Hi there: I have bulk RNA Seq data from tumor samples from 18 patients: all have the same tumor; 9 were treated with Drug A and 9 with Drug B; Drug B is a fusion of Drug A plus a second drug (let's call it Drug C). We know that the clinical effect is not just different, but opposite, and I want to contrast Drug A v Drug B to look at what is Drug C is doing to the gene expression.

The thing is that samples from the 9 pts with Drug A were processed in one batch, and samples from the 9 pts with Drug B were a different batch. I am lacking experience in analysis, but I am concerned that application of a batch correction method such as CombatSeq would potentially treat true treatment effects as batch effects and flatten detectable differences. Would it be wholly unreasonable to proceed without batch correction? Thanks for your help!

Batch is confounded with deug, you cannot do any correction. Doing DEG without it is the only option but the batch effect can either introduce or remove many DEGs unrelated to drug that entirely technical so you will be potentially piling up many false results.