Bisphenol A (BPA) and phthalates are endocrine disruptors possibly linked to adverse reproductive and neurodevelopmental outcomes. These chemicals have commonly been measured in urine in population ...surveys; however, such data are limited for large populations of pregnant women, especially for the critical first trimester of pregnancy. The aim of the study was to measure BPA and phthalate metabolites in first trimester urine samples collected in a large national-scale pregnancy cohort study and to identify major predictors of exposure. Approximately 2000 women were recruited in the first trimester of pregnancy from ten sites across Canada. A questionnaire was administered to obtain demographic and socio-economic data on participants and a spot urine sample was collected and analyzed for total BPA (GC–MS/MS) and 11 phthalate metabolites (LC–MS/MS). The geometric mean (GM) maternal urinary concentration of total BPA, uncorrected for specific gravity, was 0.80 (95% CI 0.76–0.85) μg/L. Almost 88% of the women had detectable urinary concentrations of BPA. An analysis of urinary concentrations of BPA by maternal characteristics with specific gravity as a covariate in the linear model showed that the geometric mean concentrations: (1) decreased with increasing maternal age, (2) were higher in current smokers or women who quit during pregnancy compared to never smokers, and (3) tended to be higher in women who provided a fasting urine sample and who were born in Canada, and had lower incomes and education. Several of the phthalate metabolites analyzed were not prevalent in this population (MCHP, MMP, MiNP, MOP), with percentages detectable at less than 15%. The phthalate metabolites with the highest measured concentrations were MEP (GM: 32.02μg/L) and MnBP (GM: 11.59μg/L). MBzP urinary concentrations decreased with maternal age but did not differ by time of urine collection; whereas the DEHP metabolites tended to be higher in older women and when the urine was collected later in the day. This study provides the first biomonitoring results for the largest population of pregnant women sampled in the first trimester of pregnancy. The results indicate that exposure among this population of pregnant women to these chemicals is comparable to or even lower than that observed in a Canadian national population-based survey.
Purpose It is clinically challenging to integrate genomic-classifier results that report a numeric risk of recurrence into treatment recommendations for localized prostate cancer, which are founded ...in the framework of risk groups. We aimed to develop a novel clinical-genomic risk grouping system that can readily be incorporated into treatment guidelines for localized prostate cancer. Materials and Methods Two multicenter cohorts (n = 991) were used for training and validation of the clinical-genomic risk groups, and two additional cohorts (n = 5,937) were used for reclassification analyses. Competing risks analysis was used to estimate the risk of distant metastasis. Time-dependent c-indices were constructed to compare clinicopathologic risk models with the clinical-genomic risk groups. Results With a median follow-up of 8 years for patients in the training cohort, 10-year distant metastasis rates for National Comprehensive Cancer Network (NCCN) low, favorable-intermediate, unfavorable-intermediate, and high-risk were 7.3%, 9.2%, 38.0%, and 39.5%, respectively. In contrast, the three-tier clinical-genomic risk groups had 10-year distant metastasis rates of 3.5%, 29.4%, and 54.6%, for low-, intermediate-, and high-risk, respectively, which were consistent in the validation cohort (0%, 25.9%, and 55.2%, respectively). C-indices for the clinical-genomic risk grouping system (0.84; 95% CI, 0.61 to 0.93) were improved over NCCN (0.73; 95% CI, 0.60 to 0.86) and Cancer of the Prostate Risk Assessment (0.74; 95% CI, 0.65 to 0.84), and 30% of patients using NCCN low/intermediate/high would be reclassified by the new three-tier system and 67% of patients would be reclassified from NCCN six-tier (very-low- to very-high-risk) by the new six-tier system. Conclusion A commercially available genomic classifier in combination with standard clinicopathologic variables can generate a simple-to-use clinical-genomic risk grouping that more accurately identifies patients at low, intermediate, and high risk for metastasis and can be easily incorporated into current guidelines to better risk-stratify patients.
The consequences of low prostate-specific antigen (PSA) in high-grade (Gleason 8–10) prostate cancer are unknown.
To evaluate the clinical implications and genomic features of low-PSA, high-grade ...disease.
This was a retrospective study of clinical data for 494 793 patients from the National Cancer Data Base and 136 113 patients from the Surveillance, Epidemiology, and End Results program with cT1–4N0M0 prostate cancer (median follow-up 48.9 and 25.0 mo, respectively), and genomic data for 4960 patients from the Decipher Genomic Resource Information Database. Data were collected for 2004–2017.
Multivariable Fine-Gray and Cox regressions were used to analyze prostate cancer–specific mortality (PCSM) and all-cause mortality, respectively.
