Few Actionable Genomic Alterations Identified in Renal-Cell Carcinoma

There has been an increased focus on the study of tumor alterations that may predict treatment benefit or serve as possible actionable targets in cancer. During the virtual American Urological Association 2020 Annual Meeting, Kyrollis Attalla, MD, Urology Oncology Fellow, Memorial Sloan Kettering Cancer Center, Ridgewood, NY, discussed findings of a recent study that looked at the landscape of actionable geno­mic alterations and the corresponding evidence to support these alterations as predictive of response to targeted therapy in patients with renal-cell carcinoma (RCC).

The investigators queried the Memorial Sloan Kettering sequencing database, which includes tumor samples sequenced across all cancers. Actionable alterations with clinical and/or biologic evidence supporting an association with a response to targeted therapy was stratified by the level of evidence using an oncology knowledge database.

A level of evidence classification system was developed, in which potentially actionable alterations were assigned to 1 of 4 levels based on the strength of evidence that:

  • The alteration is a biomarker recognized by the US Food and Drug Administration (FDA) (level 1) or recommended by the National Comprehensive Cancer Network or other expert panels (level 2) to an FDA-approved drug in this indication
  • Compelling clinical evidence supports the biomarker as being predictive of response to a drug in this indication (level 3A)
  • Compelling evidence supports a standard of care or investigational biomarker predictive of response to an FDA-approved drug or investigational drug in another indication (level 3B), or
  • Compelling biological evidence supports the biomarker as being predictive of response to a drug (level 4).

After querying the MSK-IMPACT database, the RCC cohort comprised 753 patients. In comparison with other cancer types, RCC ranked last, with 12% of alterations deemed actionable.

When stratified by histologic subtype, 59.7% of patients had clear-cell RCC, 8.3% had papillary RCC, 6.3% had chromophobe RCC, and 25.6% were grouped into other subtypes. Of 708 RCC samples, 63.3% came from the primary tumor and 36.7% were from metastatic sites.

In examining each RCC subtype individually, 13% of patients with clear-cell RCC harbored a targetable alteration, predominantly acquired somatic mutations, and 14% with papillary RCC harbored a targetable alteration, predominantly copy number variations (in particular, MET amplification). Only 2 of 43 patients (4%) with chromophobe RCC had targetable alterations, 1 had ALK fusion and the other a microsatellite instability (MSI)-high tumor. In the patients with other histologic subtypes, 12% harbored targetable alterations, predominantly acquired somatic mutations.

The top 3 targetable alterations accounted for approximately 71% of all alterations. The most common was TSC1, comprising 29% of targetable alterations, all of which were truncating mutations in RCC. The second most common was PIK3CA, comprising 26.9% of targetable alterations, almost all of which were missense mutations in clear-cell RCC. The third most common were MET amplifications, comprising 15.1% of targetable alterations, predominantly in papillary RCC.

“Only 1 level 1 alteration was identified, and this was an MSI-high tumor found in a chromophobe RCC,” said Dr Attalla.

The next steps are to validate these results using other data sets, he said, “and to take a deeper dive into looking at other things, such as the presence of mismatch repair deficiencies and the clonality of the identified alterations.”

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