This study represents the largest retrospective study to date comparing EGFR and KRAS mutation rates between African American and Caucasian populations. There was no difference in the frequency of EGFR mutations between the African American and Caucasian cohorts, while KRAS mutations were less frequent among African-American patients.
A few small studies have previously evaluated the prevalence of mutations by race. In one study performed in Louisiana, the frequency of KRAS
mutations was evaluated in 116 patients with lung cancer, 60 of them African-Americans.14
In contrast to our findings, African-American patients in that study were significantly more likely to harbor a KRAS
mutation as compared to Caucasian patients (37% vs 20%, p=0.048). However, consistent with our data and reports by others,14
Hunt et al. also reported a “disproportionately high number of cysteine for glycine transversions.” Cysteine missense substitutions result from a G→T transversion in the first base in either codon 12 or 13. They have been attributed to the polycyclic aromatic hydrocarbons (PAH) present in tobacco smoke.15
Hunt et. al also found a higher than expected number of serine mutations among the African-American cohort as the result of a G→A transition in the first base of either codon 12 or 13.14
This mutation was demonstrated in one African-American patient in the present study, as well as one patient in our Caucasian cohort ().
Racial differences in EGFR
mutation rates have also been evaluated in smaller numbers in prior studies (). EGFR
mutations were reported in one of 44 African American patients (2.4%) in a study of 219 patients with tissue specimen from the University of Maryland, the Mayo Clinic in Minnesota and the University of Milan, Italy.16
In comparison, 25 of the 177 (14.1%) tumors from Caucasian patients harbored EGFR
mutations. Another study from the University of Texas M. D. Anderson Cancer Center included only eight African American patients.17
While 14 EGFR
mutations were confirmed among the 159 patients included, none were reported in this small subset of African American patients. Although KRAS
mutations were also reported in 18 patients overall, their races were not specified.
Prior Studies Comparing the Frequencies of EGFR Mutations in African-American and Caucasian Patients
Most recently, Leidner et al. published an analysis of 53 tumors from African-American patients obtained from the University Hospitals Case Medical Center in Cleveland, OH.18
Patients were selected based upon availability of a tissue block as well as
uninvolved paired tissue (ie. from a lymph node). Results were compared to a Caucasian cohort of 121 patients from three separate Italian centers (Bologna, Milan, and Perugia) previously enrolled in an unrelated clinical trial to receive gefitinib, who had mutational analysis performed previously. In this study, African Americans were again less likely to have EGFR
mutations in their tumors, as compared to Caucasian patients (2% vs. 17%, p=0.022). However, the only
mutation found among the African American patients was neither of the common activating EGFR
mutations (exon 19 deletion or exon 21 L858R substitution), but a missense mutation in exon 20 L768N, a mutation in EGFR
not previously reported. Leidner et al. also reported no difference in KRAS
mutation frequencies between the two cohorts of patients.
Twice the number of African-American patients (n=121) were included in our analysis compared with 53 tumors from African-American patients tested in the article of Leidner et al. While not as robust a sample as our Caucasian cohort, a retrospective power calculation indicates that we have adequate power to detect a difference of 9.6% or more in either direction, assuming the frequency of EGFR mutations in the Caucasian population is 13%. Therefore, if it were true that EGFR mutations exist among African-American patients at a much lower frequency, as reported in previous studies (), we would have detected that difference in our analysis.
One potential source of bias in our study is the fact that African-American specimens were collected from three different centers, while Caucasian patients were collected only from MSKCC. Like the Leidner et al. study described above, patients were included based solely on tissue availability, a common criterion for translational tissue studies. No other sample selection was used, and because all African-American patients who had available tissue were included, we expect the study population to be representative of the African-American population of each participating institution. An analysis restricted to MSKCC patients found 16% of African-Americans had EGFR mutations, and 25% had KRAS mutations, both safely within the 95% confidence intervals for the total number of African-American patients included in the results.
We did not report clinical characteristics traditionally associated with response to EGFR-TKIs in our patients. Prior to the IPASS study, we relied upon histology, ethnicity, and smoking status to predict the likelihood of response to EGFR-TKI treatment. However, we now know that it is the presence of the EGFR
mutation that truly underlies sensitivity. The most meaningful demonstration of this principle from IPASS was the paltry response (1%) of Asian women never-smokers or former light smokers randomized to receive gefitinib who were found to be without EGFR mutations
in their tumors.5
Testing tumors for the presence of EGFR
mutations prior to treatment with the EGFR TKI gefitinib is now a standard of care in Europe. This standard will increasingly be adopted on all continents, and therefore attention to clinical characteristics for the purposes of predicting response to EGFR-TKIs will continue to lessen in importance.
Our data indicate that lung cancers arise from EGFR
mutations in African-Americans just as commonly as in Caucasian patients. Therefore, African-Americans patients stand to derive similar benefit from treatment with EGFR
-TKIs as other western populations. We feel these results have important diagnostic and treatment implications for African-American patients as well as any non-Asian, non-Caucasian patient with lung cancer. Irrespective of race, tumors tissue obtained from all patients with advanced lung adenocarcinoma should be screened for the presence of EGFR
mutations. Future research efforts examining other molecular mechanisms, such as MET
mutations and ALK
translocations may further elucidate the racial variations in lung cancer development.