For Gleason 8–10 disease, using PSA 4.1–10.0ng/ml (n=38 719) as referent, the distribution of PCSM by PSA was U-shaped, with an adjusted hazard ratio (AHR) of 2.70 for PSA ≤2.5ng/ml (n=3862, p<0.001) versus 1.97, 1.36, and 2.56 for PSA of 2.6–4.0 (n=4199), 10.1–20.0 (n=17 372), and >20.0ng/ml (n=16 114), respectively. By contrast, the distribution of PCSM by PSA was linear for Gleason ≤7 (using PSA 4.1–10.0ng/ml as the referent, n=359 898), with an AHR of 0.41 (p=0.13) for PSA ≤2.5ng/ml (n=37 812) versus 1.38, 2.28, and 4.61 for PSA of 2.6–4.0 (n=54 152), 10.1–20.0 (n=63 319), and >20.0ng/ml (n=35 459), respectively (pinteraction<0.001). Gleason 8–10, PSA ≤2.5ng/ml disease had a significantly higher PCSM than standard high-risk/very high-risk disease with PSA >2.5ng/ml (AHR 2.15, p=0.002; 47-mo PCSM 14% vs 4.9%). Among Gleason 8–10 patients treated with radiotherapy, androgen deprivation therapy was associated with a survival benefit for PSA >2.5ng/ml (AHR 0.87; p<0.001) but not ≤2.5ng/ml (AHR 1.36; p=0.084; pinteraction=0.021). For Gleason 8–10 tumors, PSA ≤2.5ng/ml was associated with higher expression of neuroendocrine/small-cell markers compared to >2.5ng/ml (p=0.046), with no such relationship for Gleason ≤7 disease.
Low-PSA, high-grade prostate cancer has very high risk for PCSM, potentially responds poorly to androgen deprivation therapy, and is associated with neuroendocrine genomic features.
In this study, we found that low–prostate-specific antigen, high-grade prostate cancer has a very high risk for prostate cancer death, may not respond well to androgen deprivation therapy, and is associated with neuroendocrine genomic features. These findings suggest that current nomograms and treatment paradigms may need modification.
Low–prostate-specific antigen, high-grade prostate cancer appears to be a unique entity that has a very high risk for prostate cancer–specific mortality, potentially responds poorly to androgen deprivation therapy, and is associated with neuroendocrine genomic features.
Abstract Prostate cancer (PCa) subtypes based on ETS gene expression have been described. Recent studies suggest there are racial differences in tumor location, with PCa located anteriorly more often ...among African-American (AA) compared to Caucasian-American (CA) men. In this retrospective analysis of a multi-institutional cohort treated by radical prostatectomy (179 CA, 121 AA), we evaluated associations among molecular subtype, race, anatomic tumor location, and androgen receptor (AR) signaling. Subtype (m-ERG+ , m-ETS+ , m-SPINK1+ , or triple-negative) was determined using distribution-based outlier analysis. AR signaling was investigated using gene expression profiling of canonical AR targets. m-ERG+ was more common in CA than AA men (47% vs 22%, p < 0.001). AA men were more likely to be m-SPINK1+ (13% vs 7%; p = 0.069) and triple-negative (50% vs 37%; p = 0.043). Racial differences in molecular subtypes did not persist when tumors were analyzed by location, suggesting a biologically important relationship between tumor location and subtype. Accordingly, anterior tumor location was associated with higher Decipher scores and lower global AR signaling. Patient summary This study demonstrates associations among patient race, prostate cancer molecular subtypes, and tumor location. Location-specific differences in androgen regulation may further underlie these relationships.
