Clinical and Translational Science

Standardization, Education, and Resourcing: The Way Forward for Implementing Polygenic Risk Scores in Hereditary Breast and Ovarian Cancer

ABSTRACTThe clinical utility and implementation of polygenic risk scores (PRS) in the setting of personalized risk assessment for hereditary breast and ovarian cancer (HBOC) continues to be investigated. We aimed to explore and analyze genetic healthcare providers' perspectives toward national implementation in Australia, acknowledging the vitality of provider knowledge, priorities, and support. A two‐phase exploratory, cross‐sectional, mixed‐method study was conducted, consisting of semistructured interviews and a national online survey. Participants were recruited through professional networks. Interview schedule, survey design, and analyses were informed by the Consolidated Framework from Implementation Research (CFIR), the Theoretical Domains Framework (TDF) and the Expert Recommendations for Implementing Change (ERIC) compilation of facilitative strategies. Surveys were analyzed using descriptive and inferential statistics. Twenty‐seven participants were interviewed and forty completed the survey. Participants were supportive of clinical implementation of PRS, with implementation enablers in sector culture, compatibility with practice and professional role, and providers' knowledge and skills. Concerns were raised on insufficient resourcing, equity and timeliness of delivery, and the safety and effectiveness of ovarian cancer PRS. Training and educating stakeholders and achieving standardization, including establishing an accredited test, national guidelines, care and funding models, and results reports, were implementation priorities. Findings will support the design of a provider‐informed model or framework to plan and prioritize the next steps toward national implementation. Resourcing will be a key challenge. Current enablers in the sector, evidence‐based implementation strategies, and direction of efforts toward these priorities of education and standardization will enhance implementation readiness and efficiency.

Translational findings support regimen selection for first‐in‐human study of ubamatamab (MUC16 × CD3 bispecific antibody) in patients with recurrent ovarian cancer

AbstractUbamatamab, a Mucin 16 (MUC16) × cluster of differentiation 3 (CD3) bispecific antibody that promotes T‐cell‐mediated cytotoxicity of MUC16‐expressing cells, is being investigated for the treatment of ovarian cancer. Intravenous administration of ubamatamab, with or without the anti‐programmed cell death‐1 inhibitor cemiplimab, is being evaluated in a first‐in‐human study in patients with recurrent ovarian cancer. In vitro cytotoxicity and cytokine data and projected ubamatamab human pharmacokinetic (PK) profiles scaled with monkey PK parameters enabled starting‐dose selection in humans. Mouse tumor regression studies identified ubamatamab effective concentrations. Preclinical and clinical PK, cytokine, safety, and efficacy data from dose escalation were integrated to determine expansion regimens. A starting dose of 0.1 mg was selected, which showed acceptable safety in patients. A step‐up dosing approach was used to effectively manage cytokine release syndrome. Mouse tumor regression models suggested an ubamatamab efficacious concentration range of 0.4–50 mg/L, consistent with clinical activity observed at ubamatamab trough concentrations ≥5 mg/L. Integrating preclinical and clinical data determined a target trough concentration range of 5–30 mg/L, which supports evaluation of ubamatamab 250 mg with or without cemiplimab and 800 mg monotherapy once every 3 weeks in expansion cohorts. Preclinical data (cytokine release, tumor regression, monkey PK) had translational value in supporting regimen selection in dose escalation and subsequently in dose expansion after integration with patient data from dose escalation.

Evaluation of Innate Immune System, Body Habitus, and Sex on the Pharmacokinetics and Pharmacodynamics of Anetumab Ravtansine in Patients With Cancer

ABSTRACTAnetumab ravtansine, like other ADC drugs, has high inter‐patient variability in its pharmacokinetic (PK) and pharmacodynamic (PD) outcomes, which raises concerns about whether current dosing regimens are optimal for patients. The objective of this study was to evaluate covariates, especially body habitus and the innate immune system (IIS), which may affect anetumab ravtansine PK and PD as part of two clinical trials in patients with ovarian cancer and mesothelioma. Biomarkers of Fcγ receptors(FcγR) CD64 on IIS cells, total body weight (TBW), body surface area (BSA), and other covariates, such as sex and age, were analyzed for an association with anetumab ravtansine PK. Higher FcγR CD64, TBW, and BSA were associated with higher clearance (CL) of anetumab ravtansine (p < 0.05). However, there was no relationship between TBW or BSA and FcγR CD64. Female patients had a lower anetumab ravtansine CL (0.030 ± 0.007 L/h) compared to male patients (0.042 ± 0.006 L/h) (p < 0.05). In both studies, patients with stable disease (SD) and partial response (PR) had higher anetumab ravtansine AUC0‐inf compared to patients with progressive disease (PD). Individualizing the dose of anetumab ravtansine and potentially other ADCs based only on TBW is not optimal, whereas precision dosing of an ADC based on the inclusion of novel metrics of IIS biomarkers, body habitus, and sex may be more appropriate to reduce variability in PK exposure, reduce toxicity, and improve response.

