Genetic Testing in Kidney Cancer

Kidney cancer accounts for 2.2% of new cancer cases worldwide and 1.8% of deaths. In recent years, the incidence of kidney cancer in China has shown a trend of continuous growth. Early-stage kidney cancer can be surgically removed and has a better prognosis. About 20%-30% of renal cancers will recur and metastasize after surgery. Metastatic renal cancer (mRCC) is insensitive to conventional radiotherapy and chemotherapy, with poor prognosis and high mortality, posing a great threat and impact on the life of patients.

With the advent of the era of precision medicine, individualized treatment has gradually become the trend in tumor treatment. The widespread application of genetic testing technology represented by next-generation sequencing (NGS) provides technical support for the precise treatment of tumors. In non-small cell lung cancer, breast cancer, prostate cancer, and many other cancers, molecular pathology provided by genetic testing has become a necessary part of subsequent treatment decisions, and more suitable treatment plans can be provided according to different molecular pathological types.

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Although molecular typing based on genetic testing has not been used as a reference for mRCC treatment in domestic and foreign guidelines and consensuses, in recent domestic and foreign studies, gene mutations have a certain role in the clinical diagnosis, efficacy evaluation, and prognosis prediction of renal cancer. Clinical Value.

Kidney cancer patient selection suitable for genetic testing

1. Second-line or later-line therapy for metastatic clear cell renal cell carcinoma (mccRCC)

About 70% of renal cell carcinomas are renal clear cell carcinomas, and systemic drug therapy is the standard treatment for mccRCC. The current treatment drugs mainly include tyrosine kinase inhibitors (TKIs), mTOR inhibitors and immune checkpoint inhibitors ( ICI). Once treatment is resistant, subsequent second-line or even later-line treatment options are not clearly stated in the guidelines. For mccRCC patients who have progressed on first-line therapy, genetic testing may be considered to predict drug sensitivity and optimize treatment drug selection.

2. Metastatic non-clear cell renal carcinoma (mnccRCC)

The incidence of non-clear cell renal cell carcinoma (nccRCC) is low, compared with fewer clinical trials of ccRCC, and the systemic treatment regimen recommended by the guidelines is relatively single. The response rate of nccRCC to TKIs and mTORs was lower than that of ccRCC. Genetic testing of mnccRCC can help in drug selection and provide more effective treatment options.

3. Hereditary Kidney Cancer

Hereditary kidney cancer accounts for about 5%-8% of kidney cancers. The "CSCO Kidney Cancer Diagnosis and Treatment Guidelines 2020" proposes that genetic testing is recommended for patients with onset age ≤45 years old and with bilateral, multifocal renal disease and a family history of renal cancer. At present, a series of pathogenic genes of hereditary renal cancer syndrome have been identified, such as VHL, MET, SDHB, FH, FLCN, PTEN, BAP1, etc. Genetic testing can clarify the pathological type of such patients, guide appropriate treatment, and combine genetic counseling to assess the risk of disease in immediate family members.

4. Renal cancer with specific clinical features or unknown histology

Bilateral or multifocal renal cancer accounts for 5% of all renal cancers, and approximately 90% of multifocal renal cancers occur bilaterally, usually with a higher probability of recurrence and a worse prognosis. In general, this type of renal cancer is associated with genetic susceptibility, but some patients still have a later age of onset or lack a significant family history. Therefore, genetic testing is recommended to identify the type of gene mutation in this type of kidney cancer.

In clinical treatment, there are still some renal cancers whose pathological types cannot be determined by the commonly used HE staining and immunohistochemistry. The diagnosis of such renal cancers depends on the detection at the gene level, such as Xp11.2 translocation/TFE3 gene fusion renal cell carcinoma The histological phenotype lacks typical features and requires fluorescence in situ hybridization (FISH) or TFE fusion gene testing to confirm the diagnosis.

Contents of kidney cancer genetic testing

According to different test objects and clinical needs, different NGS sequencing technologies can be selected. For the following known targeted therapy or immunotherapy-related gene tests, due to limited genes, it is recommended to test in the form of panels. to ensure cost-effectiveness.

