Preexisting <i>TP53</i>-Variant Clonal Hematopoiesis and Risk of Secondary Myeloid Neoplasms in Patients With High-grade Ovarian Cancer Treated With Rucaparib

Kwan, Tanya T.; Oza, Amit M.; Tinker, Anna V.; Ray‐Coquard, Isabelle; Oaknin, Ana; Aghajanian, Carol; Lorusso, Domenica; Colombo, Nicoletta; Dean, Andrew; Weberpals, Johanne I.; Severson, Eric Allan; Vo, Lan-Thanh; Goble, Sandra; Maloney, Lara; Harding, Thomas C.; Kaufmann, Scott H.; Ledermann, Jonathan A.; Coleman, Robert L.; McNeish, Iain A.; Lin, Kevin K.; Swisher, Elizabeth M.

doi:10.1001/jamaoncol.2021.4664

Cited by 48 publications

(43 citation statements)

References 25 publications

(47 reference statements)

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“…In a post-hoc analysis of the GOG9923 trial, germline BRCA1/2 mutated patients treated with carboplatin, paclitaxel and veliparib with or without bevacizumab did not display an increased risk of AEs compared to wild-type subjects [ 137 ]. Previous evidence suggests that inherited mutations, including BRCA1/2 , PALB2 , TP53 and CHEK2 , are frequent among pre-treated cancer survivors with therapy-related MDS/AML [ 138 , 139 , 140 ]. However, the presence of a germline mutation was not consistently associated with the risk of MDS/AML in trials of DDR-targeting agents [ 140 , 141 ].…”

Section: Future Challenges and Perspectivesmentioning

confidence: 99%

Everything Comes with a Price: The Toxicity Profile of DNA-Damage Response Targeting Agents

Martorana

Silva

Sessa

et al. 2022

Cancers

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Targeting the inherent vulnerability of cancer cells with an impaired DNA Damage Repair (DDR) machinery, Poly-ADP-Ribose-Polymerase (PARP) inhibitors have yielded significant results in several tumor types, eventually entering clinical practice for the treatment of ovarian, breast, pancreatic and prostate cancer. More recently, inhibitors of other key components of DNA repair, such as ATR, CHK1 and WEE1, have been developed and are currently under investigation in clinical trials. The inhibition of DDR inevitably induces on-target and off-target adverse events. Hematological and gastrointestinal toxicities as well as fatigue are common with all DDR-targeting agents, while other adverse events are drug specific, such as hypertension with niraparib and transaminase elevation with rucaparib. Cases of pneumonitis and secondary hematological malignancies have been reported with PARP inhibitors and, despite being overly rare, they deserve particular attention due to their severity. Safety also represents a crucial issue for the development of combination regimens incorporating DDR-targeting agents with other treatments, such as chemotherapy, anti-angiogenics or immunotherapy. As such, overlapping and cumulative toxicities should be considered, especially when more than two classes of drugs are combined. Here, we review the safety profile of DDR-targeting agents when used as single agents or in combination and we provide principles of toxicity management.

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Section: Future Challenges and Perspectivesmentioning

confidence: 99%

Everything Comes with a Price: The Toxicity Profile of DNA-Damage Response Targeting Agents

Martorana

Silva

Sessa

et al. 2022

Cancers

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“…In a more recent retrospective case–control analysis of patients with ovarian cancer enrolled on the ARIEL2 and ARIEL3 ovarian cancer studies, pre-existing TP53 CH mutations were found to be significantly associated with the development of therapy-related myeloid neoplasms after exposure to rucaparib [ 239 ]. This analysis, which was based on targeted NGS of peripheral blood cell specimens from 20 patients who developed therapy-related myeloid neoplasms and 44 patients who did not, demonstrated that the prevalence of preexisting CH variants in TP53 at a variant allele frequency of ≥1% was significantly higher at PARPi treatment initiation in peripheral blood cells from patients who ultimately developed therapy-related myeloid neoplasms compared to controls who did not (9 (45.0%) of 20 cases vs. 6 (13.6%) of 44 controls, OR 5.2 (95% CI 1.6–16.0, p = 0.009)).…”

