Publications

The first studies of epidermal growth factor receptor (EGFR) inhibitors in metastatic colorectal cancer were begun before the predictive role of RAS mutations had been elucidated. Secondary analyses of many large randomized trials have shown that mutations in exons 2-4 of KRAS and NRAS, BRAF V600E mutation, and right-sided primary tumor all predict lack of response to EGFR inhibition in the first-line setting. However, even in patient populations defined by a lack of these negative predictors, there is still not uniform response to anti-EGFR therapy. Additionally, although older adults have been shown to have the potential to both tolerate and respond to anti-EGFR therapy, the criteria for selecting the most appropriate older patients for treatment remain unclear.

Background

In a recent trial of intermittent preventive treatment in pregnancy (IPTp) in Uganda, dihydroartemisinin-piperaquine (DP) was superior to sulfadoxine-pyrimethamine (SP) in preventing maternal and placental malaria.

Methods

We compared genotypes using sequencing, fluorescent microsphere, and quantitative polymerase chain reaction assays at loci associated with drug resistance in Plasmodium falciparum isolated from subjects receiving DP or SP.

Results

Considering aminoquinoline resistance, DP was associated with increased prevalences of mutations at pfmdr1 N86Y, pfmdr1 Y184F, and pfcrt K76T compared to SP (64.6% vs 27.4%, P < .001; 93.9% vs 59.2%, P < .001; and 87.7% vs 75.4%, P = .03, respectively). Increasing plasma piperaquine concentration at the time of parasitemia was associated with increasing pfmdr1 86Y prevalence; no infections with the N86 genotype occurred with piperaquine >2.75 ng/mL. pfkelch13 propeller domain polymorphisms previously associated with artemisinin resistance were not identified. Recently identified markers of piperaquine resistance were uncommon and not associated with DP. Considering antifolate resistance, SP was associated with increased prevalence of a 5-mutation haplotype (pfdhfr 51I, 59R, and 108N; pfdhps 437G and 581G) compared to DP (90.8% vs 60.0%, P = .001).

Conclusions

IPTp selected for genotypes associated with decreased sensitivity to treatment regimens, but genotypes associated with clinically relevant DP resistance in Asia have not emerged in Uganda.