Abstract Background Decipher is a validated genomic classifier developed to determine the biological potential for metastasis after radical prostatectomy (RP). Objective To evaluate the ability of ...biopsy Decipher to predict metastasis and Prostate cancer-specific mortality (PCSM) in primarily intermediate- to high-risk patients treated with RP or radiation therapy (RT). Design, setting, and participants Two hundred and thirty-five patients treated with either RP ( n = 105) or RT ± androgen deprivation therapy ( n = 130) with available genomic expression profiles generated from diagnostic biopsy specimens from seven tertiary referral centers. The highest-grade core was sampled and Decipher was calculated based on a locked random forest model. Outcome measurements and statistical analysis Metastasis and PCSM were the primary and secondary outcomes of the study, respectively. Cox analysis and c-index were used to evaluate the performance of Decipher. Results and limitations With a median follow-up of 6 yr among censored patients, 34 patients developed metastases and 11 died of prostate cancer. On multivariable analysis, biopsy Decipher remained a significant predictor of metastasis (hazard ratio: 1.37 per 10% increase in score, 95% confidence interval CI: 1.06–1.78, p = 0.018) after adjusting for clinical variables. For predicting metastasis 5-yr post-biopsy, Cancer of the Prostate Risk Assessment score had a c-index of 0.60 (95% CI: 0.50–0.69), while Cancer of the Prostate Risk Assessment plus biopsy Decipher had a c-index of 0.71 (95% CI: 0.60–0.82). National Comprehensive Cancer Network risk group had a c-index of 0.66 (95% CI: 0.53–0.77), while National Comprehensive Cancer Network plus biopsy Decipher had a c-index of 0.74 (95% CI: 0.66–0.82). Biopsy Decipher was a significant predictor of PCSM (hazard ratio: 1.57 per 10% increase in score, 95% CI: 1.03–2.48, p = 0.037), with a 5-yr PCSM rate of 0%, 0%, and 9.4% for Decipher low, intermediate, and high, respectively. Conclusions Biopsy Decipher predicted metastasis and PCSM from diagnostic biopsy specimens of primarily intermediate- and high-risk men treated with first-line RT or RP. Patient summary Biopsy Decipher predicted metastasis and prostate cancer-specific mortality risk from diagnostic biopsy specimens.
Approved antibody-drug conjugates (ADCs) for HER2-positive breast cancer include trastuzumab emtansine and trastuzumab deruxtecan. To develop a differentiated HER2 ADC, we chose an antibody that does ...not compete with trastuzumab or pertuzumab for binding, conjugated to a reduced potency PBD (pyrrolobenzodiazepine) dimer payload. PBDs are potent cytotoxic agents that alkylate and cross-link DNA. In our study, the PBD dimer is modified to alkylate, but not cross-link DNA. This HER2 ADC, DHES0815A, demonstrates in vivo efficacy in models of HER2-positive and HER2-low cancers and is well-tolerated in cynomolgus monkey safety studies. Mechanisms of action include induction of DNA damage and apoptosis, activity in non-dividing cells, and bystander activity. A dose-escalation study (ClinicalTrials.gov: NCT03451162) in patients with HER2-positive metastatic breast cancer, with the primary objective of evaluating the safety and tolerability of DHES0815A and secondary objectives of characterizing the pharmacokinetics, objective response rate, duration of response, and formation of anti-DHES0815A antibodies, is reported herein. Despite early signs of anti-tumor activity, patients at higher doses develop persistent, non-resolvable dermal, ocular, and pulmonary toxicities, which led to early termination of the phase 1 trial.
Genomic tumour profiling informs targeted treatment options. Entrectinib is a tyrosine kinase inhibitor with efficacy in NTRK fusion‐positive (‐fp) solid tumours and ROS1‐fp non‐small cell lung ...cancer. FoundationOne® Liquid CDx (F1L CDx), a non‐invasive in vitro next‐generation sequencing (NGS)‐based diagnostic, detects genomic alterations in plasma circulating tumour DNA (ctDNA). We evaluated the clinical validity of F1L CDx as an aid in identifying patients with NTRK‐fp or ROS1‐fp tumours and assessed the genomic landscape pre‐ and post‐entrectinib treatment. Among evaluable pre‐treatment clinical samples (N = 85), positive percentage agreements between F1L CDx and clinical trial assays (CTAs) were 47.4% (NTRK fusions) and 64.5% (ROS1 fusions); positive predictive value was 100% for both. The objective response rate for CTA+ F1L CDx+ patients was 72.2% in both cohorts. The median duration of response significantly differed between F1L CDx+ and F1L CDx− samples in ROS1‐fp (5.6 vs. 17.3 months) but not NTRK‐fp (9.2 vs. 12.9 months) patients. Fifteen acquired resistance mutations were detected. We conclude that F1L CDx is a clinically valid complement to tissue‐based testing to identify patients who may benefit from entrectinib and those with acquired resistance mutations associated with disease progression.
Entrectinib is a kinase inhibitor that targets both the NTRK and ROS1 oncogenes. We show that NTRK and ROS1 fusions are present in 46% and 64%, respectively, of blood samples from patients enrolled on a clinical trial, with a response rate of 72%. Profiling blood at progression showed that resistance occurs via mutations in NTRK/ROS1 or via downstream MAP‐kinase reactivation.
Introduction
This phase 1 trial assessed the safety, pharmacokinetics, and preliminary antitumor activity of RO7297089, an anti-BCMA/CD16a bispecific antibody.
Methods
RO7297089 was administered ...weekly by intravenous infusion to patients with relapsed/refractory multiple myeloma. The starting dose was 60 mg in this dose-escalation study utilizing a modified continual reassessment method with overdose control model.