GSTP1andABCB1Polymorphisms Predicting Toxicities and Clinical Management on Carboplatin and Paclitaxel‐Based Chemotherapy in Ovarian Cancer

Variation in drug disposition genes might contribute to susceptibility to toxicities and interindividual differences in clinical management on chemotherapy for epithelial ovarian cancer (EOC). This study was designed to explore the association ofGSTandABCB1genetic variation with hematologic and neurologic toxicity, changes in chemotherapy, and disease prognosis in Brazilian women with EOC. A total of 112 women with a confirmed histological diagnosis of EOC treated with carboplatin/paclitaxel were enrolled (2014–2019). The samples were analyzed by multiplex polymerase chain reaction (PCR) for the deletion ofGSTM1andGSTT1genes.GSTP1(c.313A>G/rs1695) andABCB1(c.1236C>T/rs1128503; c.3435C>T/rs1045642; c.2677G>T>A/rs2032582) single nucleotide polymorphisms (SNPs) were detected by real‐time PCR. Subjects with theGSTP1c.313A>G had reduced risk of anemia (odds ratio (OR): 0.17, 95% confidence interval (CI): 0.04–0.69,P = 0.01, dominant model) and for thrombocytopenia (OR: 0.27, 95% CI: 0.12–0.64,P < 0.01; OR 0.18, 95% CI 0.03–0.85,P = 0.03, either dominant or recessive model), respectively. TheGSTP1c.313A>G AG genotype was associated with a lower risk of dose delay (OR: 0.35, 95% CI: 0.13–0.90,P = 0.03). TheABCB1c.1236C>T was associated with increased risk of thrombocytopenia (OR: 0.15, 95% CI: 0.03–0.82,P = 0.03), whereasABCB1c.3435C>T had increased risk of grade 2 and 3 neurotoxicity (OR: 3.61, 95% CI: 1.08–121.01,P = 0.03) in recessive model (CC + CT vs. TT). This study suggests thatGSTP1c.313A>G,ABCB1c.1236C>T, and c.3435C>T SNP detection is a potential predictor of hematological toxicity and neurotoxicity and could help predict the clinical management of women with EOC.

Comparison of glutaminase and cancer antigen 125 for distinguishing benign and malignant ovarian tumors

AbstractIncreasing demand for glutaminase (GLS) due to high rates of glutamine metabolism is considered one of the hallmarks of malignancy. In parallel, cancer antigen 125 (CA‐125) is a commonly used ovarian tumor marker. This study aimed to compare the roles of GLS and CA‐125 in distinguishing between benign and malignant ovarian tumors. The research was conducted as a comparative study, enrolling 156 patients with ovarian tumors. Preoperative serum CA‐125 and GLS levels were analyzed to evaluate their effectiveness in distinguishing between benign and malignant ovarian tumors. The results revealed that the mean levels of CA‐125 and GLS were significantly higher in malignant ovarian tumors compared with benign ones (389.54 ± 494.320 vs. 193.15 ± 529.932 (U/mL) and 17.37 ± 12.156 vs. 7.48 ± 4.095 (μg/mL), respectively). The CA‐125 and GLS cutoff points of 108.2 U/mL and 18.32 μg/mL, respectively, were associated with malignant ovarian tumors. Multivariate analyses showed that GLS had higher predictive capabilities compared with CA‐125 (odds ratio 9.4 vs. 2.1). The accuracy of using GLS combined with CA‐125 was higher than using CA‐125 alone (73.1% vs. 68.8%). In conclusion, higher levels of CA‐125 and GLS are associated with malignant ovarian tumors. GLS outperforms CA‐125 in distinguishing between benign and malignant ovarian tumors. The combination of GLS and CA‐125 demonstrated improved accuracy for distinguishing benign and malignant ovarian tumors when compared with using CA‐125 alone.