Case: Variant of Uncertain Significance
TG is a 79 yo woman diagnosed with colon cancer, with a large tumor in the right lobe of her liver. Following initial surgery, she was treated with FOLFOX which was discontinued after initial response due to toxicity. She is currently being treated with irinotecan and panitumumab. Genomic tumor testing was ordered to identify potential therapeutic targets.
Results from ActionSeq:
- Actionable variants (Tier I): none
- Variants of unknown clinical significance (Tier III): ERBB2 A386D
What is the meaning of TG’s variant for her future treatment?
A. The variant is driving tumor growth, but we don’t yet have targeted therapies for the variant.
B. There is not enough information to know whether the variant is relevant for tumor growth.
C. A variant of unknown clinical significance is a marker of poor prognosis.
D. TG should not proceed with any treatment until the significance of the variant is clarified.
The correct answer is B. There is not enough information to know whether the variant is relevant for tumor growth.
Even when treatments are available for certain variants in a gene, other variants in that same gene may not disrupt the function of the gene and contribute to tumor growth. It is not known whether or how the variant of unknown clinical significance (VUS) identified in TG is affecting her cancer cells, so the effectiveness of targeted treatments is unknown.
The clinical significance of a variant may be uncertain for several different reasons:
- A variant may be rare or novel, with very little data about its effects on the function of the gene.
- Data about the effect of the variant on the gene and on tumor growth may be conflicting.
- Even when a variant is clearly disruptive of the gene, there may not be enough evidence to confirm its role in driving tumor growth (e.g., a variant causing loss of gene function is clearly disruptive, but the effect on tumor growth is uncertain).
- Evidence may indicate that a variant is an important therapeutic target in one type of cancer, but not enough is known about its role in other types of cancer.
Incorrect answer rationale:
A. It is incorrect to say that the variant is driving tumor growth. A VUS has unknown effects on tumor growth, and should not be targeted with therapy until more is known.
C. It is incorrect to say that a VUS is a marker of poor prognosis. A VUS does not provide prognostic information. Variants are common, and not all variants are involved in the growth of a tumor.
D. It is incorrect to say that TG cannot proceed with any treatment until the significance of the VUS is clarified. The VUS is not useful for treatment planning, but that does not mean that there is no treatment available. Other factors can be used to guide treatment.
This resource was developed as part of the Maine Cancer Genomics Initiative (MCGI) and is supported by The Harold Alfond Foundation and The Jackson Laboratory.