Section: Myeloid Neoplasms Emerging With Parp Inhibitor Therapymentioning

confidence: 99%

“…This analysis, which was based on targeted NGS of peripheral blood cell specimens from 20 patients who developed therapy-related myeloid neoplasms and 44 patients who did not, demonstrated that the prevalence of preexisting CH variants in TP53 at a variant allele frequency of ≥1% was significantly higher at PARPi treatment initiation in peripheral blood cells from patients who ultimately developed therapy-related myeloid neoplasms compared to controls who did not (9 (45.0%) of 20 cases vs. 6 (13.6%) of 44 controls, OR 5.2 (95% CI 1.6–16.0, p = 0.009)). In contrast, other CH variants were not enriched in the patients who went on to develop therapy-related myeloid neoplasms [ 239 ].…”

Section: Myeloid Neoplasms Emerging With Parp Inhibitor Therapymentioning

confidence: 99%

“…Considering the entire 1052-patient cohort from ARIEL2 and ARIEL3, Kwan et al also explored the association between the presence of HR gene alterations and development of PARPi-related myeloid neoplasms [ 239 ]. While the prevalence of therapy-related myeloid neoplasms was higher in patients with ovarian cancer that harbored a deleterious mutation in BRCA1 , BRCA2 , RAD51C, or RAD51D —four genes that are commonly mutated in ovarian cancer—at 15 of 369 (4.1%) for those with mutation-containing cancers compared to 7 of 683 (1.0%) for those without mutations, the incidence was indistinguishable in patients with germline vs. somatic mutations in these genes.…”

Section: Myeloid Neoplasms Emerging With Parp Inhibitor Therapymentioning

confidence: 99%

“…While the prevalence of therapy-related myeloid neoplasms was higher in patients with ovarian cancer that harbored a deleterious mutation in BRCA1 , BRCA2 , RAD51C, or RAD51D —four genes that are commonly mutated in ovarian cancer—at 15 of 369 (4.1%) for those with mutation-containing cancers compared to 7 of 683 (1.0%) for those without mutations, the incidence was indistinguishable in patients with germline vs. somatic mutations in these genes. Instead, patients harboring ovarian cancers with HR mutations appeared to receive significantly more courses of chemotherapy, especially platinum-containing therapy, than patients with HR proficient cancers [ 239 ]. These observations provide additional assurance that patients with germline HR gene mutations are not automatically at increased risk of developing therapy-related myeloid neoplasms.…”

Section: Myeloid Neoplasms Emerging With Parp Inhibitor Therapymentioning

confidence: 99%

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PARP Inhibitors and Myeloid Neoplasms: A Double-Edged Sword

Csizmar

Saliba

Swisher

et al. 2021

Cancers

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Despite recent discoveries and therapeutic advances in aggressive myeloid neoplasms, there remains a pressing need for improved therapies. For instance, in acute myeloid leukemia (AML), while most patients achieve a complete remission with conventional chemotherapy or the combination of a hypomethylating agent and venetoclax, de novo or acquired drug resistance often presents an insurmountable challenge, especially in older patients. Poly(ADP-ribose) polymerase (PARP) enzymes, PARP1 and PARP2, are involved in detecting DNA damage and repairing it through multiple pathways, including base excision repair, single-strand break repair, and double-strand break repair. In the context of AML, PARP inhibitors (PARPi) could potentially exploit the frequently dysfunctional DNA repair pathways that, similar to deficiencies in homologous recombination in BRCA-mutant disease, set the stage for cell killing. PARPi appear to be especially effective in AML with certain gene rearrangements and molecular characteristics (RUNX1-RUNX1T1 and PML-RARA fusions, FLT3- and IDH1-mutated). In addition, PARPi can enhance the efficacy of other agents, particularly alkylating agents, TOP1 poisons, and hypomethylating agents, that induce lesions ordinarily repaired via PARP1-dependent mechanisms. Conversely, emerging reports suggest that long-term treatment with PARPi for solid tumors is associated with an increased incidence of myelodysplastic syndrome (MDS) and AML. Here, we (i) review the pre-clinical and clinical data on the role of PARPi, specifically olaparib, talazoparib, and veliparib, in aggressive myeloid neoplasms and (ii) discuss the reported risk of MDS/AML with PARPi, especially as the indications for PARPi use expand to include patients with potentially curable cancer.

