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.