Discussion
A reversion mutation is a well-discussed mechanism of resistance to PARP inhibitors. Waks et al. reported a reversion mutation as the most commonly observed mechanism of resistance to PARP inhibitors or platinum chemotherapy in eight patients with metastatic breast cancer withBRCA1/2 mutations.4 Tobalina et al. reported the occurrence of reversion mutations in 26.0% (86/327) patients withBRCA1 or BRCA2 mutations, including 27 patients with breast cancer,7 with a higher percentage in BRCA2compared to BRCA1 (30.7% vs. 22.0%).7
Pettitt et al. analyzed and reported 308 homologous recombination gene reversions associated with a PARP inhibitor or platinum resistance.8 In BRCA1 , the reversion mutations occurred throughout the BRCA1 coding sequence. However, inBRCA2 , there were “hotspots” and “deserts.” The frequency of reversions 3′ to coding sequence position 7617 (exon 16 onward) was significantly lower than the expected frequency based on the incidence dataset. However, numerous reversion mutations in the N-terminal c.750-775 regions have occurred.8 Therefore, our presented case might be relatively rare. However, as the authors’ indicated, PARP inhibitors are routinely used in clinics and some reversion mutations will no longer be considered novel enough to be reported. Therefore, reversion mutations in this area may be underestimated.
Weigelt et al. reported the detection of reversion mutations using circulating cell-free DNA in breast and ovarian cancers.9 Tumor tissue was not synchronously collected; therefore, it was not possible to validate the presence of the putative reversion mutations in the tumor, which was a limitation in Weigelt et al.’s study. Similarly, reversion mutation was not confirmed using tissue biopsy in our case herein. Repeat tumor biopsy from liver metastases and liquid biopsy to confirm the amplification of newly detected secondary variants were planned. However, these were not performed due to the deterioration of the patient’s condition and the fact that no additional treatment would be administered.
In addition, there was a concern in our case. The occurrence of true reversions to wild-type was previously reported8; however, true reversions are challenging to identify using liquid biopsy alone. Thus, the prevalence of true reversions may be underestimated, and it is possible that our case also had a true reversion.
There are several reports on treatment after PARP inhibitor resistance. Reversions have been predicted to encode immunogenic neopeptides; thus, immunotherapies may also be an option for direct targeting of the revertant protein.8 As another strategy for acquired resistance to PARP inhibitors, a cyclin-dependent kinase 12 inhibitor10 or WEE1 kinase inhibitor11 can be used. To prove the efficacy of these treatments, it is important to continue to investigate PARP inhibitor resistance cases.