COMMENTARY

Exploring the Clinical Value of KRAS Mutation Testing in Ovarian Cancer

Maurie Markman, MD

Disclosures

January 21, 2011

A KRAS-Variant in Ovarian Cancer Acts as a Genetic Marker of Cancer Risk

Ratner E, Lu L, Boeke M, et al
Cancer Res. 2010;70:6509-6515

Clinical Implications of the Cancer Genome

MacConaill LE, Garraway LA
J Clin Oncol. 2010;28:5219-5228

Summary

Previous research identified an uncommon variant of the KRAS oncogene (rs61764370) that increases levels of KRAS in in vitro assays, suggesting that it may be associated with a biologically relevant increased risk for cancer development.[1] Indeed, 2 case-control studies revealed a greater risk for the development of non-small cell lung cancer in individuals with this mutation vs those without the mutation. Although the variant is seen in fewer than 20% of patients with all solid tumors, it is present in more than 25% of patients with epithelial ovarian cancer.[1]

In the analysis by Ratner and colleagues, investigators exploring an association between the presence of rs61764370 and the risk of developing ovarian cancer found the mutation in 25% of patients examined vs only 15% of individuals in a non-cancer "control" population. Of greatest interest, however, the KRAS mutation was found in 19 (61%) of 31 patients who appeared to have a familial history of ovarian cancer but no evidence of a BRCA1 or BRCA2 mutation. When compared with families with a BRCA association, patients in this group were less likely to have Jewish Ashkenazi ethnicity, and were more likely to be older and to have a history of lung cancer within the family.

In their review article, MacConaill and Garraway identify KRAS and BRCA as classic examples of synthetic lethality, in which cancer cell growth driven by expression of an oncogene is, in turn, dependent on expression of a second gene for survival. Whether a druggable target will be found for KRAS-mutated ovarian cancer similar to poly ADP ribose polymerase (PARP) inhibitors in BRCA-mutated breast cancer[2] remains to be seen, but the identification of the KRAS mutation in this patient population certainly points to new possible avenues for therapeutic intervention.

Viewpoint

The association between BRCA1 and BRCA2 and the risk of developing breast and ovarian cancers is well established. However, it is also known that a not insignificant percentage of individuals with a recognized strong familial risk of developing ovarian cancer have no known abnormality in BRCA. While it is possible that the BRCA mutations in these patients have yet to be discovered, it has been suggested that other genetic abnormalities unrelated to BRCA may be responsible for the observed familial risk.[3]

The data from Ratner and colleagues provide strong support for the conclusion that the KRAS mutation rs61764370 may be responsible for a substantial proportion of familial ovarian cancer not accounted for by BRCA genetic abnormalities. Certainly, before making a definitive statement regarding the relevance of this mutation in this specific setting, it will be important for other groups with sizable populations of women with familial ovarian cancer to examine for the presence of rs61764370 in patients without a documented BRCA mutation. Assuming this observation is confirmed, routine testing for this KRAS variant may be indicated in patients with ovarian cancer and a family history of the malignancy in the absence of BRCA1 or BRCA2 abnormalities.

Yet, even if further research bears out the association with the KRAS variant in this population, can one justify the cost of this type of exploration when the abnormality will be present in fewer than 1 in 50 or 1 in 100 ovarian cancer patients? Do cost considerations outweigh the predictive utility associated with documenting rare genetic abnormalities outside of a pure research setting? MacConaill and Garraway note that the cost of sequencing an individual cancer genome has been steadily and rapidly decreasing; as this trend continues over the next several years, it is likely that the cost-effectiveness of these types of investigations will increase, allowing them to be more widely available for routine clinical purposes, and thus enabling patients to benefit from therapeutic advances targeting driver mutations.

Abstract

Abstract

Comments

3090D553-9492-4563-8681-AD288FA52ACE
Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.
Post as:

processing....