Relationship Between Preexisting TP53 CHIP Variants and Risk of Secondary Myeloid Neoplasms in High-Grade Ovarian Cancer

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In a study reported in JAMA Oncology, Kwan et al found that preexisting TP53 clonal hematopoiesis of indeterminate potential (CHIP) variants were associated with increased risk of secondary myeloid neoplasms in patients receiving poly (ADP-ribose) polymerase (PARP) inhibitor therapy with rucaparib for high-grade ovarian cancer.

As stated by the investigators, “A total of 1% to 3% of patients treated with a PARP inhibitor for high-grade ovarian cancer develop therapy-related myeloid neoplasms, which are rare but often fatal conditions. Although the cause of these therapy-related myeloid neoplasms is unknown, CHIP variants can increase the risk of primary myeloid malignant neoplasms and are more frequent among patients with solid tumors.”

Study Details

The study involved evaluation of peripheral blood cell samples collected before rucaparib treatment from patients in the ARIEL2 trial (n = 491) and the ARIEL3 trial (n = 561), which evaluated rucaparib for high-grade ovarian cancer in the treatment and maintenance settings, respectively. Peripheral blood cell samples from 20 patients who developed therapy-related myeloid neoplasms (cases) and 44 randomly selected patients who did not (controls) were analyzed for the presence of CHIP variants using targeted next-generation sequencing. Longitudinal analysis was performed on available ARIEL2 samples collected during treatment and at the end of treatment.

Key Findings

Among the 1,052 patients, 22 (2.1%) developed therapy-related myeloid neoplasms.  

Development of therapy-related myeloid neoplasms was associated with longer overall exposure to prior platinum therapy (13.2 vs 9.0 months in ARIEL2, P = .04; 12.4 vs 9.6 months in ARIEL3, P = .003).

Presence of germline or somatic homologous recombination repair (HRR) gene variants in tumors was associated with an increased risk of therapy-related myeloid neoplasms, with such neoplasms found in 15 (4.1%) of 369 patients with an HRR gene variant vs 7 (1.0%) of 683 with wild-type HRR genes (P = .002).

The prevalence of preexisting CHIP variants in TP53 but not other CHIP-associated genes at a variant allele frequency of ≥ 1% was significantly higher in peripheral blood cells from cases vs controls. TP53 CHIP variants were found in 9 (45.0%) of 20 cases vs 6 (13.6%) of 44 controls (P = .009).

Among all patients evaluated who had CHIP variants, prior exposure to platinum therapy was longer among 15 patients with TP53 variants vs 49 patients with other variants (mean = 14.0 vs 11.1 months, P = .02).

Longitudinal analysis in five patients in ARIEL2 who developed therapy-related myeloid neoplasms showed that preexisting TP53 CHIP variants expanded over time, suggesting that expansion of preexisting clones may contribute to the development of neoplasms.

The investigators concluded, “The findings of this genetic association study suggest that preexisting TP53 CHIP variants may be associated with therapy-related myeloid neoplasms after rucaparib treatment.”

Elizabeth M. Swisher, MD, of the Division of Gynecologic Oncology, University of Washington, Seattle, is the corresponding author for the JAMA Oncology article.

Disclosure: The study was supported by the National Breast Cancer Foundation of Australia, National Institute for Health Research Biomedical Research Centre at University College London, Clovis Oncology, and others. For full disclosures of the study authors, visit

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