Results
Overall, 27 patients were treated at doses between 60 and 1850 mg. The maximally administered dose was 1850 mg due to excipients in the formulation that did not allow for higher doses to be used. The maximum tolerated dose was not reached. The most common adverse events irrespective of grade and relationship to the drug were anemia, infusion-related reaction, and thrombocytopenia. Most common treatment-related grade ≥ 3 toxicities were ALT/AST increase and reduced lymphocyte count. Pharmacokinetic studies suggested non-linear pharmacokinetics and target-mediated drug disposition, with a trend of approaching linear pharmacokinetics at doses of 1080 mg and higher. Partial response was observed in two patients (7%), minimal response in two patients (7%), and stable disease in 14 patients (52%).
Conclusions
RO7297089 was well tolerated at doses up to 1850 mg, and the efficacy data supported activity of RO7297089 in multiple myeloma. Combination with other agents may further enhance its potential as an innate immune cell engager in multiple myeloma.
Trial Registration
ClinicalTrials.gov: NCT04434469; Registered June 16, 2020;
https://www.clinicaltrials.gov/ct2/show/NCT04434469
.
Background: Immunoparesis (IP), the suppression of one or more uninvolved immunoglobulins (Ig) below the lower limit of normal (LLN), is frequently observed in patients with multiple myeloma (MM). IP ...is associated with a negative impact on survival in patients with relapsed MM (Chakraborty et al. Br J Haematol 2019) and may increase the risk of infection in patients with MM (Pratt et al. Br J Haematol 2007). Cevostamab is a FcRH5xCD3 T-cell engaging bispecific antibody that facilitates T-cell directed killing of myeloma cells. Cevostamab has demonstrated clinically meaningful activity and a favorable toxicity profile when given once every 3 weeks for up to 17 cycles (approximately 1 year) in an ongoing Phase I trial (GO39775; NCT03275103) involving patients with heavily pre-treated RRMM (Trudel et al. ASH 2021). Hypogammaglobulinemia is a potential side effect due to the targeting of FcRH5 on normal plasma cells (Hammons et al. JAMA Netw Open 2022). The purpose of the current study was to evaluate whether reducing monoclonal Ig burden while on therapy allows for polyclonal Ig recovery, despite the mechanism of action of cevostamab. Specifically, we evaluated whether responders in the GO39775 study demonstrated evidence of immune reconstitution (IR) while on cevostamab therapy. Methods: All patients were aged ≥18 years and had RRMM for which no established therapies were available. Cevostamab was administered via intravenous infusion every 21 days for 17 cycles unless disease progression or unacceptable toxicity occurred. Patients who received concomitant IVIg therapy were excluded from the analysis. Patients were included if they were enrolled for ≥100 days, demonstrated a partial response or better, and had IP at baseline, defined as ≥1 Ig below the LLN. IR was defined as recovery of ≥1 polyclonal Ig within the normal range. Results: At data cut-off (March 1, 2023), a total of 310 patients were enrolled in GO39775. 76 patients met the inclusion criteria and were eligible for analysis. Median age was 65 years (range: 43-82), with a median of 6 previous lines of therapy (range: 2-12). 46 patients (60.5%) had IgG isotype, 10 (13.2%) had IgA isotype, and 20 (26.3%) had light chain disease. Of the 76 patients who met the inclusion criteria, 10 (13.2%) experienced IR (see Table); 5 patients had IgG isotype, 3 had IgA isotype, and 2 had light chain disease. The 10 patients with IR were treated for a median of 323 days (range: 64-364). Of these, 6 patients had IR at a median time of Day 156 (range: 123-260) while on cevostamab, while 4 patients had IR at a median time of Day 242 (range: 133-309) after stopping cevostamab. Of the 6 patients who reconstituted on cevostamab, 1 had IgG isotype, 3 had IgA isotype, and 2 had light chain disease. All 4 patients who reconstituted after stopping cevostamab had IgG isotype. Apart from disease isotype, no other baseline characteristic demonstrated a trend with IR. Discussion: The majority of patients with a response to cevostamab in the GO39775 study had baseline IP, consistent with previous findings in RRMM. Among eligible responders, 10 patients (13.2%) reconstituted ≥1 polyclonal Ig, highlighting that disease control may allow some patients to reverse IP. Of the patients who had IR, 6 had immune recovery while on cevostamab therapy, which indicates that IR is possible on cevostamab once disease control is achieved. Our findings demonstrate that despite normal plasma cell targeting, IR can occur while receiving a FcRH5xCD3 bispecific antibody. Further analysis on a larger patient pool may provide more insight into the characteristics of patients with RRMM who experience IR on cevostamab therapy.
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