeption with 16.6% objective response. There is discussed future role of ICI-TKI combination (such as nivolumab plus cabozantinib) and cabozantinib plus belzutifan [654].

8.2.3. TFEB-altered RCC

TFEB-rearranged RCC: There is a general lack of information regarding the response to moderm systemic therapy. Combination of ICI and mTOR inhibitors are discussed. TFEB-amplified RCC (it occurs in elderly patients and displays more aggressive behaviour compared to TFEB-rearranged RCC) can be treated with VEGFR targeting agents or with VEGFR-TKI combination [654].

8.2.4. Combined therapy for TFE3- and TFEB-altered RCCs

Some studies combine therapy TFE3- and TFEB-altered RCCs (because of former grouping ob both tumours to MiT family translocation RCCs). Two retrospective studies exhibit efficacy of ICI or ICI-TKI combination
[699,700]. Other study provided evidence of the activity of cabozantinib in MiT TRCC, with more durable responses than those observed historically with other VEGFR-TKIs or ICIs [701].

8.2.5. Summary of evidence and recommendation for hereditary and syndrome-specific RCC