In patients with high-grade ovarian cancer, pre-existing TP53 clonal hematopoiesis of indeterminate potential (CHIP) variants may be associated with therapy-related myeloid neoplasms (t-MNs) after treatment with rucaparib, an FDA-approved small-molecule poly(adenosine diphosphate-ribose) polymerase inhibitor (PARPi), according to results from a retrospective genetic association study published in JAMA Oncology.
t-MNs are rare but potentially fatal, and they can occur in 1%-3% of patients with high-grade ovarian cancer treated with a PARPi. While the exact etiology of t-MNs is unknown, research has shown that CHIP variants can increase the risk of primary myeloid malignant neoplasms.
“The prevalence of CHIP in patients with solid tumors is higher than in the general population. CHIP variants in DNA damage repair genes, including TP53, specifically provide fit[1]ness advantage and preferentially expand during platinum treatment, which is commonly used in ovarian cancer. The presence of CHIP in patients with solid tumors has been linked to increased risk of subsequently developing t-MNs,” explained Elizabeth M. Swisher, MD, of the University of Washington, Seattle, and colleagues.
Swisher and colleagues undertook this study to assess the potential association of pre-existing CHIP variants with the development of t-MNs after treatment with rucaparib, as well as to determine whether these CHIP variants were affected by treatment.
For genetic analysis, they collected peripheral blood cell samples from 1,052 patients (mean age: 61.7 years) enrolled in the ARIEL2 and ARIEL3 studies before they underwent treatment with rucaparib. Both studies were conducted to assess the treatment of relapsed high-grade ovarian cancers with rucaparib, and its use as maintenance therapy for platinum-responsive high-grade ovarian cancers.
Among these patients, 2.1% (n=22) developed t-MNs, and samples were available for 20, as well as for 44 randomly selected patients who did not. Using targeted next-generation sequencing, Swisher and fellow researchers analyzed samples for CHIP variants and found that t-MNs were associated with longer overall exposure to previous platinum therapies (13.2 versus 9.0 months in ARIEL2; P=0.04; 12.4 versus 9.6 months in ARIEL3; P=0.003).
Germline or somatic homologous recombination repair gene variants within tumors were associated with an increased prevalence of t-MNs, in 4.1% of 369 patients with high grade ovarian cancer associated with an HRR gene variant, compared with 1.0% of 683 patients with wild-type high-grade ovarian cancer (P=0.002).
Preexisting CHIP variants in TP53 at a variant allele frequency of 1% or greater were significantly higher in peripheral blood cell samples from women who developed t-MNs compared with those who did not (45.0% versus 13.6%, respectively; P=0.009). This was not true, however, for other CHIP-associated genes.
In women who developed t-MNs, TP53 CHIP was also associated with a longer previous exposure to platinum—a mean of 14.0 months in 15 women with TP53 CHIP compared with 11.1 months in 49 women without TP53 CHIP.
“This study found that pretreatment TP53 CHIP variants present at a VAF of 1% or greater are a risk factor for developing secondary t-MNs after rucaparib treatments. [PARPis] are increasingly being used earlier in the treatment of HGOC, 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. 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,” concluded Swisher et al.
“In patients with ovarian cancer, exposure to cytotoxic chemotherapy may promote the acquisition of oncogenic TP53 variants in hematologic stem cells, leaving a subgroup of patients vulnerable to the development of t-MNs with subsequent PARPi and chemotherapy exposure,” wrote Christine Walsh, MD, MS, of the University of Colorado School of Medicine, Denver, and Ilana Cass, MD, of Dartmouth Hitchcock Medical Center, Hanover, New Hampshire, in their accompanying editorial.
“CHIP variants were identified by next-generation sequencing in 4 of the 10 leukemia-related genes evaluated in the study, including DNMT3A, TET2, ASXL1, and TP53. At least 1 CHIP event occurred in 9 of 20 patients (45.0%) who developed t-MNs and in 11 of 44 patients (25.0%) who did not (odds ratio [OR], 2.5; 95% CI, 0.8-7.9; P=0.10). Variants were detected in more than 1 gene in 4 of 20 cases (20.0%) compared with 2 of 44 controls (4.5%) (OR, 5.3; 95% CI, 1.1-28.8; P=0.07). In addition, a statistically significant higher rate of TP53 CHIP variants was found (45.0% vs 13.6%; OR, 5.2; 95% CI, 1.6- 16.0; P=0.009),” they wrote.
In the future, concluded Walsh and Cass, results like these from Swisher and colleagues and future studies may facilitate the early and accurate identification of women who are at elevated risk of t-MNs.
Study limitations include its retrospective design and the focus on CHIP variants with a variant allele frequency of 1% or greater to the exclusion of CHIP events with lower frequencies.
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In this genetic association study, the prevalence of pretreatment TP53-variant CHIP was significantly higher among patients with high-grade ovarian cancer who developed treatment-related myeloid neoplasms (t-MNs) after rucaparib therapy versus those who did not.
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Pretreatment TP53-variant CHIP detected at a variant allele frequency of 1% or higher may be associated with development of t-MNs after rucaparib treatment.
Liz Meszaros, Deputy Managing Editor, BreakingMED™
This work was supported in part by the National Breast Cancer Foundation of Australia, Ann Rife Cox Chair in Gynecology and the Judy Reis/Albert Pisani, MD, Ovarian Cancer Research Fund, and National Institute for Health Research Biomedical Research Centre at University College London. This work was also supported by a support grant from the Memorial Sloan Kettering Cancer Center and by a grant from the US Department of Defense Ovarian Cancer Research Program, a V Foundation Translational Award, and translational research grant from Stand Up to Cancer–Ovarian Cancer Research Fund Alliance– National Ovarian Cancer Coalition Dream Team. Stand Up to Cancer is a program of the Entertainment Industry Foundation; research grants are administered by the American Association for Cancer Research, a scientific partner of Stand Up to Cancer.
Swisher reported receiving grants from the US Department of Defense during the conduct of the study.
Walsh reported receiving honoraria as a Genentech Advisory Board member and as an AstraZeneca Advisory Board member and grants from Merck outside the submitted work.
Cass reported no disclosures.
Cat ID: 692
Topic ID: 78,692,730,692,693,192,925
