TP53 CHIP Variants Might Be Associated With Therapy-Related Myeloid Neoplasms Post-Rucaparib in High-Grade Ovarian Cancer

Investigators may have identified an association between pre-existing TP53 clonal hematopoiesis of indeterminate potential (CHIP) variants and therapy-related myeloid neoplasms (t-MNs) in patients with high-grade ovarian cancer following rucaparib (Rubraca), according to results from a genetic association study published in JAMA Oncology.

Overall, preexisting CHIP variants in TP53 at a variant allele frequency of 1% or greater were significantly higher in peripheral blood cells in the t-MN cases (45.0%) compared with the controls (13.6%; OR, 5.2; 95% CI, 1.6-16.0; P = .009).

“This study found that pretreatment TP53 CHIP variants present at a [variant allele frequency (VAF)] of 1% or greater are a risk factor for developing secondary t-MNs after rucaparib treatments,” the investigators wrote. “Poly(adenosine diphosphate–ribose) polymerase inhibitors are increasingly being used earlier in the treatment of [advanced high-grade ovarian cancer], at which point TP53 CHIP variants are less frequent and the consequent risk of t-MNs is lower, which may lead to an improved benefit-risk ratio.”

The research identified t-MN cases and controls from the phase 2 ARIEL2 study (NCT01891344), which assessed rucaparib in 491 patients with platinum-sensitive, relapsed, high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer, and the phase 3 ARIEL3 study (NCT01968213), which examined rucaparib as a switch maintenance therapy following platinum-based chemotherapy in 561 patients with platinum-sensitive, high-grade serous or endometrioid epithelial ovarian, primary peritoneal or fallopian tube cancer. Of the 1052 total patients between both studies, 2.1% developed t-MNs, including 6 patients in ARIEL2 and 16 patients in ARIEL3.

For patients who developed t-MNs and those who did not, no significant differences were observed in terms of age, smoking status, ECOG performance status, or histologic findings.

In ARIEL3, patients in the rucaparib arm who developed t-MNs received treatment for a longer amount of time than similar patients who did not develop secondary malignant neoplasms (median 25.0 months vs 8.0 months; P = .003). Findings were similar in ARIEL2, although they were not statistically significant.

Prolonged overall exposure to previous platinum therapies was associated with t-MNs in both ARIEL2, with those who developed t-MNs being exposed for 13.2 months vs 9.0 months among those who did not develop secondary malignant neoplasms (P = .04); similar results were noted in ARIEL3 (12.4 months vs 9.6 months; P = .003). Moreover, the existence of germline or somatic homologous recombination repair (HRR) gene variants in high-grade ovarian cancer tumors was associated with increased t-MNs (4.1% of patients with disease associated with an HRR gene variant vs 1.0% of patients with wild-type disease, P = .002).

Variants were observed in 4 of 10 predefined CHIP-associated genes, specifically TP53, DNMT3A, TET2, and ASXL1. A CHIP event occurred in 45.0% of patients who developed t-MNs compared with 25.0% who did not (OR, 2.5; 95% CI, 0.8-7.9; P = .10). Additionally, variants were found in more than 1 gene in 20.0% of cases compared with 4.5% of controls (OR, 5.3; 95% CI, 1.1-28.8; P = .07).

The study is limited by its retrospective design. Furthermore, considering the research solely focused on CHIP variants with a VAF of 1% or greater, the significance of variants with a VAF of less than 1% remains unclear.

“How different therapies affect the expansion of preexisting TP53 CHIP clones and the benefit of screening for them require further research with careful longitudinal monitoring,” the investigators concluded.

Reference

Kwan TT, Oza AM, Tinker AV, et al. Preexisting TP53-variant clonal hematopoiesis and risk of secondary myeloid neoplasms in patients with high-grade ovarian cancer treated with rucaparib. JAMA Oncol. Published online October 14, 2021. doi:10.1001/jamaoncol.2021.4664