5515 Background: Cyclin E1 gene amplification and protein over-expression is a marker of platinum resistance in high grade serous ovarian, fallopian tube or primary peritoneal cancer (HGSC), and may predict response to WEE1 inhibition. Adavosertib, a WEE1 inhibitor, has demonstrated activity in unselected women with recurrent ovarian and serous endometrial cancer. We aimed to evaluate the efficacy of adavosertib in women with recurrent platinum resistant HGSC with cyclin E1 over-expression, with and without gene amplification. Methods: IGNITE is a multicentre, phase 2 trial with 2 cohorts of women with recurrent platinum resistant HGSC. Tumors were assessed for cyclin E1 protein expression by IHC and CCNE1 copy number by FISH. Patients were assigned to Cohort 1 if tumors were cyclin E1 over-expressed (H-score>50) and amplified (≥8 copies), and Cohort 2 if tumors were overexpressed and nonamplified. Patients with evaluable disease by RECIST v1.1 or GCIG CA-125 criteria were included. Adavosertib 300mg PO was given daily on days 1-5 and 8-12 of a 21-day cycle. The primary endpoint was investigator assessed clinical benefit (CB) defined as absence of progression for ≥ 18 weeks. Here we present the 18-week response data for the first 32 patients treated from Cohort 2, with a data cut-off of August 2021. Results: Between Jan-2020 and May-2021, 32 patients were accrued to Cohort 2. Median age was 62 years (range 42-77) and 84% had received ≥2 prior lines of chemotherapy. Median cyclin E1 IHC H-score was 120 and 28 patients (88%) had measurable disease by RECIST. Median number of cycles commenced was 8 (range 1-19). Overall response rate (ORR) was 53% and CB rate was 61% for all evaluable patients. Seventeen patients (53%) required a dose reduction, most commonly for neutropenia or fatigue. Seventeen patients experienced ≥Grade 3 treatment related adverse event, and 4 patients (15%) discontinued due to toxicity. Conclusions: The efficacy results in a biomarker-selected cohort of patients are promising with a higher response rate than reported in previous studies of adavosertib in unselected women with recurrent HGSC. Duration of response and progression free survival data will be presented as data matures. Clinical trial information: ACTRN12619001185156P. [Table: see text]
BACKGROUND:Sphincter-preserving surgery for rectal cancer is associated with long-term bowel dysfunction, yet data on outcomes in patients managed with watch-and-wait is limited. This study compared bowel function in rectal cancer survivors managed with watch-and-wait versus sphincter-preserving surgery and evaluated the performance of two instruments: the Memorial Sloan Kettering Bowel Function Instrument (MSK-BFI) and the Low Anterior Resection Syndrome (LARS) score within each cohort. PATIENTS AND METHODS:In this cross-sectional study, rectal cancer survivors treated with long-course chemoradiotherapy between 2011 and 2019 at Flinders Medical Centre were recruited. Participants without stomas completed the MSK-BFI, LARS, and comorbidity questionnaires. Demographics and clinical data were obtained from medical records. Outcomes were compared between the sustained watch-and-wait (WW) and surgical (SURG) cohorts. Associations were examined using regression models. Instrument comparisons were performed in each cohort using factor analysis. RESULTS:Of the 190 eligible survivors, 67 participants were included (WW, n=33; SURG, n=34). Surgery was associated with significantly worse bowel function across MSK-BFI domains and higher rates of Any LARS (91% vs. 67%) and Major LARS (70% vs. 36%). Female sex was independently associated with poorer bowel function. Factor analysis revealed that one factor accounted for bowel function in the SURG cohort, whereas two factors were required in the WW cohort, indicating greater complexity. CONCLUSION:Surgery and female sex are associated with significantly worse bowel function in rectal cancer survivors. The WW cohort demonstrated more complex symptom patterns, supporting concurrent use of MSK-BFI and LARS until a WW-specific tool is developed. A larger, prospective study is underway to investigate the findings further.
Introduction Newborn bloodspot screening (NBS) is freely and universally available to babies born in Australia, with nearly 300 000 newborns screened each year. The NBS programme screens for approximately 30 conditions; however, there are hundreds of childhood conditions that could be treated if identified earlier and asymptomatically. Contemporary screening platforms have relied on mass spectrometry-based technologies, limiting surveillance to conditions with validated biomarkers detectable within the neonatal period. Advancements in metabolic techniques and genomics have expanded the range of conditions that could be detected. The NewbornsInSA research study will develop, validate and evaluate a novel multi-omic model of newborn screening, integrating metabolomic and genomic newborn screening as complementary methodologies.Methods Parents can opt in to additional NBS through NewbornsInSA during pregnancy or shortly after birth. One thousand prospectively recruited families will be offered genomic NBS by whole-genome sequencing, including analysis of a virtual gene panel of over 600 genes, and concurrent metabolomic screening. Clinically actionable pathogenic or likely pathogenic genetic variants will be reported to parents and whole genome sequencing data will be available on request for diagnostic reanalysis, if required later in life.Acceptability of the NewbornsInSA programme will be evaluated through stakeholder engagement activities with healthcare professionals, members of the public and patient advocacy groups. Family experiences will be assessed using online surveys. The diagnostic yield, accuracy and the costs and consequences of the multi-omic NBS model will be assessed by comparison to standard-of-care NBS.NewbornsInSA will investigate the acceptability, feasibility and cost-effectiveness of a multi-omic newborn screening model in a prospectively recruited South Australian population. We hypothesise that this approach will increase the number of conditions identified, reduce the time to diagnosis and facilitate earlier care with better outcomes for newborns with genetic conditions.Ethics and dissemination This research study has been ethically approved by the Women’s and Children’s Health Network Human Research Ethics Committee (2022/HRE00258 and 2023/HRE00236). Findings will be disseminated through peer-reviewed publication and conferences.