Hereditary kidney cancer-related genes

Hereditary renal cancer is often accompanied by other systemic manifestations, but there are also cases where only renal cancer manifestations are present, and it is often difficult to distinguish from sporadic renal cancer only by pathology. Accurate diagnosis and identification of hereditary renal cancer is an essential part of the comprehensive treatment of renal cancer. It is necessary to detect germline mutations by NGS technology to diagnose hereditary kidney cancer.

Clinically significant mutated genes in other tumors

NCCN guidelines only recommend that renal collecting duct carcinoma, renal medullary carcinoma, and sarcomatoid differentiated renal carcinoma should be considered for chemotherapy. At present, there is no guideline recommendation for the treatment of these three types of renal cancer. The detection of chemotherapy sensitivity and toxicity prediction genes supported by evidence-based medical evidence in other tumors has certain reference significance for the selection of treatment options.

The value of genetic testing in the prognosis evaluation of renal cancer

In recent years, a series of retrospective studies have found the correlation of BAP1, PBRM1, SETD2, KDM5C, TP53, and TERT with the prognosis of renal cancer. BAP1, PBRM1, and TP53 have independent predictive values in advanced renal cancer patients treated with first-line TKIs. The updated MSKCC gene model added BAP1/TP53 and PBRM1 as independent predictors and added four risk classes. more accurate predictions. The recurrence prediction of localized renal cancer is also a hotspot of current research. The 6SNP molecular prediction model constructed based on gene detection of single nucleotide polymorphisms (SNPs) has achieved reliable prediction results (Table 6). With the widespread development of NGS detection in the clinic, these gene models have good clinical application prospects.

Kidney cancer expert group recommendation

1. For patients with advanced clear cell renal cell carcinoma, advanced renal non-clear cell carcinoma, and renal cancer patients who meet the screening criteria for hereditary renal cancer and special clinical pathology after first-line therapy, genetic testing is recommended to identify gene mutation sites. diagnosis, and provide a reference for the selection of treatment options; for first-line targeted therapy for advanced clear cell renal cell carcinoma with a clear diagnosis, genetic testing is not required.

2. In late ccRCC that has progressed after first-line therapy, genetic testing can assess the sensitivity of patients to targeted drugs, thereby assisting in drug decision-making for second-line and later-line therapy. For nccRCC, genetic testing can help select appropriate first-line therapy.

3. It is recommended to use blood as the germline mutation sample and tumor tissue (fresh tissue or paraffin block tissue) as the systemic mutation sample, and the process must meet the standard specifications.

4. The efficacy prediction markers of immunotherapy are one of the current research hotspots. In renal cancer, the predictive value of TMB, MSI and PBRM1 mutations remains to be clarified, and DDR pathway-related genes are predictive markers found in current clinical studies. Relevant gene mutations can be used as a reference factor for recommending immunotherapy, but not as a decisive factor in choosing immunotherapy. For patients at risk for hyperprogression who require immunotherapy, genetic testing is recommended to avoid risk.

5. When the tissue sample for the first genetic test is insufficient or the tissue test fails, liquid biopsy test products approved by NMPA or FDA can be used as an auxiliary or supplement.

6. For renal cancer patients who have not received targeted/immune drug therapy, tissue samples that have been pathologically evaluated should be the first choice for NGS testing. For patients who have received targeted/immunotherapy, post-treatment samples should be used whenever possible.

7. If conditions permit, if the patient is willing to obtain comprehensive genetic variation information, and patients with advanced new or postoperative recurrence of renal cancer, it is recommended to use NMPA or FDA-approved large-panel comprehensive genomic NGS detection products. Develop first-line treatment regimens on the basis of tumor genomes.

8. Pay attention to the cooperation between urologists and oncologists, pathologists, molecular biology, and bioinformatics experts, and building a new multidisciplinary diagnosis and treatment model of the molecular tumor expert committee/MDT will be an important development in the clinical and research of urological tumors direction.

for more information:ali.ma@wecistanche.com