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Association of Pathogenic Variants in Hereditary Cancer Genes With Multiple Diseases

et al. 2022

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IMPORTANCE Knowledge about the spectrum of diseases associated with hereditary cancer syndromes may improve disease diagnosis and management for patients and help to identify high-risk individuals.OBJECTIVE To identify phenotypes associated with hereditary cancer genes through a phenome-wide association study. DESIGN, SETTING, AND PARTICIPANTSThis phenome-wide association study used health data from participants in 3 cohorts. The Electronic Medical Records and Genomics Sequencing (eMERGEseq) data set recruited predominantly healthy individuals from 10 US medical centers from July 16, 2016, through February 18, 2018, with a mean follow-up through electronic health records (EHRs) of 12.7 (7.4) years. The UK Biobank (UKB) cohort recruited participants from March 15, 2006, through August 1, 2010, with a mean (SD) follow-up of 12.4 (1.0) years. The Hereditary Cancer Registry (HCR) recruited patients undergoing clinical genetic testing at Vanderbilt University Medical Center from May 1, 2012, through December 31, 2019, with a mean (SD) follow-up through EHRs of 8.8 (6.5) years.EXPOSURES Germline variants in 23 hereditary cancer genes. Pathogenic and likely pathogenic variants for each gene were aggregated for association analyses.MAIN OUTCOMES AND MEASURES Phenotypes in the eMERGEseq and HCR cohorts were derived from the linked EHRs. Phenotypes in UKB were from multiple sources of health-related data. RESULTS A total of 214 020 participants were identified, including 23 544 in eMERGEseq cohort (mean [SD] age, 47.8 [23.7] years; 12 611 women [53.6%]), 187 234 in the UKB cohort (mean [SD] age, 56.7 [8.1] years; 104 055 [55.6%] women), and 3242 in the HCR cohort (mean [SD] age, 52.5 [15.5] years; 2851 [87.9%] women). All 38 established gene-cancer associations were replicated, and 19 new associations were identified. These included the following 7 associations with neoplasms: CHEK2 with leukemia (odds ratio [OR], 3.81 [95% CI, 2.64-5.48]) and plasma cell neoplasms (OR, 3.12 [95% CI, 1.84-5.28]), ATM with gastric cancer (OR, 4.27 [95% CI,) and pancreatic cancer (OR, 4.44 [95% CI,), MUTYH (biallelic) with kidney cancer (OR, 32.28 [95% CI,), MSH6 with bladder cancer (OR, 5.63 [95% CI,), and APC with benign liver/intrahepatic bile duct tumors (OR, 52.01 [95% CI,). The remaining 12 associations with nonneoplastic diseases included BRCA1/2 with ovarian cysts (OR, 3.15 [95% CI,] and 3.12 [95% CI, 2.36-4.12], respectively), MEN1 with acute pancreatitis (OR, 33.45 [95% CI,.02]), APC with gastritis and duodenitis (OR, 4.66 [95% CI,), and PTEN with chronic gastritis (OR, 15.68 [95% CI,). CONCLUSIONS AND RELEVANCEThe findings of this genetic association study analyzing the EHRs of 3 large cohorts suggest that these new phenotypes associated with hereditary cancer genes may facilitate early detection and better management of cancers. This study highlights the potential benefits of using EHR data in genomic medicine.

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Preexisting TP53-Variant Clonal Hematopoiesis and Risk of Secondary Myeloid Neoplasms in Patients With High-grade Ovarian Cancer Treated With Rucaparib

Cited by 48 publications

References 25 publications

Everything Comes with a Price: The Toxicity Profile of DNA-Damage Response Targeting Agents

Everything Comes with a Price: The Toxicity Profile of DNA-Damage Response Targeting Agents

PARP Inhibitors and Myeloid Neoplasms: A Double-Edged Sword

Association of Pathogenic Variants in Hereditary Cancer Genes With Multiple Diseases

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