Actionable Alterations Are Few in Renal-Cell Carcinoma

TON - August 2020, Vol 13, No 4

There has been increased focus on the study of tumor alterations that may predict treatment benefit or serve as possible actionable targets for new therapeutic approaches in cancer. During the virtual 2020 American Urological Association 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 in patients with renal-cell carcinoma (RCC).

“The prevalence of actionable alterations in RCC is 12%,” he said. “The type of alteration varies by histologic subtype, and it’s noteworthy to mention that in chromophobe RCC, targetable alterations are extraordinarily rare.”

Dr Attalla and colleagues sought to describe the prevalence and landscape of actionable alterations and the corresponding evidence to support the alterations as predictive of response to targeted therapy in RCC. To accomplish this, they queried the Memorial Sloan Kettering (MSK) 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 were stratified by the level of evidence using an oncology knowledge database called OncoKB, which is a clinical support toll that instills information on whether an alteration is clinically actionable into a standardized format.

“The goal is to help clinicians interpret genomic alterations in patient tumor samples,” said Dr Attalla. Alterations are first identified from public databases and the clinical therapeutic implications of these alterations are curated from several public resources. Finally, OncoKB annotation is vetted by clinicians and cancer biologists across a number of disease management teams.

A level of evidence classification system was then 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 the 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 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, Dr Attalla noted.

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 included, 63.3% came from the primary tumor and 36.7% were from metastatic sites.

When each RCC subtype was examined individually, the researchers found that 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 an 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 renal clear cell carcinoma. 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 datasets, 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,” he concluded.

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